When to Do a “Hypercoagulable Workup”

By Kenneth A. Bauer, M.D.
Dr. Bauer is currently an Associate Professor at the Beth Israel Deaconess Medical Center at Harvard Medical School.

It is now possible to identify biologic risk factors in a substantial percentage of patients presenting with a venous thrombotic event. This has resulted from the discovery of two prothrombotic abnormalities prevalent in Caucasian populations, the factor V-Arg506Gln (factor V Leiden) and the prothrombin G20210A mutations. A hereditary deficiency of antithrombin III, protein C, or protein S can be found in smaller numbers of patients presenting with venous thrombosis. Elevated plasma homocysteine levels along with the presence of markers of the antiphospholipid antibody syndrome (either a lupus anticoagulant or elevated cardiolipin antibody titers) are other common laboratory abnormalities that predispose patients to venous as well as arterial thrombosis. For the purpose of this review, laboratory tests for these thrombotic risk factors are defined as “the hyperocoagulable workup” and their prevalence is shown in Table 1. (The lower percentages are for unselected patients and the higher values are for those with first events prior to age 50 or a history of venous thrombosis in first-degree relatives.)

In recent years, there has been considerable discussion and debate regarding the routine performance of a “hypercoagulable workup” in patients with thrombosis and some have argued that testing for the hereditary prothrombotic disorders (the factor V Leiden and prothrombin G20210A mutations; deficiencies of antithrombin, protein C, or protein S) has been prematurely adopted into routine medical practice. This is because the available data only indicate that patients with the antiphospholipid antibody syndrome or patients with multiple hereditary prothrombotic disorders should be managed any differently than those without an identifiable abnormality.

Paradoxically, the factor V Leiden and prothrombin G20210A mutations, which are risk factors for a first unprovoked episode of venous thrombosis in Caucasian patients of any age, do not confer an increased risk for recurrent events. There only appears to be a significantly higher recurrence risk in patients homozygous for one or heterozygous for two or more mutations or deficiency states. Such individuals represent only 1-2% of all patients presenting with venous thrombosis. The arguments for and against testing for hereditary prothrombotic disorders will not be reviewed here, but recommendations will be given regarding when a “hypercoagulable evaluation” should be undertaken. These are based primarily on whether or not the laboratory abnormality has been shown to be a risk factor for thrombosis in the setting of other risk factors.

The hereditary prothrombotic disorders have only clearly been shown to be risk factors for venous thrombosis so it is not advised to test for the presence of these abnormalities in patients who have only arterial thrombosis, unless they result from paradoxical (venous) emboli. Hypercoagulable evaluations in individuals with arterial thrombosis can be limited to determining fasting homocysteine levels and testing for the presence of markers of the antiphospholipid antibody syndrome.

Clinical features of thrombosis in patients who do have a hereditary prothrombotic disorder include: a first thrombotic event at an early age (<50 years); a positive family history of thrombosis; or recurrent thrombosis. Such patients warrant a complete “hypercoagulable workup” (Table 2), which is ideally performed several weeks after the cessation of oral anticoagulation. In addition to patients with venous thromboembolism who have any of these clinical characteristics, patients with thrombosis in the cerebral, mesenteric, or portal venous systems warrant a complete hypercoagulable evaluation. In patients with a first unprovoked venous thrombotic event after age 50 and a negative family history, testing for the factor V Leiden and prothrombin G20210A mutations can be undertaken; determination of the levels of antithrombin III, protein C, and protein S, however, can be omitted as these deficiency states will infrequently be identified in such patients.

In patients with thrombosis, acquired causes of hypercoagulability should be sought. These include recent major surgery or immobilization, trauma, active malignancy, systemic lupus erythematosus, inflammatory bowel disease, a myeloproliferative disorder, and heparin-induced thrombocytopenia. The hereditary prothrombotic disorders have not been identified at increased frequency in patients who develop thrombosis in association with these conditions. Therefore, when thrombosis occurs in any of these settings, hypercoagulable evaluations are not routinely recommended. The exceptions are those under age 50 at the time of thrombosis, or with a positive family history of venous thrombosis in first degree relatives, or with previous thrombosis: such patients should be tested. This is in contradistinction to venous thromboembolism in association with oral contraceptive use, hormone replacement therapy, or pregnancy and the puerperium, which frequently do trigger venous thrombotic events in women with hereditary prothrombotic disorders: all such patients should be tested.

Along with venous or arterial thrombosis, recurrent fetal loss is one of the cardinal features of the antiphospholipid antibody syndrome as a consequence of placental infarction. Case-control and retrospective cohort studies also indicate that there is a significantly increased risk of recurrent second- and third-trimester fetal loss in association with the hereditary prothrombotic disorders. Thus it is appropriate to consider a complete “hypercoagulable workup” (Table 2) in such women. It is controversial whether other complications of pregnancy such as preeclampsia are likewise associated with hereditary or acquired prothrombotic disorders, and testing in such patients is discouraged.

While superficial venous thrombosis has been reported in association with the hereditary prothrombotic disorders, testing is warranted only if the event is relatively severe (e.g., thrombosis involving veins in the thigh, extending on conservative therapy such as anti-inflammatory medications, or recurrent). It is reasonable to do a “hypercoagulable workup” in otherwise healthy patients with unprovoked axillary vein thrombosis though these events are frequently associated with vascular abnormalities (stenosis); laboratory testing should not be undertaken in patients with catheter-associated thrombosis. The hereditary prothrombotic disorders have not been shown to be risk factors for retinal vein thrombosis so routine testing in patients with this condition cannot be recommended.

A number of other coagulation abnormalities have been implicated as risk factors for venous thrombosis, including elevated factor VIII coagulant activity, elevated antigenic levels of factor XI, factor IX, and thrombin-activatable fibrinolysis inhibitor, and reduced levels of free tissue factor pathway inhibitor. The mechanism(s) responsible for these abnormalities have yet to be elucidated, and routine testing for these clotting factors is not recommended.

Venous thromboembolism is now viewed as a multifactorial disorder in which many susceptible individuals will have one or more genetic mutations and will manifest symptoms upon exposure to acquired prothrombotic stimuli. While we are able to identify laboratory abnormalities in a large percentage of venous thrombosis patients, this information cannot yet be used to target those requiring primary antithrombotic prophylaxis or most of those requiring extended secondary prophylaxis. The coming years will see progress in achieving these objectives as new hemostatic risk factors are identified and other laboratory tests (such as D-dimer) are incorporated into diagnostic algorithms derived from prospective studies. The present reality however is this: when a “hypercoagulable workup” uncovers abnormalities predisposing to venous thrombosis, the strongest risk factor for recurrence is the prior event itself, particularly if unprovoked or idiopathic.

Suggested Reading
1. Bauer KA. The thrombophilias: well-defined risk factors with uncertain therapeutic implications. Ann Int Med 2001;135:367-73.

2. Walker ID, Greaves M, Preston FE. Investigation and management of heritable thrombophilia. Br J Haematol 2001;114:512-28.

3. Crowther MA, Kelton JG. Congenital thrombophilic states associated with venous thrombosis: a qualitative overview and proposed classification system. Ann Intern Med 2003; 138:128-134.

4. Levine JS, Branch DW, Rauch J. The antiphospholipid syndrome. N Eng J Med. 2002; 346:752-763.