Upon completion, the participants will be able to describe that coagulation factor V (FV) circulates as a procofactor to both a procoagulant cofactor and as an anticoagulant. The circulating FV has little or no procoagulant activity. It is activated by thrombin or FXa which cleave several peptide bonds surrounding the large activation B domain. Anticoagulant activity of FV is charactierized as a synergistic cofactor to activated protein C (APC) with protein S in the regulation of FVIIIa when it is part of the tenase complex (FIXa,FVIIIa and negatively charged phospholipids). A second anticoagulant activity is primarily expressed by a splice variant of FV called FV-Short and it is characterized as a synergistic cofactor to TFPIa with protein S.
Upon completion, the participants will be able to describe that a common mutation in coagulation factor V (FV) is associated with an increased risk of venous thrombosis. The mutation predicts replacement of Arg506 with a Gln which results in a loss of one of three APC-cleavage sites in FV. The mutation, which is referred to as FVLeiden results in the phenotype of APC resistance. Dual mechanisms result in a shift in the balance between pro- and anticoagulant forces of FV. The first is that the APC cleave site at position 506 in FVa is lost, which impairs the regulation of FVa activity by APC. The second is that FVLeiden functions poorly as a synergistic APC cofactor with protein S in the regulation of FVIIIa activity.
Upon completion, the participants will be able to describe the mechanisms of bleeding associated with the East Texas bleeding disorder. They will be able to discuss how a point mutation in the B domain of FV results in activation of a splice donor site which results in an in frame deletion of 702 amino acid residues from the B domain. The participants will be able to describe how this deletion results in the exposure of a high affinity binding site in the B domain for TFPIa (tissue factor pathway inhibitor). The truncated FV is called FV-Short and functions as a synergistic TFPIa cofactor with protein S. The participants with be able to describe how FV-Short, TFPIa and protein S form a circulating high affinity complex which efficiently inhibits FXa. Under normal conditions the concentration of the circulating complex is low (sub nanomolar) but in individuals affected by the East Texas bleeding it is increased around 10-fold due to the high concentrations of FV-Short.
