Intraosseous venous thrombosis appears to be a major pathoetiology for nontraumatic osteonecrosis (ON). We assessed thrombophilia and hypofibrinolysis as risk factors for femoral head ON in 190 cases with ON, 75 primary (93% white, 31% female), and 115 (95% white, 53% female) secondary to high dose, long-term corticosteroids. Polymerase chain reaction methods were used to characterize thrombophilic (V Leiden, prothrombin, MTHFR, platelet glycoprotein A1/A2) and hypofibrinolytic (PAI-1 4G4G) gene mutations in cases and 274 healthy normal controls (87% white, 46% female). Primary ON cases differed from controls for 4G4G homozygosity (35% vs 22%, p = .03), for 4G allele frequency (57% vs 44%, p = .01), for MTHFR homozygosity (23% vs 12%, p = .035), and for the C677T/A1298C MTHFR allele (43% vs 31%, p = .007). Secondary ON cases differed from controls for the V Leiden mutation (8.6% vs 2.6%, p = .018), and for 4G allele frequency (55% vs 44%, p = .014). Serologic methods were used to characterize thrombophilia (proteins C, free S, antithrombin III, homocysteine, ACLA IgG and IgM, Factor VIII, Factor XI) and hypofibrinolysis (plasminogen activator inhibitor activity, Lp[a]) in primary ON (median age 48) and secondary ON (median age 45) cases vs 76 adult controls (92% white, 53% female, median age 41). Primary ON cases differed from controls for low (< 65%) free protein S (15% vs 3%, p = .015), and for high (> 150%) Factor VIII (24% vs 6%, p = .017). Secondary ON cases differed from controls for high Factor VIII (24% vs 6%, p = .003). Heritable thrombophilia (MTHFR homozygosity, low free protein S, high Factor VIII) and hypofibrinolysis (PAI-1 gene 4G4G) are associated with primary ON. Heritable thrombophilia (V Leiden, high Factor VIII) and hypofibrinolysis (4G allele) are associated with secondary ON. Thrombophilic and hypofibrinolytic risk factors for venous thrombosis are associated with nontraumatic ON of the femoral head. When primary ON is associated with thrombophilia-hypofibrinolysis, enoxaparin (60 mg/day, 90 days) given at Ficat stages I-II, before segmental collapse of the head of the femur, may prevent progression of primary hip ON, preserving the head of the femur, thus reducing the need for total hip replacement.
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