Updates in venous thromboembolism

Updates in Venous

Thromboembolism

Gamal Rabie Agmy, MD, FCCP Professor of Chest Diseases, Assiut university

Fibrin Platelets RBCs

Thrombosis

Blood

vessel wall

Venous Thromboembolism (VTE) =

1. Deep vein thrombosis (DVT)

2. Pulmonary embolism (PE)

Risk factors

Small DVT Big DVT PE Death

Deep vein thrombosis (DVT)

Thrombus in one or more deep veins

- legs >>> arms

- portal, mesenteric, splenic, cerebral, renal

Proximal DVT - Popliteal iliac veins

- Lead to >90% of PE

Distal or calf DVT - Distal to popliteal

- Posterior tibial, peroneal veins

- Most calf DVT asymptomatic

- Rarely lead to PE

Superficial thrombosis - Not DVT; don’t lead to PE

Risk factor(s)

PROXIMAL DVT

Calf DVT

Resolves

spontaneously

80-90% 10-20%

Pulmonary embolism

Death

>50% rare

What Causes the Blood to Clot when it Should (and Shouldn’t)?

Venous

stasis Activation of

coagulation

Injury to the

blood vessel

wall

THROMBOSIS

Virchow’s Triad

Procedure-related:

Cancer > benign

Open > laparoscopic

GA > regional anesthesia

Duration of procedure

VTE Risk Factors in General Surgery

Patient-related: Age

Previous VTE

Obesity

Reduced mobility

Infection

+ FH, ?coag

abnormality

tamoxifen

hernia

repair

age

Triggering factor

Predisposing factors

? Genetic factor

DVT

VTE is often multifactorial

D-dimer (“D-dummer”)

Formed by effect of plasmin on fibrin

Increased in VTE

Also increased:

Generally useless; may be misleading

NEVER done on inpatients or patients at high

risk of having a positive result

Virtually no role in surgical patients

plasmin

Fibrin FDPs (incl D-dimer)

after surgery

trauma

cancer

acute infection

inflammatory disease

liver disease

uncomplicated pregnancy

healthy elderly

etc

Appearance of Pulmonary Embolus on CTPA

◙ The key diagnostic findings of PE on CTPA are central or wall-

adherent filling defects in the pulmonary arteries leading to either

complete or partial obstruction. There are a number of mimickers of

PE, which can be divided into anatomic and technical mimickers.

Familiarity with these helps to avoid diagnostic errors. These pitfalls

are discussed later in this tutorial. In the CTPA sequence of images

below scroll to see the filling defects created by the PE.

◙ Below you can find the CTPA of an acute PE in first image, followed by a

1-month follow-up and then a 1-year follow-up.

A

B C

Diagnostic Test of Choice for most Patients with Suspected PE

CT pulmonary angiogram (CTPA) = very

accurate for PE (?too sensitive)

Requires contrast, a lot of radiation

Ultrasonography

◙ If there is an ultrasound confirmation of deep venous thrombosis

(DVT) associated with pulmonary symptoms, this may indirectly

confirm the diagnosis of PE. Since therapy is often the same for both

conditions, further investigation to exclude PE may not be necessary.

Prevalence of DVT is 82% in patients with PE

◙ Compression Duplex ultrasound is the primary diagnostic test for

DVT in patients having proximal leg symptoms, with a reported

sensitivity and specificity of 97 and 94%, respectively. Although the

diagnosis of a DVT below the knee is more controversial, reported

prevalence of lower limb (infra-popliteal level) DVT is as low as 13%

in the patients with proven acute PE. Major restrictions of US

imaging limiting its sensitivity in the diagnosis of DVT are the

challenging evaluation of calf veins, iliac veins and the inferior vena

cava as well as its operator/equipment dependency.

Ultrasonography

Ultrasonography

Schematic representation of the parenchymal, pleural and vascular features

associated with pulmonary embolism.(Angelika Reissig, Claus Kroegel.

Respiration 2003;70:441-452 )

V/Q Scan

◙ Pulmonary perfusion scanning was the most widely utilized

screening test to rule out clinically important pulmonary embolism

prior to the advent of computed tomography pulmonary angiography

(CTPA). It has been shown that a normal test result almost certainly

excludes the presence of pulmonary embolism.

◙ A high probability ventilation-perfusion (VQ) scan usually indicates

the presence of clinically significant PE. 88% of patients with a high

probability VQ scan had angiographic evidence of PE in the PIOPED I

study.

◙ However, in patients with a prior history of PE and high probability

VQ scans the presence of acute PE was proven in only 74%

angiographically. In addition, of all patients diagnosed with acute PE

in the PIOPED I study, only 41% had a scan pattern thought to

represent a high probability VQ scan.

V/Q Scan

◙ Patients presenting in either the intermediate or indeterminate group of

VQ scans are difficult to interpret and the technique is also not helpful in

patients with a low probability scan in the setting of a high clinical

suspicion. Unfortunately, the majority of patients undergoing perfusion

scanning have nondiagnostic results (more than 60% of all patients in the

PIOPED I study). Also, in the PIOPED II study, VQ scanning has been

used for the diagnosis or exclusion of PE evaluated by CTA. Only 30% of

all patients had a high probability and normal VQ findings. It is for this

reason that other screening techniques for PE have been developed.

◙ Compression Duplex ultrasound is the primary diagnostic test for DVT

in patients having proximal leg symptoms, with a reported sensitivity and

specificity of 97 and 94%, respectively. Although the diagnosis of a DVT

below the knee is more controversial, reported prevalence of lower limb

(infra-popliteal level) DVT is as low as 13% in the patients with proven

acute PE. Major restrictions of US imaging limiting its sensitivity in the

diagnosis of DVT are the challenging evaluation of calf veins, iliac veins

and the inferior vena cava as well as its operator/equipment dependency.

The addition of a ventilation scan improves the overall test performance

only marginally.

Magnetic Resonance Pulmonary Angiography (MRPA)

◙ Magnetic resonance pulmonary angiography (MRPA), although still

considered a second-line imagine technique behind CTPA, has been

gaining acceptance in the evaluation of VTE. In contrast to CT, MR

imaging does not expose the patient to ionizing radiation, and its

main contrast agent, gadolinium chelate, shows a much lower

potential for allergic reactions and nephrotoxicity than does

iodinated contrast. There is however the risk of developing

nephrogenic systemic fibrosis (NSF) in patients on dialysis or with

renal insufficiency (reference). However, longer acquisition times and

poorer spatial resolution have historically limited its applicability in

the imaging of the pulmonary arterial system.

Magnetic Resonance Pulmonary Angiography (MRPA)

◙ As MR techniques improve these historic limitations are slowly

being overcome. The advent of more rapid imaging sequences in

conjunction with parallel imaging has diminished motion artifact,

allowing for improved resolution of the pulmonary vascular system.

Additionally, dynamic imaging during contrast injection now offers

the functional information of perfusion imaging. The systemic

venous structures can be simultaneously evaluated, using MR

venography (MRV), to assess for pelvic and lower extremity VTE.

Recent published literature suggests that MR imaging of acute VTE

(MRI, MRPA, MR perfusion, MRV) indeed may rival the accuracy of CT

in the detection of VTE and PE (at least centrally). These data have

yet to be validated in larger prospective studies. As it continues to

evolve, MR imaging is expected to play an increased role in the

future evaluation of PE.

MR Direct Thrombus Imaging

◙ MR direct thrombus imaging (MRDTI) makes use of direct

detection of methemoglobin in a thrombus, which appears bright on

T1-weighted sequences owing to its T1 shortening effect. Utilization

of this endogenous contrast permits visualization of a thrombus

without the use of any contrast agent (hence the term “direct

thrombus imaging”), and it is non-invasive. MRDTI can be used to

detect subacute thrombosis. Deep vein thrombosis and pulmonary

embolism can be both confirmed by MRDTI. Also, it does allow the

detection of venous thromboembolic disease with a single imaging

modality. The most significant advantage of MRDTI is the direct

visualization of the thrombus, while other sequences rely on the

detection of thrombus through a filling defect. Another advantage is

that MRDTI allows to differentiate between old and new clots (high

signal intensity indicates subacute thrombosis).

MR Direct Thrombus Imaging

◙ Several studies have been performed to determine the efficacy of

MRDTI in detection of thrombus. In a study comparing MRDTI with

contrast venography the sensitivity of MRDTI was 96% in 338

patients. In a smaller PE study involving 13 patients the sensitivity

and specificity of MRDTI was 100% for both. MRDTI allowed the

detection of three additional emboli not seen on conventional

pulmonary angiography. A randomized trial of MRDTI for diagnosis of

pulmonary embolism in 157 patients demonstrated similar patient

outcomes compared with more extensive diagnostic strategies,

including CT, VQ and D-dimer testing. These results make it possible

that MRDTI may have a significant role in the future for the diagnosis

and management of venous thromboembolism.

MR Perfusion Imaging ◙ Contrast-based perfusion MRI is generally used in combination with

ultra-fast three dimensional MR angiography (3D MRA), demonstrating

contrast agent entering into the pulmonary circulation as well as imaging

of the vessel morphology. Techniques without or with parallel imaging

technology are effective. These permit both the identification of perfusion

defects and imaging of the vessel morphology, hence facilitating the

diagnosis of pulmonary vascular disease. Highly promising results have

been reported from the initial work in this field.

◙ A recent study of 33 patients evaluated the feasibility of MR perfusion for

short-term follow-up of patients with acute PE. The study also purposed to

evaluate temporal changes of pulmonary perfusion and thrombus

characteristics of a thrombus that might be helpful in determining the age

of the thrombus. All patients were examined by CT and, MRA, real-time

MRI and MR pulmonary perfusion imaging initially and 1 week after

treatment. A follow-up diagnostic work-up was feasible for all patients after

treatment. MRA and CT were concordant for a diagnosis of PE in all

patients. They have also indicated that MRI has potential role for

determining the age of embolic material. The technique currently has to be

considered experimental and its value in clinical practice remains to be

demonstrated.

Pulmonary Angriography

◙ Pulmonary angiography is considered the gold standard for the

diagnosis of PE, although recent evidence does not necessarily

always support that. Pulmonary angiography is an invasive

procedure and due to its costs and potential risks is usually reserved

for patients in whom more information or certainty of the diagnosis

of PE are necessary. Indications for angiographic evaluation of

patients suspected of having PE are the need to confirm the

diagnosis of PE in the presence of contraindications to

anticoagulation or if IVC filter placement or surgical embolectomy are

contemplated.

◙ In addition, patients with a high index of clinical suspicion but

nondiagnostic noninvasive studies and patients with pulmonary

hypertension of unknown cause commonly undergo the exam . The

unequivocal establishment of the diagnosis of PE in younger

patients facing life-long anticoagulation therapy or IVC filter

placement is another indication. With modern techniques and

nonionic contrast media, the risks of the procedure are exceedingly

low with major nonfatal complication rates less than 2% and a

mortality of the procedure of 0.1%.

Pulmonary Angriography

◙ Life threatening complications are typically secondary to acute cor

pulmonale in patients with pre-existing severe pulmonary

hypertension and failing right ventricle. Therefore, the measurement

of the right ventricular enddiastolic pressure (RVEDP) is mandatory

before performing the angiographic runs and if this is 20 mmHg or

higher it should be acknowledged that the patient has a significantly

higher risk of a serious complication and therefore either should not

have the study performed or have a superselective study using more

runs with smaller amounts of contrast.

◙ It has been shown that digital angiography helps to reduce both

time and amount of contrast necessary to perform pulmonary

angiography if compared to conventional cut-film angiography. It

also has been shown to have similar performance without sacrifices

in sensitivity or specificity

Pulmonary Embolism During Pregnancy

◙ The diagnosis of PE during pregnancy imposes special

challenges. Both CTPA and VQ scanning expose the mother and the

fetus to radiation, with the fetus being particularly susceptible. The

International Commission on Radiological Protection (ICRP) has

made recommendations regarding the minimization of radiation

exposure to both patient and fetus and many countries have

introduced legislation to this end. In general terms, the fetal dose is

much higher with VQ scanning than with CTPA (depending on the

protocol up to 200 times higher) (700 – 800 µGy, vs 3 – 131 µGy) while

the maternal dose is typically lower with VQ scanning (1.4 mSv

versus 2.2 – 6.0 mSv).


◙ This fetal dose advantage for CTPA even applies to protocols

specifically modified for pregnant patients like half-dose perfusion scans

(140 – 250 µGy). Other considerations are the somewhat higher risk for

the mother to develop breast cancer with CTPA and the lack of human

safety data for the effects of iodinated contrast media on the fetus,

although they approved to be safe in animal experiments. Therefore, any

search for PE in a pregnant patient should involve a thorough discussion

of the risks and benefits with the patient. If imaging is necessary with

ionizing radiation, the currently available data support the preferential use

of CTPA, if possible with a modified low-dose technique and limited

anatomical coverage.

Automated tube modulation should be used for all scans, regardless

if the patient is pregnant or not. However, as a first step, an

ultrasound of the legs is recommended as a surrogate test for

pulmonary embolism.


◙ The D-dimer concentration is usually increased in the second and

third trimester of the pregnancy and normalizes 4 to 6 weeks after

delivery. Thus, the test is clearly less useful during pregnancy. As

significant controversy exists on this topic and because no study

has ever validated a negative D-dimer test for t he exclusion of PE in

pregnancy, the use D-dimer testing as a stand-alone test to exclude a

PE can currently not be recommended in this setting.


◙ This fetal dose advantage for CTPA even applies to protocols

specifically modified for pregnant patients like half-dose perfusion scans

(140 – 250 µGy). Other considerations are the somewhat higher risk for

the mother to develop breast cancer with CTPA and the lack of human

safety data for the effects of iodinated contrast media on the fetus,

although they approved to be safe in animal experiments. Therefore, any

search for PE in a pregnant patient should involve a thorough discussion

of the risks and benefits with the patient. If imaging is necessary with

ionizing radiation, the currently available data support the preferential use

of CTPA, if possible with a modified low-dose technique and limited

anatomical coverage.

Automated tube modulation should be used for all scans, regardless

if the patient is pregnant or not. However, as a first step, an

ultrasound of the legs is recommended as a surrogate test for

pulmonary embolism.

Pitfalls of CTPA

◙ Anatomic Pitfalls: PA’s run with bronchi, PV’s run

independent, Unopacified veins, Mucoid impaction,

Lymphadenopathy and perivascular tissue, Other

pathologies (Shunts, Sarcomas)

◙ Imaging Artifacts: Streak artifacts, Motion artifacts,

Improper bolus timing, inconsistent (“fractured”) bolus

Edge-enhancing reconstruction algorithm, Inadequate

window settings, Patient size

Pitfalls of CTPA

Computed tomography

pulmonary arteriography:

pitfalls lymphadenopathy.

Lymphadenopathy in a patient

with silicosis and shortness of

breath mimicking acute

pulmonary embolus. There are

multiple lymph nodes adjacent to

vessels that occasionally could

impose problems differentiating

from partially organized thrombus

(arrows).

Pitfalls of CTPA

Computed tomography pulmonary arteriography: pitfalls - nonopacified

pulmonary vein. Image on the left has been occasionally misdiagnosed as

acute pulmonary embolus (arrow). However, following the brnach towards the

left atrium helps clarify this question in all cases (arrow).

Pitfalls of CTPA

Computed tomography pulmonary arteriography: pitfalls - mucoid

impaction. This shows the typical appearance of mucous-filled bronchi (arrows)

adjacent to the enhanced arteries. This finding should not be mistaken for

pulmonary embolism.

Pitfalls of CTPA

Computed tomography pulmonary arteriography: pitfalls - volume

rendering. (Left) Pulmonary arteries that run in-plane parallel with bronchi can

occasionally appear less dense than the arteries running perpendicular to the imaging

plane. This is caused by partial volume averaging of the air-filled bronchi into the

pulmonary artery, thus artificially reducing its density (arrow). Reconstruction of the dataset

with thinner slices and/or oblique perpendicular multiplanar reconstructed images usually

help resolve this issue. (Right) True pulmonary embolus in a small branch to the middle

lobe running in-plane (arrow). There are also other emboli (arrowheads).

Flowchart for Diagnosing Pulmonary Embolus

Traditional Anticoagulants

XII

XI

IX

VIII VII

V LMWH warfarin

X

heparin

1. INDIRECT inhibitors of coagulation

2. MULTIPLE SITES of action

THROMBUS

fibrinogen fibrin

II

AT

AT

The new/novel oral anticoagulants (NOACs)

rivaroxaban (Xarelto®)

apixaban (Eliquis®)

dabigatran (Pradaxa®)

[edoxaban (Savaysa®)]

New Oral Anticoagulants (NOACs)

XII

XI

IX

VIII VII

V LMWH warfarin

X

Oral Xa inhibitors

rivaroxaban (Xarelto)

apixaban (Eliquis)

edoxaban (Savaysa)

Oral IIa inhibitors

dabigatran (Pradaxa)

heparin

1. DIRECT inhibitors of coagulation

2. SINGLE SITES of action

fibrinogen fibrin

II

THROMBUS

NOACs: Advantages

Property Advantages

Rapid onset of action No need for IV/SC anticoag

Less variability in

anticoagulant effect

Fixed dose (or limited options)

No routine lab monitoring Convenient for patients, docs

Relatively rapid offset of

action

Simplifies pre-procedure Mx

Relatively inexpensive Generally affordable

All of the above Potential for greater/longer use

fewer thromboemboli

ACCP guidelines 2016

In patients with DVT of the leg or PE and

no cancer, as long-term (first 3 months)

anticoagulant therapy, we suggest

dabigatran, rivaroxaban, apixaban, or

edoxaban over vitamin K antagonist

(VKA) therapy (all Grade 2B).

Remarks: Initial parenteral anticoagulation

is given before dabigatran and edoxaban, is

not given before rivaroxaban and apixaban,

ACCP guidelines 2016

In patients with a proximal DVT of the leg or

PE provoked by surgery, we recommend

treatment with anticoagulation for 3 months

over (i) treatment of a shorter period (Grade

1B), (ii) treatment of a longer time-limited

period (eg, 6, 12, or 24 months) (Grade 1B),

or (iii) extended therapy (no scheduled stop

date) (Grade 1B)

Laboratory Monitoring of New OAC

Assessment of “reversal”

dabigatran aPTT

rivaroxaban PT / INR

apixaban none

Monitoring of blood level (limited avail)

dabigatran Hemoclot test

rivaroxaban Anti-Xa

Poor correlation between standard coag tests

(PT, PTT) and drug level

Major variability in reagent/analyzer

Timing of the test is critical

0 24

Updates in venous thromboembolism

Health & Medicine

Transcript of Updates in venous thromboembolism