Dysregulated coagulation associated with hypofibrinogenaemia and plasma hypercoagulability: Implications for identifying coagulopathic mechanisms in humans

Rita Marchi; Bethany L. Walton; Colleen S. McGary; Feng-Chang Lin; Alice D. Ma; Rafal Pawlinski; Nigel Mackman; Robert A. Campbell; Jorge Di Paola; Alisa S. Wolberg

doi:10.1160/TH12-05-0355

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2012; 108(03): 516-526
DOI: 10.1160/TH12-05-0355

Blood Coagulation, Fibrinolysis and Cellular Haemostasis

Schattauer GmbH

Dysregulated coagulation associated with hypofibrinogenaemia and plasma hypercoagulability: Implications for identifying coagulopathic mechanisms in humans

Authors

Rita Marchi

¹Laboratorio Biologia del Desarrollo de la Hemostasia, Instituto Venezolano de Investigaciones Cientificas (IVIC), Caracas, Venezuela

²Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
Bethany L. Walton

²Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
Colleen S. McGary

²Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
Feng-Chang Lin

³Department of Biostatistics and North Carolina Translational and Clinical Sciences Institute, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
Alice D. Ma

⁴Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
Rafal Pawlinski

⁴Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
Nigel Mackman

⁴Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
Robert A. Campbell

⁵Program in Molecular Medicine, University of Utah, Salt Lake City, Utah, USA
Jorge Di Paola

⁶Department of Pediatrics and Human Medical Genetics and Genomics Program, University of Colorado, Denver, Colorado, USA
Alisa S. Wolberg

²Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA

Abstract

Summary

Identifying coagulation abnormalities in patients with combined bleeding and thrombosis history is clinically challenging. Our goal was to probe the complexity of dysregulated coagulation in humans by characterizing pathophysiologic mechanisms in a patient with both bleeding and thrombosis. The patient is a 56-year-old female with a history of haematomas, poor wound healing, and thrombosis (retinal artery occlusion and transient cerebral ischaemia). She had a normal activated partial thromboplastin time, prolonged thrombin and reptilase times, and decreased functional and antigenic fibrinogen levels, and was initially diagnosed with hypodysfibrinogenaemia. This diagnosis was supported by DNA analysis revealing a novel FGB mutation (c.656A>G) predicting a Q189R mutation in the mature chain that was present in the heterozygote state. However, turbidity analysis showed that purified fibrinogen polymerisation 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. Interestingly, plasma thrombin generation testing revealed the patient’s thrombin generation was higher than normal and could be attributed to elevated levels of factor VIII (FVIII, 163–225%). Accordingly, in an arterial injury model, hypofibrinogenaemic mice (Fgn^+/−) infused with factor VIII demonstrated significantly shorter vessel occlusion times than saline-infused Fgn^+/− mice. Together, these data associate the complex bleeding and thrombotic presentation with combined hypofibrinogenaemia plus plasma hypercoagulability. These findings suggest previous cases in which fibrinogen abnormalities have been associated with thrombosis may also be complicated by co-existing plasma hypercoagulability and illustrate the importance of “global” coagulation testing in patients with compound presentations.

Keywords

Thrombin generation - factor VIII - hypofibrinogenaemia - thrombosis - bleeding

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Referenzen

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