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Laboratory Evaluation of Long-Term Thrombophilic Disorders
Abnormal thrombosis is a result of a pathologic shift in the balance between antihemorrhagic (prothrombotic) and antithrombotic factors toward conditions that favor thrombus formation at the wrong time and/or in the wrong location. The Virchow triad of blood stasis, inflammation, endothelial injury, and alterations of blood components, can all contribute to the pathologic event. Frequently the cause of a venous clot is not difficult to discern and is clearly due to the physiologic state of the patient, possibly significant trauma, neoplasia, and prolonged immobility. At other times there may not be an entirely obvious explanation for a pathologic thrombus, and a laboratory evaluation for thrombophilic tendency is considered.
Long-term thrombophilia may occur secondary to acquired chronic disorders such as antiphospholipid antibody syndrome and paroxysmal nocturnal hemoglobinuria (PNH) due to inherited gene mutations that cause alterations of factors involved in the clotting cascade, or due to inherited conditions that influence clotting, or the fibrinolysis cascade indirectly. The strongly prothrombotic congenital defects such as most homozygous or compound heterozygous antithrombin (AT), protein C (PC), and protein S (PS) deficiencies are very rare and are either lethal in the embryonic stage or cause dramatic thrombotic complications in infants. Deficiency of another natural anticoagulant, the tissue factor pathway inhibitor, is not known to occur in humans, presumably due to early embryonic lethality. For more frequently encountered congenital defects, the excess risk of venous thromboembolism (VTE) is relatively modest ( Table 147.1 ). While these defects can cause thrombosis without obvious provocation, frequently it is the interplay between the mild physiologic provocation and relatively modest congenital or acquired risk factors that tilts the hemostatic system to produce a pathological thromboembolic event. For instance, pregnant women who are carriers of factor V Leiden (FVL) mutation (a modest risk factor for venous thromboembolic event) are at substantially increased risk of serious thrombotic complications compared with either noncarrier pregnant women or nonpregnant carriers of FVL. The presence of multiple congenital thrombophilia risk factors greatly increases the risk of VTE. The estimates of risk of VTE for carriers of compound defects are as high as 50–80 times than those of unaffected subjects.
Table 147.1
Congenital Venous Thrombosis Risk Factors in Caucasians
| Approximate Lifetime Relative Risk (Fold) | Approximate Population Prevalence | |
|---|---|---|
| Factor V Leiden (heterozygous) | 2–5 | 3%–7% |
| Prothrombin G20210A mutation | 2–4 | 1%–3% |
| Protein C deficiency | 3–15 | 0.2%–0.4% |
| Protein S deficiency | 3–15 | 0.03%–0.17% |
| Antithrombin deficiency | 3–15 | 0.02%–0.04% |
| Persistent elevation of FVIII (>150 IU/dL) | 1.5–5.5 | 2%–10% |
| Congenital dysfibrinogenemia | Depends on specific mutation | Very rare |
Testing Recommendations
Defining which patients to test for thrombophilia tendencies is challenging. Screening the general population is clearly not indicated, as the low prevalence of any of the risk factors ( Table 147.1 ) would lead to an unacceptably high rate of false-positive results. Moreover, the significance of some risk factors for thrombophilia in otherwise asymptomatic subjects outside of the thrombophilic kindreds is unclear. Current testing guidelines are primarily focused on selecting appropriate groups of patients with a high prevalence of long-term thrombophilia. Broadly, this includes patients who have suffered a VTE or thrombotic pregnancy complication without a sufficient external provocation to fully explain the event. For this patient population with unprovoked thrombosis, thrombophilia testing should be considered only if results would change management and testing should be performed after routine anticoagulation treatment (e.g., 3 months) is completed. Alternatively, in patients in which longer anticoagulation treatment is being considered, a two-stage approach for thrombophilia testing may be indicated: performed tests that can provide reliable results while on anticoagulation ( Table 147.2 ) and if these results are normal then remaining thrombophilia testing can be performed once anticoagulation treatment is completed. An additional group is the female relatives of patients with known congenital high-risk thrombophilia such as PC, PS, and AT deficiency who are considering estrogen use or pregnancy. Again, in these cases, thrombophilia testing should be considered only if the results would change management and testing should be limited to the known thrombophilia in the affected family members.
Table 147.2
Anticoagulant Interference in Thrombophilia Testing
| Thrombophilia | Available Tests | Interference | No Interference |
|---|---|---|---|
| APC resistance | FVL DNA test | None | All |
| APCR | DTI, Xa inhibitors | Heparin a , coumadin | |
| Prothrombin G20210A mutation | Mutational analysis | None | All |
| Protein C deficiency | Chromogenic protein C function | Coumadin b | Xa inhibitors, DTI, heparin |
| Protein C clottable | All | None | |
| Protein S deficiency | Protein S free Antigen | Coumadin b | Xa inhibitors, DTI, heparin |
| Protein S clottable | All | None | |
| Antithrombin deficiency | Chromogenic (residual Xa activity) | Xa inhibitors, heparin c | DTI, coumadin |
| Chromogenic (residual IIa activity) | DTI, heparin c | Xa inhibitors, coumadin | |
| Persistence elevation of FVIII | Chromogenic FVIII | Xa inhibitors | Heparin a , DTI, coumadin |
| Clottable FVIII | All | None | |
| Lupus anticoagulant | DRVVT | Xa inhibitors, DTI | Heparin a , coumadin |
| PTT-based (STACLOT-LA) | Xa inhibitors, DTI | Heparin a , coumadin | |
| Dysfibrinogenemia | Fibrinogen activity | DTI | Heparin a , coumadin, Xa inhibitors |
| thrombin time | Heparin, DTI | Coumadin, Xa inhibitors |
APCR , activated protein C resistance; AT , antithrombin; FVL , factor V Leiden.
a Therapeutic levels of heparin should not interfere.
b Physiologic decrease of vitamin K–dependent factors.
c Approximately 30% decrease in AT within 3–5 days of heparin treatment due to increased clearance of heparin–bound AT.
Approximately 60% of patients from carefully chosen populations with unexpected thrombosis will have one or more of the identifiable heritable thrombophilia risk factors. Conversely, although the prevalence of risk factors is by definition elevated in patients with unexpected thromboembolic events, the risk of VTE recurrence among carriers and noncarriers is either similar or only mildly elevated in most instances. The phenomenon is likely attributable to the presence of yet undiscovered or multifactorial risk determinants in a substantial subset of the remaining VTE patients. Moreover, neither thrombophilia testing lowers the risk of thrombosis recurrence nor does the presence of known thrombophilia has an impact on the long-term survival of VTE patients. Thus, clinical management of patients with identified thrombophilia is often driven by clinical rather than laboratory findings. In many situations, the greatest beneficiaries of testing may be the asymptomatic relatives of patients in whom a congenital risk factor for thrombosis is demonstrated. In that cohort, appropriate measures may be taken to prevent the first provoked thrombosis in those who test positive.
Testable Thrombophilia Risk Factors
The most commonly tested thrombophilia risk factors are deficiencies of PC, PS, AT, activated protein C resistance (APCR), prothrombin gene mutation G20210A , and persistent increase in FVIII and lupus anticoagulant. Under certain clinical circumstances, such as abdominal vein thrombosis, testing for PNH is indicated. Homocysteine and dysfibrinogenemia testing indications are controversial, and only dysfibrinogenemia testing may be warranted. The risk factors can be loosely divided into the four categories described below.
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