Abstract
Although heritable thrombophilias and hypofibrinolysis predominantly cause venous thrombosis, they may also promote arterial thrombosis, synergistic with atherosclerosis, producing atherothrombotic cardiovascular (ATCVD) events. In 70 men and 16 women with ≥ 1 premature myocardial infarction (n = 60)-angioplasty (n = 52)-coronary artery bypass grafts (n = 33) (≤ age 45 years), we assessed whether and to what degree heritable thrombophilia-hypofibrinolysis contributed to 145 ATCVD events ≤ age 45. Hereditary thrombophilias studied by PCR included the G1691A factor V Leiden, G20210A prothrombin, MTHFR C677T-A1298C, and platelet glycoprotein PL A1/A2 mutations, with serologic studies of ACLA IgG and IgM, the lupus anticoagulant, proteins C and S, antithrombin III, homocysteine, and factors VIII and XI. Hypofibrinolysis studies included the 4G4G plasminogen activator inhibitor 1 mutation (PAI), PAI activity (PAI-Fx), and Lp(a). Cases were compared with healthy normal controls (149 men for PCR, 40 for serologic tests, 109 women for PCR and for serologic tests). At entry, hypertension was present in 46% of men and 31% of women, diabetes in 19% and 13%, and cigarette smoking in 26% and 13%, respectively. In the 70 male cases, mean ± SD age was 49 ± 11, BMI 29.5 ± 4.2, LDLC 102 ± 45, HDLC 41 ± 15, and TG 204 ± 229 mg/dL. In 16 female cases, mean ± SD age was 43 ± 7, BMI 28.1 ± 5.5, LDLC 103 ± 32, HDLC 45 ± 11, and TG 191 ± 170 mg/dL. Male cases were more likely than male controls to have factor V Leiden (6 of 60, 10% vs 4 of 149, 3%, p = .035), high Lp(a) (≥ 35 mg/dL) (25 of 69, 36% vs 7 of 40, 18%, p = .039), high PAI-Fx (> 21.1 U/mL) (15 of 61, 25% vs 3 of 39, 8%, p = .036), high (> 150%) factor VIII (15 of 57, 26% vs 1 of 38, 3%, p = .003), and high (> 150%) factor XI (9 of 55, 16% vs 0 of 38, 0%, p = .0096). Female cases were more likely then female controls to have high factor VIII (5 of 14, 36% vs 13 of 109, 12%, p = .033) and were more likely to have low free protein S (3 of 14, 21% vs 3 of 107, 3%, p = .02). In patients sustaining MI-angioplasty-CABG events ≤ age 45, we speculate that hereditary thrombophilias (factor V Leiden, factor VIII, factor XI, low free protein S) and hypofibrinolysis (PAI-Fx, Lp(a)) promote arterial thrombosis that may be synergistic with atherosclerotic endothelial injury. In patients with MI-angioplasty-CABG events ≤ age 45 and concurrent hereditary thrombophilia, we speculate that thromboprophylaxis may have value in secondary prevention of subsequent ATCVD.