Venous thromboembolism prophylaxis using the Caprini score · 250 I. Golemi, J.P. Salazar Adum and...

Disease-a-Month 65 (2019) 249–298

Contents lists available at ScienceDirect

Disease-a-Month

journal homepage: www.elsevier.com/locate/disamonth

Venous thromboembolism prophylaxis using

the Caprini score

Iva Golemi, MD

a , ∗, Juan Pablo Salazar Adum, MD

a , Alfonso Tafur, MD, MS, RPVI b , Joseph Caprini, MD, MS, RVT

c

a Department of Medicine, NorthShore University HealthSystem, Evanston, IL, USA b Department of Medicine, Division of Cardiovascular Medicine, NorthShore University HealthSystem, USA c The University of Chicago Pritzker School of Medicine, Evanston, IL, USA

a r t i c l e i n f o

a b s t r a c t

Venous thromboembolism (VTE) including pulmonary em-

bolism (PE) and deep vein thrombosis (DVT) is one of the

leading causes of preventable cardiovascular disease in the

United States (US) and is the number one preventable cause

of death following a surgical procedure. Post-operative VTE is

associated with multiple short and long-term complications.

We will focus on reviewing the many faces of VTE in detail

as they represent common challenging scenarios in clinical

practice.

© 2018 Elsevier Inc. All rights reserved.

PART ONE: THE MANY FACES OF VENOUS THROMBOEMBOLISM INCLDING RISK FACTORS

Introduction

Venous thromboembolism (VTE) is the number one preventable cause of death following

a surgical procedure. 1 Anticoagulant prophylaxis postoperatively saves lives without increas-

ing bleeding deaths. 2 Surgeons are understandably reluctant to employ these drugs for fear

of bleeding complications which in some cases can result in poor clinical outcomes. 1 This re-

view will demonstrate the value of individual risk assessment to tailor the use of anticoagulant

∗ Corresponding author: Address: 2650 Ridge Ave, Evanston, IL 60201, USA.

E-mail addresses: [email protected] (I. Golemi), [email protected] (J.P. Salazar Adum),

[email protected] (A. Tafur), [email protected] (J. Caprini).

https://doi.org/10.1016/j.disamonth.2018.12.005

0011-5029/© 2018 Elsevier Inc. All rights reserved.


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250 I. Golemi, J.P. Salazar Adum and A. Tafur et al. / Disease-a-Month 65 (2019) 249–298

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rophylaxis. Patients with a low risk for thrombotic complications can be spared from the use

f anticoagulants without increasing thrombosis event rates and death from this serious disor-

er. High-risk patients who are at great risk for developing thrombotic episodes including death

an be targeted using appropriate drug regimes. These patients need drug prophylaxis for the

ntire period they are at risk in order to achieve the best results. Randomized control trial data

rom 160 centers over a 30-year period in 43,0 0 0 patients demonstrate that 7–10 days of anti-

oagulants is the proper course of prophylaxis to prevent most VTE events. 2–5 However, thirty

ays of prophylaxis has been shown to be more effective and is recommended for the highest

isk patients especially those with cancer and a previous VTE. 6 The popular policy of adminis-

ering anticoagulants only during hospitalization or until the patient is ambulatory has not been

roven to prevent most thrombotic events. A significant number of patients develop VTE after

ischarge from the hospital and often are not protected with anticoagulants. 7 The most pow-

rful risk associated with surgical patients is a history or family history of thrombosis. 8 These

atients are particularly prone to fatal VTE events and often patients are not specifically queried

bout this history. Those identified with this past history are often not protected due to the

erceived low risk of simple surgical procedures. Understanding that a minor surgical proce-

ure may be associated with a major thrombotic risk is not well understood. The incidence of

atal VTE events even in young people having so called “minor surgical procedures” is far too

ommon and almost totally preventable if their risk was properly assessed. 9 , 10 The administra-

ion of appropriate anticoagulant prophylaxis for the period of time that they remain at-risk

s relatively uncommon. This review will discuss these issues and illustrate the value of these

rinciples based on the vast body of available literature that exists today.

ajor public health concern

The precise number of people affected by DVT/PE is unknown, although as many as 60 0,0 0 0

eople could be affected (1 to 2 per 1,0 0 0) each year in the United States. 11 Estimates suggest

hat 60,0 0 0–10 0,0 0 0 Americans die of DVT/PE including 10 to 30% of people who will die within

ne month of diagnosis. Sudden death is the first symptom in about 25% of people who have a

E. 12 Among people who have had a DVT, one-half will have long-term complications including

he post-thrombotic syndrome, which presents with swelling, pain, discoloration, and scaling in

he affected limb. A number of other complications can also occur and will be subsequently de-

cribed. One-third of people with DVT/PE will have a recurrence within 10 years. Approximately

to 8% of the U.S. population has one of several genetic risk factors (inherited thrombophilias)

hat increase the risk for thrombosis. 13

Venous thromboembolism (VTE) is a major health problem, with over one million events

very year in Europe. 14 The annual incidence of fatal pulmonary emboli across Western Eu-

ope was estimated via an epidemiological model when the annual estimates for symptomatic

TE events were estimated to be 465,715 (404,664–538,189) cases of deep-vein thrombosis,

95,982 (242,450–360,363) cases of pulmonary embolism (PE), and 370,012 (300,193–483,108)

TE-related deaths. Of these deaths, an estimated 27,473 (7%) were diagnosed as being ante-

ortem; 126,145 (34%) were sudden fatal PE, and 217,394 (59%) followed undiagnosed PE. Al-

ost three-quarters of all VTE-related deaths were from hospital-acquired VTE. The estimated

otal number of VTE events (DVT and PE: 148 per 10 0,0 0 0 and 95 per 10 0,0 0 0, respectively) in

he EU is higher than that reported for US communities. Sandler et al demonstrated that pul-

onary embolism is a frequent complication in hospital patients with 10% of 2388 patients who

nderwent autopsy having died from PE. 15

eed for increased awareness

The International Society of Hemostasis and Thrombosis reported on the occasion of World

hrombosis Day (October 13th). This date was chosen since it was Professor Virchow’s birthday.

Thrombosis including VTE, ischemic heart disease, and ischemic stroke is a major contributor

I. Golemi, J.P. Salazar Adum and A. Tafur et al. / Disease-a-Month 65 (2019) 249–298 251

to the global health burden.” The authors estimate that one of every 4 deaths worldwide are

due to these thrombotic events. In the US alone, the Center for Disease Control and Prevention

estimated that there were more than 50 0,0 0 0 adult hospitalizations with the diagnosis of VTE

each year from 20 07–20 09. VTE is responsible for more deaths each year than breast cancer, HIV

disease, and motor vehicle crashes combined. Furthermore, approximately 60% of VTE cases are

associated with a recent hospital stay, and the World Health Organization (WHO) patient safety

program found that hospital-associated VTE was the leading cause of death and disability as-

sociated with hospitalization among all countries and accounted for more deaths and disability

than nosocomial pneumonia, catheter-related bloodstream infections and adverse drug events.

Public awareness of VTE remains low with only 44% and 54% of respondents in a global survey

were aware that most cases are preventable. An important education goal of the World Throm-

bosis Day is to equip patients and family with the adequate knowledge to advocate for VTE

preventions especially in high risk settings like hospitalization. 16

The many faces of VTE

There is a group of physicians who believe the only important postoperative venous throm-

botic issue is symptomatic and fatal pulmonary emboli during hospitalization. 17 The following

section summarizes the numerous issues associated with a postoperative thrombosis including

short and long-term complications. These issues represent compelling rationale to prevent “The

Many Faces Of VTE” rather than just focus on only one aspect of this enormous health problem.

Pulmonary emboli (PE)

Pulmonary emboli (PE) represent the most dramatic of the thrombotic events and fatal em-

boli are seen in 1–5% of those with > 4 risk factors. One-third of all fatal events present as sud-

den death. The mortality in those that survive the initial event approaches 17% at 3 months. 18 , 19

Non-fatal pulmonary emboli may be severe and some massive events may dictate fibrinolytic

therapy occasionally associated with serious bleeding. The Pulmonary Embolism Response Team

concept (PERT) represents integrated and multidisciplinary teams designed to provide the best

standard of care for patients suffering from acute PE. These teams are becoming more com-

mon in clinical practice and it may soon become a new standard of care in patients with PE.

Kabherl et al reported on a 30 month follow up on patients for whom PERT was activated. Even

though PERT was initially conceptualized for patients with higher risk PE they found out that

the PERT team was incredibly valuable for patients with low risk PE or with complex/unstable

issues without confirmed PE. PERT has the ability to quickly mobilize resources that benefit pa-

tients, save lives, and provide efficient and prompt care. 20

Chronic pulmonary hypertension

One of the most serious consequences that patients who suffer and survive a PE is chronic

pulmonary hypertension. Chronic thromboembolic pulmonary hypertension (CTEPH) etiology re-

mains poorly understood but is thought to most often result from obstruction of the pulmonary

vascular bed by non-resolving thromboemboli. 21 , 22 Chronic emboli can result after acute or

recurrent PE or DVT. Increased pulmonary vascular resistance (PVR) leads to progressive pul-

monary hypertension and right heart failure. In the non-occluded areas, pulmonary arteriopa-

thy manifests in small to medium-sized muscular pulmonary arteries as intimal cellular prolif-

eration with focal disruption of the internal elastic lamina and media by “glomeruloid” small

vascular channels. These channels ramify into alveolar septal capillaries, can be indistinguish-

able from pulmonary arterial hypertension (PAH) and can contribute to disease progression. 23

The incidence of CTEPH is unknown, and it remains controversial if CTEPH is a direct conse-

quence of acute PE, but studies suggest that incidence of CTEPH may be 1% −3.8% within 2 years

of acute pulmonary embolism. 22 A prospective international registry reported a history of PE


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n 74.8%, and a history of DVT in 56.1% of CTEPH patients, thus labeling CTEPH as a chronic

omplication of VTE. 22 Some risk factors for CTEPH and VTE include: previous splenectomy, in-

ected ventriculo-atrial shunts, indwelling venous catheters and leads, thyroid replacement ther-

py, cancer, and chronic inflammatory states. 22

Symptoms are absent in the initial phases of CTEPH and once symptomatic, symptoms are

onspecific and clinically indistinguishable from PAH, PE, or acute PE superimposed on pre-

xisting CTEPH. 22 Right-sided heart failure can manifest at later stages of the disease secondary

o right ventricular functional impairment. The incidence after a PE remains low, thus routine

creening for CTEPH is not feasible. 22 , 24

Without treatment, the prognosis of CTEPH is poor and depends on the hemodynamic sever-

ty of pulmonary HTN. 25 , 26 In contrast with other pulmonary hypertension subgroups CTEPH is

otentially curable by surgical intervention. 22 Pepke-Zaba et al reported results from an interna-

ional prospective registry of 679 newly diagnosed patients ( ≤ 6 months) who were followed for

years. 427 patients (62.9%) were considered operable while 247 (36.4%) were non-operable,

nd 5 (0.7%) had no operability data.

Operable patients did not differ from non-operable patients relative to symptoms, New York

eart Association class, and hemodynamics. At the time of CTEPH diagnosis, 37.7% of patients

nitiated at least 1 pulmonary arterial hypertension–targeted therapy (28.3% operable, 53.8%

on-operable). Pulmonary endarterectomy was performed with a 4.7% documented mortality

ate. This study concluded that given the similarities between the groups, careful diagnostic

orkup is necessary to assess which patients will be good candidates for operative procedures.

hey also noticed that patients in the operable group were more likely to have thrombophilic

isorders. This registry data highlights the importance of previous venous thromboembolism

vents as a causal factor for the development of CTEPH, along with a significant role for as-

ociated medical risk factors as coexisting mechanisms in the disease process. The registry data

lso indicate that, although pulmonary endarterectomy can be performed with a low in-hospital

ortality rate, operability rates may vary considerably across centers and countries. 27

Removal of the obstructive material from the pulmonary vasculature is the treatment of

hoice to alleviate pulmonary obstruction and reduce resistance, but in 50% of patients the ob-

tructions are technically inaccessible, or the risk/benefit ratio is unfavorable. 22 , 28 Lately, bal-

oon pulmonary angioplasty (BPA) has emerged as a valuable treatment option for inoperable

TEPH.

The ELOPE study indicates that almost half of PE patients can be considered to have a post-PE

yndrome characterized by exercise limitation at 1 year which impairs their quality of life (QOL)

nd degree of dyspnea. Predictors of post-PE syndrome include male sex, younger age, higher

MI and smoking. Cardiopulmonary exercise testing (CPET) or 6-minute-walk test (6MWT) at 1

onth many help to identify patients with higher risk for post-PE syndrome at 1 year. 29

eep vein thrombosis (DVT)

Deep vein thrombosis (DVT) is a serious and sometimes life-changing event for many pa-

ients. Major DVT requires appropriate anticoagulation treatment for months or in many cases

or years when the event results from an unknown cause. The use of anticoagulants may dic-

ate refraining from contact sports, or activities such as skiing, and other winter sports for fear

f excessive bleeding in case of injury. Rarely the use of anticoagulants may be associated with

eparin-induced thrombocytopenia with or without thrombosis. 30 Warfarin-induced skin necro-

is is also a rare but potentially devastating complication. 31 Venous gangrene with limb loss may

e a result of these complications.

ilent venous thromboembolism

Borow reported that 66% of patients having surgery who had a previous DVT suffer a recur-

ent event without postoperative prophylaxis. 32 The incidence of recurrent DVT in those with


previous asymptomatic events is unknown but likely to be greater than those without that his-

tory. One study enrolled 150 high-risk patients in an internal medicine service with consecutive

hospitalization for another diagnosis, not DVT, who underwent Doppler US of the lower extrem-

ities. Four and one-half percent of patients were diagnosed with proximal DVT and 16% with

distal DVT (dDVT). Female sex, elevated age and renal and electrolyte abnormalities were sig-

nificantly associated with dDVT (p = 0.014, p = 0.009 and p = 0.046, respectively). Decreased mo-

bility was independently associated with dDVT [OR 7.97 (95% CI 2.42–26.27), p = 0.001)]. A high

mortality rate, for non-VTE-related causes, was found, especially in the first week, among dDVT

patients. 33 Another study evaluated 294 patients over a 24-month period in a surgical inten-

sive care unit. Prevalence of DVT was 7.5% in this population and no clinical signs of DVT were

present. DVT was identified within major vessels including iliac vein 1.7%, common femoral vein

2.7%, superficial femoral vein 2% and popliteal vein 1%. In this study age, APACHE II score ≥ 12

and emergent procedure were identified as risk factors for presence of DVT. 34 Another study

included 71 patients who underwent total hip arthroplasty (THA) and 30 patients who under-

went total knee arthroplasty to study the prevention of asymptomatic DVT with fondaparinux

prophylaxis. In patients who received fondaparinux for 14 days after THA surgery, the incidence

of DVT was 0% on the day of the surgery, 13.6% at day 1, 27.1% at day 4, and 11.9% at day 14.

In patients who received fondaparinux for 14 days after TKA surgery, the incidence of DVT was

4.2% on the day of surgery, 50.0% at day 1, 58.3% at day 4, and 20.8% at day 14. The incidence of

DVT after THA or TKA surgery at day 14 was significantly reduced compared to that at day 4. 35

Asymptomatic DVT remains an understudied entity and more data is necessary to understand

its prevalence and clinical significance.

Post-Thrombotic syndrome (PTS)

Incidence ranges from 25–50% following DVT and the clinical manifestations may not be ap-

parent for 2–5 years after the DVT. In a considerable portion of patients, the thrombus fails to

resolve resulting in obstructive changes or valvular incompetence years after the event. 22 This

syndrome can occur in cases of not only proximal DVT but calf DVT and asymptomatic DVT.

Chronic complications from DVT and/or PE can occur. PTS is associated with symptoms and

signs that can vary between patients but most frequently include: pain, heaviness, cramps and

persistent swelling of the affected extremity. Edema, telangiectasia, hyperpigmentation, lipoder-

matosclerosis and ulceration might be present. Prognosis depends on the affected anatomic seg-

ment and the patency of the involved vessel. 22 Proximal DVT has an increased risk for develop-

ing PTS compared with calf or popliteal vein DVT. 22 , 36 Iliofemoral DVT carries a higher risk of

recurrence, and the incidence of PTS is high despite anticoagulation. 37 PTS is diagnosed based

on clinical symptoms and venous duplex US. Symptoms can be exacerbated by exercise and im-

prove with rest. 22 Different scoring systems for PTS exist including The Villalta scale, Ginsberg

score, and Brandjes score. 38 The Villalta score combined with a venous disease-specific quality-

of-life questionnaire is considered the current gold standard for diagnosis and classification of

PTS. 38

Use of elastic compression stockings (ECS) after DVT is the first treatment choice to prevent

PTS by reducing leg edema, promoting venous blood return and improving venous pump func-

tion. 22 Several studies have shown the benefits of using ECS. 39 Brandjes et al. observed a 50% re-

duction in the incidence of PTS due to ECS. 40 Elastic compression stockings are also helpful once

PTS has developed as they increase fibrinolytic activity, stimulate collateral formation and help

prevent venous ulceration. 22 , 41 Aspirin 300 mg daily was tested in a small RCT and improved

rates of ulcer healing. 42 Pentoxifylline is a xanthine derivative that has been used for several

decades in the symptomatic management of intermittent claudication. 43 It also influences mi-

crocirculatory blood flow and oxygenation in ischemic tissues even though the mechanism is

uncertain. 44 In a Cochrane literature review of 12 trials 864 participants were included to as-

sess the role of pentoxifylline in treating venous leg ulcers. Pentoxifylline is more effective than

placebo in terms of complete ulcer healing (RR 1.70, 95% CI 1.30 to 2.24). Pentoxifylline plus


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ompression stockings is more effective than placebo plus compression (RR 1.56, 95% CI 1.14 to

.13). Pentoxifylline in the absence of compression appears to be more effective than placebo or

o treatment (RR 2.25, 95% CI 1.49 to 3.39). More adverse effects were reported in people re-

eiving pentoxifylline (RR 1.56, 95% CI 1.10 to 2.22). Nearly three-quarters (72%) of the reported

dverse effects were gastrointestinal including nausea, indigestion and diarrhea. 44

Several years ago a large placebo controlled randomized trial was published indicating that

CS do not prevent PTS in the first 2 years in patients with a first proximal DVT 45 The authors

onclude-“ECS did not prevent PTS after a first proximal DVT, hence our findings do not support

outine wearing of ECS after DVT .” This statement is misleading since many physicians routinely

rescribe ECS to control the acute symptoms of pain, swelling, heaviness, and other symptoms

requently associated with acute DVT. I would have preferred a statement saying that the trial

oes not support the routine use of ECS to prevent PTS, but these stockings may indeed be

seful to control the patient’s symptoms. A number of methodological issues exist with this

rial and are best summarized in an editorial commenting on this trial. 46 It is apparent that

ore research is needed to identify the role of ECS for the prevention of PTS.

In selected patients with PTS surgical or endovascular treatments can be performed to re-

ieve symptoms. 22 Percutaneous transdermal recanalization of the iliac venous outflow tract by

tent angioplasty is an emerging trend for treatment of PTS. 22 The CaVent study tested Catheter-

irected thrombolysis (CDT) using Alteplase to reduce PTS and the absolute risk reduction was

4.4%. 47 PTS has been associated with higher healthcare expenses and worse quality of life of

atients and its adverse impact is comparable with diabetes and congestive heart failure. 22 , 48 , 49

large NIH supported clinical trial has recently been completed comparing standard antico-

gulation to pharmaco-mechanical fibrinolysis. “(catheter-mediated or device-mediated intra-

hrombus delivery of recombinant tissue plasminogen activator and thrombus aspiration or

aceration, with or without stenting). The primary outcome was development of the post-

hrombotic syndrome between 6 and 24 months of follow-up. The study showed that the addi-

ion of pharmaco-mechanical catheter-directed thrombolysis to anticoagulation did not result in

lower risk of the post-thrombotic syndrome but did result in a higher risk of major bleeding. 50

enous insufficiency-induced lymphedema

Lymphedema is classified into primary and secondary types. Primary lymphatic dysfunction

s of congenital or idiopathic origin. Secondary lymphedema is from damage to lymphatic struc-

ures from parasites, surgery, radiation, infection, most commonly cellulitis or chronic venous

ypertension due to chronic venous disease (CVD). 51 , 52 Up to 1/3 of patients with CVD will have

ymphatic dysfunction by isotope lymphangiography suggesting that secondary lymphedema is

robably more common than the primary variety. Treatment of lymphedema is a necessary step

hen treating extremity ulcers. 51 , 53 Raju et al concluded that clinical features, isotope lymphan-

iography, routine duplex imaging, and venography (sensitivity 61%) cannot reliably rule out a

enous cause for lymphedema and suggested that intravascular ultrasound IVUS (sensitivity 88%)

e routinely used. Swelling improved significantly after stent placement with significant pain re-

ief [complete swelling relief was 16% and 44% ( P < 0.001); pain relief at 40 months was 87% and

3%, respectively ( P = 0.3), with 65% and 71%, experiencing complete pain relief in the abnormal

nd normal lymphangiographic groups]. 51

Compression stockings can be helpful for lymphedema management. 51 There is little data

bout the optimal amount of pressure needed for edema reduction. The International Society

f Lymphology recommends the highest level tolerated; however, Partsch suggests that even

ow pressures can achieve significant lymphedema reduction. 53 Inelastic compression bandages

hould be applied at the start of treatment for patients with chronic edema, as they provide

igh pressures both when standing and walking. They also have a strong massaging effect and

ffer intermittent compression during walking and a low pressure when lying down, and tend

o be well tolerated by the patient over time due to the reduction in edema which decreases

he leg circumference. However, inelastic systems retain stiffness, thereby maintaining effective


pressure in the upright position for several days. 53 The commonly used elastic (ACE) bandages

are ineffective for reducing edema, and swelling may increase with these bandages in place. 54

One of the major issues with compression stockings is noncompliance among patients even

in the presence of severe symptoms, and medical supervision and patient education have not re-

sulted in better compliance. Manual drainage and decongestive therapy are effective techniques

when properly administered. Massage techniques do not correct the basic pathology, however,

and intensive lifelong daily compliance is necessary. In venous lymphedema, it is best used in

conjunction with correction of venous pathology. 53

A most important compression modality for the treatment of leg swelling including lym-

phedema is Velcro compression. A number of devices are available which consist of overlapping

Velcro straps made from inelastic material. They are quite easy to apply and remove, and as the

leg swelling decreases they can be tightened to further reduce leg swelling.

Paradoxical embolus

Paradoxical embolism (PDE) describes the passage of venous or right-sided cardiac thrombus

into the arterial systemic circulation. 55 PDE should be suspected in cases where ischemic stroke

occurs in the absence of conventional risk factors for cerebral vascular disease indicating an al-

ternative mechanism. Forty percent of strokes have no identifiable or proven cause. This occurs

most commonly through an intracardiac defect at the atrial level, but it can also occur via in-

terventricular or pulmonary arteriovenous malformations. 55 , 56 It has been suggested that PDE

could account for as many as 47,0 0 0 unexplained ischemic strokes in young patients each year.

In a small retrospective study with 13 patients with PDE, saline solution contrast echocardiogra-

phy was used as a useful method to demonstrate patent foramen ovale (PFO). Treatment varied,

but all patients received anticoagulation initially with heparin. The duration of therapy was in-

dividualized with patients receiving 6–12 months of anticoagulation. Surgical embolectomy was

performed for 8 patients presenting with limb-threatened ischemia. Intravenous unfractionated

heparin was administered followed by oral anticoagulation. An IVF filter was placed below the

renal veins and no acute limb loss was reported. One patient had surgical closure of PFO with

right atrial thrombectomy. 55 PFO rates are higher in cryptogenic stroke than in the general popu-

lation. In a meta-analysis of 23 case-control studies the odds ratio for PFO in cryptogenic stroke

patients compared with those with stroke from known cause was 2.9 (95% CI 2.1–4.0) which

was similar to Handek et al who prospectively studied 503 consecutive acute stroke patients

and observed that compared with stroke from a determined cause, the PFO rate in cryptogenic

stroke is significantly greater. 56 , 57 Another prospective study of 504 patients investigated the

presence of patent foramen ovale (PFO) in patients younger and older than 55. Two hundred

twenty seven patients with cryptogenic stroke were compared with 276 patients with known

causes of stroke. All patients received transesophageal echocardiogram for PFO evaluation in-

cluding the 131 younger patients.

Concluding that there is an association between the presence of patent foramen ovale and

cryptogenic stroke between both older and younger patients odds ratio, 3.70; 95% CI, 1.42 to

9.65; P = 0.0 08) and the older group (odds ratio, 3.0 0; 95% CI, 1.73 to 5.23; P < 0.001) 57

The above data reflect the enormous burden on society as a result of the many faces of VTE,

and these disorders provide compelling evidence for employing appropriate thrombosis prophy-

laxis to patients based on their level of risk. Balancing the risks of thrombosis and bleeding in

each individual is critical to minimize adverse postoperative events. The authors wish to em-

phasize that deaths from prophylactic anticoagulation are extremely rare, while deaths from

withholding anticoagulation for “at-risk” patients are common. Data published over the last 4

decades will support these strong statements.

Risk assessment

Evaluation of the individual patient represents a complex problem. A list of individual risk

factors that are associated with VTE have been known for a long time. 19 Over the years new


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actors have appeared that increase the risk of a thrombotic event. It is a daunting task to review

ll of these factors but if one fails to account for a potentially important risk factor, appropriate

rophylaxis for that level of risk may not be prescribed. The result may be a serious or fatal VTE

vent. Complicating this analysis is that the tendency of these factors to result in thrombosis

aries; i.e, bedrest is not as strong a risk factor as cancer or major surgery. A past history of

TE was identified as one of the greatest risks for developing a VTE postoperatively. 7 Borow

1981) found that in patients not receiving prophylaxis, there was a 66% chance of recurrent

hrombosis postoperatively in those with a past VTE history. Young age is associated with a

inimal increase in risk compared to older patients where the risk is quite substantial. 58 Howel

t al demonstrated that congestive heart failure was an independent risk factor for VTE, and the

isk increased with decreasing left ventricular ejection fraction. 59 Summarizing, the more risk

actors present the higher incidence of VTE. The more potent the risk factor, the more likely a

TE will result. A past history of VTE or current malignancy are among the most powerful risk

actors that may result in a postoperative thrombotic event.

For many years there was little understanding of how these various risk factors interact in a

uantitative manner to determine the position of each patient along a continuous spectrum of

hromboembolic risk. During this era, clinical trial data in specific surgical populations was used

o estimate risk according to the type and complexity of the surgical procedure. 60

onsensus guidelines vs. Clinical judgment

We discourage blindly following consensus guidelines without first determining whether the

atients in studies used to develop the guidelines fit a particular patient in question. As seen

n the quote below the guidelines emphasize the importance of careful clinical analysis of the

atients’ risk before deciding about the prophylaxis strategy for that individual. This means one

ay not follow the guideline recommendations for an individual patient because their risk pro-

le has not been tested in clinical trials. These trials commonly exclude very high-risk patients

specially those with a history or family history of thrombosis, or multiple comorbidities. These

atients must be protected due to their level of risk. The Caprini score provides an acceptable

ethod to calculate individual risk, and recommend a prophylactic program tied to the final

core. The Boston Hospital system described later in the chapter is a good example of how this

ystem works. 61

The CHEST Guidelines included the following statement: “In this review, thromboprophylaxis

s recommended for groups of patients for whom the benefits of this intervention appear to

utweigh the risks. Decisions about prescribing thromboprophylaxis for the individual patient

re best made by combining knowledge of the literature (including the recommendations pro-

ided herein) with clinical judgment, the latter based on specific knowledge about each patient’s

isk factors for VTE, the potential for adverse consequences with thromboprophylaxis, and the

vailability of various options within one’s center.

Since most thromboprophylaxis studies excluded patients who were at particularly high

isk for either VTE or adverse outcomes, their results may not apply to those with previous

TE or with an increased risk of bleeding. In these circumstances, clinical judgment may ap-

ropriately warrant use of a thromboprophylaxis option that differs from the recommended

pproach.”62

The following quote from the CHEST 2012 guidelines may help to clarify the spirit of this

iscussion. 63 “A Cochrane systematic review analyzed data from six randomized trials involving close

o 1,500 patients who required lower-leg immobilization for at least 1 week and comparing once-

aily LMWH vs no thromboprophylaxis continued, typically, until the cast or brace was removed.27 We identified an additional multicenter study that has remained published only in abstract form28 and updated the meta-analysis by performing our own analysis. We did not extract the data

ound in the Cochrane review. PE was diagnosed in two of 585 patients in the placebo group and

ne of 576 in the LMWH group. Results failed to demonstrate or exclude a beneficial effect of LMWH

n symptomatic DVT (RR, 0.34; 95% CI, 0.09–1.28), and two major bleeding events were seen with


LMWH vs none in the placebo group. The patient population was quite heterogeneous, and

patients with a higher risk for VTE were excluded. Detailed information was not provided

with regard to immobility. ”

Based on that text the summary statement in the guidelines is as follows:

“3.0. We suggest no prophylaxis rather than pharmacologic thromboprophylaxis in patients

with isolated lower-leg injuries requiring leg immobilization (Grade 2C).”

Let us now try to apply those guidelines to an individual patient.

Clinical vignette

A 60-year-old male was struck by a car while riding his bicycle. He suffered a compound

fracture of the ankle involving both bones and requires an external fixator to stabilize the frac-

ture until the wound heals and definitive surgery can be done. His mother had a DVT and his

sister suffered a non-fatal pulmonary embolus. Patient has limited mobility due to the hardware

and painful nature of the injury.

He is very high-risk due to the nature of his injury, marked immobility, and family history of

thrombosis. Anticoagulant prophylaxis in my view is required in this situation and selecting an

approach not recommended in the guidelines may be life-saving.

The patient had a pulmonary embolus and died 10 days after the injury. He did not receive

anticoagulant prophylaxis. The surgeon defended his approach stating the guidelines do not rec-

ommend anticoagulant prophylaxis. Hypothetically if you were that surgeon would you provide

prophylaxis to a future patient you encounter with the same set of clinical circumstances? This

type of patient with these characteristics has not been tested in clinical trials. The clinician must

use judgment, knowledge of risk factors, experience, and in some cases common sense to pro-

vide protection for the patient. In the final analysis, the decision to use anticoagulant prophy-

laxis is based on carefully weighing the evidence for thrombosis vs. bleeding, and providing the

safest course of action for the patient. It also stands to reason, but not often mentioned, that

the prophylaxis for thrombosis needs to be continued as long as the patient remains at risk. In

the case of braces and casts that period continues until these devices have been removed and

the patient is ambulating normally.

Those who have practiced for any length of time fully realize that individual patient decisions

are based on clinical judgment and experience as well as the guidelines. When the individual

patient does not fit the criteria outlined in the guidelines, or when following the guidelines

results in a poor clinical outcome, a different course of action is warranted. Clinical experience

over the years continues to refine this process.

Risk factors associated with the development of VTE

Age

Borow (1981) studied the relationship of age to the development of DVT and found a linear

relationship. 7 The incidence of DVT in those 40–60 years of age was 20%, and in those 61–

70 years of age the incidence was 36.4%, while when patients 71 years of age or more this

incidence rose to 62.5%. He also reported that in patients receiving prophylaxis the incidence of

DVT although lower overall, doubled in patients 61–70 years, and tripled in those 71 years of

age and above.

Anderson and colleagues conducted a community-wide study in 16 short-stay hospitals to

examine the incidence and case-fatality rates of DVT and PE in patients during an 18-month

period starting in July 1985. There were 151,349 acute-care discharges from the 16 hospitals and

VTE was found in 1372 patients (0.9%). Furthermore, the proportion of patients with clinically

suspected DVT in whom the diagnosis was confirmed by objective testing increased with the


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umber of risk factors. The incidence of thrombosis was 100% in patients who had 5 risk factors

nd were suspected clinically of having a DVT. They found that the incidence rates of DVT and

E increased exponentially with age. These incidence rates increase with age and rising Caprini

core that assigns points based on the age of the patient beginning with age over 40 years.

besity

Obesity is a common finding in the population with a prevalence of 20–25% and has been

efined as a body mass index (BMI) ≥ 30 kg/m

2 . Studies have shown that the risk of thrombosis

s increased twofold in these patients. On the other hand, women with a BMI > 25 kg/m

2 are at

ncreased risk for developing thrombosis, and if they are taking oral contraceptive a synergistic

ffect occurs increasing their risk by 10-fold. The thrombotic risk is increased with advanced

ge, but adjustment for clotting factor levels were shown not to affect the risk estimate for

besity. 64 White and colleagues, using an administration database in patients who underwent

otal hip arthroplasty, found that a body-mass index of 25 kg/m

2 or greater was associated with

ubsequent re-hospitalization for thromboembolism. 65

Obesity has emerged as a global health issue and there is moderate association with VTE.

besity appears to be associated with increased risk for first occurrence of VTE. 66 In a metanal-

sis of 8125 patients with VTE and 23,272 control patients indicated that the likelihood of first

pontaneous VTE among obese patients was more than twice that of individuals with normal

MI (odds ratio (OR) = 2.33; 95% confidence interval (CI), 1.68 – 3.24). 67

Increase in BMI above normal values has been reported to be associated with rising risk

f VTE. One study of 87,226 women in the Nurses’ Health Study showed that the relative risk

f unprovoked PE is raised by 8% per 1 kg/m

2 increase in BMI and approaches nearly six fold

reater risk in individuals with BMI ≥ 35 (p < 0.001). 68 In a large Danish study that enrolled

9,340 women and 26,674 men found that VTE was [HR: 1.45 ((1.03–2.05)], [HR: 1.81 (1.27–

.56)], [HR: 2.82, (1.96–4.04)] in females and [HR: 0.98, (0.73–1.31)], [HR:1.32 (0.98–1.79)] and

HR: 1.72 (1.27–2.33)] in men with BMIs of 23.7 – 26.3 (24.4 – 26.8), 26.3 – 29.9 (26.8 – 29.4),

nd > 29.9 ( > 29.4) respectively after adjusting for age, physical activity, smoking, height, choles-

erol, hypertension, diabetes mellitus, and use of hormone replacement therapy. 69

Several studies have indicated a relationship between obesity and VTE recurrence. 66 In one

tudy 1107 patients were followed for an average of 46 months after termination of anticoagu-

ation therapy and they found the frequency of recurrent VTE was 9.3% (95% CI, 6.0% – 12.7%)

mong patients with a normal BMI and 17.5% (95% CI, 13.0% – 22.0%) among patients who were

bese. 70

The association between VTE-related mortality and PE has yet to be explained. Unexpectedly,

besity appears to be protective and associated with lower mortality among patients with PE

the so called “obesity paradox”71

istory of VTE

Individuals who have suffered a previous VTE event are at increased risk for developing an-

ther thrombosis including a fatal pulmonary embolus. This factor is particularly important in

atients requiring surgery, subject to prolonged immobilization, or serious illness especially can-

er. In an observational study of 1231 patients, Anderson and colleagues reported that 19% of

hese individuals had a prior history of thrombosis. 72 In another case-controlled study, patients

ere eight times more likely to suffer a recurrent event during a high-risk period than those

ithout a VTE history. 73 Borow & Goldson many years ago reported in a large venographic-

ased study that 66% of patients with a prior history of VTE suffered a recurrent event postop-

ratively. 74 , 75


Family history of VTE

Family history of thrombosis has been the most neglected risk factor and is frequently not

even asked preoperatively. Several widely used thrombosis risk assessment models in medical

patients do not even include family history. Studies show that family history is a risk indica-

tor for a first venous thrombosis regardless of the other risk factors identified in an individual

patient. In clinical practice family history may be more useful for risk assessment than throm-

bophilia testing. 76 Family history of VTE may reflect family genetic risk factors. We know that

carriers of one or more genetic risk factors are at increased risk of the first venous thrombosis,

particularly when exposed to environmental triggers. These triggers may include surgery, muscle

ruptures or sprain, immobilization, plaster cast, extended bed rest, hospitalization, pregnancy or

puerperium, use of oral contraceptives or hormonal therapy, diagnosis of malignancy, etc. The

relative risk of thrombosis increases with the number of risk factors identified. The combination

of a genetic and acquired risk factor can result in a risk 60-fold higher than for those with no

known risk factors and a negative family history. One study showed a positive family history

increased the risk of venous thrombosis more than twofold regardless of the risk factors precip-

itating the thrombosis. 76 In that same study 29.7% of patients with a positive family history had

a genetic risk factor when tested. In addition, the chance of finding a genetic risk factor was up

to 36.1% for patients with several affected relatives. The authors also concluded that the relative

risk associated with a positive family history was of similar magnitude as the risk associated

with a genetic risk factor. The authors conclude that in clinical practice, family history may be

more useful for risk assessment than thrombophilia testing.

One extremely important and valuable case-cohort study was done to determine the famil-

ial risk of VTE in first, second, and third-degree relatives of affected individuals. 77 This was the

Swedish Multi-Generation Register which was linked to Hospital Discharge Register data for the

period 1987–2009, and involved 183,515 individuals. The authors found an increased VTE risk

among not only first-degree relatives but also second and third degree relatives and non-biologic

relatives. They concluded that the genetic component of the familial clustering of VTE is strong.

We agree with the authors that the family history is potentially useful for clinical VTE risk as-

sessment even in second and 3rd degree relatives.

Ambulation

This risk factor has been difficult to standardize but a practical working definition has been

published a number of years ago when studies not only tracked symptomatic events but also

used venography to identify asymptomatic DVT. The authors defined ambulation as the abil-

ity to independently walk a distance of > 10 m [30 feet]). The authors studied thrombosis pro-

phylaxis in medical patients using two doses of low molecular weight heparin compared to a

placebo group. 78 They compared enoxaparin with placebo for the prevention of venous throm-

boembolism in acutely ill medical patients. 78 Another study published a few years ago sheds

light on this issue. 56 The authors examined the relationship between the use of prophylaxis, VTE

risk, and ambulatory status. They found that despite becoming ambulatory, patients remained at

risk and benefited from the use of low molecular weight heparin prophylaxis 40 mg daily. This

makes sense since ambulation does not affect underlying risk factors but removes only the risks

of bedrest. Furthermore, the mean duration of prophylaxis was 7.6 days. The authors comment

that data are lacking to support the concept of stopping pharmacologic prophylaxis when the

patient is ambulatory or discharged after a short hospitalization. The period of time demon-

strating efficacy for thrombosis prophylaxis in hospitalized patients is at least one week. This

agrees with more than one hundred-sixty studies done over the last 30 years establishing ef-

ficacy as 7–10 days. 3–5 There is considerable data in over 1 million patients to suggest that a

short course of one or two days of prophylactic anticoagulation is ineffective in reducing the

incidence of venous thrombosis. 79–81 These data will be dealt with more completely in another


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ection. The Caprini score defines bedrest as inability to ambulate 30 feet (10 M), and walking a

hort distance to the bathroom or sitting in the chair does not qualify as ambulation using the

aprini score.

Fig. 1. Endothelial damage from venous distention due to slow blood flow.

ajor vs. Minor surgery

There are major and minor surgical procedures which are usually classified by the complexity

r extent of the operative procedure. For example, a pancreatic or liver resection would be con-

idered major surgery, whereas an inguinal hernia or interval appendectomy is considered minor

urgery. The problem is that the definition of a major operation from the thrombosis standpoint

s different and very specific. In order to better understand this concept, let us examine the work

f Rudolf Virchow, a German doctor, pathologist and anthropologist well-known for his achieve-

ents including the pathophysiology involved in the development of venous thrombi. Virchow’s

riad describes venous stasis, hypercoagulability and vessel wall injury as the three cornerstones

hat contribute to thrombosis formation. 82 Anesthesia can affect the three components of the

riad. It can lead to venous stasis due to calf muscle paralysis. Anesthesia also can cause venous

ver-distention due to slow blood flow causing endothelial cracks ( Fig. 1 ). 83

Major surgery from the thrombosis standpoint is related to the use of a general or regional

nesthetic as an additional factor besides the patient’s type of surgery, underlying pathology, and

ny additional thrombosis risk factors. The effects of an anesthetic including the muscle paralysis

econdary to the muscle relaxants given to facilitate intubation cause the veins of the lower ex-

remity to dilate up to 3 times normal size. Muscle paralysis secondary to a regional anesthetic

an have the same effect. 84 This venous dilatation may cause over distention of the veins, crack-

ng the endothelium which exposes subendothelial collagen allowing thrombi to form in these

racks. 83 Pooling of the blood also occurs. This slow blood flow can affect the white blood cells,

ransforming them into adhesion molecules due to the stasis. These adhesion molecules release

nflammatory cytokines creating a local inflammatory response. Eventually these molecules at-

ach to and penetrate the capillary wall permanently damaging these tiny vessels. The attached

dhesion molecule attracts other molecules that pile up and adhere to the damaged area. As

result, the exchange of vital nutrients to the tissues, and release of metabolic waste material

nto the bloodstream are badly impaired. These waste products can produce local hypercoagula-

ility by activating the clotting system. Surgical stress and patient risk factors such as cancer or

nfection can increase the hypercoagulable state.


This hypercoagulability may be compounded by other risk factors most notably a past his-

tory or family history of thrombosis, the tendency to develop significant or fatal VTE may be

quite likely. If the legs are in stirrups, or straps around the legs are tight, venous stasis may be

increased. Complete extension of the knee may compress the popliteal vein, further promoting

venous stasis; and this process is known as the popliteal entrapment syndrome. 85 This phe-

nomenon narrows or completely closes the popliteal vein which results in diverting the blood

flow through the superficial veins of the leg bypassing the popliteal fossa resulting in slowing

blood flow out of the leg. That is why it is important to put a pillow under the knees during the

operation to prevent complete extension of the knee.

The reverse Trendelenburg (head up) position used for many laparoscopic procedures along

with elevated intra-abdominal pressure due to distension of the abdominal cavity with gas in-

tensifies venous stasis further distending the veins. These mechanisms represent Virchow’s triad

of venous stasis, vascular injury, and hypercoagulability and have been shown many years ago

to represent causative factors for venous thrombosis. Pneumatic compression during the proce-

dure helps to minimize these changes. The longer the procedure, the more these changes can

occur. Tourniquets during surgery can also have these effects. The clinical proof of these con-

cepts starts with the work of Dr. Borow showing how the length of surgery affects the incidence

of VTE. The longer the surgical procedure, the more these factors can intensify and lead to a ve-

nous thrombosis. 7 , 32 The Caprini score assigns 2 points for any anesthetic over 45 minutes and

this is considered major surgery from the thrombosis viewpoint despite the fact that the surgical

procedure is considered minor. Some authors add an extra point for surgery longer than 2 hours,

and the Boston Studies (Cassidy et al) score 5 points if the operation lasts 6 hours. 86 A surgi-

cal procedure might be considered minor, but can pose major thrombotic risks if the anesthetic

lasts more than one hour. 74

Length of surgery

Operations that lasted from 1–2 hours were associated with a 20% DVT incidence in the con-

trol group. The incidence rose to 46.7% for operations lasting between 2–3 hours, and the in-

cidence rose to 62.5% for operations over 3 hours. One must remember that at that time in

the early 1980’s fibrinogen scanning with venographic confirmation was the best method for

determining the total incidence of DVT in a patient population. This included a large number

of asymptomatic events. Furthermore, thrombosis prophylaxis was not the standard of care, so

most patients were not receiving prophylaxis. Studies during this era looking at venographically

documented thrombosis in patients not receiving prophylaxis were of immense value in justify-

ing the administration of anticoagulants to surgical patients. The incidence of bleeding problems

was minuscule compared to the results achieved reducing the incidence of postoperative throm-

bosis. Borow’s landmark study involved studying five methods of prophylaxis for the preven-

tion of postoperative venous thrombosis. The groups were (1) control, (2) low-molecular weight

dextran, (3) mini-dose heparin, (4) bilateral pneumatic compression devices, (5) and elastic com-

pressive stockings. DVT was evaluated using fibrinogen scanning confirmed by venography. Over-

all, 36% of patients, in the control group suffered a DVT. All of the treatment groups lowered the

incidence of DVT including aspirin.

Laparoscopic surgery

A great number of procedures are done with a more minimal approach including

laparoscopically-assisted surgical procedures and arthroscopic surgery. Despite the advantages

including earlier ambulation, decreased pain and discomfort, these procedures still represent a

risk of thrombosis due to the anesthetic and length of surgery. Nguyen and his group from the

Department of surgery, University of California Irvine published a very interesting study compar-

ing the VTE incidence between open and laparoscopic approach for four common surgical pro-


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edures. These included appendectomy, cholecystectomy, anti-reflux surgery, and gastric bypass

uring the period of time between 2002 and 2006. He studied a total of 138,595 patients hav-

ng one of these surgical procedures. Overall the thrombosis incidence was significantly higher

n the open cases compared with the laparoscopic cases (P < 0.01). The incidence of VTE after

aparoscopic surgery continues to be lower than that of open surgery even when the data are

tratified according to the level of severity of illness. This study corrected an earlier opinion we

ad regarding adding 2 points to the score if the procedure was done laparoscopically, and we

o longer add extra points for this minimally invasive approach. We do not reduce the score

owever since the score also reflects time of anesthesia. The approach is only one factor that

etermines thrombotic risk and careful overall risk assessment needs to be done to properly

haracterize risk.

We feel that this was an excellent study although these types of investigations where all the

atients are grouped together without very careful individual risk assessment may not reflect

he true nature of individual thrombotic risk.

linical vignette

A 75-year-old obese male having a laparoscopic cholecystectomy for acute cholecystitis re-

uiring a two-hour anesthetic, may not reflect the thrombotic risk of the average younger, la-

aroscopic cholecystectomy patient in this series. If this patient had a past history or fam-

ly history of VTE, that would increase the risk even further (Caprini score = 9). Therefore, al-

hough this series showed a lower overall risk of VTE for the average laparoscopic cholecys-

ectomy patient compared to the equivalent open cholecystectomy patient, that may not hold

rue when individual risk assessment is employed since a much higher level of risk may ex-

st in individual patients such as this example. The concept of evaluating thrombotic risk ac-

ording to type of procedure may be important but only when taken in the context of the

ndividual risk factors of a given patient. We have seen many examples where the overall

ow incidence of thrombosis for an individual procedure changes drastically when individual

isk assessment is applied. This patient would benefit from 30 days of LMWH prophylaxis

ostoperatively.

Reza Fazl Alizadeh and his colleagues, again from the University of California Irvine Depart-

ent of Surgery continue to do pioneering research in this area and have published a subse-

uent study involving 750,159 patients from the period of 2005 to 2014. They used the Na-

ional Surgical Quality Improvement Program database and looked at the overall incidence of

TE within 30 days of operation. Overall incidence of VTE was 0.32% in patients with benign

isease who underwent laparoscopic abdominal operations including colorectal surgery, bariatric

urgery, cholecystectomy, esophageal surgery, abdominal wall hernia repair, and appendectomy.

olorectal surgery had the highest incidence of VTE (1.12%) and was associated with signifi-

antly the longest length of stay and operative times. Those patients who develop thrombosis

ad a higher mortality and worse outcomes compared to those who did not suffer a throm-

otic event. They concluded that laparoscopic colorectal procedures for benign disease represent

higher risk for the development of thrombosis compared with other laparoscopic abdominal

perations. This study had some limitations since the National Surgical Quality Improvement

rogram database does not include details about past history of thrombosis, family history of

hrombosis, type of prophylaxis postoperatively, dose of any anticoagulants used, and does not

ecord the length of any of these prophylactic treatments. We know that all of these variables

ffect the VTE incidence for an individual.

Another individual patient factor is conversion from the laparoscopic approach to an open

peration. This factor needs to be considered when assessing the patient risk. Excessive opera-

ive time that may be associated with certain laparoscopic robotic procedures also may increase

he level of risk. The Boston group has assigned a higher score to patients who have operative

rocedures lasting 5 hours or more. Their impressive results using the score tied to a mandatory

rophylaxis protocol will be discussed later in this chapter.


Previous major surgery

Landmark studies of Borow, 18% of patients developing a postoperative thrombosis had a

past history of a major surgical procedure at some previous time. When the Caprini score was

designed, we considered those procedures done within one month to be a minor risk factor (1).

Cancer

Cancer is a major risk factor leading to the development of VTE and approximately 20% of pa-

tients with cancer will develop this complication. The score does not stratify between different

types of cancer thus there is expected variation in rate as some cancers have higher associated

risk for developing VTE. 87 VTE is also recognized as one of the leading causes of death in cancer

patients. Rates of thrombosis vary widely depending upon the type of cancer, with the high-

est rates observed in brain, pancreatic, gastric cancer, and a variety of hematologic malignan-

cies. Patients with cancer have an increased level of thrombotic risk especially when additional

risk factors are present. 88 The Khorana and Vienna scores are two additional scores that try to

predict risk of VTE in cancer patients, but neither of them is validated for perioperative risk.

Khorana score aims to identify ambulatory patients with cancer at increased risk of VTE by us-

ing two clinical variables (tumor site and body mass index) and three laboratory measurements

(platelet, hemoglobin and leukocytes). Vienna score is a modification of the Khorana score (ad-

dition of biomarkers D-dimer and soluble P-selectin). 89

Chemotherapy

The prothrombotic state associated with malignant tumors has been shown to be further

increased by chemotherapy. This is a complex issue since frequently central lines are necessary

for the continued administration of these drugs which also increases the thrombotic risk. Many

times, chemotherapy is used for patients with metastasis which in itself is also a risk factor for

thrombosis. The type of chemotherapy also influences the risk of incidental VTE which appears

more frequent in patients receiving platin-based drugs. However, with the multiple changes in

the agents it is hard to individualize the expected risk with each agent. 90

Thrombophilia

Thrombophilia is a congenital or acquired condition that is characterized by an imbalance in

the hemostasis producing a hypercoagulable state. It is often diagnosed by a first episode of VTE

associated with increased risk of recurrence. It is recognized in about 50% of subjects who had

experienced a VTE.

Hereditary thrombophilia

The most common entities of hereditary thrombophilia include antithrombin deficiency, pro-

tein C deficiency, protein S deficiency, resistance to activated protein C due to the mutation of

Factor V Leiden, and G20210A mutation in the prothrombin gene (FII G20210A). These defects

increase the chance of a VTE. Hereditary causes of VTE should be suspected in recurrent or

life-threatening thromboembolism, young age ( < 45 years old), multiple abortions or stillbirths,

family history of VTE, or where there are no obvious acquired risk factors. 91 In a prospective

cohort study of 202 patients with colorectal cancer were stratified in those with thrombotic

mutations (PTM + ) and without thrombotic mutations (PTM-). These patients were screened for


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actor V Leiden and prothrombin G20210A mutations which are the 2 most common defects in

he western population. Coagulation markers including platelet counts, fibrinogen and D-dimer

evels were measured and symptomatic VTE was observed. In the post-prophylactic period 2–12

onths after surgery symptomatic VTE was observed. In the prophylactic period VTE incidence

n PTM + and PTM - was 0% and 1.6% respectively (p = 0.73). Levels of coagulation markers were

omparable in both patient cohort within 28 days postoperatively. In the post-prophylactic pe-

iod, VTE incidence in PTM + and PTM – was 15% and 5.5% respectively. There was significantly

ncreased incidence of lower extremity DVT in patients with factor V Leiden (17.6%). 92

Antithrombin deficiency was initially described by Egeberg in 1965. 93 Protein C and S

eficiency were found to be a cause of hereditary thrombophilia as reported in the early

0s. 94 , 95 Factor V Leiden mutation related to activated protein C resistance and the mutation

20210A on the prothrombin gene were identified as causes of hereditary thrombophilias in

he early 90’s. 96 These are the 2 most common defects. Unprovoked VTE occurs more fre-

uently in patients with hereditary thrombophilia than patients without thrombophilia HR 22.3

P = 0.003) and the presence of hereditary thrombophilia increases the risk of VTE approximately

-fold. 97

Other causes of thrombophilia are elevated concentration of coagulation factors (FVIII, FIX,

XI), deficiency of FXII or hyperhomocysteinemia.

cquired thrombophilia

The most common causes of acquired thrombophilia are antiphospholipid syndrome (APS),

cquired deficiency of natural inhibitors of coagulation, myeloproliferative syndromes and the

resence of the mutation JAK2V617F, and nocturnal paroxysmal hemoglobinuria.

APS is a condition that increases the risk of vascular occlusion and is frequently seen in

atients with pregnancy complications. It is an autoimmune disorder characterized by the pres-

nce of antibodies directed against proteins and phospholipids such as antiphospholipid anti-

odies (aPL) or anticardiolipid antibodies (aCL) or antibodies against the β2 glycoprotein I (anti-

2GPI) of IgG or IgM class.

The acquired deficiency of natural coagulation inhibitors (AT, PC or PS) are also independent

isk factors for VTE ( Table 1 ).

aroxysmal Nocturnal Hemoglobinuria (PNH)

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, potentially life-threatening hemato-

ogic disorder characterized by chronic intravascular hemolysis caused by uncontrolled activa-

Table 1

Thrombophilia testing recommendations.

Recommendations Explanation

Do not test with concomitant VTE event Test at completion of anticoagulant therapy for provoked VTE Test after

treatment for acute event for unprovoked VTE, if cessation of

anticoagulant therapy is considered and test results might change

management.

Do not test when receiving anticoagulation

therapy

Test when warfarin has been stopped for a minimum of 2 weeks,

DOAC has been stopped for 2 days or longer and UFH or LMWH for

antithrombin levels has been stopped for more than 24 hours

Do not test if VTE is provoked by strong

risk factors

Risk factors are trauma, surgery, immobility, severe illness

Consider testing VTE episodes at a young age in association with no clear provoking

factors Strong family history of VTE

Recurrent VTE

Modified from: Connors et al. 98


tion of the terminal complement pathway. Complement systems and coagulation systems are

closely integrated with each influencing the activity of the other. 99 Clinical manifestations may

include involvement of unusual sites of thrombosis especially (hepatic (Budd-Chiari being one of

the most common sites), mesenteric, cerebral (superior sagittal sinus thrombosis, dermal veins).

Thrombophilia is a major cause of morbidity and mortality in PNH. When thrombosis occurs, in-

definite anticoagulation is recommended. This disease is also associated with breakthrough and

recurrent thrombosis. The physician should have a high index of suspicion in cases of throm-

bosis at unusual sites, breakthrough thrombosis on adequate therapy, and excessive abdominal

pain associated with well-treated visceral thrombosis such as portal vein or mesenteric throm-

bosis.

Eculizumab is a new available drug that controls intravascular hemolysis in PNH and inhibits

the complement system. This drug needs to be given life-long. 99 It enables patients who may

die in their 30’s to have a normal life span. In a study including 195 patients that were followed

for 66 months 3-year survival was estimated to be 97.6% with patients showing reduction in

lactate dehydrogenase levels reflecting inhibition of chronic hemolysis. Thromboembolic events

decreased by 818%, with 96.4% of patients remaining thromboembolic event free. Transfusion

independence increased by 90.0% from baseline, with the number of red blood cell units trans-

fused decreasing by 54.7%. 100 Eculizumab was well tolerated, with no evidence of cumulative

toxicity and a decreasing occurrence of adverse events over time. 100

History of superficial venous thrombosis

The incidence of superficial venous thrombosis (SVT) varies in different populations from 3%

to 11%. 101–103

The prevalence during the third decade of life is 0.05/10 0 0 per year and 0.31/10 0 0 per

year in men and women respectively. It increases during the eighth decade of life to 1.8/10 0 0

per year and 2.2/10 0 0 in men and women respectively. SVT is more common in women (50–

70%). 101 , 104 , 105

The development of SVT in patients who concomitantly have varicose veins ranges from 4–

59%, 101 , 105–107 whereas SVT in patients without varicose veins is found in approximately 5–10%

of all cases. 105 , 108 , 109 SVT is a risk factor for the development and recurrence of DVT and it

may even coexist with DVT in 6–53% of patients and the most common presentation is exten-

sion from the great saphenous vein into the femoral vein. 75 , 103 , 105 , 106 , 110–121 SVT above knee is

associated with 17–19% incidence of DVT versus SVT located below the knee segment has an

incidence of DVT in 4–5% of patients. 112 , 122 , 123 SVT is a risk factor for DVT and recurrent PE. PE

has been seen in a wide range from 1.5 to 33% of patients with SVT. It has been reported in

18% of patients when the SVT was involved in the great saphenous vein above the knee and 4%

when in the small saphenous vein. 103 , 105 , 108 , 117 , 124

The diagnosis of SVT should include a complete duplex scan with full evaluation of the entire

deep venous system of the leg.

Varicose veins

Varicose veins are an entity within the spectrum of chronic venous disease (CVD); the pre-

sentation may vary from spider telangiectasias to reticular veins, and true varicosities. It affects

approximately 23% of adults in the US and it is more commonly seen in women and older adults.

Varicose veins affect approximately 22 million women and 11 million men between the ages of

40 to 80 years. 125 The prevalence increases to 80% in men and 85% in women if all forms of

varicose veins are included (spider telangiectasias, reticular veins and true varicosities). 126

Risk factors for varicose veins include estrogen exposure (female), lifestyle (prolonged sitting

or standing, smoking), acquired (obesity, pregnancy, DVT, age) and inherited (family history, tall

height, congenital syndromes that affect venous pressure, valvular incompetence and venous ob-


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truction). The major mechanisms resulting in varicose veins include venous valvular incompe-

ence, venous hypertension, inflammation, structural changes in the vein wall and shear stress.

Varicose veins may advance in severity and extent if causative factors are not corrected and

reatment is not initiated. Advanced forms of chronic venous insufficiency may develop includ-

ng lower extremity edema and venous ulceration. Varicose veins were associated with a 7-fold

ncreased risk of DVT in a large observational cohort study. 127

Management options include lifestyle modifications, compression therapy, local/endovascular

blative therapies and surgical interventions. The majority of patients with varicose veins will

equire a multisystemic approach.

A retrospective evaluation of prospectively collected data undergoing procedures for varicose

eins from March 2008 until June 2014 was completed. Patient clinical severity scores pre- and

ost-procedure, treatment choice and perioperative complications were collected. Venous clin-

cal severity scores improved more with radiofrequency ablation + trans illuminated powered

hlebotomy as compared to radiofrequency ablation alone. (3.8 ± 3.4 vs. 3.2 ± 3.1, p = 0.018).

egarding deep venous thrombosis, there was no significant difference between radiofrequency

blation + trans illuminated powered phlebotomy in patients vs. radiofrequency ablation alone.

his study demonstrated that ablation of axial reflux plus trans illuminated powered phlebotomy

roduces improved outcomes as measured by venous clinical severity score, with slight increases

n minor post-operative complications and should be strongly considered as initial therapy when

atients present with significant symptomatic varicose veins and superficial venous insufficiency.

mplementation of a standardized thromboprophylaxis protocol with individual risk assessment

esults in few significant thrombotic complications among high-risk patients, thus potentially

bviating the need for routine post-operative duplex. 128

Königsbrügge et al demonstrated that the presence of varicose veins is associated with an

levated risk of VTE in cancer patients. In a prospective cohort study 1270 cancer patients were

ecruited and followed for 590 days. Sixty-six patients (5.2%) had a history of VTE, superficial

hrombophlebitis was seen in 79 patients (6.2%), and varicose veins seen in 160 patients (12.6%).

inety-eight patients (7.7%) developed VTE during follow-up. The hazard ratios for the risk of

TE in patients with a history of VTE or superficial thrombophlebitis were 1.44 (95% confidence

nterval: 0.67–3.07) and 1.94 (1.04–3.61), respectively, and 2.01 (1.26–3.21) in those with varicose

eins. In multivariate analysis including history of VTE, history of superficial thrombophlebitis,

resence of varicose veins, and other patient-related factors, the presence of varicose veins (2.10

1.29–3.41]) remained significantly associated with an increased risk of VTE. 129

hronic Venous Disease (CVD)

CVD is a very common problem affecting more than 25 million adults in the United States

nd more than 6 million with more advanced venous disease. 130

The most common manifestations of CVD are telangiectasias, reticular veins, and varicose

eins. Chronic venous insufficiency (CVI) is a condition in which the venous system of the lower

xtremities is affected. It is associated with persistent ambulatory venous hypertension causing

ain, edema, skin changes, and ulcerations. The edema seen in CVI is dependent and pitting. The

orefoot is often spared to help distinguish it from other causes of edema such as lymphedema.

ue to the obstruction of lymphatic drainage, lymphedema leads to accumulation of fluid that

xtends into the foot and toes.

Lipedema is characterized by accumulation of fatty tissues instead of fluid, therefore it is not

itting and often spares involvement of the feet, usually with a cuff of tissue at the ankle.

Post thrombotic syndrome (PTS) is characterized by lower extremity pain upon standing, de-

endent edema, and development of tender induration of the subcutaneous tissues (lipoder-

atosclerosis). The clinical picture of PTS is nonspecific, as clinical conditions other than DVT

ay result in a similar constellation of signs and symptoms of the lower extremity, including

uperficial venous insufficiency, trauma and obesity. Pruritus and eczematous skin changes are

ommonly seen. Ulceration of the affected area arises in a considerable number of patients. In


some patients these changes may result in permanent disability. PTS is often triggered by mi-

nor trauma, and is mostly chronic and indolent with a high recurrence rate. Rarely, patients

with persistent obstruction may experience venous claudication, which mimics arterial claudi-

cation. 131

It is known that venous hypertension may be a precursor of PTS. Patients with extensive

thrombosis including major involvement of the iliofemoral segment, frequently have venous hy-

pertension. Venous hypertension can be modified by appropriate compression garments includ-

ing stockings and Velcro devices. 132 Appropriate compression modalities including GEC stockings

are a necessity to control pain and edema, frequently on a permanent basis. 133

Leg swelling and Lymphedema

Swelling of distal leg characterized by loss of definition of the normal bony prominences

about the ankle. This can be seen with PTS, venous insufficiency, or lymphedema.

Chronic venous insufficiency which does not involve the foot so the veins of the foot are

visible. Lymphedema presents with a hump over the dorsum of the foot which obliterates the

venous pattern, along with a positive Stemmer’s sign (inability to pinch the tissue at the base

of the toes). When considering this risk factor, we score one point for either one or both legs

affected with swelling from any cause.

Stroke

Stroke remains the third leading cause of death in the United States. 134 DVT commonly de-

velops in patients admitted to hospital with acute stroke, and may then lead to PE. 135 It is as-

sociated with increased mortality and long-term morbidity. 136

The estimated rate of DVT in hospitalized patients who have a stroke is 20% −50% and two

thirds of these are calf DVTs. 62 , 137 The risk of fatal PE is estimated to be 4.9-fold higher in

immobilized patients with a neurological disease. 138 In a 19-year study period that analyzed

deaths from the United States Bureau of the Census Compressed Mortality File, demonstrated

that the corrected rate of fatal PE among patients with ischemic stroke ranges from 1.5% to

2.1%. 139 Recurrent venous thromboembolism (VTE) is also more common in patients with limb

paresis following stroke. 140 The risk is even higher in patients with brain tumors presenting as

stroke. 141

Inflammatory bowel disease

Data suggest that most patients with inflammatory bowel disease (IBD) have active disease

at the time of the diagnosis of VTE. 142 , 143

It has been shown that patients with active IBD have a three-fold increase in risk of VTE and

that has led to the use of thromboprophylaxis as the standard of care for patients in the hospi-

tal. 144 Approximately 50% of VTE episodes developing concomitantly with IBD occur in patients

who have been hospitalized within the past 3 months. 145

In a cohort study from the General Practice Research Database, 13,756 patients with inflam-

matory bowel disease and 71,672 matched controls were included in the analysis. Patients with

IBD had a higher risk of VTE versus control group (HR 3 • 4, 95% CI 2 • 7–4 • 3; p < 0 • 0 0 01; AR 2 • 6per 10 0 0 person-years). It was seen that at the time of a flare, this increase in risk was much

higher (8 • 4, 5 • 5–12 • 8; p < 0 • 0 0 01; 9 • 0 per 10 0 0 person-years). Interestingly, the relative risk at

the time of a flare was higher in non-hospitalized patients (15 • 8, 9 • 8–25 • 5; p < 0 • 0 0 01; 6 • 4 per

10 0 0 person-years) compared to hospitalized patients (3 • 2, 1 • 7–6 • 3; p = 0 • 0 0 06; 37 • 5 per 10 0 0

person-years). 146


Fig. 2. Surgical specimen of colon in IBD.

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Figure 2 is an illustration of advanced inflammatory bowel disease in a surgical specimen

rom a diseased colon.

epsis- Infection requiring IV antibiotics

The association between acute infection and VTE is of paramount clinical importance due

o the high rates of both entities. Acute infection it is associated with systemic inflammation

hich may increase the risk of VTE causing at least one or even more of the three components

f Virchow triad: venous stasis, hypercoagulability and vessel wall injury. 146–148

In a population-based case–control study conducted in Denmark, of approximately 15,0 0 0

atients diagnosed with a first VTE episode in the hospital during the period 1999–2009 among

ll cases of hospital-diagnosed infections and community prescriptions for antibiotics 1 year

receding the VTE were evaluated. Schmidt, et al, found that, skin, intra-abdominal, respira-

ory tract, urinary tract and bacteremic infections diagnosed in hospital or treated as outpatient

ere associated with twofold increased VTE risk. The authors observed that this association was

trongest within the first 2 weeks after the onset of the infection, and gradually lessening sub-

equently. 149

cute Myocardial Infarction

Acute myocardial infarction is associated with a transient increased VTE risk independently

f traditional atherosclerotic risk factors. The estimate was particularly high for PE. Rinde et al

ecruited 29,506 participants with a median follow up of 15.7 years. This Study concluded that

ighest risk of PE was observed in the first 6 months after the MI (HR 8.49; 95% CI 4.00–18.77).

I explained 6.2% of the PEs in the population (population attributable risk) and 78.5% of the


PE risk in MI patients (attributable risk). 150 In an older study 89 patients were followed after an

acute MI and 27% of patients developed VTE. These patients were more likely to be over 60 years

old and had a previous history of angina and developed congestive heart failure with significant

dysrhythmias. 151 In a large population-based case controlled Danish study, inpatient diagnosis of

heart disease was associated with a markedly increased risk factor for venous thromboembolism.

The relative risk was particularly high for isolated pulmonary embolism without a concurrent

diagnosis of primary deep venous thrombosis. There was an increased risk with myocardial in-

farction especially if MI occurred less than three months after VTE. The risk extended beyond 3

months past the initial hospitalization for heart disease; however, the association got weaker. 152

In 41,259 patients with VTE from the RIETE registry 22,633(55.6%) experienced a provoked VTE.

Those with provoked events were more likely to have diabetes (OR 1.04; 95%; CI: 1.02 - 1.07),

history of coronary artery disease (OR: 1.03; CI: 0.9–1.2), or prior stroke (OR 1.09; CI:1.06–1.1).

During follow-up, patients with provoked VTE were 32% more likely to develop major adverse

cardiac events (MACE) and major adverse limb events (MALE) than patients with non-provoked

VTE (hazard ratio [HR]: 1.32; 95% CI: 1.1–1.5). The association was strong with recent immobility

(HR: 1.37; 95% CI: 1.5–12.1), and cancer (HR: 1.7; 95% CI: 1.4–1.9), but not for other risk factors

for VTE. After adjusting for multiple conventional cardiovascular risk factors, provoked VTE was

independently associated with an increased risk for MACE (HR Adj: 1.39; 95% CI: 1.1–1.7). Cancer

remained an adjusted predictor for both MACE (HR Adj: 1.7, 95% CI: 1.4–2.1) and MALE (HR Adj:

2.1; 95% CI: 1.01–4.6) outcomes. 153

Serious lung disease

Several lung conditions have been associated with VTE. Chronic obstructive pulmonary dis-

ease (COPD) is a leading cause of mortality and morbidity worldwide that is characterized by

systemic inflammation. COPD patients are at increased risk of VTE because of immobilization,

heightened systemic inflammation, cigarette smoking and venous stasis. The overall reported

prevalence of VTE during COPD exacerbation ranges from 5% to 29%. 154 VTE remains underdiag-

nosed in this population because it can present similarly to COPD exacerbation. Post mortem

studies of COPD patients have found pulmonary embolism (PE) in 28% −51% of cases. 155 , 156 Fur-

thermore, increased COPD severity is associated with VTE severity when measured in terms

of lung function impairment [OR] moderate: mild = 1.16; 95% confidence intervals [CIs] = 1.03, 1.32)

or medication usage (OR severe: mild/ moderate = 1.17; 95% CIs = 1.06, 1.26). However, there is no evi-

dence that frequent exacerbation is associated with greater risk of VTE OR = 1.06; 95% CIs = 0.97,

1.15). 157

Idiopathic Pulmonary fibrosis (IPH) poses a higher risk for VTE. Sprunger et al used data

from National Center for Health Statistics from 1988–2007 and identified 218,991 patients with

pulmonary fibrosis. Risk of VTE in pulmonary fibrosis was 34% higher than in the background

population and 44% and 54% greater for patients with COPD and lung cancer respectively. Pa-

tients with VTE died at a younger age than patients with IPH alone (females: 74.3 versus 77.4

years (p < 0.0 0 01); males: 72.0 versus 74.4 years (p < 0.0 0 01). 158

Pneumonia is also associated with an increase in VTE. 159 Pneumococcal infection specifically

has been associated with host coagulation/anticoagulation stimulated by components of the bac-

terial cell wall. 160 The cell wall also stimulates an inflammatory response including recruitment

of leukocytes, cytokine production such as TNFa, IL-1 and IL-05 reducing barrier function and

exposing extracellular matrix. 161 , 162 This leads to exposure of subendothelial tissue factor which

in combination with circulating factor VII induces coagulation. 159 Platelet activating factor (PAF)

has also been implicated in pneumococcus-associated VTE. 163 In a large multicenter database

of surgical patients it was shown that preoperative pneumonia may increase risk of developing

venous thrombosis DVT, OR:8.20 (95% CI 6.75–9.96) and PE, OR: 5.07 (95% CI 3.63–7.07). 164

A prospective population-based ARIC cohort concluded that obstructive spirometry patterns

(COPD pattern, low FEV1 and low FEV1/FVC) are associated with elevated risk of VTE (HR 1.35,


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5% CI 1.08–1.68). Patients with respiratory symptoms and normal spirometric results also had

ignificantly increased risk of VTE (HR 1.40, 95% CI 1.12–1.73).

Restrictive lung disease pattern was not significantly related with increased risk of VTE (HR

.52, 95% CI 0.93–2.49). 165

ongestive heart failure

Patients with reduced cardiac function are thought to have a higher risk of venous throm-

oembolism (VTE). Thromboembolic events in hospitalized patients with heart failure (HF) seem

o be under-recognized and can contribute to increased mortality and morbidity. 166 More severe

F as defined by high NT-proBNP was associated with increased risk of VTE. 167 Congestive heart

ailure has been described as a significant risk factor for VTE in bariatric surgery. 168 In a retro-

pective analysis of the National Inpatient Sample database from 2005–2014 patients with VTE

nd heart failure had higher length of hospitalization. There was also an upward trend of VTE

elated hospitalization among patients with HF. 169

leep apnea

Sleep apnea can also be associated with VTE. In a systematic review of 15 studies obstructive

leep apnea was found to be an independent factor of VTE with risk of DVT or PE being two-

hree-fold higher in patients with obstructive sleep apnea than those without. 170

iabetes

VTE incidence appears to be 2 times higher among diabetic patients < 65YO vs no diabetes. 171

n a population-based study patients with diabetes who develop venous thromboembolism are

ore likely to suffer a complicated course and diabetes was an independent predictor for recur-

ent vein thrombosis. 172 A Taiwanese study with 56,158 patients concluded that the incidence

f VTE was higher in Type 2 diabetes mellitus (T2DM) patients than in controls [adj HR: 1.44

5% CI 1.27–1.63). The risks of DVT (aHR = 1.43, 95% CI = 1.23–1.65) and PE (adjHR = 1.52, 95%

I = 1.22–1.90. 173 In one study that included 358 patients undergoing total knee arthroplasty the

ncidence of DVT 14 days after TKA was significantly higher with than without diabetes OR: 2.71

95% CI 1.183–6.212, p = 0.018). 174

Metabolic syndrome is associated with increased plasma levels of fibrinogen, factor VII and

actor VIII potentially leading to a hypercoagulable state. 175 In a case control study a total of 200

atients, metabolic syndrome was independently associated with idiopathic DVT (OR 1.94; 95%

I 1.04, 3.63). 176 Prevalence of metabolic syndrome in recurrent venous thromboembolism was

igher than in controls in a study of 116 patients with confirmed recurrent venous thromboem-

olism [OR:2.1 (95% CI 1.2, 3.7)]. 177 In another case control study in Korean population metabolic

yndrome was associated with VTE (OR: 1.56; 95% CI: 1.07 to 2.27, P = 0.020) and especially with

diopathic VTE (OR: 1.71; 95% CI: 1.04 to 2.81, P = 0.033). 178

ypertension

Hypertension can also be a risk factor for DVT. In a metanalysis of 16 articles regarding hy-

ertension, including 68,955 males and 53,057 females, this factor was associated with DVT after

rthopedic surgery (OR 2.89, 95% CI 2.18–3.83, Z = 7.38, P < 0.05). Hypertension was also associ-

ted with an increase of VTE patients in newly diagnosed lung cancer OR 1.8; 95% CI 1.0–3.3). 179


Central Venous Access

Catheter-related thrombosis is a common complication of all anatomical sites and especially

smaller veins. Presence of catheter within the lumen of a vein decreases flow and can created

stasis leading to thrombosis. Nifong et al used fluid mechanics to calculate relative flow rates as a

function of the ratio of the catheter to vein diameters. They determined that there is a decrease

in fluid flow rate with catheter size ( < 0.001). PICCs in particular may contribute to substantial

decrease in venous flow as much as 93%. 180

Several studies have indicated that catheters are associated with increased risk of thrombo-

sis. The MITH study included 299 patients with catheter-related thrombosis. Upper extremity

DVT constituted 51% of all deep vein thrombosis. The use of central venous catheters (CVC)

was associated with a 14.0-fold increased risk of upper extremity DVT (95% CI, 5.9–33.2). 181

Post mortem examination of catheterized veins vs controls in 72 autopsied patients showed that

in the catheters sheath fibril and staph can adhere to fibrin producing enzymes that promote

thrombogenesis. 182 In an 18-month long study, 208 central venous catheters including jugular

and subclavian were analyzed with duplex sonography less than 24 hours after catheter removal.

Mean duration of catheterization was 9 days. In these patients, catheter-related thrombosis was

33% with 42% localized in the internal jugular vein and 10% in subclavian veins. 183 In patients

with catheter associated staph aureus bacteremia, 48 patients had venous duplex US and out-

comes were assessed at 12 weeks. Thrombosis by US was present in 71% of patients. 184 In a

prospective study of 105 patients undergoing chemotherapy having ≥ 2 positive cultures was as-

sociated with thrombosis (71% vs 3% in patients with negative or single positive culture). 185 In a

case study CVC related thrombosis was associated with paradoxical embolism through a patent

foramen ovale. 186 Thrombosis of a CVC can also lead to a superior venacava syndrome. 187

Peripheral Inserted Central Catheters (PICC) lines can cause trauma to the vein wall and pre-

dispose patients to upper extremity venous thrombosis. 188 PICC lines complications versus cen-

tral venous catheters were analyzed in surgical patients. PICC lines did not differ from infectious

complications with central venous catheters and thrombotic complications appeared more sig-

nificant in PICC lines, also appearing earlier after catheterization. 189

Hip, Leg, or pelvic fracture

The incidence of DVT is higher in patients with proximal extremity fractures than distal ex-

tremity fractures. In one study 102 patients underwent lower extremity venography 9 days af-

ter operative fixation and followed for 6 weeks. The overall incidence of clinically occult DVT

was 28% with 40% in the femoral shaft, 43% in the tibial plateau, 22% in the tibial shaft and

12.5% in the tibial plateau. 190 Multiple injured patients with pelvic fracture are at an increased

risk of venous thrombosis. The incidence of pulmonary emboli in these patients has been re-

ported to be from 0.5 to 8.3%. In a prospective study 198 patients with pelvic trauma were

followed for 3 years. The incidence of pulmonary embolism was related to the Injury Severity

Score ISS (ISS < 15 = 0% vs ISS > 15 = 4%, P < 0.05). 191 In a Canadian study of 349 patients with

major trauma, DVT occurred in 58% of the single cohort with major trauma who did not re-

ceive prophylaxis. Patients with highest risk were those with injures of the lower extremities

and spinal cord that were followed over 2 years. DVT was associated with spinal cord injury,

fracture of the femur or tibia. 192 Britt et al. reviewed the incidence of lower extremity DVT in

1093 patients with pelvic and lower extremity fractures. They found an incidence of 13% DVT

and patients with DVT (1.3% PE),15% in patients with both pelvic and lower extremity fractures

(0.99% PE), and 9% in patients with lower extremity fractures only (0.63% PE). 193

Lower extremity DVT can occur in patients with lower extremity trauma not undergoing

surgery. The lower extremity DVT in patients with brace or immobilization can be from 0–

17%. 194 , 195 Use of prophylaxis in these patients significantly reduces the incidence of VTE but

there is wide variation between physicians using anticoagulants. 195 , 196


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Patients treated with surgery following lower extremity trauma have a reported risk of 2.1%

f DVT despite being anticoagulated with LMWH in the first 24 hours of admission. 197 , 198 A

etrospective review of 57,0 0 0 ankle traumas revealed a rate of 0.05% due to VTE. 199 In patients

ndergoing surgery for hip or femur fracture DVT presence was 10%. 200

Upper extremity trauma is also related to a higher risk of VTE. Incidence of VTE reported in

hese patients is 1–5%. 197 In a recent study between trauma patients, rate of VTE in patients

ith upper extremity trauma was reported to be 4.95% similar to the rate of VTE of all trauma

atients. 201

ultiple trauma with involvement of different organ systems

Trauma is also a risk factor for VTE. The incidence of VTE after injuries depends on the pop-

lation being described, nature of their injuries and prophylactic measures used. 202 Patients at

isk have an incidence of DVT that ranges from 10–20% and PE 1–2%, but mortality can be as

igh as 20–50%. 202 Geerts et al performed a prospective study in 349 patients and 58% of them

ad clots. 192 The occurrence of VTE during post-traumatic hospitalization is associated with mor-

idity and mortality. In a study from the German Trauma Surgery registry, 7937 were included

nd from them 146 developed clinically relevant VTE events with an overall incidence of 1.8%.

wo-thirds of the VTE events occurred in the first 3 weeks of admission while patients were ei-

her receiving mechanical or chemical prophylaxis. Multivariate analysis identifies injury sever-

ty score, number of operative procedures, pelvic injury and concomitant disease as indepen-

ent risk factors for VTE. Presence of VTE was also associated with higher frequency of sepsis,

ultiple organ failure and prolonged hospital stay. Mortality in the VTE group was 13.7% vs

.4% in the non VTE group (P-0.004). Presence of PE was associated with mortality of 25.7%. 203

nudson et al used the American College of Surgeons national trauma data bank and found that

ge ≥ 40, pelvic fracture, LE fracture, spinal cord injury with paralysis, ventilator days, venous

njury, shock on admission and major surgery were associated with VTE. 202 Ratan et al ana-

yzed 5,151,617 patients in Nationwide Readmission Database from 2010–2014 and 1.2% of these

atients were readmitted within one year with VTE. The yearly cost of one-year readmission

or VTE was $256.9 million accounting for one-third of the cost. 204 The risk assessment profile

core (RAP) identifies trauma patients at risk for DVT. In the prospective study there were 102

igh-risk (64%) and 58 low-risk (36%) individuals studied. Eleven of the high-risk group (10.8%)

xperienced the development of DVT (asymptomatic, 64%). None of the low-risk group was diag-

osed with DVT. Five of the 16 RAP factors were statistically significant for DVT. Eliminating pro-

hylaxis and Doppler scans in low-risk patients resulted in a total savings of $18,908 in hospital

harges. The RAP score correctly identified trauma patients at increased risk for development of

VT, and despite prophylaxis the high-risk group warranted surveillance scans. 205

A recent study using hospital discharge data in a pediatric population from 19 states indi-

ated that DVT occurred at a rate of 0.77 per 10 0 0 discharged among injured patients. 206 , 207

n a pediatric trauma population risk factors included older age, injuries to the head, thorax,

bdomen, lower extremity, spinal cord injury and use of central catheters. 202

cute spinal cord injury (paralysis)

VTE remains a cause of significant mortality in patients with spinal cord injuries. Venous sta-

is is a major concern in these patients as well as DVT. These patients exhibit all 3 components

f Virchow’s triad and the incidence of DVT is reported to be greater than 50% with incidence

f final PE as high as 5%. 208 Prevalence of DVT has been described to range from 14–100%. 209 In

retrospective chart review of 151 patients with spinal cord injury (SCI) 17 (11%) had symp-

omatic VTE (9 PEs, 6 lower extremity DVT, 1 upper extremity DVT, and 1 with DVT and PE). In

he univariable analyses, male sex and having other sites of injuries along with SCI were signifi-

ant risk factors. In stepwise Cox modeling, independent risk factors were other sites of injuries


(hazard ratio [HR] 6.07, 95% confidence interval [CI] 1.89–19.47, p = 0.002), age (HR 1.05 per year,

95% CI 1.02–1.08, p = 0.002) and the presence of leg paresis (HR 2.7, 95% CI 0.72–10.54, p = 0.14),

whereas hypertension appeared to reduce the risk (HR 0.18, 95% CI 0.04–0.78, p = 0.02). 210 In a

metanalysis of 23 studies, there was strong evidence to support use of LMWH for thrombophy-

laxis. 208

VTE remains a common complication following spinal cord injury. Because patients with SCI

might not report the initial symptoms that are associated with VTE oftentimes the initial pre-

sentation includes extensive DVT and PE including sudden death. Furthermore, DVT in patients

with spinal cord injury resolves more slowly and can lead to chronic venous occlusion. Early

thromboprophylaxis is the most effective way to reduce the burden of this complication in the

spinal cord injury patient population. Clinical practice guidelines are in place to guide clinicians

in management of VTE in this patient population. 211

Risk factors affecting female patients

VTE is a specific reproductive health risk for women. There is a synergistic effect between

thrombophilia and various reproductive risk factors. VTE in women occurs during pregnancy,

with the use of reproductive hormones and as a consequence of ovarian stimulation. In preg-

nancy, the risk of VTE is increased ∼5 fold while the use of combined hormonal contra-

ception (CHC) doubles the risk including contraceptive pills containing desogestrel, gestodene

and drospirenone when compared with levonorgestrel. Hormone replacement therapy (HRT)

increases the VTE risk 2–4 fold. In women who are at high risk, CHC and HRT should be

avoided.

Pregnancy increases the risk of VTE 4-5-fold over that in the non-pregnancy state. 212 , 213 VTE

can occur at any trimester in pregnancy but is more common during the first half of preg-

nancy. 214 DVT during pregnancy is more common in the left leg compared to the right. This

might be a consequence of May-Thurner syndrome in which the left iliac vein is compressed by

the right iliac artery. 215 Also 12% of DVT’s are in pelvic veins and VTE remains common in the

post-partum period. 216 In a 30-year-population-based study, Heit et al concluded the risk of VTE

and pulmonary embolism was 5-fold to 15-fold respectively in the postpartum period compared

to during pregnancy. 213

In a large primary care database containing 376,154 pregnancies ending in live birth or still-

birth, pregnancy ending in stillbirth was associated with a 6-fold increase in the rate of VTE

compared with a live-birth outcome. In the postpartum phase still birth was the strongest risk

factor with VTE (AR, 24 4 4/10 0 0 0 0 person-years; IRR, 6.2/10 0, 0 0 0 person-years). 217

Recurrent miscarriages affect 2–5% of women. 218 , 219 The cause of recurrent miscarriage is

only identified in 50% of patients. 220 Thrombophilic disorders nowadays are thought to play a

part in the cause of recurrent miscarriages, particularly the antiphospholipid antibody syndrome

(ACA) syndrome. 221 Women who are thought to have higher risk of thrombophilia prior to preg-

nancy show an increased risk of thrombotic events during pregnancy and/or abortion. 222

Estrogen influences hemostasis by increasing the levels of clotting factors (VII, VIII, X, fibrino-

gen) and plasminogen and lowering antithrombin III and protein S levels and altering activated

protein C (ACP) resistance which decreases factor V activity. 223 In a large case control study

that compared VTE risk associated with levonorgestrel containing pills (2nd generation) and 3rd

generation pills (desogestreol, gestodene) included 1524 cases and 1750 controls. Overall OCPs

were associated with a fivefold increased risk of VTE. The risk was lower with levonorgestrel-

containing pills (odds ratio [OR] 3.6; 95% CI 2.9–4.6) when compared with pills containing des-

ogestrel (OR 7.3; 95% CI 5.3–10), gestodene (OR 5.6; 95% CI 3.7–8.4), drospirenone (OR 6.3; 95%

CI 2.9–13.7), or cyproterone acetate (OR 6.8; 95% CI 4.7–10). The risk for VTE was highest in the

first 3 months of use (OR 12.6; 95% CI 7.1–22.4), but even at 1 year a fivefold increased risk was

detected. Among those who used the pill for at least 2 years, the risk was still elevated with

desogestrel- (OR 1.9; 95% CI 1.3–2.9) and gestodene- (OR 1.5; 95% CI 0.9–2.6) containing pills

when compared with levonorgestrel-containing pills. 224


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In a systematic review of progesterone only contraception (POCs) did not suggest an increase

n odds of venous or arterial events with use of most POCs. Limited evidence suggested in-

reased odds of VTE with use of injectables and use of POCs for therapeutic indications. 225

Hormonal therapy is also a risk factor for VTE in women. Route of hormonal therapy is also

mportant in risk for VTE. Oral but not transdermal estrogens are associated with a higher risk of

ecurrent VTE in postmenopausal women [HR, 1.0; 95% CI, 0.4–2.4, transdermal and [HR 6.4; 95%

I, 1.5–27.3, oral therapy]. 226 Treatment with tamoxifen has also been associated with increased

isk of VTE. In a Danish population study of 16,289 women found that patients taking tamoxifen

ave a higher risk of VTE. The 5-year risk of DVT/PE was 1.2% for women receiving tamoxifen

nd 0.50% for women not receiving tamoxifen. Women treated with tamoxifen were at a higher

isk for DVT/PE during the first 2 years after exposure (RR, 3.5; 95% confidence interval [95% CI],

.1–6.0). Subsequently, their risk was not found to be substantially increased (RR, 1.5; 95% CI,

.88–2.5). Older women taking tamoxifen appeared to be at higher risk than younger women

uring the first 2 years of exposure. 227

ND OF PART ONE

ART TWO: RISK ASSESSMENT USING THE CAPRINI SCORE

isk assessment models (RAM’s)

A variety of RAM’s have been proposed ranging from those looking at a few major factors

o very detailed models designed to capture all of the important factors that could lead to a

hrombotic event. Most of these models attempted to simplify the assessment process by in-

luding only the most frequently associated factors known to increase the incidence of VTE. The

roblem with this approach is many patients with risk factors not included in the model may be

enied prophylaxis but remain at high risk. Scores such as the Padua score and Improve score

hat do not include family history of thrombosis, or obstetrical-related complications, are good

xamples. These scores do identify most of the patients that are “at risk” for VTE but anytime

patient with family history of thrombosis, or history of an obstetrical complication is encoun-

ered, the patient may be misclassified. We began development of a RAM designed for surgical

atients in 1986 inspired by the work of Professor Maxwell Borow who demonstrated that the

ore risk factors, the more likely the patient would suffer a thrombosis. He further observed

hat there was a linear relationship between the age of the patient and the length of surgery

nd development of a postoperative thrombosis. 7 , 32 He also reported that 25–40% of patients

aving an operative procedure lasting over one hour developed a postoperative thrombosis. The

ate was even higher when additional risk factors were present. He further documented that a

hysical method of compression when combined with an anticoagulant resulted in a very low

ate of postoperative thrombosis.

aprini risk model

Risk assessment is the first step in preventing death and disability from VTE. A multidisci-

linary team put together a list of common risk factors and weighted these factors assigning a

oint score to each factor based on the literature of the day. The points were totaled, and the

core correlated with the 30 and 60 days clinically evident VTE events ( Fig. 1 ). This system ac-

ounted for most of the risk factors known at the time to be associated with VTE. The underuti-

ization of VTE prophylaxis seems to be a global problem. In a large international cross-sectional

tudy across 32 countries, 39.5% only of at-risk medical patients received VTE prophylaxis. 228 On

national level, in 2011 around 20 0 0 VTE events and 940 deaths have been avoided in England

y implementing a compulsory VTE risk assessment tool developed by British investigators. 229

hat tool like the Caprini score includes family history of VTE as a risk factor.

The Caprini RAM was first published in 1991. This model was subsequently modified and

pdated to its most widely used version in 2005 to reflect new evidence and improved


Fig. 3. Original Caprini Score.

understanding of VTE predictors as seen in Fig. 3 . 230 The value of the Caprini risk model resides

on the ability to divide patients into four categories based on the VTE risk instead of assigning

patients into a sole pool. The Caprini RAM uses individual risk factors such as age, weight, per-

sonal history of VTE and also surgery-related variables such as type and length of the procedure.

Thirty-nine factors are included in the original score plus a box for additional risk factors. It is

important to remember that additional risk factors not specifically listed but known in the liter-

ature to be associated with the development of VTE can be included in this OTHER box. Some of

the well-known risk factors since the appearance of the original score are discussed in a subse-

quent section. Point values are assigned to risk factors to derive an aggregate score, which places

patients into low, moderate, high and highest risk for VTE.

Caprini risk scoring method

This scoring tool involves assigning a point value to each risk factor according to the power of

that risk factor based on the available literature. Next the point totals are calculated to obtain an

overall score. This score has been validated in more than 100 publications comparing the score

result to the 30-day real venous thromboembolism event rates. Based on a number of studies

the scores are placed in one of three categories.


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Low-risk patients are spared anticoagulant prophylaxis postoperatively since the incidence of

0-day clinically evident venous thromboembolism events is less or equal to the risk of bleeding

rom anticoagulation. Different set points for this low-risk group have been established depend-

ng upon the population studied. In general, those patients with a score of less than five fall into

his category. As many as 50% of patients fall into this category although a recent meta-analysis

uggests this number may even be higher. 231

Standard-risk patients are those that have a risk score reflecting a VTE incidence that ex-

eeds the incidence of bleeding events using anticoagulation. Point totals in this group average

etween five and eight although those numbers may shift slightly depending on the population

ested. We feel that there is strong evidence that patients in this group require 7 to 10 days

f anticoagulant prophylaxis postoperatively. This opinion is based on the premise that patients

ho are at risk to develop venous thromboembolic events need to be protected for the period

f time that has been shown in the literature to effectively prevent thrombosis. This large body

f evidence will be discussed in a subsequent section. The results of all of these trials indicate

he appropriate period is at least 7–10 days.

High-risk patients are those whose point totals indicate that they are at great risk to develop

enous thromboembolism postoperatively, and merit anticoagulant protection for 30 days. There

s strong evidence in the literature that 30 days of prophylaxis are more effective than shorter

ime periods in patients who are at very high risk for thrombosis which would include people

n this group. Point totals for these patients are > 8 for general surgery, 10 or greater for total

oint replacement, and 12 or more following hip fracture.

The process of collecting these data has evolved over time, and we now feel that the most

ppropriate method is to have the patient fill out a patient friendly questionnaire prior to the

perative day. Patients are encouraged to complete the document in the presence of their family

o that thorough historical perspectives including family history of thrombosis can be uncovered.

he patient should then submit this form ahead of time especially using the electronic medical

ecord portal or other means so that at the time of the admitting history and physical, the

ppropriate healthcare provider can double check the form and ask a few final questions.

Some of the critiques of the Caprini RAM are its complexity and its time-consuming process.

owever, a patient-completed form of the Caprini RAM was recently devised and tested . 232 The

uthors demonstrated an almost perfect correlation between patient and physician-completed

cores. Having the patient fill out the form with their family removes the onus of exten-

ive patient questioning and simplifies the face-to face encounter with the admitting physi-

ian. Collecting all of these data using the EMR and linking the score to a treatment plan is

deal ( Fig. 4 ).

Fuentes and colleagues in a multistep process developed and validated this patient friendly

orm that is highly accurate compared to the same form being filled out by a trained physician.

heir studies have shown that the average patient can complete a form in about five minutes,

nd the physician or healthcare provider completing and checking the document can accom-

lish that task in another five minutes. The authors have found that patients often fail to an-

wer family history questions correctly, and do not understand how to calculate the BMI. Fe-

ale patients often do not understand the questions regarding obstetrical complications and

heir importance in the risk assessment process. The examiner can quickly correct these simple

roblems as well as look for certain physical findings. These include leg edema and clinically

ignificant varicose veins. Finally, the most important objection to collecting the Caprini score

ist of 39 variables has been resolved and this system is now published in four languages, with

ranslations into Thai, Turkish, and at least one Chinese dialect on the way. Paz et al validated

he Caprini score in Spanish, Arabic and Polish speaker languages and reported excellent agree-

ent comparing physician and patient results ( κ = 0.93) and high correlation 0.97 ( P < 0.01) for

he overall score. 232

One of the unique features of the scoring system is the dynamic nature of data collection pos-

ible. During hospitalization the score can be revised depending upon the appearance of certain

linical problems including infection, central lines for administration of antibiotics or chemother-

py, unexpected diagnosis of cancer, or emergent reoperation for anastomotic leaks, or infection.


A final score can be calculated upon hospital discharge, but revisions are still possible if events

occur in the post hospitalization period due to the appearance of infection, or unexpected im-

mobility. In these cases, the 7 to 10 day course of anticoagulants may be prolonged, and in some

cases significantly extended depending upon the nature of the complication (Fig. 4) .

We strongly discourage chart review for obtaining these data since one never knows if all the

questions were asked and during what time frame. The dynamic nature of the tool is lost and if

the score was obtained just prior to the operation many inaccuracies are possible.

We feel the preoperative holding area is the wrong place to try to determine the score ex-

cept for emergency surgery. The nurses in the preoperative holding area are not trained to take

detailed history and physical examinations, and the patient’s mind is focused on the planned

operative procedure. The concerns of most patients at that time include–will the operation be

Fig. 4. Caprini Patient Friendly Score.


Fig. 4. Continued

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uccessful? will the surgeon find something abnormal including cancer? will the surgeon have a

ad day? how much pain will I be in after surgery? and finally how long will I be out of work?

rying to have a preoperative patient focus on detailed historical items including family history

nd obstetrical complications while waiting preoperatively is not appropriate.

The National Surgical Quality Improvement Program (NSQIP) developed by the American Col-

ege of Surgeons is a fantastic data pool of approximately 5 million surgical patients and growing

ll the time. 233 Unfortunately, history of venous thromboembolism in the patient, family history

f venous thromboembolism, the use, type, and duration of prophylaxis are not data points in

his program. As a result, it is very difficult to analyze these data to determine the actual risk of

ndividual patients as well as the effects of thrombosis prophylaxis including the anticoagulants

odifying the venous thromboembolism event rate.

Pannucci and colleagues presented some very compelling data to indicate how venous throm-

oembolism risk is underestimated when chart reviews are compared to live patient interviews.

ey questions regarding obstetrical complications, and family history of thrombosis including

elatives of different degrees are much more likely to be discovered with face-to-face patient

hysician interactions. 234

We have observed that VTE related studies involving large groups of patients in a certain

pecialty, type of operative procedure, or following a traumatic injury do not accurately repre-

ent the group studied unless specific and detailed risk assessment is done. The purpose of this

nalysis is to separate out those very high-risk patients who may require a lot of prophylaxis to

hose low-risk individuals that may not even need any anticoagulation.

ndividual risk factor criteria interpretation for the healthcare provider

ge

Patients aged 41–60 score = 1 point; 61–74 years = 2 points; age 75 + = 3 points.


Minor surgery

Patients having surgery with an anesthesia time of less than 45 minutes = 1 point.

Past major surgery

Individuals having surgery with an anesthesia time of greater than 45 minutes during the

past month = 1 point.

Major surgery

Planned major surgery with an anesthesia time lasting longer than 45 minutes (including

laparoscopic and arthroscopic procedures) = 2 points.

Total hip or knee replacement

These operations are scored as 5 points each due to their high-risk nature. It should be un-

derstood if additional risk factors are present, that further increases the level of risk. It is a

misnomer to conclude that since all of these procedures are high risk, there is no need to risk

assess. It is important to understand as the level of risk escalates above what is seen in the av-

erage patient, the type, duration, and intensity of the thrombosis prophylaxis must be adjusted.

Patients with scores at the highest level may want to postpone or not have one of these elective

quality-of-life improving procedures.

Visible Varicose Veins

Patients with visible bulging veins would receive a score of 1. This risk factor does not refer to

a patient with spider veins or a patient with a history of surgically removed varicose veins. = 1

point.

Inflammatory Bowel Disease

History of Inflammatory Bowel Disease (IBD) and includes Crohn’s disease or ulcerative coli-

tis. This risk factor includes both active and inactive inflammatory bowel diseases such as ulcer-

ative colitis or regional ileitis. This would not include irritable bowel syndrome or diverticulo-

sis. = 1 point.

Swollen legs (current)

Swollen legs include pitting edema of any level, loss of definition of the bony prominences,

obscured surface foot veins, or indentation of the leg when a stocking is removed. This factor

refers to either one or 2 legs affected. = 1 point.


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verweight or obese (Body mass index above 25 kg/m

2 )

This weight level was associated with patients developing symptomatic thrombosis readmit-

ed following total hip replacement and women developing thrombosis. 65 The combination of

MI 25 kg/m

2 and oral contraceptives increased the thrombotic risk 10-fold. 64 = 1 point.

eart attack

This refers to an acute myocardial infarction during the past 30 days. = 1 point.

ongestive Heart Failure

This risk factor includes patients who have had an episode within the last month. Addition-

lly, patients who are currently being treated with medication for CHF are included, even if they

ave not had an acute episode within the past month. An ejection fraction alone should not be

sed when determining if a patient qualifies for this risk factor. = 1 point.

erious infection (e.g. Pneumonia)

A “serious infection” is defined as a patient who requires hospitalization and intravenous an-

ibiotics for treatment. For example, if a patient has a cellulitis requiring hospitalization with IV

ntibiotics they would receive one point for this risk factor. Treatments that are less severe and

re managed on an outpatient basis with oral antibiotics are not included. Serious infections

ould include diverticulitis, bacterial infection of the bladder and lungs, and septicemia. = 1

oint.

ung disease (e.g. Emphysema or COPD)

In addition to emphysema or COPD these criteria also include any interstitial lung disease

r patients with abnormal pulmonary function tests. This would include, but not limited to,

ny patient with sarcoidosis, pulmonary fibrosis, pulmonary hypertension, and bronchiectasis.

atients who present with more than one diagnosis meeting the criteria for lung disease will

eceive a point for each diagnosis. For example, if the patient has a diagnosis of sarcoidosis and

OPD they would receive a total of 2 points for this risk assessment. Asthma is not considered a

lung disease” for the purpose of the risk assessment score. Additionally, patients with restrictive

ulmonary disease related to obesity would not be included in these criteria. = 1 each point.

ed rest (Restricted Mobility) [1 or 2 points depending on duration]

We define restricted mobility (bedrest) as any individual who is unable to ambulate con-

inuously more than 30 feet. We have chosen this definition based on the prospective ran-

omised, double-blind, placebo-controlled trial in MEDical patients with ENOXaparin (MEDE-

OX), which was a large prospective study where this definition was used. 78 The rate of VTE in


non-ambulatory medical patients without prophylaxis was 19.7% compared to 10.6%; (p = 0.03)

in those that were ambulatory without prophylaxis. 235 Furthermore, the incidence of VTE in

non-ambulatory patients in the LMWH group was reduced to 9.0% compared with 19.7% seen in

the placebo group [RR = 0.46; 95% CI,0.23 − 0.91; p = 0.02] (10.7% absolute risk reduction). In the

ambulatory group, VTE incidence was 3.3% with enoxaparin 40 mg compared with 10.6% in the

placebo group (RR = 0.31; 95% CI, 0.13 − 0.78; p = 0.008. The absolute risk reduction was 7.3%.

We assign one point to those fitting the definition of bedrest < 72 hrs. We realize that there

are other definitions regarding ambulation but we feel the above data are the most robust. 236

Critics ask why isn’t everyone who spends a night in bed sleeping also at risk? We would

answer that the bedrest in hospitalized patients is associated with their underlying disease pro-

cess. For example, a person who has congestive failure, severe pain, infection, stroke, etc. is at

bedrest because of their disease process. A normal person goes to bed to get necessary rest, not

because of a specific illness. Patients moving short distances to the bathroom or sitting in a chair

are not ambulatory according to this definition. Although we use the term medical patients at

bedrest, these scores apply to all patients.

Patients who are using a cane or walker for stability are not considered as having restricted

mobility if they are using their calf muscles for ambulation.

Patients who are unable to ambulate 30 feet continuously for > 72 hrs. receive 2 points total

for restricted mobility. (We do not add an additional point for the first 24 hrs.)

A patient who requires crutches and is non-weight bearing would pass the restricted mobility

criteria but would receive 2 points if they are not using calf muscles in one leg due to a brace,

boot, or cast even though they can ambulate 30 feet.

Non-Removable Plaster Cast Or Mold (Worn For > 72 Hours) That Prevents Leg Movement Within

The Last Month (2 points)

The intent of this criterion is to capture any limitation in leg mobility which would interfere

with calf muscle pumping action such as a leg brace or cast. 237 Remember that patients using

crutches who are non weight bearing on one leg would also be included. The use of an assistive

device for stability, such as a walker, would not meet the criteria if the patient is using their calf

muscles. = 2 points.

Confined to bed for 72 hours or more (unable to ambulate continuously 30 feet)

“Confined to bed” is confusing terminology and should be referred to as impaired mobility.

The patient is unable to ambulate continuously 30 feet. This would also apply to any patient

who is unable to ambulate using both leg muscles. For example, a patient who requires crutches

and is non-weight bearing would be considered as restricted mobility even though they can

ambulate 30 feet. Patients who are using a cane or walker for stability are not included in this

group if they are using their calf muscles for ambulation. Patients moving a short distance to

the bathroom or sitting in a chair are not ambulatory according to this definition. = 2 points.

Central Venous Lines

Tube in blood vessel in the neck or chest that delivers blood or medicine directly to the heart

within the last month (e.g. central venous access, PICC line, port). = 2 points.

Current Or Past Malignancies (Excluding Skin Cancer But Including Melanoma)

Whether the cancer diagnosis is remote or recent the patient will receive a score of 2. This

is because patients with a remote history of cancer are always at risk for occult metastasis

which would increase their risk for thrombosis. Every incidence of cancer is considered sepa-

rately and scored accordingly. For example, a patient who has a remote history of breast cancer

and is recently diagnosed with uterine cancer would receive a score of 4 (2 points for each

episode of cancer). For the purpose of this document Ductal Carcinoma in situ (DCIS) would

also receive a score of 2 as there is always the potential of an invasive cancer. Myelodys-

plastic Syndrome (MDS) would be scored as 2 points only if the disease requires chemother-


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py treatment. The patient would also receive an additional point for the chemotherapy

reatment.

History of Blood Clots, Either DVT or PE. This Also Includes History of Superficial Venous Throm-

osis (SVT) = 3 points

Arterial blood clots are not included in the scoring. A CVA due to a paradoxical embolus

ould be given 3 points; however, a DVT must be documented by an objective measure in this

ase. Each episode of a DVT or PE is captured as a separate event for scoring. For example, a

atient with a medical history of DVT in 2014 and PE in 2015 would be given a cumulative

core of 6. However, PE and DVT events that occur simultaneously would be scored as 3 points.

VT must be captured and scored a 3 here as well. 238

Family History VTE = 3 points

Family history of VTE should include first-degree relatives (sibling, son/daughter, parent),

econd-degree relatives (maternal half-sibling, paternal half-sibling, niece/nephew), and third-

egree relatives (cousin). Younger age of first VTE and male relative increase the risk. 77

Personal or family history Of positive blood test indicating an increased risk Of blood clotting (e.g.

enetic Or Acquired Thrombophilia)

A patient will receive a score of 3 points for each genetic thrombophilia marker. If a family

ember has a proven genetic marker the patient will receive a score of 3 unless it has been

onfirmed that the patient does not have this genetic marker. Genetic (inherited) factors: Fac-

or V Leiden/Activated protein C resistance, Antithrombin III deficiency, Protein C & S deficiency,

ysfibrinogenemia, homozygous MTHFR, 20210A prothrombin mutation. Acquired factors: Lupus

nticoagulant, antiphospholipid antibodies, myeloproliferative disorders (including thrombocyto-

is), disorders of plasminogen and plasmin activation, Heparin-induced thrombocytopenia, hy-

erviscosity syndromes, homocysteinemia. Human immunodeficiency virus (HIV) infection is an

cquired thrombophilia. 239

Fracture of the Hip, Pelvis, Or Leg

Fractures requiring surgical repair would receive 5 points for the fracture and will also

e assessed additional points depending on the type of surgery. Patients undergoing an open

eduction and internal fixation (ORIF) would be given 2 points for “surgery over 45 min-

tes”. Patients requiring a hemi-arthroplasty would receive 5 points “for elective hip replace-

ent surgery”. For example, a patient with a fractured ankle undergoing an ORIF would re-

eive a score of 7; 5 points for the fracture and 2 points for the surgical repair. An addi-

ional 2 points would be added if a cast or brace is applied or the patient is non-weight

earing.

Serious trauma (E.G. Multiple Broken Bones Due To A Fall Or Car Accident) = 5 points

Now or within the past month. There is some overlap between this category and the previous

ne and only one of these categories should be chosen.

Spinal Cord Paralysis or Stroke = 5 points

Now or within the last month.

Women Only

Current use of birth control or Hormone Replacement Therapy (HRT)

This includes estrogen contraceptives of any type. This also includes estrogen-like drugs, in-

cluding raloxifene, tamoxifen, anastrozole, and letrozole. Exemestane has not been shown

to increase the risk for DVT. Additionally, estrogen plus progestin, and progestin with or

without estrogen are independent VTE risk factors. 240 Recent publications have shown

that there is no increased risk of DVT in men who are on long term testosterone ther-

apy, therefore, testosterone is excluded. = 1 point.


Pregnancy or postpartum In The Last Month = 1 point

History of unexplained stillborn infant, recurrent spontaneous abortion (more than 3), premature

birth with toxemia or growth r estricted infant = 1 point

Recurrent fetal loss is associated with antiphospholipid antibody syndrome, procoagulant

platelet microparticles and some inherited thrombophilias such as Factor V Leiden. There have

been reports of both heritable and acquired thrombophilias being associated with pre-eclampsia,

intrauterine growth restriction (IUGR) and abruption. However, these associations are not con-

sistently reported with hereditary thrombophilias. 241

Additional risk factors not specifically validated in the original Caprini model

A number of additional risk factors that have been associated with the development of VTE

although not specifically listed in the 2005 score should be considered as additional risks. Note

that there is a category for others in the original 2005 document and no audit has been done to

indicate what additional risk factors have been scored over the past 13 years. Each one may be

scored as one point.

Smoking 242 Smoking is defined as the inhalation of anything that burns, including tobacco,

marijuana, or vaping = 1 point.

BMI > 40 , 243 244 Individuals who are physically fit or athletes but very large are not exempt

from this risk factor. The increased body mass is associated with stress on the cardiovascular

and respiratory systems and thrombotic risk = 2 points.

Diabetes requiring insulin 173,173,172 Only insulin products are included in the risk assessment

score. This does not include any other oral or parenteral medications used for the treatment of

diabetes = 1 point.

Chemotherapy 90,245 Chemotherapy treatments used for any medical condition are included

in the scoring. For example, a patient receiving Methotrexate for Rheumatoid Arthritis, re-

gardless of the dose given, would receive a point for this risk assessment. Patients diagnosed

with essential thrombocytosis taking hydroxyurea would also receive a point here, in addi-

tion to 3 points for “personal history of positive blood test indicating increased risk for blood

clotting”.

Blood Transfusions 246 Add one point for one or more blood transfusions

Length Of Surgery Over 2 Hours 7 Actual current surgery time exceeding 2 hours, including

anesthesia time. Do not add to the “5” for total hip or knee replacement surgery (add 1 point).

Meta-analysis involving selected studies using the Caprini score

One of the most valuable features of the Caprini Score is the ability to protect low-risk pa-

tients from receiving anticoagulant prophylaxis. Multiple studies have shown that the incidence

of clinical thrombotic events in patients with a score of 4 or less is below 1%, 247 and Pannucci

has published a meta-analysis involving 13 studies (14,776 patients) showed that 75% of patients

had a score of 6 or less, and could be spared anticoagulant prophylaxis. 231 They also found that

these patients did not have a significant VTE risk reduction with chemoprophylaxis. On the other

hand, those individuals not receiving prophylaxis had a 14-fold variation in clinical VTE risk de-

pending upon their score (0.7% to 10.7%). These findings underscore the importance of knowing

the type, dose, and extent of thrombosis prophylaxis in a surgical population for proper overall

evaluation of VTE incidence.

One must remember that meta-analysis only analyzed 13 of over 100 studies as of this date.

CHEST 2012 guidelines suggest that a Caprini score of 5 or more is associated with up to a 6%

incidence of clinical VTE, and these individuals benefit from anticoagulant prophylaxis. 249

Leonardi has shown that the bleeding complications associated with anticoagulants are not

trivial. He found that the incidence of wound hematoma, mucosal bleeding, and those having


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rophylaxis ranges from 2.0 to 5.5%. 250 These data emphasize the importance of using the score

o target truly at-risk individuals.

This meta-analysis is an excellent example of how the Caprini score works. The low risk

ategory comprises people who are spared of anticoagulation since the risk of bleeding exceeds

he risk of anticoagulants to prevent VTE. The second group of patients that have risks factors for

TE and prophylaxis is clearly warranted. The high and highest risk subgroups comprise patients

t high risk of thrombosis in whom extended thromboprophylaxis should be given after leaving

he hospital up to 30 days post discharge.

eneral and vascular surgery

Bahl and associates from the University of Michigan published a landmark study to validate

he Caprini score in a retrospective analysis. A total of 8,216 surgical patients from the National

urgical Quality Improvement Program were included (general, urology, and vascular surgery),

he majority (52.1%) of the patients were classified to the highest risk level; 36.5% were high-

isk, 10.4% as moderate risk, and 0.9% as low risk. The overall incidence of acquired VTE within

0 days post procedure was 1.44%. The incidence of DVT was associated with an increased risk

ccording to the level of the patient’s risk (highest risk level 1.94%); (high-risk patients 0.97%);

moderate risk patients 0.70%); and (low-risk patients 0%). The difference between high and

ighest risk levels was statistically significant ( p: 0.001). 247 The University of Michigan hospitals

ave used this risk assessment tool along with mandatory care pathways since 2008. Physicians

ust opt-out of the standard algorithm for using thrombosis prophylaxis during hospitalization.

ithout enforcing care pathways, they are often ignored.

enchmark study for reducing the VTE rate

Cassidy, et al, from the Boston Medical Center, the largest safety-net urban hospital in New

ngland, developed a strategy to reduce VTE complications using the Caprini RAM. The scores

btained indicated the nature and length of thromboprophylaxis including an outpatient setting.

he investigators used mechanical (pneumatic compression boots) and pharmacologic (unfrac-

ionated or low molecular weight heparin) as dictated by the risk stratification tool comparing

he National Surgical Quality Improvement Program VTE outcomes (DVT, PE) before and after ap-

lying the standardized risk-stratified protocol in conjunction with a postoperative mobilization

rogram.

The study resulted in decreasing the incidence of DVT observed by 84%, from 1.9% to 0.3%

p < 0.01), with implementation of VTE prevention efforts.

The PE incidence decreased 55%, from 1.1% to 0.5% (p < 0.01). Risk-adjusted VTE outcomes

teadily declined from an OR of 3.41 to 0.94 (p < 0.05). The authors concluded with the follow-

ng statement “A patient care program, emphasizing early postoperative mobilization along with

andatory VTE risk stratification and commensurate electronic prophylaxis recommendations,

ignificantly reduced the likelihood of VTE complications among our patients”. 61 Key elements

n this program centered on mandatory compliance with an opt-out clause for the physician

ombined with providing prophylaxis according to risk for the period of time shown in the lit-

rature to be efficacious. The highest risk patients (score 9 + ) received 30 days of LMWH and

here was 77% compliance in these patients. Patients with a score of 5–8 received 7–10 days of

MWH prophylaxis with a compliance rate of 89%.

lastic and reconstructive surgery

In a retrospective analysis from the Venous Thromboembolism Prevention Study Network,

annucci et al. investigated the validity of the Caprini RAM in plastic and reconstructive surgery


patients. A total of 1126 patients were included. The overall incidence of VTE was 1.69%. Patients

with a Caprini score 8 were significantly more likely to develop VTE when compared with pa-

tients with Caprini score of 3 to 4 (OR: 20.9, p 0.001), 5 to 6 (OR: 9.9, p 0.001), or 7 to 8 (OR:

4.6, p 0.015). Approximately 1 in 9 patients (11.3%) with Caprini score 8 had a VTE event. It was

noted that VTE risk was not limited to the immediate postoperative period (days 1–14) among

patients with Caprini score 7 to 8 or Caprini score 8. Among these high-risk patients, more than

50% of VTE events were diagnosed in the late postoperative period (days 15–60). 248

Trauma surgery

A single center, retrospective case-control study of 78 patients with VTE versus 156 non-VTE

patients who were randomly selected in a 2:1 ratio and admitted to the intensive care unit due

to their critically ill status was done. The Caprini RAM was used to obtain the VTE risk score

and VTE risk classification in critically ill VTE patients and non-VTE patients in order to prove

the validity of the Caprini RAM. Zhang et al., found that patients with VTE had a higher Caprini

score compared to the control group ( p < 0.001). Critically ill VTE patients classified at high risk

and very high accounted for 88.4% according to the Caprini RAM. Compared to low-risk patients,

the incidence risk of VTE patients at high-risk and very high-risk was significantly higher (OR:

2.042 in high-risk; OR: 11.681 in very high-risk patients). The logistic regression model identi-

fied eight risk factors in the Caprini RAM as predictors of VTE: bed-bound in internal medicine

wards, severe lung disease ( < 1 month), sepsis ( < 1 month), large operation ( < 1 month), ma-

lignant tumor, VTE personal history, VTE family history, and thrombosis with multiple trauma

( < 1 month). The authors concluded that the Caprini RAM was applicable for critically ill pa-

tients, and had good predictive value for risk of VTE. 251

Otolaryngology

One of the Boston University studies involved patients from the Otolaryngology Service.

Seven hundred and four patients were included in this study and the average score was 9.87 for

those patients suffering a VTE event. The score for those without thrombosis was 5.62. Patients

with a score of six and below did not suffer any thrombotic events. The incidence of throm-

bosis with a score of 7 to 8 was 3.01%percent while those with a score of greater than nine

was 13.16%. The authors concluded that a score of over eight predicts a high risk of thrombosis

despite chemoprophylaxis during the hospitalization. This is a good example of how the score

threshold should be derived in individual surgical specialties to target the use of prophylaxis

with anticoagulation to those at or above the threshold rather than a shotgun approach giving

anticoagulants to all postoperative patients. 252

Another study in 2016 otolaryngology patients from the University of Michigan demonstrated

the use of the Caprini Score to risk stratify this patient population. Those with the score of six

or less had a DVT incidence of 0.5% while those with a score of seven or eight the incidence

rose to 2.4%. Finally, in those with a score of > 8, the incidence of thrombosis was 18.3%. These

statistics were based on 30-day follow-up of the patients and in this study these patients did

not receive prophylactic anticoagulation. 253

Chest surgery

The Caprini score was evaluated in a retrospective study of 232 patients operated for lung

cancer from 2005–2013 at Boston University. All of the patients received inpatient prophylaxis

with UFH 50 0 0 units TID, and were followed for 60 days. The overall incidence of VTE at 60

days was 5.2%, and 33% of the events occurred post-discharge. No VTE events were seen with


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atients scores of < 5, while 1.7% of patients had a VTE event with a score of 5–8. The very

igh-risk group with a score of 9 + had a 10.3% incidence of VTE events. The authors suggested

hat these data should result in establishing a policy for outpatient anticoagulant prophylaxis for

hose with high scores. 254

In another study from Boston University thromboembolism rates were compared using a

reintervention group of thoracic surgery patients retrospectively analyzed from 2005–2013 in-

luding some patients in the previous study. The patients included both those having lung

urgery as well as a group of esophagectomy patients. These patients all received inpatient pro-

hylaxis with UFH only (302 patients). This patient group was compared to a post-intervention

roup (64 patients) starting in 2014 which divided patients into 3 categories according to a

reviously established protocol in general surgery described elsewhere. The most important el-

ment of this protocol was continuing prophylaxis with LMWH beyond discharge for a total of

0 days. In addition, those with a BMI > 40 received 40 mg injections twice daily instead of once

aily in the lower weight patients. Provider adherence to the protocol was 100% and the pa-

ient adherence was 97.4%. The preintervention group had an incidence of VTE events of 7.3%

22/302), and the post intervention group had a VTE incidence of 3.2% 2/64. There were no

leeding complications and although these results are not statistically significantly different, the

ositive trend and high patient acceptance of extended prophylaxis, the authors felt, supports

his approach. 255

rthopedic surgery

A prospective study involving 92 fracture patients was done to evaluate clinical predictors

or preoperative DVT. Specifically, clinical signs, d -dimer, DVT risk assessment score both with

ells and Caprini scores and Doppler ultrasonography were done preoperatively. The incidence

f preoperative DVT was 16.3% and in these patients the Wells and Caprini scores were statis-

ically significantly higher than those not suffering a thrombosis (p < 0.05 all). 256 The authors

oncluded that patients with a Caprini score of 12 or more should be screened with a preoper-

tive ultrasound examination to rule out DVT.

A very recent publication involving 1078 patients has appeared comparing the results of a

rospective department-based protocol in patients undergoing total joint replacement to the

aprini risk assessment model retrospectively in the same patient group. 257 The investigators’

oal was to determine if the department protocol or the Caprini score would better identify VTE

vents after total joint replacement. All therapeutic decisions regarding thrombosis prophylaxis

ere based on the department protocol not the Caprini score. The department protocol divided

atients into low or high risk based on the presence or absence of one or more of the follow-

ng criteria. Patients were considered high risk if they had a VTE within the prior year, morbid

besity with a BMI greater than 40 with additional comorbidities, active malignancy, bilateral

taged total joint replacement, and inherited or acquired thrombophilia. If none of these criteria

ere present the patient was considered low risk. Total hip and knee replacement patients who

ere considered low risk received aspirin 325 mg twice daily for six weeks. Those patients con-

idered high risk received 12 days of a DOAC anticoagulant followed by twice daily aspirin for

n additional four weeks. At the conclusion of the study a retrospective chart review of every

atient was conducted and a Caprini score determined for each of these individuals. Statistical

nalysis indicated that the high-risk cutoff for the Caprini score was 10 or above.

Eight patients in this study suffered a symptomatic venous thromboembolic event and ac-

ording to the department protocol, 7 of these individuals were considered low risk receiving

nly aspirin prophylaxis. On the other hand, seven of the eight patients with the thrombotic

vent were correctly placed in the high-risk group with a Caprini score of 10 or more. Once the

esults of this study became available, the department protocol was abandoned in the Caprini

core is now used prospectively to classify these total joint replacement patients and provide

ppropriate prophylaxis. A large multicenter trial is being proposed to verify these preliminary

esults. We feel it is possible in the future, based on additional studies, to define the population


where aspirin is the most appropriate choice and selectively use the more powerful anticoagu-

lants where the risk is clearly greater.

Medical patients

A number of studies have addressed the Caprini score in medical patients over the past few

years. 258–265 These studies in many cases have compared the Caprini Score to the Padua Score

which has been recommended by CHEST 2012 for use in medical patients. CHEST consensus

leaders did not look at the Caprini score at that time despite several reports indicating the util-

ity of this score in medical patients. Since that time a number of reports have documented the

Caprini score as being more valuable in identifying patients at high risk for VTE. Several impor-

tant factors are recorded in the Caprini score that are missing in the Padua score and other more

recent scores proposed for use in medical patients. The most important missing factor in these

other scores is family history of thrombosis. This factor is discussed in detail elsewhere, and

represents a powerful predictor of VTE. Obstetrical complications are another important missing

question not addressed in other scores. These obstetrical complications may be associated with

the Antiphospholipid Antibody Syndrome which may be associated with an increased risk for

thrombosis. Another simple fact is no other risk scores look at as many variables, and we know

the more thorough a history and physical, the more comprehensive analysis of risk is possi-

ble. Unfortunately life is not simple and just looking at some common risk factors often results

in missing important variables. 266 The latest guidelines for thrombosis prophylaxis in medical

patients have just been published. They discuss the use of the Padua or IMPROVE scores but

acknowledge that –“Although optimal strategies for VTE risk assessment and decision making

on prophylaxis are yet to be identified, when clinicians and health care systems use these ASH

VTE guidelines, they should integrate VTE and bleeding risk assessments into clinical decision

making processes.” We assume that despite the number of publications addressing the Caprini

Score in medical patients none of that data was considered relevant for their review. 267 We look

forward to more studies using the Caprini score in this patient population. A number of large

hospitals have suggested that using a hospital-wide risk assessment tool is preferred for a num-

ber of practical reasons.

Bleeding Vs. Thrombosis

It is important to understand that skilled surgeons are rightfully concerned about postopera-

tive bleeding that may result from prophylactic anticoagulants. Certain bleeding events may be

associated with significant postoperative complications including infection, reoperation, or de-

creased functional outcomes in the case of total joint replacement procedures. While that’s a

major concern it is important to realize that bleeding deaths are very rare using prophylaxis.

Withholding anticoagulation and in surgical patients who are at significant risk may be associ-

ated with an increased incidence of fatal pulmonary embolism.

Kakkar and associates published a randomized prospective multicenter trial involving pro-

phylaxis against fatal pulmonary emboli using low-dose unfractionated heparin. 268 They en-

rolled 4121 patients undergoing major surgery in this trial. Anticoagulant prophylaxis was used

for one week, and objective endpoints including venography were employed. In the 24 centers

involved, 16 fatal pulmonary emboli occurred in the control group versus two patients in the

group treated with heparin prophylaxis for one week. The authors concluded that low-dose un-

fractionated heparin saved 7 lives for every 1,0 0 0 operated patients. The overall incidence of

deep vein thrombosis was reduced from approximately 30% in the controls to 10% in the treated

patients. No deaths from bleeding were observed in the patients receiving heparin prophylaxis.

Many surgeons were skeptical of these results since at that time (1975) it was unheard of to

give surgical patients anticoagulants which might result in postoperative bleeding. Public opin-


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on changed when Rory Collins published the results from the analysis of 70 evenly random-

zed trials of perioperative unfractionated heparin compared to controls in general, orthopedic,

nd urological surgery. 269 There were over 12,0 0 0 patients in this study and the results were

emarkably similar to the original Kakkar trial 15 years earlier. The risk of fatal pulmonary em-

olism was reduced from 0.9% to 0.3% representing a 66% relative risk reduction in the treated

atients. The overall incidence of pulmonary emboli was 3% in the control group and 1.7% in

he treated subjects. There was no difference in bleeding deaths between controls and treated

atients. In 1988 one could conclude that in 94 centers around the world over a 15-year period

ighly statistically significant reduction of venous thromboembolism including deaths resulted

rom administering unfractionated heparin in small doses to postoperative patients. Of great sig-

ificance was the fact that there was no difference in bleeding deaths between the controls and

he treated patients. THE TREATMENT PERIOD FOR ALL OF THESE STUDIES WAS 7–10 DAYS.

A randomized double-blind comparison of LMWH with unfractionated heparin involving

3,078 surgical patients given prophylaxis for 5 to 20 days was carried out in 67 worldwide

enters and the results reported in 2005. 270 Autopsy adjudicated fatal pulmonary emboli repre-

ented the primary endpoint in the trial and occurred in 0.15% of patients in either group. There

ere no deaths from anticoagulant related bleeding in the 23,078 patients. One may conclude

rom these results that administration of one of these anticoagulants for at least five days prac-

ically eliminated the possibility of a fatal pulmonary embolus despite many patients at signifi-

ant risk for venous thromboembolism. The combined results of the above three trials involved

3,0 0 0 patients, 160 centers worldwide given anticoagulant prophylaxis for ONE WEEK estab-

ishing efficacy with objective diagnostic endpoints. Remember these studies were conducted

ver a 30-year period.

The CHEST 2012 guidelines reported on the results of a meta-analysis of 51 randomized con-

rolled trials comparing low molecular weight heparin to low-dose unfractionated heparin in

8,0 0 0 general and abdominal surgical patients who were treated for at least SEVEN days, and

he thrombotic risk was 30% lower in the low molecular weight heparin groups. 271 Unfortu-

ately, the CHEST 2012 consensus guidelines did not emphasize providing prophylaxis for one

eek despite the fact that this period was shown to be efficacious in these 51 trials they ana-

yzed.

ength of prophylaxis

The Surgical Care Improvement Program (SCIP) was a nationwide program established in

006 to improve surgical care. One of the initiatives involved the administration of a single dose

f anticoagulant medication within 24 hours of surgery to patients who were judged to be at

isk for venous thromboembolism and did not have a contraindication from bleeding (SCIP-VTE

easure). It was a required Joint Commission measure for all hospitalized surgical patients. 272

ltom and associates published a large trial involving 30,531 patients having surgery from 2006

o 2009 in a database linked with the Veterans Administration surgical quality improvement

rogram data. 80 Compliance with the measure was documented in 89.9% of the patients and

he incidence of venous thromboembolism in these patients was 1.4%. Noncompliance was doc-

mented in 10.1% of the patients, and the incidence of venous thromboembolism in these indi-

iduals was 1.3%. The authors concluded that there was no association between SCIP-VTE adher-

nce and the incidence of postoperative venous thromboembolism. Although those results were

ublished in 2012 this practice continues in many hospitals to this day despite the fact that this

easure has been discontinued by the centers for Medicare and Medicaid services.

A study involving 50 0,0 0 0 US venous thromboembolism events annually was reported by

ohn Heit from the Mayo Clinic in 2017. 79 Half of these events were related to hospitalization

n patients where near universal in-hospital VTE prophylaxis was provided. The mean duration

f hospital stay was 70 hours. The authors concluded that a short course of anticoagulant is

neffective in lowering the VTE rate.


Another study, this time following total joint replacement, found that the rate of pulmonary

emboli increased from 0.87% prior to the SCIP-VTE measure to 1.3% following implementation of

the measure. 273 The authors concluded that this measure was not successful in reducing com-

plications in total joint replacement patients.

The largest study demonstrating the discordance between SCIP-VTE adherence and postoper-

ative outcomes involves 779,922 patients followed for 30 days over a five-year period and re-

ported in 2017. 81 During that time adherence to the measure improved from 14.6% to 20%. The

postoperative DVT rate increased by 7.1% and the postoperative PE rate increased by 3.7%. The

authors concluded that short-term anticoagulant prophylaxis postoperatively does not lower the

VTE rate. Lowering the VTE rate after surgery requires at least one week as previously shown in

more than 160 centers over the past 40 years.

Extended prophylaxis

The RIETE worldwide database was queried in 2008 by Arcelus and colleagues and they re-

ported on the time course in clinical presentation of postoperative VTE using these registry data.

They observed that 77% of patients developed their thrombotic event after leaving the hospital

and 55% of these thrombotic events were diagnosed after prophylaxis was discontinued. 274 These

data emphasize the need for continued prophylaxis after hospitalization for at least a week or

in cases of very high risk up to 30 days postoperatively.

CHEST 2004 guidelines considered history of thromboembolism in the highest risk group of

patients along with cancer and indicated that the risk of thrombosis was as high as 40 to 80%

with a 1% to 5% chance of a fatality. 60 These data were based on objective endpoints including

asymptomatic thrombotic events. They recommended continuing thrombosis prophylaxis for 28

days on the basis of these event rates. The 2008 CHEST guidelines emphasized that patients

who have undergone major cancer surgery or have previously had VTE should be considered to

receive LMWH prophylaxis for 28 days. 275

The CHEST 2012 guidelines suggested that risk of VTE remains elevated for at least 12 weeks

following surgery. 249 This edition of the guidelines included three excellent studies including

one meta-analysis in patients having surgery for benign and malignant disease. All three studies

concluded that extended duration prophylaxis reduces the risk of symptomatic or asymptomatic

DVT by at least 50% and two of them reported that proximal DVT was reduced by 75%. The

CHEST authors reiterated their suggestion that for patients undergoing major cancer surgery 28

days of prophylaxis should be considered, but failed to include a past history of DVT in these

recommendations despite the fact that the prior two editions of the guidelines made that rec-

ommendation. We find that conclusion odd considering that the data in the 2012 guidelines

regarding extended prophylaxis was much more robust than in the previous editions. This in-

cluded the meta-analysis involving patients with both cancer and benign diseases. 276 We would

suggest based on all of these data as well as the excellent study from Boston University that

patients considered to be very high risk using the Caprini score should receive 30 days of anti-

coagulant prophylaxis with LMWH. The very high-risk group in that study and related studies in

the Boston Hospital system was defined as a score of > 8. 61 We also suggest that in an individual

population the very high-risk score be determined prospectively. Several orthopedic groups per-

forming joint replacement use a score of 10 + as the very high-risk category, 257 and one study

uses 12 + in hip fracture patients. 256

Conclusions

1. Avoid chart reviews since they depend on the accuracy of the data collection including did

the examiner ask all of the questions. Face-to-face encounters are critical as well as using

the patient-friendly form. Patients welcome the invitation to participate in their care.


1

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2. Mandatory compliance must be enforced for prophylaxis protocols based on risk score

to have a lasting effect lowering the VTE rate. The physician should be given the opt-

out option based on individual clinical circumstances; otherwise, the protocol should be

automatic.

3. Use of clinical judgment to select a prophylaxis option in the face of patients with a history

or family history of VTE, or increased risk of bleeding, instead of relying on guidelines is

critical and may be lifesaving. The guidelines commonly exclude patients at high risk for VTE

as well as those with a past history or family history of VTE.

4. Understanding that bleeding deaths from the use of prophylaxis are very rare, while with-

holding anticoagulation in surgical patients “at risk” is associated with an increased risk of

fatal pulmonary emboli.

5. Administering anticoagulant prophylaxis to high risk patients for one week as shown in 160

trials involving 43,0 0 0 patients should be followed since that is the time period shown to be

efficacious for thrombosis prevention. It is important to avoid the temptation of short courses

of anticoagulants during brief hospital stays, or outpatients in high-risk individuals

6. Prescribe anticoagulant prophylaxis for at least 30 days in very high-risk individuals. It is

important to remember that most patients develop thrombosis after leaving the hospital,

and when short courses of anticoagulants are discontinued.

7. Ambulation has no effect on existing risk factors such as cancer or history of venous throm-

boembolism and only decreases the risk associated with immobility.

8. Remember that 66% of patients having surgery, who had a history of venous thrombosis suf-

fered a postoperative thrombosis when prophylaxis with anticoagulants was omitted.

9. Understand the value of family history as a risk indicator for venous thrombosis and pul-

monary emboli. Note that this is the most frequently missed or ignored risk factor which

can result in a serious postoperative thrombotic event. This history should include all 3 de-

grees of relatives.

0. Continue appropriate anticoagulant prophylaxis long-term in patients with ongoing risks

such as immobilization, infection, casts, rigid leg braces, or metastatic cancer.

cknowledgment

The authors wish to acknowledge Dr. Thomas Wakefield for reviewing this manuscript.

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Venous thromboembolism prophylaxis using the Caprini score · 250 I. Golemi, J.P. Salazar Adum and...

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