Abstract 416: Dysregulated Coagulation from Coexisting Hypofibrinogenemia and Elevated Factor VIII

Abstract

Introduction and Objective— Although abnormal clotting factors are typically identified and examined in isolation, dysregulated coagulation can result from multiple independent, co-existing abnormalities. Herein, we probed the complexity of dysregulated coagulation in humans by characterizing pathophysiologic mechanisms in a patient with both bleeding and thrombosis. Methods and Results— A patient with a normal activated partial thromboplastin time (29.6 sec), prolonged thrombin and reptilase times (22.6 and 21.3 sec, respectively), and decreased functional and antigenic fibrinogen levels (162 and 148 mg/dL, respectively) was initially diagnosed with hypodysfibrinogenemia. This diagnosis was supported by DNA analysis revealing a previously unreported FGB mutation (c.656A>G) predicting a novel Q189R mutation in the mature ββ chain that was present in the heterozygote state. Interestingly, however, turbidity analysis showed purified fibrinogen polymerization and degradation were indistinguishable from normal, and Bβ chain subpopulations appeared normal by two-dimensional difference in-gel electrophoresis, indicating the mutated chain was not secreted. Of note, the patient’s peak plasma thrombin generation was significantly higher than normal (267±20 versus 183±16 nM, respectively, p<0.05), attributable to an elevated level of factor VIII (163-225%). Spiking normal plasma with factor VIII to 225% (final) produced a thrombin generation peak that was indistinguishable from the patient. In a carotid artery injury model, hypofibrinogenemic mice (Fgn+/-) infused with factor VIII demonstrated significantly shorter vessel occlusion times than saline-infused Fgn+/- mice (11.8±5.8 versus 20.9±14.7 minutes, respectively, p<0.05). Conclusions— These data associate the patient’s complex bleeding and thrombotic presentations with co-existing hypofibrinogenemia plus elevated FVIII, and indicate hypofibrinogenemia does not mitigate the prothrombotic effects of plasma hypercoagulability. Together, these findings illustrate the challenges of diagnosing complex coagulopathies and underscore the importance of global coagulation testing in patients with compound presentations.