Evaluating adult patients with established venous thromboembolism for acquired and inherited risk factors

INTRODUCTION — The most common presentations of venous thromboembolism (VTE) are deep vein thrombosis of the lower extremity and pulmonary embolism. Risk factors for VTE, either acquired or hereditary, can be identified in the majority of patients who present with VTE [1-3].

The evaluation of the adult patient with established VTE for acquired and inherited risk factors is discussed here. Screening for thrombophilia in asymptomatic patients and management of thrombophilic disorders are discussed separately. (See "Screening for inherited thrombophilia in asymptomatic adults" and "Inherited thrombophilias in pregnancy" and "Thrombophilia testing in children and adolescents".)

INITIAL APPROACH — All patients with established VTE should undergo a thorough history and physical examination combined with review of diagnostic imaging studies and routine laboratory testing [1-3]. This may reveal an acquired condition (eg, major surgery) predisposing to the thrombotic event (table 1) or provide clues to the presence of inherited thrombophilia (eg, first-degree relatives with VTE at a young age). As venous thrombosis is a multifactorial disorder, some patients will have more than one major risk factor. (See "Overview of the causes of venous thrombosis" and 'Evaluation for occult malignancy' below.)

History and examination — A careful history should evaluate for the following:

●Common risk factors include major surgical procedures or trauma, recent hospitalization (within the previous 90 days), infections (especially coronavirus disease 2019 [COVID-19] [4]), pregnancy, and immobility. The presence or absence of a provoking event should be identified since duration of anticoagulation and the utility of further testing is different in patients with unprovoked compared with provoked VTE. (See "Venous thromboembolism: Anticoagulation after initial management", section on 'Duration of treatment' and 'First episode of uncomplicated unprovoked VTE' below.)

●A past history of thromboembolism or the presence of significant prothrombotic disorders (eg, collagen-vascular disease such as systemic lupus erythematosus, myeloproliferative neoplasms, nephrotic syndrome, inflammatory bowel disease). (See "Overview of the causes of venous thrombosis", section on 'Acquired risk factors'.)

●Drugs that increase the risk of thrombosis (eg, oral contraceptives, hormone replacement therapy, heparin, and rarely with certain COVID-19 vaccines in association with thrombocytopenia). (See "Overview of the causes of venous thrombosis", section on 'Drugs' and "Management of heparin-induced thrombocytopenia" and "COVID-19: Vaccine-induced immune thrombotic thrombocytopenia (VITT)".)

●An obstetric history in women, since recurrent fetal loss suggests the possible presence of antiphospholipid antibodies; late fetal loss (2^nd or 3^rd trimester) may suggest an underlying inherited thrombophilia [5,6]. (See "Overview of the causes of venous thrombosis", section on 'Drugs' and "Clinical manifestations of antiphospholipid syndrome" and "Inherited thrombophilias in pregnancy" and "Antiphospholipid syndrome: Obstetric implications and management in pregnancy".)

●A family history of venous thrombosis, since a well-documented history in one or more first-degree relatives strongly suggests the presence of hereditary thrombophilia. (See "Overview of the causes of venous thrombosis", section on 'Inherited thrombophilia' and "Overview of the causes of venous thrombosis", section on 'Elevated clotting factors and chemokines'.)

●Findings that suggest an underlying malignancy include constitutional symptoms (eg, loss of appetite, weight loss, and fatigue) and specific symptoms (eg, cough, hemoptysis, change in bowel habits, and hematuria). (See "Overview of the causes of venous thrombosis", section on 'Malignancy'.)

The physical examination may reveal signs of malignancy (eg, lymphadenopathy or breast masses), hepatic vein thrombosis (eg, ascites and hepatomegaly), polycythemia vera (eg, unexplained splenomegaly), and nephrotic syndrome (eg, edema). (See "Budd-Chiari syndrome: Epidemiology, clinical manifestations, and diagnosis", section on 'Clinical manifestations' and "Hypercoagulability in nephrotic syndrome" and "Overview of heavy proteinuria and the nephrotic syndrome", section on 'Thromboembolism'.)

Laboratory tests and imaging — The initial laboratory and radiographic evaluation in patients with VTE may reveal clues as to the underlying cause of VTE. Any abnormality found on initial testing should be investigated thoroughly. Initial testing should include the following:

●Complete blood count with smear − Elevations in the hematocrit or platelet count, especially in patients with splenomegaly, should lead to consideration of one of the myeloproliferative disorders (eg, polycythemia vera, essential thrombocythemia) [7]. Anemia, leukopenia, and thrombocytopenia may be associated with paroxysmal nocturnal hemoglobinuria (PNH). Thrombocytopenia concurrent with heparin therapy should always prompt consideration of the diagnosis of heparin-induced thrombocytopenia, a disorder which has thrombotic sequelae in a significant proportion of cases. (See "Overview of the myeloproliferative neoplasms", section on 'Complications' and "Clinical manifestations and diagnosis of paroxysmal nocturnal hemoglobinuria" and "Clinical presentation and diagnosis of heparin-induced thrombocytopenia" and "Approach to the patient with thrombocytosis", section on 'Reactive thrombocytosis' and "Diagnostic approach to the patient with erythrocytosis/polycythemia", section on 'Causes of absolute polycythemia'.)

Evidence of red cell fragmentation or schistocytes (picture 1) on the blood smear may suggest disseminated intravascular coagulation and the thrombotic microangiopathies (thrombotic thrombocytopenic purpura-hemolytic uremic syndrome). A leukoerythroblastic picture with nucleated red blood cells and immature white cells (picture 2) may suggest the possibility of bone marrow involvement by tumor.

●Routine coagulation studies − An otherwise unexplained prolongation of the activated partial thromboplastin time (aPTT), which does not correct on 1:1 dilution with normal plasma, is suggestive of the presence of a lupus anticoagulant (ie, one of the laboratory criteria for assigning a diagnosis of the antiphospholipid syndrome). An elevated international normalized ratio (INR) may suggest underlying liver disease. (See "Clinical manifestations of antiphospholipid syndrome" and "Clinical use of coagulation tests", section on 'Evaluation of abnormal results'.)

●Serum chemistries including liver and renal function tests and urinalysis − Abnormal liver and renal function tests, or hematuria on urinalysis may suggest underlying liver or renal disease.

●Other laboratory tests – Some clinicians request an erythrocyte sedimentation rate (ESR) or hemoccult stool, although most clinicians do not specifically order such testing. A markedly elevated ESR (eg, >100 mm/hour) may suggest an underlying malignancy or a connective tissue disorder. The identification of blood in stool may suggest an underlying gastrointestinal malignancy.

●Imaging – For most patients, extensive imaging other than that required for the diagnosis of VTE (eg, lower extremity ultrasound, computed tomographic pulmonary angiogram) is not necessary. The following findings on diagnostic imaging may suggest underlying risk factors for VTE. As examples:

•Incidental abdominal or chest findings on diagnostic testing may suggest malignancy (eg, abdominal or chest mass, lymphadenopathy, splenomegaly).

•Multiple thromboses or thrombosis in unusual organs (eg, mesenteric, hepatic, portal, splenic, renal, and cerebral veins) may suggest malignancy, myeloproliferative neoplasm, inherited thrombophilia, nephrotic syndrome, and, rarely, paroxysmal nocturnal hemoglobinuria. (See "Overview of the causes of venous thrombosis", section on 'Inherited thrombophilia' and "Clinical manifestations, pathogenesis, and diagnosis of essential thrombocythemia", section on 'Thrombosis and hemorrhage' and "Clinical manifestations and diagnosis of polycythemia vera", section on 'Thrombosis and hemorrhage' and "Clinical manifestations and diagnosis of paroxysmal nocturnal hemoglobinuria".)

•Arterial thrombosis or embolization is suggestive of antiphospholipid syndrome or myeloproliferative disorders, but can also occur in the nephrotic syndrome and malignancy. (See "Overview of the causes of venous thrombosis", section on 'Inherited thrombophilia' and "Clinical manifestations of antiphospholipid syndrome", section on 'Thrombotic events' and "Clinical manifestations, pathogenesis, and diagnosis of essential thrombocythemia", section on 'Thrombosis and hemorrhage' and "Clinical manifestations and diagnosis of polycythemia vera", section on 'Thrombosis and hemorrhage'.)

PATIENT SELECTION FOR ADDITIONAL TESTING — For all patients with a diagnosis of VTE, any abnormality found on initial testing should be investigated thoroughly. (See 'Laboratory tests and imaging' above.)

In this section we discuss our preference for selecting patients in whom testing for hypercoagulable disorders and malignancy should be performed. Testing patients with a first episode of VTE for hypercoagulable disorders (especially inherited thrombophilias) and malignancy is controversial.

For all patients in whom testing is being considered, it is critical that patient values and preferences be discussed in the context of the benefits or lack thereof associated with testing.

Our approach to selecting patients for additional testing and imaging is discussed in the sections below.

Patients at risk for hypercoagulable disorders — We agree with other experts that routine evaluation for hypercoagulable disorders in unselected patients with a diagnosis of VTE is not warranted [8,9]. However, we perform testing in the following select populations (see 'Evaluation for hypercoagulable disorders' below):

●Patients with a family history of VTE – Most experts agree that patients with VTE who have at least one first degree relative with documented VTE before the age of 45 years should be tested for all five inherited thrombophilias (levels of protein S, protein C, and antithrombin, the factor V Leiden [FVL] and prothrombin gene mutations). Testing for antiphospholipid syndrome (APS) is not generally warranted in this population because APS is not an inherited condition. (See 'Patients with a family history of VTE' below and 'Inheritable thrombophilia panels' below.)

●Patients without a family history of VTE – We will generally test for hypercoagulable disorders in the following patients with VTE:

•Young patients (<45 years) (inherited thrombophilias and APS). (See 'Young patients (<45 years)' below and 'Inheritable thrombophilia panels' below and 'Tests for antiphospholipid syndrome' below.)

•Patients with recurrent thrombosis (inherited thrombophilias and APS). (See 'Patients with recurrent thrombosis' below and 'Inheritable thrombophilia panels' below and 'Tests for antiphospholipid syndrome' below and 'Other high-risk populations' below.)

•Patients with thrombosis in multiple venous sites or in unusual vascular beds (eg, portal, hepatic, mesenteric, or cerebral veins) should be tested for inherited thrombophilias and APS. Patients with hepatic and portal vein thromboses should also be evaluated for JAK2 mutations and paroxysmal nocturnal hemoglobinuria. (See 'Patients with thrombosis in unusual vascular beds' below and 'Other high-risk populations' below and 'Tests for antiphospholipid syndrome' below and 'Inheritable thrombophilia panels' below and 'Other' below.)

•Patients with a history of warfarin-induced skin necrosis are at increased risk of protein C deficiency (rarely protein S deficiency or FVL). (See 'Patients with a history of warfarin-induced skin necrosis' below and 'Inheritable thrombophilia panels' below.)

•Patients with arterial thrombosis are at risk of having APS. (See 'Patients with arterial thrombosis' below and 'Tests for antiphospholipid syndrome' below.)

Although testing in these select populations of patients with VTE leads to the increased identification of hypercoagulable states, it infrequently alters the duration of anticoagulation or prevents VTE-related death. Thus, the major purpose of evaluating for a hypercoagulable state in patients with VTE is the documentation of a biologic risk factor and for genetic counseling/testing of first-degree relatives in patients with inherited thrombophilia. Our approach is consistent with guidelines published by the British Committee for standards in Hematology and the International Consensus statement on the prevention and treatment of venous thromboembolism [8,9].

We consider the major benefits of testing these selected patients with established VTE for a hypercoagulable disorder to be the following:

●The management of conditions that potentially increase the risk of a future thrombotic event. As an example, patients with a hypercoagulable disorder may be considered for more aggressive thromboprophylaxis when exposed to additional risk factors during their lifetime (eg, future major surgery).

●The potential for altered management. As an example, the identification of an inherited thrombophilia in first-degree relatives may result in the avoidance of hormonal contraception in women of childbearing age or the administration of thromboprophylaxis to some patients during pregnancy (eg, antithrombin deficiency) (table 2). (See "Venous thromboembolism in pregnancy: Prevention" and "Inherited thrombophilias in pregnancy", section on 'Prevention of VTE' and "Contraception: Counseling for women with inherited thrombophilias".)

●The provision of information to women of reproductive age regarding the risk of, or reason for, unexplained fetal loss during pregnancy (eg, APS). (See "Antiphospholipid syndrome: Obstetric implications and management in pregnancy".)

These benefits should be weighed against the harms of testing including a lack of improved survival, or inappropriate anticoagulation and undue anxiety in the patient (and/or asymptomatic relatives) [10,11]. For patients who have a strong preference to know whether or not they have an inherited thrombophilia, patient understanding and management decisions based on test results should be understood and made clear BEFORE the tests are performed [8,9].

Patients at risk for an occult malignancy — We agree with other experts that, other than age- and sex-appropriate screening, routine evaluation for occult malignancy in unselected patients with a diagnosis of VTE is not warranted. Evaluation for occult malignancy is controversial. However, patients that may benefit are listed below (see 'Evaluation for occult malignancy' below):

Testing strategies vary with the population studied and are discussed below. (See 'Testing strategies for occult malignancy' below.)

EVALUATION FOR HYPERCOAGULABLE DISORDERS — It is generally agreed that routine testing for hypercoagulable disorders (inheritable thrombophilia and antiphospholipid syndrome) in unselected patients with a diagnosis of VTE is not warranted [8,9]. This is because in most patients with VTE, the identification of an inheritable defect does not alter therapeutic or prophylactic anticoagulant management, and consequently it has not been associated with improved outcomes (eg, mortality or recurrence) [12-14]. For example, several trials of patients with unselected VTE report no difference in recurrence rates in patients with or without inherited thrombophilia, on or off anticoagulation [14-20].

However, we and others perform testing in those considered at risk of having a hypercoagulable disorder, in particular those with strong family history of VTE (one first degree relative with documented VTE before the age of 45 years). We and others also test other populations at high risk for such disorders (eg, patients <45 years, recurrent thrombosis) (see 'Patients who may benefit' below). The rationale for testing these selected populations is presented above (see 'Patients at risk for hypercoagulable disorders' above), and details about the risk of hypercoagulable disorders in such patients are discussed below. (See 'Patients with a family history of VTE' below and 'Patients without a family history of VTE' below.)

Data from observational studies report that the rate of identifying an inherited thrombophilia in this population ranges from 5 to 40 percent (table 3) compared with about 0.2 to 10 percent in the general population [21-27]. Among unselected patients with VTE, rates vary according to the type of inherited thrombophilia [21,22]. As examples:

●In one prospective study of 2132 patients with VTE, a thrombotic disorder was reported in 17 percent, including protein S deficiency (7 percent), protein C deficiency (3 percent), antithrombin deficiency (0.5 percent), antiphospholipid antibodies (4 percent), and combined deficiencies (1 percent) [21].

●In another prospective study of 277 patients with deep venous thrombosis (DVT), the overall prevalence of deficiencies of protein S and C, and antithrombin was 8 percent as compared with 2 percent in age- and sex-matched historical controls [22].

●In a population-based case-control study of 301 patients with DVT, the frequency of activated protein C resistance (ie, factor V Leiden [FVL]) was 21 percent compared with 5 percent in age- and sex-matched historical controls [25]. (See "Factor V Leiden and activated protein C resistance".)

●In a case-control study of 281 patients with VTE, the prothrombin gene mutation was found in approximately 8 percent of patients, compared with 3 percent of controls and was associated with a fourfold increase in the risk of thrombosis [27]. (See "Prothrombin G20210A".)

These data largely reflect patients who present with DVT. Comprehensive studies examining the rate of inherited thrombophilia in patients with pulmonary embolism (PE) are lacking. One systematic review of 18 studies of patients who presented with isolated PE reported that the rates of FVL and prothrombin gene mutations were 2 and 2.5 times more common in patients with isolated PE than in the general population [28].

The identification of an inheritable disorder in an individual should prompt consideration of testing asymptomatic relatives for the same disorder. (See "Screening for inherited thrombophilia in asymptomatic adults".)

Importantly, patients who test positive for inherited thrombophilia or the presence of a lupus anticoagulant and/or elevated antiphospholipid antibody levels should not be therapeutically anticoagulated in the absence of documented thrombosis.

Patients who may benefit

Patients with a family history of VTE — Most experts agree that patients with VTE who also have at least one first degree relative with documented VTE before the age of 45 years should be tested for the presence of all five inherited thrombophilias (protein S, C, and antithrombin deficiencies, FVL and prothrombin gene mutation). We perform testing in this population because it is the population that has the highest risk of having an inheritable thrombophilia disorder. The identification of an inheritable disorder in an individual should prompt consideration of testing asymptomatic relatives for the same disorder. (See 'Patients at risk for hypercoagulable disorders' above and "Screening for inherited thrombophilia in asymptomatic adults" and 'Inheritable thrombophilia panels' below.)

Data from observational studies report that the highest rates of inheritable thrombotic disorders are in those with a family history of VTE (table 3) [21,22]. As examples:

●In one prospective study of 2132 unselected patients with VTE, the presence of a family history of VTE doubled the rate of inherited thrombophilic disorders when compared with those without a family history of thrombosis (23 versus 11 percent) [21]. There was no testing for FVL or the prothrombin gene mutations in this study.

●In another prospective study of 277 unselected patients with DVT, the positive predictive value of identifying an inheritable abnormality when a family history was present was 16 percent [22].

The absolute risk of VTE in families with each of the inheritable disorders is discussed separately. (See "Overview of the causes of venous thrombosis", section on 'Thrombotic risk in families'.)

Patients without a family history of VTE — The rationale for testing the additional populations listed below is based upon the higher probability of identifying a hypercoagulable disorder in such patients [21-24]. (See 'Patients at risk for hypercoagulable disorders' above.)

Young patients (<45 years) — While some experts disagree, we typically test for all five inherited thrombophilias (protein S, C, and antithrombin deficiencies, FVL and prothrombin gene mutation) and APS in those who are young (<45 years) (table 3) [21,29]. Data from observational studies that support this approach include (see 'Inheritable thrombophilia panels' below and 'Tests for antiphospholipid syndrome' below):

●In one prospective study of 2132 unselected patients with VTE, the rate of thrombophilic disorders (deficiencies of protein S, protein C, or antithrombin) in those with VTE before the age of 45 years was almost double that of patients with thrombosis after the age of 45 years (18 versus 10 percent respectively) [21].

●In another analysis of unselected patients with VTE and a median age of 43 years, at least one thrombophilic disorder was identified in half of the cohort [29]. The probability of detecting a hereditary thrombophilia declined significantly with advancing age (49 percent in patients ≤20 years versus 22 percent in patients ≥70 years).

Patients with recurrent thrombosis — We typically test for an inheritable thrombophilia and antiphospholipid syndrome in this population because such patients are at high risk for both disorders.

●In one prospective study of 277 unselected patients with DVT, the positive predictive value for identifying an inheritable abnormality in those with recurrent disease was 9 percent [22]. (See 'Inheritable thrombophilia panels' below.)

●Although the recurrence rate in patients with APS is variable, it is thought to be about twice that of patients who do not have the disorder. (See 'Tests for antiphospholipid syndrome' below and "Clinical manifestations of antiphospholipid syndrome", section on 'Thrombotic events'.)

Additional testing for malignancy is also indicated in this population, which is discussed separately. (See 'Other high-risk populations' below.)

Patients with thrombosis in unusual vascular beds — Patients with thrombosis in the portal, hepatic, mesenteric, or cerebral veins should be tested for all five inherited thrombophilias (protein S, C, and antithrombin deficiencies, FVL and prothrombin gene mutation) and for APS. (See 'Inheritable thrombophilia panels' below and 'Tests for antiphospholipid syndrome' below.)

Data that supports testing in these populations are discussed separately:

●Hepatic vein (Budd-Chiari) (see "Etiology of the Budd-Chiari syndrome", section on 'Other hypercoagulable states')

●Portal vein (see "Epidemiology and pathogenesis of portal vein thrombosis in adults", section on 'Pathogenesis')

●Mesenteric vein (see "Mesenteric venous thrombosis in adults", section on 'Clinical presentations')

●Cerebral vein (see "Cerebral venous thrombosis: Etiology, clinical features, and diagnosis", section on 'Evaluation for thrombophilic state')

Patients with hepatic and portal vein thrombosis should also be evaluated for JAK2 mutations and paroxysmal nocturnal hemoglobinuria (PNH) (see 'Other' below). Calreticulin mutations are found in a significant proportion of JAK2-negative patients; however, these mutations do not appear to be associated with increased thrombosis risk [30].

This population is also at high risk for malignancy, the testing for which is discussed separately. (See 'Other high-risk populations' below.)

Patients with a history of warfarin-induced skin necrosis — Warfarin-induced skin necrosis is a rare complication of warfarin that is most commonly due to protein C deficiency. Rare cases of protein S deficiency or FVL have been also been reported and are discussed separately. (See "Warfarin and other VKAs: Dosing and adverse effects", section on 'Skin necrosis'.)

Patients with arterial thrombosis — This population should be specifically tested for the presence of antiphospholipid antibodies (aPL) as part of the routine investigation for the etiology of arterial thrombosis. The evidence that such patients have a higher risk for APS is presented elsewhere. (See "Clinical manifestations of antiphospholipid syndrome" and "Overview of the evaluation of stroke", section on 'Blood tests' and "Renal infarction", section on 'Etiology and pathogenesis' and 'Tests for antiphospholipid syndrome' below and "Overview of intestinal ischemia in adults", section on 'Etiologies of ischemia'.)

Testing for inherited thrombophilia is not justified in patients presenting with arterial thrombosis since hereditary thrombophilia is principally a risk factor only for venous thrombosis [31]; an exception is those with suspected paradoxical emboli (eg, in the setting of a patent foramen ovale).

Patients who do not benefit — With the exceptions listed in the above sections (see 'Patients who may benefit' above), most patients who present with VTE do not benefit from testing for hypercoagulable disorders. This is because in most patients with an initial episode of VTE, the identification of an inherited defect does not alter therapeutic or prophylactic anticoagulant management nor has it been shown to reduce mortality or VTE recurrence [12-14].

Despite an increased likelihood of having a hypercoagulable disorder, patients with a first episode of unprovoked VTE and those with an upper extremity VTE do not benefit from testing. Data that support the avoidance of testing in specific populations in these patient populations are discussed in the sections below. (See 'First episode unprovoked VTE' below and 'Upper extremity thrombosis' below.)

Additional examples of patients that do not need testing include patients with:

●First episode provoked VTE

●Active malignancy (see "Anticoagulation therapy for venous thromboembolism (lower extremity venous thrombosis and pulmonary embolism) in adult patients with malignancy")

●Inflammatory bowel disease (see "Pulmonary complications of inflammatory bowel disease", section on 'Pulmonary embolism')

●Myeloproliferative disorders (see "Clinical manifestations and diagnosis of polycythemia vera", section on 'Thrombosis and hemorrhage' and "Clinical manifestations, pathogenesis, and diagnosis of essential thrombocythemia", section on 'Thrombosis and hemorrhage')

●Heparin-induced thrombocytopenia with thrombosis (see "Clinical presentation and diagnosis of heparin-induced thrombocytopenia" and "Management of heparin-induced thrombocytopenia")

●Retinal vein thrombosis including that in the setting of preeclampsia (see "Preeclampsia: Clinical features and diagnosis")

First episode unprovoked VTE — We do not routinely test patients with a first unprovoked (ie, idiopathic) DVT in the legs or pulmonary embolism despite the fact that up to 42 percent may have one or more inherited thrombotic disorders [19]. This is because in this population, it is the unprovoked nature of the thrombotic event, rather than any underlying risk factors, that determines both the risk of future recurrence and the duration of anticoagulation. (See "Selecting adult patients with lower extremity deep venous thrombosis and pulmonary embolism for indefinite anticoagulation", section on 'First episode proximal DVT and/or symptomatic PE without identifiable risk factor'.)

Several studies of patients with a first episode of unprovoked VTE have found that the recurrence rate in this population is independent of the presence of inheritable thrombophilia and a positive family history for VTE [15-19]:

●In a 12-year prospective study of 474 patients with a first unprovoked DVT, most of whom had completed a 3 to 12 month course of warfarin, the risk of a recurrent event in those with thrombophilic defects was not significantly different from that in patients without an underlying defect (3.4 versus 3.2/100 patient-years; hazard ratio [HR] 1.2, 95% CI 0.7-2.2) [18].

●In another prospective study of 661 patients who were fully anticoagulated for unprovoked VTE, the probability of recurrence over a two-year period was similar for patients with and without one or more hypercoagulable defects (HR 0.7, 95% CI 0.2-3.4) [19].

●In a prospective study of 826 patients with a first unprovoked episode of VTE in whom anticoagulation was stopped, the recurrence rate at five years was no different between those with or without an affected first-degree relative (20 versus 18 percent) [17].

Upper extremity thrombosis — We do not suggest testing for hypercoagulable disorders in patients with upper extremity (UE) thrombosis despite a higher rate of such disorders in this population. Identification of a hypercoagulable disorder is unlikely to change management and the impact of such disorders on the risk of future recurrence is unclear.

Observational studies suggest that the rate of hypercoagulable disorders in patients with UE thrombosis is increased. While one study reported similar rates of hypercoagulable disorders in patients with UE thrombosis and historical controls (15 versus 12 percent) [32], several other observational studies have since reported rates that range from 17 to 42 percent, with the highest rates consistently observed in those with idiopathic UE thrombosis [33-38]. Data that describe this risk are discussed separately. (See "Catheter-related upper extremity venous thrombosis in adults" and "Primary (spontaneous) upper extremity deep vein thrombosis".)

Conflicting data have been reported in patients with UE thrombosis regarding the effect of hypercoagulable disorders on the risk of future recurrence. One retrospective study of 224 patients with unselected UE thrombosis reported that the presence of hypercoagulable disorders did not affect the rate of future recurrence at three years (13 percent) [37]. In contrast, another prospective study of 115 patients with idiopathic UE thrombosis reported a higher recurrence rate at five years in those with inherited thrombophilia compared with those without a thrombophilic disorder (4 versus 2 percent patient-years; HR 2.7, 95% CI 0.7-9.8) [34].

Timing of tests and effect of anticoagulants — Acute thrombosis and anticoagulants (heparin, warfarin, direct thrombin inhibitors, factor Xa inhibitors) affect the levels and/or functional activity of many of the anticoagulant factors that are typically measured in hypercoagulable panels (table 4). For patients undergoing testing, we prefer that all tests be performed a minimum of two weeks following discontinuation of anticoagulation, when feasible. Although not all tests are affected by acute thrombosis or anticoagulants, this approach avoids repeated testing, erroneous test results, and recurrent office visits.

The effect of anticoagulation and acute thrombosis varies with the test of interest, which is discussed separately:

●Antithrombin (see "Antithrombin deficiency", section on 'Timing of testing')

●Protein C (see "Protein C deficiency", section on 'Timing/effects of anticoagulants')

●Protein S (see "Protein S deficiency", section on 'Timing of testing and effect of anticoagulants')

●Factor V Leiden (see "Factor V Leiden and activated protein C resistance", section on 'Diagnosis')

●Prothrombin gene mutation (see "Prothrombin G20210A")

●Antiphospholipid antibodies (see "Diagnosis of antiphospholipid syndrome", section on 'Timing of testing')

Occasionally, these tests are performed at the time of diagnosis (ie, in the setting of acute thrombosis) or after the patient has initiated anticoagulation. In such settings, the following general principles apply (table 4):

●Acute thrombosis can reduce the plasma concentrations of antithrombin and protein S. There is little evidence that acute thrombosis by itself lowers protein C levels.

●Heparin can reduce the plasma concentration of antithrombin and falsely lead to the detection of a lupus anticoagulant (LA).

●Warfarin can reduce the functional activity, and to a lesser extent antigenic levels of protein S and protein C, and can affect the detection of LA.

●The direct thrombin inhibitor, dabigatran, can lead to overestimates of antithrombin and protein S and C levels, depending upon the assay used to measure such proteins [39]. The factor Xa inhibitors (eg, rivaroxaban, apixaban) can produce overestimates of antithrombin levels, depending upon the assay used to measure it [39].

●If plasma levels of antithrombin and protein S and C are obtained at presentation prior to the administration of anticoagulant therapy and are well within the normal range, then a deficiency of these proteins is excluded. In contrast, a low concentration in the setting of acute thrombosis must be confirmed by repeat testing after anticoagulation has been discontinued.

●For patients in whom the risk of recurrent thrombosis is too great to temporarily discontinue anticoagulation and a diagnosis is necessary, protein C or protein S levels can be measured while the patient is anticoagulated with heparin for another reason (eg, bridging anticoagulation for surgery). Conversely, a "clinically confident" diagnosis of antithrombin deficiency may be made in most patients while the patient is on warfarin.

Hypercoagulable tests — For patients in whom a decision has been made to test for hypercoagulable disorders, not every test that is available is necessary and testing should be individualized. Patient selection for testing is discussed separately. (See 'Patient selection for additional testing' above.)

Inheritable thrombophilia panels — Common tests in inheritable thrombophilia panels include the following:

●APC resistance/FVL – FVL can be detected by genetic testing (DNA testing) or a functional coagulation test for activated protein C (APC) resistance using a "second-generation" assay. Either of these approaches will generally give an accurate diagnosis of FVL, and the choice of diagnostic test can be based on cost and institutional availability. Patients with a low APC resistance ratio should then be genotyped for the mutation. (See "Factor V Leiden and activated protein C resistance", section on 'Diagnosis'.)

●Prothrombin gene mutation – The prothrombin 20210A gene mutation is best detected by molecular analysis. (See "Prothrombin G20210A", section on 'Diagnosis'.)

●Proteins C and S – The best screening test for protein C deficiency is a functional assay which detects both quantitative and qualitative defects. The best screening test for protein S deficiency is the free protein S antigen assay. (See "Protein C deficiency", section on 'Diagnostic evaluation' and "Protein S deficiency", section on 'Diagnosis'.)

●Antithrombin – The antithrombin-heparin (AT) cofactor assay using factor Xa or thrombin detects all currently recognized subtypes of familial AT deficiency. (See "Antithrombin deficiency", section on 'Diagnostic evaluation'.)

Although FVL and the prothrombin gene mutation have been identified in only 1 percent of the African American population who present with VTE, we test for all five inheritable defects, when indicated [40].

Tests for antiphospholipid syndrome — A marker for the presence of antiphospholipid syndrome (APS) is an unexplained prolongation of the activated partial thromboplastin time (aPTT), although it’s not always prolonged. If APS is suspected based upon this or other clinical findings (eg, young patient with unprovoked VTE), testing for elevated levels of antiphospholipid antibodies (aPL; anticardiolipin and beta2-glycoprotein I antibodies) and the presence of a lupus anticoagulant (LA) should be performed initially and again at three months. Persistent presence of a LA or very elevated levels of cardiolipin or beta2-gylcoprotein antibodies are diagnostic of APS. The diagnosis of APS can be difficult such that consulting an expert in the diagnosis of thrombotic disorders is appropriate. (See "Diagnosis of antiphospholipid syndrome", section on 'Antiphospholipid antibody testing' and "Clinical manifestations of antiphospholipid syndrome".)

Other — Less common clotting abnormalities that are not typically part of a hypercoagulable panel but may be considered on a case-by-case basis or in specific patients include the following:

●Analysis for the JAK2 mutation should be performed in patients with Budd-Chiari syndrome, portal vein, and mesenteric vein thrombosis because of the high prevalence of this mutation in these disorders. However, routine screening for this mutation in patients with arterial thrombosis, lower extremity venous thrombosis, or cerebral vein thrombosis is not recommended in the absence of an elevated hematocrit or platelet count [41-45]. (See "Overview of the myeloproliferative neoplasms", section on 'JAK2 mutations' and "Etiology of the Budd-Chiari syndrome", section on 'Myeloproliferative disorders' and "Overview of the causes of venous thrombosis", section on 'Myeloproliferative neoplasms and PNH'.)

●Homocysteine levels and mutational analysis for the responsible gene, methylene tetrahydrofolate reductase (MTHFR), should NOT be performed. Although elevated levels of homocysteine can be found in patients with thrombosis, the causal role of hyperhomocysteinemia in thrombosis is unclear. In addition, lowering homocysteine levels with folic acid, pyridoxine, and vitamin B12 does not appear to reduce the rate of VTE in patients with hyperhomocysteinemia. (See "Overview of homocysteine".)

●Assessment for paroxysmal nocturnal hemoglobinuria. (See "Clinical manifestations and diagnosis of paroxysmal nocturnal hemoglobinuria", section on 'Diagnosis and classification'.)

EVALUATION FOR OCCULT MALIGNANCY — In general, other than age-appropriate cancer screening, routine evaluation for occult malignancy in unselected patients with a diagnosis of VTE or patients with provoked VTE is not warranted. However, we perform additional testing in patients in populations who are thought to be at high risk of having a malignancy (eg, recurrent thrombosis on anticoagulation).

Although testing leads to the increased identification of cancer, no convincing survival advantage due to any testing strategy has been shown in patients who present with VTE. Thus, the major purpose of evaluating this population for malignancy is the early identification of cancer, rather than the prevention of cancer-related death.

In unselected patients presenting with VTE, the reported incidence of a subsequent diagnosis of malignancy varies from 2 to 25 percent (on average 10 percent) with the highest risk in the first six months following the initial diagnosis [46-55]. The most common cancers that are found include hematologic malignancies and occult cancers of the ovary, pancreas, liver, kidney, and lung.

Studies that report an increased incidence of cancer in unselected patients who present with VTE include the following:

●A 2018 meta-analysis of four randomized or quasi-randomized trials reported no consistent mortality benefit with extensive screening strategies (odds ratio 0.49, 95% CI 0.15-1.67), although cancer was detected at an earlier stage [56]. Adding positron emission tomography/computed tomography (PET/CT) to standard screening did not confer any benefit either.

●A meta-analysis of 40 reports published between 1982 and 2007 found a threefold excess risk of occult cancer in patients with unselected VTE compared with individuals without VTE (relative risk [RR] 3.2, 95% CI 2.4-4.5) [47].

●A retrospective study of 1383 patients with deep venous thrombosis (DVT) reported that, compared with patients without DVT, a higher incidence of subsequent malignancy was observed in patients with thrombosis (11 versus 7.5 percent) [48].

●A nested case-control study of patients with cancer reported that, compared with those who did not have VTE, patients with VTE had a higher risk of developing a second cancer (RR 1.3, 95% CI 1.1-1.4) [57]. The risk of developing a second cancer was greatest in patients who had VTE one year or more after their first cancer was diagnosed (RR 1.4).

First episode of uncomplicated unprovoked VTE — We believe that an evaluation for cancer in patients with a first unprovoked (idiopathic) episode of VTE should be limited to a complete history and examination, basic laboratory testing, and age-appropriate cancer screening. Any abnormality observed on initial testing should then be investigated. Age-appropriate cancer screening tests and the components of a limited testing strategy are discussed separately. (See 'Limited' below and "Overview of preventive care in adults", section on 'Cancer screening'.)

This approach is supported by the International Society on Thrombosis and Hemostasis and is based upon meta-analyses and retrospective cohort studies of patients with VTE that demonstrated an increased likelihood of a cancer diagnosis when the VTE event was unprovoked [46-53,58-61]. However, prospective studies and a randomized trial in this population did not demonstrate a survival advantage with more aggressive approaches [62,63]:

●A prospective cohort study compared limited cancer testing with extensive cancer testing in 630 adults over age 40 with a first episode of unprovoked VTE [63]. Limited testing consisted of a medical history and physical examination, erythrocyte sedimentation rate (ESR), CBC, laboratory tests of renal and hepatic function, serum calcium, and chest radiography. Extensive testing consisted of the components of limited testing plus an abdominal CT scan and mammography (for women). Although more cancers were detected in those who underwent extensive testing (3.5 versus 2.4 percent) during the 2.5-year followup period, the mortality was similar in both groups (8 percent in both groups).

●A randomized trial compared extensive testing with no testing in 201 adults over age 25 with unprovoked VTE in whom the initial baseline testing had excluded cancer [62]. Extensive testing included abdominal and pelvic ultrasound and CT scanning, evaluation of the upper and lower gastrointestinal tract, sputum cytology, and tumor markers (carcinoembryonic antigen, alpha-fetoprotein, and CA 125). Women also underwent mammography and a Papanicolaou smear, and men had prostatic specific antigen (PSA) testing and transabdominal prostate ultrasound. Although extensive testing identified more cancers at an earlier stage (13 versus 10 percent), the mortality at two years was not significantly different from those whose cancer presented symptomatically during the same period (2 versus 4 percent). This trial was terminated early and several methodologic flaws during the randomization period suggest that it should be interpreted with caution.

●In one randomized trial of 854 patients with a first unprovoked episode of VTE, a limited evaluation for occult cancer screening (basic laboratory testing, chest radiography, and breast, cervical, and prostate cancer screening) was compared with a more comprehensive strategy (limited evaluation plus CT of the abdomen and pelvis) [54]. Cancer-related mortality at one year was no different between limited or comprehensive strategies (1 percent). However, the young age at the time of evaluation (54 years old), low incidence of age-appropriate screening, and absence of more extensive testing in the comprehensive strategy group may have limited the number of cancers detected.

In addition to the absence of survival benefit from extensive testing, a limited evaluation identifies most cancers in patients with unprovoked VTE:

●In the aforementioned trial of 854 patients with a first unprovoked episode of VTE, a limited strategy identified two-thirds of the total number of patients that developed cancer at one year [54]. The detection rate for cancer was not significantly increased when a comprehensive strategy was used (4.5 versus 3.2 percent).

●In a meta-analysis of 10 studies evaluating cancer screening strategies in patients with unprovoked VTE, the prevalence of cancer at 12 months was 5 percent. Although extensive strategies detected more cancer than limited strategies, it was not significant at 12 months [59].

●In one retrospective cohort study of 142 patients with idiopathic DVT in whom cancer was subsequently diagnosed (12 percent), every patient with cancer had abnormalities suggestive of malignancy on initial testing [64].

●In a prospective cohort series that followed 400 patients for six months after a diagnosis of idiopathic DVT, among those who subsequently developed cancer, 77 percent had abnormal clinical findings on initial testing suggestive of malignancy [65].

The ability to predict those at risk is challenging, although one retrospective study reported that the RIETE score may be valuable [61].

Other high-risk populations — A more aggressive/extensive and symptom-directed approach to testing for cancer may be performed in patients considered at high risk for malignancy [65-69]. Examples of patients considered at high risk and data that support testing these populations are discussed separately:

●Patients with symptoms/signs suggestive of an underlying malignancy [68] (see 'History and examination' above)

●Patients with recurrent VTE (see "Anticoagulation therapy for venous thromboembolism (lower extremity venous thrombosis and pulmonary embolism) in adult patients with malignancy")

●Patients with hepatic and portal vein thrombosis (see "Epidemiology and pathogenesis of portal vein thrombosis in adults", section on 'Pathogenesis' and "Etiology of the Budd-Chiari syndrome", section on 'Malignancy')

●Patients with arterial thromboembolism suggestive of nonbacterial thrombotic endocarditis (see "Nonbacterial thrombotic endocarditis")

●Patients with splanchnic vein thrombosis or cerebral vein thrombosis where testing for JAK2 V617F mutations is appropriate to look for an underlying myeloproliferative disorder [60]. (See "Overview of the myeloproliferative neoplasms", section on 'JAK2 mutations' and "Overview of the causes of venous thrombosis", section on 'Myeloproliferative neoplasms and PNH'.)

Testing strategies for occult malignancy

Limited — The components of a limited testing strategy in patients with a first episode of uncomplicated unprovoked VTE include the following:

●A complete history for the signs and symptoms of malignancy

●A thorough physical examination, including digital rectal examination, testing for fecal occult blood, and pelvic examination in women

●Basic laboratory testing including complete blood count (CBC) and smear, ESR, urinalysis, electrolytes, calcium, creatinine, and liver function tests

●Routine age-appropriate cancer screening

●Chest radiograph

The components of age-appropriate screening are discussed separately. (See "Overview of preventive care in adults", section on 'Cancer screening'.)

Extensive — The components of an extensive testing strategy for occult cancer in a high risk population are unknown. Investigations are frequently symptom-directed. They may include but are not limited to the following:

●All the components of a limited strategy described in the section above (see 'Limited' above)

●A chest, abdominal, and pelvic CT scan

●Tumor markers (carcinoembryonic antigen, alpha-fetoprotein, CA 19-9, CA 125, PSA)

●Mammography and a Papanicolaou smear in women

●Upper and lower gastrointestinal tract evaluation (eg, endoscopy or CT colonography)

Positron emission tomography (PET) or PET combined with computed tomography (PET/CT) has not been validated in a large, randomized setting for routine use as a tool for the evaluation of cancer and is, therefore, not recommended. One small prospective cohort of 99 patients with a first episode of VTE reported occult cancer identified by PET/CT in 23 percent of cases with a sensitivity and negative predictive value of 77 and 97 percent, respectively [70]. Another randomized study of 399 cancer patients study reported no benefit to a strategy that included PET/CT [71].

Timing of tests — For patients with VTE in whom testing for occult cancer is indicated, we suggest testing within six months of presentation, preferably at the time of admission, before the cancer becomes symptomatic.

Most studies report that the incidence of cancer diagnosis is greatest in the first six months following VTE, and subsequently declines by one year to rates that are either similar to, or slightly above, those in the general population [46,49-53,65,72].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Anticoagulation".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Factor V Leiden (The Basics)")

●Beyond the Basics topics (see "Patient education: Deep vein thrombosis (DVT) (Beyond the Basics)" and "Patient education: Antiphospholipid syndrome (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Initial approach – All patients with established venous thromboembolic disease (VTE) should have a thorough history and physical examination combined with routine laboratory testing (complete blood count and smear, coagulation studies, serum chemistries, erythrocyte sedimentation rate, Hemoccult stool) and review of diagnostic imaging studies. This may provide clues to an inherited thrombophilia or reveal an acquired condition (eg, surgery) predisposing to the thrombotic event (table 1). Testing for inherited thrombotic disorders and malignancy can lead to the discovery of risk factors but does not improve mortality. Thus, shared decision-making is critical to select patients for testing. (See 'Initial approach' above.)

●Patient selection – Evaluation and testing for hypercoagulable disorders and malignancy following a first episode of VTE is controversial. The following is our approach:

•Unselected patients with a diagnosis of VTE or patients with a diagnosis of provoked VTE – For unselected patients with a diagnosis of VTE or patients with a diagnosis of provoked VTE, we suggest not routinely testing for hypercoagulable disorders and malignancy (Grade 2C). (See 'Patient selection for additional testing' above.)

•One first degree relative with documented VTE before the age of 45 years or young age – For patients with VTE who have at least one first degree relative with documented VTE before the age of 45 years, we suggest testing for all five inherited thrombotic disorders (antithrombin, protein S and C deficiencies, factor V Leiden and prothrombin gene mutations) (Grade 2C). For patients with VTE who are <45 years old, we also suggest testing for all five inherited thrombotic disorders as well as for antiphospholipid syndrome (Grade 2C). (See 'Patients at risk for hypercoagulable disorders' above and 'Patients with a family history of VTE' above and 'Patient selection for additional testing' above and 'Young patients (<45 years)' above.)

•First episode of unprovoked VTE – In patients with a first episode of unprovoked VTE, we suggest limited testing for cancer, including a history and physical examination, complete blood count, serum chemistries, liver function tests and urinalysis, age-appropriate cancer screening, and chest radiography (Grade 2C). (See 'Patients at risk for an occult malignancy' above and 'First episode of uncomplicated unprovoked VTE' above and 'Limited' above.)

•Recurrent, multiple, and unusual thromboses – In patients with recurrent thrombosis, multiple thromboses, and thrombosis in unusual vascular beds (eg, hepatic or portal vein thrombosis), we suggest testing for inherited thrombotic disorders, antiphospholipid syndrome, and malignancy (Grade 2C). Additionally, patients with hepatic or portal vein thrombosis should be evaluated for JAK2 mutations and paroxysmal nocturnal hemoglobinuria. (See 'Patient selection for additional testing' above and 'Patients with recurrent thrombosis' above and 'Patients with thrombosis in unusual vascular beds' above and 'Other high-risk populations' above.)

•Warfarin-induced skin necrosis – In patients with VTE who have a history of warfarin-induced skin necrosis, we suggest testing for protein C deficiency (Grade 2C). (See 'Patients at risk for hypercoagulable disorders' above and "Warfarin and other VKAs: Dosing and adverse effects", section on 'Skin necrosis'.)

•Arterial thrombosis – In patients with arterial thrombosis, we suggest testing for markers of the antiphospholipid syndrome (Grade 2C). In patients with arterial thrombosis suggestive of nonbacterial thrombotic endocarditis, we suggest additionally testing for malignancy(Grade 2C). (See 'Patients at risk for hypercoagulable disorders' above and 'Patients with arterial thrombosis' above and 'Other high-risk populations' above.)

●Test timing – For patients undergoing testing for hypercoagulable disorders, we prefer that all tests be performed two weeks following the discontinuation of anticoagulation, when feasible. Not every test that is available is necessary such that testing should be individualized. (See 'Timing of tests and effect of anticoagulants' above and 'Hypercoagulable tests' above and 'Patient selection for additional testing' above.)

●Test type – For patients undergoing testing for malignancy, we prefer limited strategies rather than extensive strategies. Extensive strategies may be reserved for those at greatest risk for cancer (eg, patients with signs and symptoms of malignancy, or recurrent thromboses despite therapeutic anticoagulation). (See 'Limited' above and 'Extensive' above.)