East Texas bleeding disorder
Overview
East Texas bleeding disorder a novel bleeding disorder inherited as an autosomal dominant trait in a family from East Texas.
Symptoms
The disorder was characterized clinically by easy bruising, life-threatening bleeding with trauma or surgery, and menorrhagia in affected women. Laboratory studies demonstrated prolongation of the prothrombin time and activated partial thromboplastin time in affected individuals. Paradoxically, assays of known coagulation factors were all within normal limits.
Source:
Blood 2001 Mar 15;97(6):1549-54.
Causes
The autosomal dominantly inherited east Texas bleeding disorder is linked to an A2440G variant in exon 13 of the F5 gene. Affected individuals have normal levels of coagulation factor V (FV) activity, but demonstrate inhibition of global coagulation tests. The A2440G mutation causes upregulation of an alternatively spliced F5 transcript that results in an in-frame deletion of 702 amino acids of the large activation fragment, the B domain. The approximately 250-kDa FV isoform (FV-short), which can be fully activated by thrombin, is present in all A2440G carriers’ plasma (n = 16). FV-short inhibits coagulation through an indirect mechanism by forming a complex with tissue factor pathway inhibitor-α (TFPIα), resulting in an approximately 10-fold increase in plasma TFPIα, suggesting that the TFPIα:FV-short complexes are retained in circulation. The TFPIα:FV-short complexes efficiently inhibit thrombin generation of both intrinsic and extrinsic coagulation pathways.The east Texas bleeding disorder–associated F5A2440G leads to the formation of the TFPIα:FV-short complex, which inhibits activation and propagation of coagulation.
Source:
J Clin Invest (2013) 123(9), 3777–3787
Prevention
FV-short works indirectly to inhibit coagulation, and it associates with TFPIα in affected family members. Presumably the binding of TFPIα to FV-short in affected family members’ plasma results in its retention in circulation, thus causing the higher TFPIα plasma concentrations.
Diagnosis
Blood test in thrombin time, functional fibrinogen level, von Willebrand antigen and ristocetin cofactor, bleeding time, and platelet number and aggregation.
Treatment
Genes make proteins that do everything from giving cells shape and structure to helping carry out biological processes. To make the proteins, genes go through a process called alternative splicing that creates coded portions, called exons. The researchers discovered that a mutation in exon 13 of the coagulation FV gene caused a short form of the protein due to changes in the splicing of the exons. That FV-Short protein was unexpectedly found to form a complex in blood with tissue factor pathway inhibitor (TFPI), a protein that inhibits coagulation of the blood. An overabundance of the combined FV-Short/TFPI in the bloodstream keeps the blood from clotting in the affected family members. Other researchers have been looking at ways to inhibit TFPI, which could lead to a treatment for this family's clotting disorder.