Thrombophilias (hypercoagulable disorders)
Also known as: hypercoagulable disorders, hypercoagulable state
Thrombophilia is an increased tendency to form blood clots, caused by inherited or acquired abnormalities in the coagulation system. Affected patients develop venous thromboembolism — most often deep vein thrombosis and pulmonary embolism — at unusually young ages or without a clear provoking cause.
Normal hemostasis balances clot formation against natural anticoagulants such as protein C, protein S, and antithrombin. Thrombophilia describes any condition that tips that balance toward clotting. Clinically it should be suspected when thrombosis occurs before age 50, recurs, appears in an unusual site such as the cerebral or mesenteric veins, arises without a provoking factor, or accompanies a family history of clots or recurrent pregnancy loss.
Inherited causes cluster around a few defects. Factor V Leiden is by far the most common: a point mutation makes factor Va resistant to inactivation by activated protein C. The prothrombin G20210A mutation increases prothrombin levels. Deficiencies of protein C, protein S, or antithrombin are less common but more thrombogenic per patient. Two clinical clues follow directly from the mechanism: antithrombin deficiency blunts the expected rise in PTT when heparin is given, and starting warfarin in a patient with protein C or S deficiency can cause skin necrosis, because those short-lived anticoagulant proteins fall before the procoagulant factors do.
Acquired causes are more common overall. Antiphospholipid syndrome produces both venous and arterial thrombosis and recurrent fetal loss, and paradoxically prolongs the PTT in vitro — a prolongation that fails to correct on a mixing study. Malignancy raises clot risk broadly and classically causes migratory superficial thrombophlebitis, known as Trousseau syndrome. Other acquired contributors include pregnancy and the postpartum period, estrogen-containing contraceptives, prolonged immobility, major surgery, nephrotic syndrome with urinary antithrombin loss, and heparin-induced thrombocytopenia. All of these can be organized under Virchow's triad: stasis, endothelial injury, and hypercoagulability.
USMLE Step 1 tests thrombophilias in the hematology and oncology section. Expect vignettes describing an unprovoked deep vein thrombosis in a young patient and asking for the underlying defect, the reason a laboratory value behaves unexpectedly, or the mechanism behind warfarin-induced skin necrosis.
Key takeaways
- Thrombophilia is an inherited or acquired tendency toward pathologic clotting, usually venous thromboembolism.
- Factor V Leiden is the most common inherited cause, producing resistance to activated protein C.
- Deficiencies of protein C, protein S, or antithrombin are less common but strongly thrombogenic; antithrombin deficiency blunts heparin's effect on PTT.
- Antiphospholipid syndrome prolongs the PTT in vitro yet causes clotting in vivo, and is associated with recurrent pregnancy loss.
- Virchow's triad — stasis, endothelial injury, and hypercoagulability — organizes the acquired risk factors.