ecallantide and Venous-Thrombosis

Cardiovascular disease, including stroke, myocardial infarction, and venous thromboembolism, is one of the leading causes of morbidity and mortality worldwide. Excessive coagulation may cause vascular occlusion in arteries and veins eventually leading to thrombotic diseases. Studies in recent years suggest that coagulation factors are involved in these pathological mechanisms. Factors XIa (FXIa), XIIa (FXIIa), and plasma kallikrein (PKa) of the contact system of coagulation appear to contribute to thrombosis while playing a limited role in hemostasis. Contact activation is initiated upon autoactivation of FXII on negatively charged surfaces. FXIIa activates plasma prekallikrein (PK) to PKa, which in turn activates FXII and initiates the kallikrein-kinin pathway. FXI is also activated by FXIIa, leading to activation of FIX and finally to thrombin formation, which in turn activates FXI in an amplification loop. Animal studies have shown that arterial and venous thrombosis can be reduced by the inhibition of FXI(a) or PKa. Furthermore, data from human studies suggest that these enzymes may be valuable targets to reduce thrombosis risk. In this review, we discuss the structure and function of FXI(a) and PK(a), their involvement in the development of venous and arterial thrombosis in animal models and human studies, and current therapeutic strategies.

Topics: Animals; Arterial Occlusive Diseases; Blood Coagulation; Blood Coagulation Disorders; Blood Coagulation Factors; Disease Models, Animal; Enzyme Activation; Factor Xa Inhibitors; Factor XI Deficiency; Factor XIa; Humans; Mice; Mice, Knockout; Plasma Kallikrein; Prekallikrein; Protein Processing, Post-Translational; Species Specificity; Thrombophilia; Thrombosis; Venous Thrombosis

We evaluated 10 single-nucleotide polymorphisms (SNPs) identified in three European case-control studies as risk factors for venous thrombosis.. We sought to replicate the positive findings from this report among Whites and to evaluate the association of these SNPs with venous thrombosis for the first time among Blacks.. These SNPs were evaluated in a case-control study of deep vein thrombosis and pulmonary embolism that included 1076 cases and 1239 controls. About 50% of subjects were African Americans. We measured plasma factor (F) XI on a subset of subjects.. Among Whites, positive findings for rs13146272 in the CYP4V2 gene, for rs3087505 in the KLKB1 gene and for rs3756008 and rs2036914 in the F11 gene were found. We did not find significant associations for rs2227589 in the SERPINC1 gene and for rs1613662 in the GP6 gene. Among Blacks, rs2036914 in F11 and rs670659 in RGS7 were related to venous thrombosis, but the study had limited statistical power for many SNPs. Among Blacks, plasma FXI was related to two SNPs and the OR relating to the 90th percentile of the control distribution of plasma FXI was 2.6 (95% CI, 1.4, 5.0).. Our study supports the finding that genetic variants in the F11 gene are risk factors for venous thrombosis among both Whites and Blacks, although the findings in Blacks require confirmation. A meta-analysis of five case-control studies indicates that rs2227589 in the SERPINC1 gene, rs13146272 in the CYP4V2 gene and rs1613662 in the GP6 gene are risk factors for venous thrombosis among Whites.

Topics: Adult; Antithrombin III; Black or African American; Case-Control Studies; Cytochrome P-450 Enzyme System; Cytochrome P450 Family 4; Factor XI; Female; Genetic Predisposition to Disease; Glucose-6-Phosphatase; Humans; Linkage Disequilibrium; Male; Middle Aged; Plasma Kallikrein; Polymorphism, Single Nucleotide; Pulmonary Embolism; Risk Factors; Venous Thrombosis; White People

Venous thromboembolism (VTE) is associated with excessive coagulation activity, which in part can be attributed to activation of contact system. However, the knowledge regarding the impact of contact activation in acute VTE is limited.. To unravel the involvement of contact activation in acute VTE.. Contact activation was investigated in patients with acute VTE (n = 321) and population controls without a history of VTE (n = 300). For comparison, Factor XI(a) levels, activity, and plasma kallikrein (PKa) activity were determined in plasma samples with an activated partial thromboplastin time- or thrombin generation-based assay (free FXI concentration [FXI:c] and calibrated automated thrombogram:FXIa, respectively) and with enzyme-linked immunosorbent assays for enzyme-inhibitor complexes (FXIa:alpha-1-antitrypsin [α1AT], FXIa:antithrombin [AT], FXIa:C1-inhibitor [C1Inh], and PKa:C1-inh).. In patients with VTE, higher FXI:c levels (124 ± 37% vs 114 ± 28%), but lower calibrated automated thrombogram:FXIa levels were apparent. This was accompanied by increased FXIa:α1AT, FXIa:AT, and PKa:C1-inh levels in patients compared with controls (312pM [238-424] vs 203pM [144-288]; 29pM [23-38] vs 23pM [20-30]; 1.9nM [1.2-4.7] vs 1.4nM [0.7-3.5], respectively), whereas FXIa:C1-inh levels did not differ. Logistic regression models showed good discriminatory values for FXI:c and FXIa:α1AT (area under the curve = 0.64 [0.6/0.69] and 0.73 [0.69/0.77], respectively). After a 2-year follow-up, 81 recurrent VTE events or deaths occurred in the patient cohort, for which the baseline levels of FXIa:α1AT and FXIa:C1Inh had a significant prognostic value (Hazard ratios per SD [95% CI], 1.26 [1.10-1.45]; p =.0012 and 1.19 [1.05-1.36]; p =.0082, respectively).. Our study revealed elevated FXIa levels and activity in acute VTE, which was also associated with recurrent VTE, suggesting an important risk contribution of FXI activation to VTE. The evidence provided by this study supports the utility of FXIa inhibition in the setting of acute VTE.

Topics: Anticoagulants; Antithrombin III; Blood Coagulation; Factor XI; Factor XIa; Humans; Plasma Kallikrein; Venous Thromboembolism; Venous Thrombosis

Plasma kallikrein is a multifunctional serine protease involved in contact activation of coagulation. Deficiency in humans is characterised by prolonged activated partial thromboplastin time (aPTT); however, the balance between thrombosis and haemostasis is not fully understood. A study of plasma kallikrein-deficient mice revealed increased aPTT, without prolonged bleeding time. Prekallikrein antisense oligonucleotide (ASO) treatment in mice suggested potential for a positive therapeutic index. The current goal was to further define the role of plasma kallikrein in coagulation. Blood pressure and heart rate were normal in plasma kallikrein-deficient mice, and mice were completely protected from occlusion (100 ± 1.3% control flow) in 3.5% FeCl3 -induced arterial thrombosis versus heterozygotes (20 ± 11.4%) and wild-type littermates (8 ± 0%). Vessels occluded in 8/8 wild-type, 7/8 heterozygotes, and 0/8 knockouts. Anti-thrombotic protection was less pronounced in 5% FeCl3-induced arterial injury. Integrated blood flow was 8 ± 0% control in wild-type and heterozygotes, and significantly (p<0.01) improved to 43 ± 14.2% in knockouts. The number of vessels occluded was similar in all genotypes. Thrombus weight was significantly reduced in knockouts (-47%) and heterozygotes (-23%) versus wild-type in oxidative venous thrombosis. Average tail bleeding time increased modestly in knockout mice compared to wild-type. Average renal bleeding times were similar in all genotypes. These studies confirm and extend studies with prekallikrein ASO, and demonstrate that plasma kallikrein deletion prevents occlusive thrombus formation in mice with a minimal role in provoked bleeding. Additional support for the significance of the intrinsic pathway in the coagulation cascade is provided, as well as for a potential new anti-thrombotic approach.

Topics: Animals; Bleeding Time; Chlorides; Disease Models, Animal; Ferric Compounds; Hemorrhage; Hemostasis; Heterozygote; Mice; Mice, Knockout; Oligonucleotides, Antisense; Partial Thromboplastin Time; Phenotype; Plasma Kallikrein; Prekallikrein; Thrombosis; Time Factors; Venous Thrombosis