Heritability of Clot Formation, Morphology, and Lysis

Abstract

Objective-The relative balance between clot formation and fibrinolysis is considered to reflect thrombotic potential following vascular injury. The aims of the present study were to (1) to determine the contribution of genetic and environmental factors to variance in measures of clot structure/function in the Leeds Family Study, and (2) Key Words: heritability Ⅲ coagulation Ⅲ fibrinolysis Ⅲ metabolic syndrome Ⅲ cardiovascular disease T he development of cardiovascular disease (CVD) is associated with a major thrombotic component initiated by underlying vascular damage. In occlusive arterial disease the development of a platelet rich thrombus is supported by a fibrin mesh, with fibrin formation dependent on complex interactions between components of the coagulation cascade. A significant contribution of additive genetic factors in determining risk for thrombosis was indicated by the GAIT Study, in which genetic factors accounted for Ϸ60% of variation in risk. 1 All the genes encoding hemostatic factors are potential candidates for thrombosis and studies in families and twins have demonstrated significant contributions of additive genetic factors to variance in these intermediate phenotypes. [2][3][4][5][6][7][8][9] Significant genetic correlations between hemostatic factors and thrombosis were identified in the GAIT study, indicating shared genes regulate plasma levels of hemostatic factors and susceptibility to thrombosis. 1 Although genetic factors contribute to variance in hemostatic factors, associations between common genetic variants of the genes encoding a variety of hemostatic components and CVD have generally been inconsistent. 10 Clot formation and fibrinolysis are dynamic processes, and identification of genetic factors regulating individual hemostatic factors may be less informative in relation to cardiovascular risk than identifying genetic factors influencing more complex phenotypes reflecting fibrin structure/function. A study in twins indicated heritabilities of 0.39 and 0.46 for clot permeability and clot density, 11 suggesting that genetic factors are important determinants of these phenotypes.The limited studies which have evaluated fibrin clot structure/function in relation to CVD indicate that dense structures, with increased stiffness, decreased permeability, and decreased clot lysis are observed in subjects with CVD 12,13 and in relatives of individuals with CVD. 14 Further understanding of the genetic and environmental determinants of fibrin structure/function may help to identify novel factors which influence vascular risk, and, in the longer term, inform the development of novel therapeutics.The aims of the present study were to (1) to determine the contribution of genetic and environmental factors to variance in measures of clot structure/function in the Leeds Family Study and (2) to determine the relationship between measures of clot structure/function and the metabolic syndrome as an indicator of cardiovascular risk.

Evidence that fibrinogen γ′ regulates plasma clot structure and lysis and relationship to cardiovascular risk factors in black Africans

“…23,27 Turbidity curves are often used as a measure of clot formation and structure in large data sets due to its high-throughput methodology. 28 Its relevance is further supported by the fact that final clot structure is to a large extent kinetically controlled and information on clot formation is therefore critical in determining clot structure.…”

A novel mechanism for hypofibrinolysis in diabetes: the role of complement C3

“…Fibrinolysis of plasma samples A turbidity assay was conducted to assess fibrinolysis as previously described [22]. Lysis time was measured from full clot formation to 50% clot lysis.…”

Upregulation of Monocyte Tissue Factor Activity Is Significantly Associated With Low-Grade Chronic Inflammation and Insulin Resistance in Patients With Metabolic Syndrome

“…16 In addition, subjects with MetS had prolonged clot lysis times compared with those without MetS, partly because of increased circulating levels of PAI-1. TF, a potent activator of the extrinsic coagulation cascade is widely expressed in atherosclerotic plaques in ACS and found in macrophages and peripheral monocytes.…”