John A. Heit

A genome‐wide association study of venous thromboembolism identifies risk variants in chromosomes 1q24.2 and 9q

Summary.  Objectives:  To identify venous thromboembolism (VTE) disease‐susceptibility genes.

Venous Thromboembolism Associated With Hip and Knee Arthroplasty: Current Prophylactic Practices and Outcomes

Joint registry and hospital data bases for 5,024 total hip and total knee arthroplasties done between 1986 and 1988 at the Mayo Clinic were used to study prophylactic measures and frequency of symptomatic deep venous thrombosis and pulmonary embolism. In virtually all patients, graduated compression stockings were used, with or without another type of prophylaxis. Only 44 of 3,115 patients who underwent hip arthroplasty (1.4%) and 32 of 1,909 patients who underwent knee arthroplasty (1.7%) had definite or probable deep venous thrombosis or pulmonary embolism. Death definitely or possibly attributable to pulmonary embolism occurred in 11 patients who underwent hip arthroplasty (0.35%) and 1 patient who underwent knee arthroplasty (0.05%). Although patients with a history of deep venous thrombosis or pulmonary embolism were more likely to receive warfarin than were patients without such a history, the relative risk of symptomatic deep venous thrombosis or pulmonary embolism in patients who underwent hip arthroplasty and received warfarin postoperatively was approximately half that in patients who received other types of prophylaxis. The risk of death from pulmonary embolism was similarly diminished in the group that received warfarin. The lower rates of these complications in the patients who received warfarin support the prophylactic use of this agent after total hip arthroplasty.

Genetic variation within the anticoagulant, procoagulant, fibrinolytic and innate immunity pathways as risk factors for venous thromboembolism

Summary.  Background: Venous thromboembolism (VTE) is highly heritable (estimated heritability [h2] = 0.62) and likely to be a result of multigenic action. Objective: To systematically test variation within genes encoding for important components of the anticoagulant, procoagulant, fibrinolytic and innate immunity pathways for an independent association with VTE. Methods: Non‐Hispanic adults of European ancestry with objectively‐diagnosed VTE, and age‐ and sex‐ matched controls, were genotyped for 13 031 single nucleotide polymorphisms (SNPs) within 764 genes. Analyses (n = 12 296 SNPs) were performed with plink using an additive genetic model and adjusted for age, sex, state of residence, and myocardial infarction or stroke. Results: Among 2927 individuals, one or more SNPs within ABO, F2, F5, F11, KLKB1, SELP and SCUBE1 were significantly associated with VTE, including factor (F) V Leiden, prothrombin G20210A, ABO non‐O blood type, and a novel association with ABO rs2519093 (OR = 1.68, P‐value = 8.08 × 10−16) that was independent of blood type. In stratified analyses, SNPs in the following genes were significantly associated with VTE: F5 and ABO among both genders and LY86 among women; F2, ABO and KLKB1 among FV Leiden non‐carriers; F5, F11, KLKB1 and GFRA1 in those with ABO non‐O blood type; and ABO, F5, F11, KLKB1, SCUBE1 and SELP among prothrombin G20210A non‐carriers. The ABO rs2519093 population‐attributable risk (PAR) exceeded that of FV Leiden and prothrombin G20210A, and the joint PAR of FV Leiden, prothrombin G20210A, ABO non‐O and ABO rs2519093 was 0.40. Conclusions: Anticoagulant, procoagulant, fibrinolytic and innate immunity pathway genetic variation accounts for a large proportion of VTE among non‐Hispanic adults of European ancestry.

Clinical Importance of Positive Test Results for Lupus Anticoagulant and Anticardiolipin Antibodies

OBJECTIVES To assess the performance of 4 clotting assays for lupus anticoagulant (LA) detection, to determine the prevalence of LA and anticardiolipin antibodies (aCL), and to correlate LA and aCL prevalence with systemic disease and thrombosis. PATIENTS AND METHODS We studied 664 consecutive patients at the Mayo Clinic in Rochester, Minn, who were referred for laboratory testing because of a clinical suspicion of LA or thrombophilia between June 25, 1990, and July 1, 1991. RESULTS Of 664 patients tested for LA, 584 also were tested for aCL. Of patients tested for both LA and aCL, 137 (235%) had positive results for one or both tests (13 [95%], LA-positive only; 76 [555%], aCL-positive only; and 48 [35.0%], positive for both). The dilute Russell viper venom time (DRVVT) was the most frequently positive LA assay (74% of the 61 patients with positive results for LA). Twenty-two patients (36.1% of the 61) had positive results for all 4 LA assays, whereas 21 (34.4% of the 61) had positive results for only 1 LA assay: activated partial thromboplastin time (3 patients [4.9%]), plasma clot time (5 patients [8.2%]), kaolin clot time (5 patients [8.2%]), or DRVVT (8 patients [13.1%]). Thromboembolism prevalence was not definitely associated with positive test results (LA only, aCL only, or LA plus aCL), nor was it strongly associated with aCL isotype or titer. Furthermore, thromboembolism prevalence was not increased when all LA assays were positive, although a history of deep venous thrombosis or pulmonary embolism was nonsignificantly associated with positive results for all 4 LA tests. The likelihood of having both LA- and aCL-positive test results was higher among patients with systemic lupus erythematosus (26 [19.0%] of 137 patients with positive results for one or both tests), but they had no more thrombotic events or fetal loss than other patients in our study group. CONCLUSIONS The DRVVT identified more patients with LA than the other LA tests, but more than 1 LA test was required to identify all patients with LA. Positive results were much more common for aCL than for LA. No single LA test or anticardiolipin isotype correlated with thrombosis or systemic disease in this population.

Activated protein C resistance caused by factor V gene mutation: Common coagulation defect in chronic venous leg ulcers?

Activated protein C resistance (APCR) may occur in up to one fourth of patients with venous leg ulcers and has recently emerged as the most frequent cause of venous thrombosis. Deep venous thrombosis often precedes deep venous insufficiency and is of major importance in the pathogenesis of venous leg ulcers. APCR is most frequently caused by a point mutation in the factor V gene (fV R506Q), resulting in reduced inactivation of activated factor V and imbalance of the hemostatic system. Recent data suggest that APCR/fV R506Q may be common in patients with venous leg ulcers. We review APCR as a genetically determined risk factor that may contribute to the development of venous leg ulcers. New diagnostic developments are discussed, and therapeutic guidelines specifically directed toward the prevention of thrombosis are suggested.

Incidence of venous thromboembolism after elective knee arthroscopic surgery: a historical cohort study

The incidence of symptomatic venous thromboembolism (VTE) after knee arthroscopy is uncertain.