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Poster Abstract PresentationsSession Title: Poster Session III

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

Rita Marchi, Bethany L Walton, Colleen S McGary, Feng-Chang Lin, Alice D Ma, Rafal Pawlinski, Nigel Mackman, Robert A Campbell, Jorge DiPaola, Alisa S Wolberg
Arteriosclerosis, Thrombosis, and Vascular Biology. 2012;32:A416
Rita Marchi
Instituto Venezolano de Investigaciones Cientificas, Caracas, Venezuela, Bolivarian Republic of
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Bethany L Walton
Univ of North Carolina at Chapel Hill, Chapel Hill, NC
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Colleen S McGary
Univ of North Carolina at Chapel Hill, Chapel Hill, NC
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Feng-Chang Lin
Univ of North Carolina at Chapel Hill, Chapel Hill, NC
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Alice D Ma
Univ of North Carolina at Chapel Hill, Chapel Hill, NC
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Rafal Pawlinski
Univ of North Carolina at Chapel Hill, Chapel Hill, NC
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Nigel Mackman
Univ of North Carolina at Chapel Hill, Chapel Hill, NC
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Robert A Campbell
Univ of Utah, Salt Lake City, UT
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Jorge DiPaola
Univ of Colorado, Denver, CO
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Alisa S Wolberg
Univ of North Carolina at Chapel Hill, Chapel Hill, NC
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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.

  • fibrinogen
  • thrombosis
  • mouse
  • © 2012 by American Heart Association, Inc.
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    Abstract 416: Dysregulated Coagulation from Coexisting Hypofibrinogenemia and Elevated Factor VIII
    Rita Marchi, Bethany L Walton, Colleen S McGary, Feng-Chang Lin, Alice D Ma, Rafal Pawlinski, Nigel Mackman, Robert A Campbell, Jorge DiPaola and Alisa S Wolberg
    Arteriosclerosis, Thrombosis, and Vascular Biology. 2012;32:A416, originally published October 20, 2015

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    Abstract 416: Dysregulated Coagulation from Coexisting Hypofibrinogenemia and Elevated Factor VIII
    Rita Marchi, Bethany L Walton, Colleen S McGary, Feng-Chang Lin, Alice D Ma, Rafal Pawlinski, Nigel Mackman, Robert A Campbell, Jorge DiPaola and Alisa S Wolberg
    Arteriosclerosis, Thrombosis, and Vascular Biology. 2012;32:A416, originally published October 20, 2015
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