Approximately 2 million people in the United States die each year from an arterial or venous thrombosis. Effective prophylaxis and treatment for venous thrombosis are available, but are often not administered because testing for hypercoagulable disorders is not routinely performed and risk factors are not fully understood. Known acquired and hereditary thrombotic risk factors are summarized below.
Acquired thrombotic risk factors
Surgery or trauma
Immobilization
Malignancy
Pregnancy
Oral Contraceptives
Estrogen replacement therapy
Lupus anticoagulant
IgG anticardiolipin antibody
Obesity
Nephrotic syndrome
Polycythemia vera
Smoking
Hereditary thrombotic risk factors
Activated protein C resistance (Factor V Leiden mutation)
Prothrombin G20210A mutation
Hyperhomocysteinemia (can also be acquired)
Protein C deficiency
Protein S deficiency
Antithrombin deficiency
Hereditary Risk Factor
Prevalence in Caucasian Population
Prevalence in Patients with DVT
Relative Risk
Factor V Leiden
5%
20%
8
Prothrombin
2%
6%
3
Homocysteinemia
5%
10%
2.5
Protein C
0.3%
3%
10
Protein S
0.3%
2%
10
Antithrombin
0.02%
1%
10-50
According to the “second hit” theory for initiation of thrombosis, the presence of more than one risk factor is needed to manifest thrombosis in most patients. For example, 1 hereditary risk factor plus 1 acquired risk factor results in thrombosis. A patient with the factor V Leiden mutation (1st hit) who uses oral contraceptives (2nd hit) greatly increases their risk of thrombosis by combining the 2 risk factors. The clinical relevance of the various inherited and acquired prothrombotic risk factors and the strength of their interactions are only partially understood. In some instances it is not known whether patients with inherited thrombophilia should be treated differently from those without these disorders, particularly with regard to duration of oral anticoagulant therapy following a thrombotic episode. In general, patients with a history of VTE may be stratified into three risk categories for recurrent thrombosis.
1. Low-risk category:
Patients with a single episode of VTE that occurred in the presence of one or more transient risk factors (such as surgery, immobilization, pregnancy, the puerperium, oral contraceptive or hormone replacement therapy). In general, these patients receive relatively short-term anticoagulation (3-6 months).
2. High-risk category:
Patients with the most severe forms of thrombophilia
Antithrombin deficiency
Antiphospholipid antibodies
Homozygous factor V Leiden
Multiple thrombophilic defects
Malignancy
Recurrent VTE.
Longer-term anticoagulation is usually recommended in these patients (12 months to indefinite).
3. Intermediate category
Patients with relatively mild thrombophilia
Heterozygous protein C and protein S deficiency
Heterozygous factor V Leiden
Heterozygous prothrombin gene mutation
Patients with thrombosis in a life-endangering location (such as portal, mesenteric or cerebral vein, or massive pulmonary embolism).
The proper duration of anticoagulation for this group has not been established, since data in the literature regarding the risk of recurrent thrombosis is conflicting. Studies are currently underway to resolve some of these issues. Until definitive guidelines are available, it is recommended that decisions regarding the duration of anticoagulation be tailored to the individual patient.
The laboratory investigation of hypercoagulable disorders is a rapidly expanding field.
Indications for laboratory testing include:
1. A history of venous or arterial thrombosis with one or more of the following features:
Idiopathic / unexplained
Recurrent
Family history of thrombotic tendency
Unusually young age
Unusual site e.g. subclavian or mesenteric vessels
Resistant to conventional anticoagulant therapy
Associated with pregnancy or oral contraceptive therapy
2. A history of one of the following complications of pregnancy:
Second trimester pregnancy loss
Intrauterine growth restriction
Severe or recurrent preeclampsia
In order to comply with the most common ordering practices of our clients, the following hypercoagulability panels are offered.
Antiphospholipid I panel includes only coagulation tests for diagnosis of lupus anticoagulant. Indications for this panel include investigation of an unexplained APTT prolongation, or follow-up of a previously diagnosed or borderline lupus anticoagulant. Tests include APTT, PT, mixing studies, hexagonal phase phospholipid test, dilute Russell viper venom time and thrombin time. Specific components of the panel will vary according to the results obtained.
Antiphospholipid II panel includes all components of Antiphospholipid I panel plus anticardiolipin IgG and IgM antibodies and anti-beta-2-glycoprotein I IgG and IgM antibodies. Anti-beta-2-glycoprotein antibody is more closely associated with clinical features of the antiphospholipid antibody syndrome than the presence of anticardiolipin antibodies. This panel is the minimum required for diagnosis of the antiphospholipid antibody syndrome in patients with arterial or venous thrombosis or complications of pregnancy.
Venous Thrombosis I panel is appropriate for laboratory diagnosis of the most common and well-defined hereditary and acquired hypercoagulable disorders. It includes all of the tests in the Antiphospholipid II panel plus activated protein C (APC) resistance, factor V Leiden (if APC resistance is abnormal), prothrombin gene mutation, homocysteine, protein C functional, Protein S activity, antithrombin and Factor VIII activity.
An elevated factor VIII activity level (>150%) is an independent, common risk factor for venous thrombosis. It should be kept in mind that factor VIII is an acute phase reactant, which limits usefulness of this assay immediately after an acute event.
Acquired deficiencies of the naturally occurring anticoagulants, protein C, protein S, and antithrombin, are very common in various pathological and physiological conditions, as shown in the following table.
Condition
Protein C
Protein S
Antithrombin
Acute thrombosis
¯
¯
¯
Liver disease
¯
¯
¯
DIC
¯
¯
¯
Coumadin
¯
¯
-
Vitamin K deficiency
¯
¯
-
Acute phase reaction
¯
¯(free)
-
Pregnancy
-
¯
¯
Oral contraceptives
¯
¯
Estrogen therapy
¯
¯
Nephrotic syndrome
-
¯(free)
¯
Heparin
-
-
¯
Testing should be avoided when it is likely that an acquired deficiency may exist, since this makes interpretation of results difficult. An acquired decrease in antithrombin, protein C and protein S may be seen in acute thrombosis, DIC, and liver disease. An acquired decrease in protein C and protein S may be associated with any acute phase reaction. During pregnancy there is a significant acquired decrease in protein S levels (total and free). If there has been a recent acute event (including thrombosis), it is advisable to defer testing for 4 to 6 weeks.
Protein C and S assays should not be run while a patient is taking Coumadin, because it produces a decrease in protein C and protein S levels and results cannot be reliably interpreted. If Coumadin therapy cannot be stopped, it can be temporarily discontinued for 5 days prior to testing, while the patient is covered with heparin. Heparin may cause a mild acquired decrease in antithrombin.
In general, if a deficiency of antithrombin, protein C or protein S is observed, it is recommended that testing be repeated after an interval to confirm persistent deficiency. As a rough guide, the level of antithrombin in hereditary antithrombin deficiency is usually < 65%, and the level of protein S in hereditary protein S deficiency is usually < 50%. For both protein C and total protein S assays there is considerable overlap in values between normal individuals and those with the genetic deficiency. Family studies may be helpful.
Reference ranges are:
