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Tintinalli’s Emergency Medicine: A Comprehensive Study Guide, 8e

Chapter 234: Chapter 234: Clotting DisordersClotting Disorders Jessie G. Nelson; Robin R. Hemphill

INTRODUCTIONINTRODUCTION

Most patients who develop an arterial or venous thrombosis do so because of local factors (e.g., a focalatherosclerotic lesion producing a thrombus in an coronary artery) or major systemic events (e.g., trauma,surgery, or prolonged immobilization). However, several inherited genetic mutations predispose patients tovenous thromboembolism with some studies finding up to 50% of patients with venous thromboembolism

having a thrombophilia (Table 234-1Table 234-1).1 Importantly, risk for clotting from genetic, acquired, andenvironmental factors is additive or even multiplicative; a patient with mild deficiency may develop a deep

venous thrombosis when started on estrogen.2

TABLE 234-1

Hypercoagulable StatesHypercoagulable States

InheritedInherited AcquiredAcquired

Activated protein C resistance due to factor V Leiden

mutation

Pregnancy

Oral contraceptives/hormone replacement

therapy

Prothrombin gene mutation 20210A Malignancy

Protein C deficiency Heparin-induced thrombocytopenia

Protein S deficiency Antiphospholipid syndrome

Antithrombin deficiency Warfarin-induced skin necrosis

Hyperhomocysteinemia, severe Hyperviscosity syndromes

Human immunodeficiency virus (HIV)

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PATHOPHYSIOLOGYPATHOPHYSIOLOGY

Several physiologic systems ensure that blood clots do not extend beyond the necessary area. The two mostclinically important pathways involve antithrombin and protein C (see Figures 232-1 and 232-2 and TableTable234-2234-2). Antithrombin is a plasma-based protein that inhibits several activated coagulation factors, primarilythrombin, factor Xa, and factor IXa. Both unfractionated heparin and low-molecular-weight heparin possessanticoagulant activity by increasing the rate by which antithrombin inhibits these factors: approximately2000- to 4000-fold for thrombin, about 500- to 1000-fold for factor Xa, and about a million-fold for factor IXa.Protein C is a vitamin K–dependent plasma protein that binds to the endothelial cell surface and is activatedby thrombin. Activated protein C cleaves both factor Va and factor VIIIa, inhibiting both the common pathwayand the intrinsic pathway. Protein S, another vitamin K–dependent plasma protein, is a cofactor thatincreases the inhibitory action of activated protein C by about 20-fold.

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TABLE 234-2

Functions of Coagulation Proteins in Protein C and Antithrombin SystemsFunctions of Coagulation Proteins in Protein C and Antithrombin Systems

FactorFactor FunctionFunction Pertinent DisordersPertinent Disorders

Prothrombin

(factor II)

Precursor to thrombin, which converts fibrinogen to

fibrin.

Prothrombin mutations, 20210A

and others

Factor V,

activated

Complexes with Factor Xa, calcium, and phospholipid

to convert prothrombin to thrombin.

Activated protein C resistance

due to factor V Leiden mutation

Protein C,

activated

Cleaves activated factors Va and VIIIa. Congenital protein C deficiency

Activated protein C resistance

due to factor V Leiden mutation

Neonatal purpura fulminans

Warfarin-induced skin necrosis

Protein S Cofactor for activated protein C.

Cofactor for tissue factor pathway inhibitor (which

inhibits extrinsic pathway of coagulation).

Counteracts factor Xa's protection of factor Va from

degradation.

Congenital protein S deficiency

Neonatal purpura fulminans

Warfarin-induced skin necrosis

Antithrombin Inhibits thrombin, factor Xa, and factor IXa.

Binds heparins, leading to increased antithrombin

activity.

Antithrombin deficiency

Phospholipids Present on cell membranes of endothelial cells that

line blood vessels.

The activity of several proteins in the coagulation

cascade is enhanced when bound to phospholipids.

Antiphospholipid syndrome

CLINICAL FEATURESCLINICAL FEATURES

Thrombophilic disorders are rarely diagnosed in the ED. Instead, the emergency physician's primaryresponsibilities are to (1) recognize higher risk of thrombosis in patients with a known thrombophilia, and (2)

obtain pertinent information to suspect an undiagnosed hypercoagulable state (Table 234-3Table 234-3).3

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TABLE 234-3

Features Suggestive of ThrombophiliaFeatures Suggestive of Thrombophilia

Early thrombosis (age 45 y and younger)

Recurrent thrombotic events or fetal loss

Family history of thrombosis or recurrent fetal loss

Thrombosis in unusual location (mesenteric, cerebral, axillary, or portal veins)

DIAGNOSISDIAGNOSIS

Laboratory testing specific for hypercoagulable conditions is not helpful in an ED setting.4,5 Some factorlevels cannot be reliably measured in the setting of acute thrombosis or while the patient is taking a vitaminK antagonist such as warfarin. The focus is to suspect the thrombophilia, refer for evaluation, andappropriately manage acute thrombosis. The ED diagnostic approach to individual episodes of suspectedthrombosis in a thrombophilic patient is site specific (e.g., cerebral circulation, coronary circulation, orperipheral venous system). Using a normal serum Using a normal serum dd-dimer level to exclude venous thromboembolism in-dimer level to exclude venous thromboembolism in

patients with known hypercoagulable disorders has not been validated.patients with known hypercoagulable disorders has not been validated.

TREATMENT AND DISPOSITIONTREATMENT AND DISPOSITION

Initial management and disposition of individual episodes of confirmed thrombosis in a patient withthrombophilia is similar to that of a patient without known thrombophilia. Duration of treatment does di�er(Table 234-4Table 234-4).

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TABLE 234-4

Management of Inherited and Acquired ThrombophiliasManagement of Inherited and Acquired Thrombophilias

SituationSituation ManagementManagement

First episode of

thrombosis

Unfractionated heparin or low-molecular-weight heparin for 5 d and/or until

therapeutic anticoagulation achieved with an oral anticoagulant.

Continue anticoagulation for 6 mo to 2 y; some advocate lifelong treatment.

Second episode

of thrombosis

Lifelong anticoagulation.

Pregnancy Begin unfractionated heparin or low-molecular-weight heparin at diagnosis of

pregnancy.

May use warfarin in postpartum period.

Active

malignancy

Use low-molecular weight heparin for treatment of venous thromboembolic events

Oral

contraception

Avoid.

Hormone

replacement

therapy

Avoid.

Patients not currently on anticoagulation should consider prophylactic anticoagulants for high-risksituations such as surgery, pregnancy and the postpartum period, and prolonged travel. Estrogen-based oralcontraceptive pills and hormone replacement therapy should be avoided in patients with knownthrombophilia because of the thrombotic risk.

SPECIFIC CONDITIONS ASSOCIATED WITH THROMBOPHILIASPECIFIC CONDITIONS ASSOCIATED WITH THROMBOPHILIA

INHERITED CLOTTING DISORDERSINHERITED CLOTTING DISORDERS

ACTIVATED PROTEIN C RESISTANCE (FACTOR V LEIDEN)ACTIVATED PROTEIN C RESISTANCE (FACTOR V LEIDEN)

Activated protein C resistance caused by the factor V Leiden mutation is the most prevalent inheritedhypercoagulable disorder; approximately 5% of the U.S. population of European descent is heterozygous for

this mutation.6 In this disorder, the gene for factor V has a single point mutation that makes factor Va

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resistant to inhibition by activated protein C (factor V Leiden). This leads to overabundant conversion ofprothrombin to thrombin. Factor V Leiden is inherited in an autosomal dominant pattern, with most patientsbeing heterozygous for the mutation. Heterozygotes for factor V Leiden have a sevenfold increased risk ofdeep venous thrombosis compared with noncarriers, with homozygotes having a 20-fold increase in risk.

Factor V Leiden is more highly associated with deep vein thrombosis than pulmonary embolism6 and has

been observed in up to 21% of patients with first-time deep venous thrombosis.7 Activated protein Cresistance also produces pregnancy complications such as severe pre-eclampsia, placental abruption, fetalgrowth restriction, and stillbirth.

PROTHROMBIN GENE MUTATIONPROTHROMBIN GENE MUTATION

The most common mutation of the prothrombin gene (20210A) leads to increased prothrombin biosynthesiswith about a 30% increase in circulating prothrombin levels, creating a hypercoagulable state. Prothrombinmutations are inherited in an autosomal dominant manner with mutations in the prothrombin gene present

in about 2% of Caucasians.2 Heterozygotes account for up to 10% of patients with initial episodes of deep

venous thrombosis.7 Patients with prothrombin gene mutation present with increased risk of venousthromboembolism and pregnancy complications, similar to activated protein C resistance from factor VLeiden.

ANTITHROMBIN DEFICIENCYANTITHROMBIN DEFICIENCY

Several mutations to the antithrombin gene exist, many leading to antithrombin deficiency. Two percent of

patients with a history of thrombosis have an antithrombin deficiency,8 and it is more prevalent in Asianpopulations. Antithrombin deficiency is classified into two main groups. In type 1, the measured level ofantithrombin is diminished, whereas patients with type 2 have a normal amount of antithrombin, but thefunction is greatly diminished due to conformational changes in the protein. Antithrombin deficiency isinherited in an autosomal dominant fashion. Heterozygous patients have a fivefold increased risk ofthrombotic events, typically pregnancy complications and venous thromboembolism. Homozygousantithrombin deficiency is incompatible with life.

PROTEIN C AND S DEFICIENCIESPROTEIN C AND S DEFICIENCIES

Protein C and protein S deficiencies, like antithrombin deficiency, are transmitted in an autosomal dominantfashion, but with more varied clinical presentations. Prevalence can only be estimated, because not allpatients with heterozygous defects develop inappropriate thrombosis. Heterozygous protein C deficiency isthought to be present in 1:250 to 1:500 people, and heterozygous protein S deficiency is estimated to occur in

about 1:500 individuals.9 Homozygous protein C or S deficiency is rare and presents as neonatal purpurafulminans. Patients with heterozygous protein C or S deficiency are at higher risk for venousthromboembolism, and like antithrombin deficiency, these disorders can be associated with eitherdecreased total amount of protein C or S or decreased functional activity. In general, lower protein function isassociated with higher risk and frequency of thrombotic events. Protein C and S deficiency, like antithrombin

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deficiency, is more prevalent in the Japanese and Chinese populations with up to 65% percent of adults with

venous thromboembolism having a deficiency of protein C, protein S, or antithrombin.9

Patients with heterozygous protein C or S deficiency are at higher risk for warfarin-induced skin necrosisbecause warfarin inhibits protein C and S synthesis. Warfarin-induced skin necrosis is rare and is preventedby both avoiding loading doses of warfarin and continuing heparin products until the INR is therapeutic.Therefore, any patient who develops warfarin-induced skin necrosis should be evaluated for protein C or Sdeficiency.

HYPERHOMOCYSTEINEMIAHYPERHOMOCYSTEINEMIA

Three enzymes are involved in the metabolism of homocysteine: methylenetetrahydrofolate reductase,cystathionine β-synthase, and methionine synthase. Inherited functional deficiency in the first two enzymes

is associated with an increased risk of both arterial and venous thrombosis, as well as atherosclerosis.2 Thepresence of elevated homocysteine in the blood is a marker of the functional enzyme deficiency.Heterozygotes for a variant mutation in either methylenetetrahydrofolate reductase or cystathionine β-synthase are found in approximately 15% of individuals with European, Middle Eastern, and Asian ancestry,compared with approximately 1% to 2% of African Americans.

Patients with profound hyperhomocysteinemia, generally because of homozygous inheritance of adysfunctional enzyme, have the condition termed congenital homocystinuria, and have significant skeletaland ocular problems as well as mental retardation, developmental delay, and thrombotic events.Heterozygotes for a dysfunctional enzyme do not have the skeletal, ocular, or mental complications, but havea two- to fourfold increased risk for venous thrombosis. As with other hypercoagulable disorders, thepresence of hyperhomocysteinemia can combine with other thrombotic conditions to greatly increase therisk of venous thrombosis; factor V Leiden mutation combined with hyperhomocysteinemia produces about

a 20-fold increase in the risk for venous thrombosis.2,10

ACQUIRED CLOTTING DISORDERSACQUIRED CLOTTING DISORDERS

PREGNANCY AND ESTROGEN USEPREGNANCY AND ESTROGEN USE

The coagulation changes in pregnancy (Table 234-5Table 234-5) represent an adaptive measure to prevent excessive

hemorrhage with delivery.11 Many of these changes are anatomic in nature, whereas some are related to therelatively high estrogen state. These changes promoting thrombosis are similar but less profound in womentaking oral contraceptive and hormone replacement therapy.

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TABLE 234-5

Factors Contributing to Hypercoagulable State in PregnancyFactors Contributing to Hypercoagulable State in Pregnancy

AnatomicAnatomic HematologicHematologic

Venous occlusion from gravid uterus. Increased thrombin generation

from placental secretion of

tissue factor

Trauma to pelvic veins during delivery.

Tissue injury during surgical delivery. Increased production of

procoagulant proteins

Le� iliac vein crosses over le� iliac artery, leading to relative compression

(le� leg deep venous thrombosis is three times more likely than right in

pregnant patients).

Decreased free and total

protein C

Increased platelet activation

and platelet turnover

The exact mechanism of how exogenous estrogen therapy leads to a hypercoagulable state is complex andnot completely understood, but higher doses of estrogen clearly confer a higher risk for clotting. The currentlow doses for estrogens in oral contraceptives are associated with a smaller but still clinically significantlyincreased risk of thrombosis. Estrogen use has been associated with modest increases in severalprocoagulant proteins (factors VII, VIII, X, prothrombin, and fibrinogen) as well as decreases in anticoagulantproteins (antithrombin, protein S, protein C). Use of oral contraceptives or hormone replacement therapy in apatient with known heterozygosity for factor V Leiden puts the patient at an even higher risk for thrombosis,approximately a 15-fold increase.

MALIGNANCYMALIGNANCY

Malignancy is associated with increased risk for thrombus formation, but the exact mechanisms are not

completely understood.12,13 For patients with the new diagnosis of cancer, the risk of venousthromboembolism is highest in the first 3 months a�er diagnosis, with an odds ratio of about 50. Some typesof cancers are more likely to promote thrombosis than others, with pancreatic, brain, acute myelogenousleukemia, gastric, esophageal, gynecologic, kidney, and lung cancers having the highest association withthrombosis. Cancer also increases the incidence of arterial thrombotic events, such as myocardial infarction

and ischemic stroke.12 Other manifestations of hypercoagulability in cancer patients include chronicdisseminated intravascular coagulation, nonbacterial thrombotic endocarditis, migratory superficial

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thrombophlebitis, and thrombotic microangiopathy. Chemotherapy itself can also a�ect coagulation inmany ways, such as downregulation of proteins C and S, induction of tissue factor production by endothelialcells, and direct cell damage.

Use low-molecular-weight heparin for the initial treatment of venous thromboembolism in patients with

active cancer.13 Long-term anticoagulation following the diagnosis of venous thromboembolism in these

patients should be with a low-molecular-weight heparin for 6 months as opposed to warfarin.13 Prophylacticanticoagulation for primary prevention of venous thromboembolism in ambulatory medical oncology

patients is not recommended.13

HEPARIN-INDUCED THROMBOCYTOPENIAHEPARIN-INDUCED THROMBOCYTOPENIA

Heparin-induced thrombocytopenia is a consumptive coagulopathy in which components of the clotting

cascade are inappropriately activated, forming arterial and venous thrombus.14 Platelet factor 4 is a cell-signaling molecule that plays a central role in this syndrome. Platelet factor 4 neutralizes heparin andheparin-like endogenous compounds, and the heparin–platelet factor 4 combination inhibits localantithrombin activity, thereby promoting coagulation. Heparin-induced thrombocytopenia develops whenpatients develop antibodies against the heparin–platelet factor 4 complex. A complex of heparin, plateletfactor 4, and the antibody binds to platelets, activating them. The platelets then form small microparticlesthat initiate clot formation. The measured platelet count falls because platelets are bound in both small andlarge clots. Also, the heparin–platelet factor 4 antibody complex can stimulate endothelial cells andmonocytes to release tissue factor, which further triggers the coagulation cascade.

The typical presentation of heparin-induced thrombocytopenia has the platelet count falling to 50,000 to

60,000/mm3 (50 to 60 × 109/L) within 5 to 15 days a�er starting heparin treatment. Despite the low plateletcounts, the patient is hypercoagulable for days to weeks, even a�er heparin is stopped. Rarely, patients candevelop a rapid-onset presentation within hours of initiation of heparin.

With more outpatients being treated with heparin products for venous thromboembolism or otherthrombophilias, patients with heparin-induced thrombocytopenia may present to the ED with this

syndrome.14 The diagnosis of heparin-induced thrombocytopenia hinges on laboratory findings and cannot

be definitely diagnosed on clinical grounds alone.15 Thrombocytopenia is almost universally present (withthe exception being patients with preexisting thrombocytosis). Suspect the syndrome when platelets havedropped approximately 50% from a recent value in a patient currently or recently taking a heparin product.All heparin products, both unfractionated and low-molecular-weight, must be stopped. These patients need

anticoagulation because the risk for thrombosis is highest in the first week a�er diagnosis.14 Vitamin Kantagonists, such as warfarin, should be avoided in acute heparin-induced thrombocytopenia because thesecan increase the risk of microvascular thrombosis acutely due to transient relative protein C deficiency.Hematology consultation should be sought.

WARFARIN-INDUCED SKIN NECROSISWARFARIN-INDUCED SKIN NECROSIS

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Warfarin inhibits the production of vitamin K–dependent coagulation factors, with the serum levels of theindividual factors decreasing according to their half-life. Upon initiation of warfarin, protein C is decreasedbefore most of the procoagulant proteins. This decrease in protein C leads to a transient relative protein Cdeficiency, which can lead to clinically significant hypercoagulability.

Warfarin-induced skin necrosis presents with painful, red lesions usually located over the extremities,

breasts, trunk, or penis.16 Lesions typically start with an initial central erythematous macule, extending overhours to a localized edema, developing central purpuric zones and then necrosis. Prevention of thiscomplication is one of the reasons loading doses of warfarin are avoided. Thrombin inhibitors, such as low-molecular-weight heparin, should be administered and continued until therapeutic anticoagulation is

achieved with warfarin.16 Rarely, warfarin-induced skin necrosis occurs despite appropriate initiation ofheparin treatment. When it does, approximately one-third of patients will prove to have an inherited proteinC deficiency.

ANTIPHOSPHOLIPID SYNDROMEANTIPHOSPHOLIPID SYNDROME

Antiphospholipid syndrome (APS) is an autoimmune disorder that is a cause of acquired thrombophilia.17

Many of the specific antibodies discovered have targets that are not phospholipids, but rather proteins thatinteract with phospholipids, such as prothrombin, protein C, and protein S. The most common specificantibodies associated with APS are β2-glycoprotein I and lupus anticoagulant. Lupus anticoagulant was

initially discovered in patients with systemic lupus erythematosus and prolongation of the activatedthromboplastin time; hence, the name lupus anticoagulant. However, in vivo, the lupus anticoagulant acts as

a procoagulant and is associated with thrombosis.17

Prevalence of APS is about 40 to 50 cases per 100,000 persons. Up to 5% of normal, healthy young peoplehave antiphospholipid antibodies; this number increases with age and comorbid conditions, but only aminority of these patients develops APS. Antiphospholipid antibodies are positive in approximately 13% of

patients with stroke, 11% with myocardial infarction, and 9.5% with deep venous thrombosis.18 As with mostautoimmune disorders, APS is more common in women and is diagnosed from a combination of laboratoryfindings and clinical findings (Table 234-6Table 234-6).

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TABLE 234-6

Clinical Manifestations of Antiphospholipid SyndromeClinical Manifestations of Antiphospholipid Syndrome

SystemSystem ExamplesExamples

Venous Deep venous thrombosis: extremities, cerebral, portal, hepatic, renal, retinal

Arterial Premature atherosclerosis

Acute coronary syndrome

Ischemic stroke

Vascular stenosis or occlusion: extremities, aorta, renal, retinal

Obstetric Fetal loss: o�en a�er 10-wk gestation

Preterm labor

Low birth weight

Pre-eclampsia

Neurologic Stroke

Migraine

Sneddon's syndrome—clinical triad of stroke, hypertension, and livedo

reticularis

Cognitive dysfunction

Subcortical dementia

Chorea

Dysphagia

Guillain-Barré syndrome

Seizures

Optic neuritis

Skin Livedo reticularis

Cardiac Valvular abnormalities (Libman-Sacks endocarditis)

Syndrome X (angina-like chest pain, cardiac stress test positive for ischemia,

normal coronary angiography)

Skeletal Osteonecrosis

Renal Thrombotic microangiopathy

Renal artery or vein thrombosis

Renal artery stenosis with hypertension

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SystemSystem ExamplesExamples

Pulmonary Pulmonary embolus

Pulmonary hypertension (from recurrent emboli)

GI Budd-Chiari syndrome (hepatic vein thrombosis)

Mesenteric ischemia

Hepatic infarction

Acalculous cholecystitis with gallbladder necrosis

Hematologic (other than

thrombosis)

Bleeding diathesis (rare)

Acquired hypoprothrombinemia

Thrombocytopenia

Hemolytic anemia

Catastrophic

antiphospholipid syndrome

Fulminant multisystem organ failure

Most patients with APS have no other predisposing conditions (primary APS). However, many patients withAPS also have other conditions thought to be associated with their APS (secondary APS). Typical conditionsinclude other rheumatologic or autoimmune disorders such as systemic lupus, infections, and drugexposures (e.g., phenytoin, hydralazine, cocaine).

Although most patients with APS present with isolated, recurrent thrombotic events, about 1% have a rapidlyprogressive form known as catastrophic antiphospholipid syndrome, representing acceleration in the

pathophysiologic processes of APS with widespread small-vessel occlusions in multiple organs.19 It isunknown why some APS patients develop such a severe course. Common triggers include infection, trauma,anticoagulation problems, and cancer. However, 40% of the time, no obvious trigger can be found. Mortalityof catastrophic APS is approximately 50% despite treatment.

Obviously, APS patients with recurrent thrombotic events need lifelong anticoagulation. Pregnant womenwith APS need anticoagulation with subcutaneous unfractionated or low-molecular-weight heparin or low-dose aspirin therapy. Because many normal healthy patients have antiphospholipid antibodies, prophylaxiswithout a personal history of thrombosis is not recommended. In the rare event of catastrophic APS, amultipronged approach involving anticoagulation, steroids, plasmapheresis, and/or IV γ-globulin is typicallyused.

HYPERCOAGULABILITY ASSOCIATED WITH OTHER DISORDERSHYPERCOAGULABILITY ASSOCIATED WITH OTHER DISORDERS

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1. 

2. 

3. 

4. 

5. 

6. 

Many other conditions are associated with increased risk of clotting. Patients with nephrotic syndromenephrotic syndrome havean increased risk of hypercoagulability for complex reasons. In several cases, this is simply a matter ofincreased urinary excretion of anticoagulant proteins. The nephrotic syndrome can also lead to increasedendothelial injury and platelet aggregation. Patients with several di�erent forms of vasculitisvasculitis, such asBehçet's syndrome, antineutrophil cytoplasmic antibody–associated vasculitis, and granulomatosis withpolyangiitis have a slightly increased risk of thrombosis. Hyperviscosity syndromes,Hyperviscosity syndromes, such as essentialthrombocythemia, polycythemia vera, Waldenström's macroglobulinemia, multiple myeloma, and sickle celldisease, also place patients at increased risk for thrombosis. Most risk factors for cardiovascular disease,

such as smoking and diabetes, are also risk factors for venous thromboembolism to varying degrees.20

DiabetesDiabetes alone slightly increases the risk for thrombosis in younger patients without other obvious risks for

thrombosis.21 Patients with human immunodeficiency virushuman immunodeficiency virus have a 2- to 10-fold increased risk for venous

thromboembolism compared to the general population.22

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