The prevalence of this hypercoagulable state in the general population is unknown, and protein S deficiencies have been found in only 1% of patients with a history of deep vein thrombosis (DVT).3,8 Although this hypercoagulable state is less common than other hereditary thrombophilias, 74% of people with this disorder develop DVT—half of them before the age of 25.2
Hyperhomocysteinemia. Elevations in homocysteine may occur as a result of a hereditary disorder (deficiencies in cystathionine beta-synthase or methylene-tetrahydrofolate reductase). Hyperhomocysteinemia may also be an acquired condition, associated with deficiencies in vitamins B6, B12, or folic acid; chronic kidney disease; hypothyroidism; and certain malignancies.
The prevalence of hyperhomocysteinemia varies, based on the underlying disorder. Only about 0.3% of the general population has a cystathionine beta-synthase deficiency. Methylene-tetrahydrofolate reductase deficiency, however, is common among Italian and Hispanic populations (occurring in about 20%), but rare (<1%) among African American people.3
When to test for thrombophilias
Idiopathic venous thrombosis is probably the most common reason for ordering testing for inherited hypercoagulable states, and an underlying thrombophilia is found in about 50% of cases.9 Other indications for testing include thrombus development in an unusual site (eg, splanchic, renal, retinal, or ovarian veins; cerebral venous sinuses; or upper limbs), recurrent venous thromboembolism (VTE), venous thrombosis at an early age (<45 years) or in a patient with a strong family history of VTE, and unexplained recurrent pregnancy loss.
Testing may also be considered for relatives of patients with known inherited hypercoagulability disorders, but this should be done only if the results could affect a treatment decision: Can a man safely undergo surgery with a high postoperative risk for thrombosis, for example? Should a woman take oral contraceptives (OCs), start hormone replacement therapy (HRT), or attempt another pregnancy?
Overall, testing for inherited hypercoagulable states should focus on the identification of individuals most likely to benefit from it; only tests yielding useful data should be performed. Testing of asymptomatic individuals for the sole purpose of initiating long-term prophylactic therapy is not recommended.
Which tests for which patients?
In some cases, selective assays may be more useful than test panels, for reasons associated with patient presentation as well as cost. Proper selection of specific tests should be individualized based on the patient’s age, thrombotic presentation, and family history, and on potential effects on patient management.
For patients with heparin resistance, cerebral vein thrombosis, intra-abdominal vein thrombosis, or recurrent superficial thrombophlebitis, AT testing may be in order. Patients with recurrent superficial thrombophlebitis may also benefit from testing for factor V Leiden mutation, and protein C and protein S testing may be beneficial for patients with warfarin skin necrosis, recurrent superficial thrombophlebitis, or neonatal purpura fulminans. Cerebral vein thrombosis in the general population and in women using OCs, in particular, is suggestive of a G20210A mutation,9 and is a possible indication for testing. Hyperhomocysteinemia testing may be considered for patients with premature arterial and venous thrombosis, as well as mental retardation, skeletal abnormalities, and vitamin B6 or B12 deficiency.
Many physicians prefer to order testing in stages, starting with tests for the most common thrombophilias. When ordering tests for the conditions detailed above and in the TABLE, be aware that test panels vary among facilities, so it may be necessary to check with the testing laboratory to ensure that it offers the tests that are indicated for a particular patient.
TABLE
Suspect a hereditary hypercoagulable disorder? Testing considerations to keep in mind2,3,8,9,11,12
| Disorder | Potential indication(s) for testing | Timing of test | Interaction with warfarin | Interaction with LMWH and UFH |
|---|---|---|---|---|
| Factor V Leiden mutation | Recurrent superficial thrombophlebitis | Not during an acute event | Modified aPTT test does not interact | Modified aPTT test does not interact |
| Prothrombin G20210A mutation | Cerebral vein thrombosis | Not during an acute event | No | No |
| Protein C deficiency |
| 7-10 days after cessation of warfarin therapy | Yes | No |
| Antithrombin III deficiency |
| 7-10 days after cessation of warfarin therapy | Yes | Yes |
| Protein S deficiency |
| 7-10 days after cessation of warfarin therapy | Yes | No |
| Hyperhomocysteinemia |
| Not during an acute event | No | No |
| aPTT, activated partial thromboplastin time; LMWH, low-molecular-weight heparin; UFH, unfractionated heparin. | ||||
Timing of tests, and other specifics
Acute thrombosis, anticoagulation therapy, and some disease states—eg, liver disease, nephritic syndrome, disseminated intravascular coagulation, and acute illness—can affect levels of AT, protein C, and protein S. Within the first 48 hours of warfarin therapy, for example, a patient’s protein C and protein S levels decline about 50%; after 2 weeks, the levels rise to about 70% of their normal range. Because of warfarin’s effect on these proteins, evaluation for these deficiencies should be performed at least 1 week to 10 days after cessation of a 3- to 6-month course of anticoagulation therapy. Abnormal findings should be confirmed with a second test approximately 3 weeks later.2,3,9