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Thromb Res. 2019 Aug 8;182:43-50. doi: 10.1016/j.thromres.2019.07.020. [Epub ahead of print]

Mathematical model of thrombin generation and bleeding phenotype in Amish carriers of Factor IX:C deficiency vs. controls.

Author information

1
Indiana Hemophilia and Thrombosis Center, Indianapolis, IN, United States of America. Electronic address: sgupta@ihtc.org.
2
University of Vermont, Colchester, VT, United States of America. Electronic address: mbravo@uvm.edu.
3
Indiana Hemophilia and Thrombosis Center, Indianapolis, IN, United States of America.
4
University of Vermont, Colchester, VT, United States of America. Electronic address: kbrummel@uvm.edu.
5
Division of Blood Disorders, National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, GA, United States of America. Electronic address: cmiller2@cdc.gov.

Abstract

INTRODUCTION:

Factor IX:C (FIX:C) levels vary in hemophilia B carriers even in pedigrees with a unifying genetic defect. Analyzing the balance between pro-and anticoagulants might increase our understanding of carriers' bleeding potential.

AIM:

In this research study, we evaluated bleeding scores (BS) and a novel mathematical model of thrombin generation (TG) in Amish FIX:C deficient carriers and controls.

METHODS:

Blood samples and BS were obtained from post-menarchal females, including 59 carriers and 57 controls from the same extended pedigree. Factors II, V, VII, VIII, IX, X, antithrombin, tissue factor pathway inhibitor and protein C were assayed to generate mathematical models of TG in response to 5pM tissue factor (TF) and for TF + thrombomodulin. BS was based on a modification of the MCMDM-1VWD scoring system.

RESULTS:

Carriers had a lower mean FIX:C (68% vs. 119%), von Willebrand factor antigen (108 vs.133) and Tissue activatable fibrinolysis inhibitor (103 vs. 111) compared to controls; both groups had a similar mean BS. Carriers demonstrated significantly lower TG parameters on both mathematical models compared to controls. Carriers with FIX:C ≤ 50% had lower TG curves than those >50% but similar BS.

CONCLUSION:

Thrombin generation showed significant differences between carriers and controls, between low (≤50%) and high (>50%) FIX:C carriers, and specifically in the TF + thrombomodulin model, between high FIX:C carriers and controls, although the BS were not different.

KEYWORDS:

Bleeding scores; Carriers; Hemophilia B; Mathematical model; Thrombin generation

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