Thrombophilias & Hypercoagulable States

Virchow Triad and Patterns of Thrombosis

Virchow triad. Thrombosis follows stasis (immobility, atrial fibrillation, venous obstruction), endothelial injury (surgery, trauma, catheters, atherosclerosis), and hypercoagulability (inherited or acquired). Many thrombophilia carriers clot only after a second hit such as surgery, pregnancy, or estrogen.

Venous vs arterial clots. Venous thrombi form in slow flow (stasis, hypercoagulability) as red thrombi of fibrin and trapped red cells, causing DVT, pulmonary embolism, and splanchnic or cerebral vein thrombosis; they are treated with anticoagulants (heparins, warfarin, DOACs). Arterial thrombi form in fast flow on injured endothelium or ruptured plaque as pale, platelet-rich thrombi, causing MI, stroke, and limb ischemia; they are prevented with antiplatelet drugs (aspirin, P2Y12 inhibitors).

The classic inherited thrombophilias cause mainly venous clots. Clots in both arteries and veins point to antiphospholipid syndrome, HIT, hyperhomocysteinemia, PNH, or a myeloproliferative neoplasm.

Inherited Thrombophilias

Factor V Leiden. The most common inherited thrombophilia (about 5% of people of European descent). The Arg506Gln (R506Q) substitution removes the site where activated protein C (APC) cleaves factor Va, so Va stays active and thrombin generation continues. PT and aPTT are normal; the defect shows as APC resistance (the aPTT fails to lengthen normally when APC is added) and is confirmed by PCR genotyping. Heterozygotes have roughly a 5-fold venous thrombosis risk and homozygotes a much higher risk; estrogen multiplies it further.

Prothrombin G20210A. The second most common inherited thrombophilia. A G→A change in the 3′ untranslated region of the prothrombin (F2) gene stabilizes its mRNA, so carriers make about 30% more normal prothrombin. It causes venous clots, including cerebral venous sinus thrombosis, and is diagnosed only by genotyping.

Antithrombin deficiency. Antithrombin is a serine protease inhibitor that neutralizes thrombin and factor Xa. Heparin works only by accelerating antithrombin about 1000-fold. Deficiency therefore causes heparin resistance (the aPTT barely rises despite large doses), and a direct thrombin inhibitor such as argatroban is used instead. Inherited deficiency is autosomal dominant. Acquired deficiency comes from consumption in DIC, reduced synthesis in cirrhosis, and urinary loss in nephrotic syndrome, where antithrombin is lost with albumin while the liver overproduces large procoagulants (fibrinogen, factor VIII, von Willebrand factor); renal vein thrombosis in membranous nephropathy is the classic result.

Protein C and protein S deficiency. Thrombin bound to endothelial thrombomodulin activates protein C, which, with its cofactor protein S, cleaves and inactivates factors Va and VIIIa. Both are vitamin K–dependent. About 60% of protein S is bound to C4b-binding protein; only the free fraction is active, and free protein S falls in pregnancy and with estrogen. Heterozygous deficiency causes venous thrombosis. Homozygous protein C deficiency causes neonatal purpura fulminans: skin necrosis with DIC within days of birth.

Warfarin skin necrosis. Protein C has a half-life of about 8 hours, like factor VII, whereas prothrombin lasts about 60–72 hours. Warfarin therefore lowers protein C before factors II and X, creating a transient hypercoagulable state even as the INR rises (the early rise mostly reflects falling factor VII). In protein C deficiency, dermal vessels thrombose in the first days, causing necrosis of the breasts, thighs, and abdomen. Prevention is to overlap heparin for at least 5 days and until the INR is 2–3 for 24 hours. The same mechanism causes venous limb gangrene when warfarin is started alone during acute HIT.

Hyperhomocysteinemia. Homocysteine injures endothelium and raises the risk of both arterial (MI, stroke) and venous thrombosis. Causes include folate or B12 deficiency (impaired remethylation to methionine), B6 deficiency, MTHFR variants, and renal failure. Classic homocystinuria from cystathionine β-synthase deficiency adds downward lens subluxation, a marfanoid habitus, and intellectual disability; in Marfan syndrome the lens moves upward and thrombosis is not a feature. Lowering homocysteine with B vitamins has not been shown to prevent cardiovascular events.

Antiphospholipid Syndrome

The antibodies. Antiphospholipid antibodies bind phospholipid-associated proteins, chiefly β2-glycoprotein I, and are detected as lupus anticoagulant (a clotting assay), anticardiolipin, and anti-β2-glycoprotein I (immunoassays). The syndrome is primary or secondary to SLE.

The paradox. In the test tube, the antibodies tie up the phospholipid in the reagent, prolonging the aPTT and the dilute Russell viper venom time (dRVVT). Mixing with normal plasma does not correct the prolongation, because an inhibitor is present, but adding excess phospholipid does. In the patient, the same antibodies activate endothelium, platelets, and complement, causing venous and arterial thrombosis and placental infarction, with no bleeding tendency. "Lupus anticoagulant" is thus a double misnomer: most patients do not have lupus, and it promotes clotting.

Diagnosis. A clinical event plus persistent antibodies. Events are thrombosis (venous, arterial, or small-vessel) or pregnancy morbidity: three or more unexplained consecutive losses before 10 weeks, fetal death at or after 10 weeks, or delivery before 34 weeks for preeclampsia or placental insufficiency. Antibodies must be positive on two occasions at least 12 weeks apart. Because nontreponemal tests (VDRL, RPR) use a cardiolipin antigen, patients may have a false-positive syphilis screen with a negative treponemal test (FTA-ABS).

Treatment. After a thrombosis, long-term warfarin is standard (usually INR 2–3). DOACs are avoided, especially in triple-positive or arterial disease, because rivaroxaban led to excess arterial events in trials. Heparin is monitored with anti-Xa levels, since the lupus anticoagulant already prolongs the aPTT. In pregnancy, LMWH plus low-dose aspirin is used: heparins do not cross the placenta, whereas warfarin is teratogenic and DOACs are avoided.

Acquired Hypercoagulable States

Malignancy. Tumors, especially mucin-secreting adenocarcinomas of the pancreas, stomach, lung, and ovary, express tissue factor and shed procoagulant mucin. Results include DVT and PE, migratory superficial thrombophlebitis (Trousseau syndrome), and nonbacterial thrombotic (marantic) endocarditis. An unprovoked VTE can be the first sign of an occult cancer; chemotherapy, central lines, and surgery add risk.

Estrogen and pregnancy. Estrogen from combined oral contraceptives, hormone replacement, or pregnancy, and the SERMs tamoxifen and raloxifene, increases hepatic fibrinogen and factors II, VII, VIII, and X, lowers protein S, and induces acquired APC resistance. Pregnancy adds venous stasis from compression by the gravid uterus. VTE risk is highest in the first 6 weeks postpartum and multiplies with factor V Leiden. Combined estrogen contraception is avoided after VTE, with a known thrombophilia, and in smokers aged 35 or older.

PNH and myeloproliferative neoplasms. Clots in unusual sites (hepatic veins causing Budd-Chiari syndrome, or portal, mesenteric, and cerebral veins) suggest one of these clonal disorders. In PNH, a PIGA mutation blocks GPI anchoring, so cells lack CD55 and CD59 and red cells are lysed by complement; thrombosis is the leading cause of death, and eculizumab blocks C5. JAK2 V617F neoplasms, especially polycythemia vera, also cause splanchnic thrombosis, and JAK2 testing is reasonable in any unexplained splanchnic vein thrombosis, even with normal counts.

Heparin-induced thrombocytopenia. IgG antibodies to platelet factor 4–heparin complexes crosslink platelet FcγRIIa receptors, activating platelets and producing a thrombin burst. Platelets fall by more than 50% about 5–10 days after heparin exposure, with venous and arterial thrombosis. All heparin, including LMWH and line flushes, is stopped and a non-heparin anticoagulant (argatroban, bivalirudin, or fondaparinux) is started; warfarin is delayed until platelets recover. A mild, nonimmune drop in the first days (type 1) is harmless.

Thrombophilia Testing: What and When

Timing. Acute clots consume proteins C and S and antithrombin, anticoagulants alter levels and clot-based assays, and only DNA tests and antibody immunoassays are unaffected.