Use of Global Assays to Predict Bleeding Severity In Congenital Factor VII Deficiency.
Authors: Greene Lindsey A. , Goldenberg Neil A. , Bombardier Chris , Acharya Suchitra S. , Grunzke Mindy L. , Santiago-Borroro Pedro J. , Cambara Alejandro , DiMichele Donna M. 
Published: October 2019

Abstract
Abstract 3668

Background:
Congenital FVII deficiency, the most common of the autosomal recessive rare coagulation disorders (RCDs), is characterized by genotypic variability as well as phenotypic heterogeneity ranging from absent to severe hemorrhage, and rarely thrombosis. Prothrombin time (PT) and FVII activity assays do not reliably predict bleeding phenotype. Global assays of coagulation and fibrinolysis may better characterize overall hemostatic balance and could aid in the assessment of hemorrhagic and thrombotic risk in RCDs.

Objective:
We sought to investigate whether a global assay might better predict bleeding phenotype in FVII deficiency.

Methods:
Four North American centers enrolled 24 known FVII deficient subjects (21 heterozygotes (FVII:C 20–60 U/dl) and 3 homozygotes/compound heterozygotes (FVII:C < .01U/dL)) at asymptomatic baseline in a collaborative cross-sectional study. Venipuncture was performed for determination of baseline factor VII activity (FVII:C) and prothrombin time (PT) in plasma. The Clot Formation and Lysis (CloFAL) global assay and the Simultaneous Thrombin and Plasmin generation (STP) assay were performed centrally at the University of Colorado by previously described methods (Goldenberg et. al, Haemophilia 2008 and Grunzke et al., J Thromb Haemost 2009 (abstract)). Bleeding history data were obtained retrospectively and locally using a standardized case report form, in order to assign each subject a bleeding score (0-3.2) as previously described by Mariani et al. (Thromb Haemost, 2005), but slightly modified as follows: 0 (asymptomatic); 1 (mild): 1–2 symptoms excluding hemarthrosis, CNS and GI bleeding; 2 (moderate): >/=3 symptoms excluding hemarthrosis, CNS or GI bleeding; 3 (severe): hemarthrosis, CNS or GI bleeding. Within each score, decimals indicated the # of symptoms.

Results:
Median values (ranges) for age, FVII:C, and bleeding score were as follows: age, 12 years (3-36 years); FVII:C, 39 U/dL (<1- 60 U/dL); bleeding score: 1.1 (0-3.2). FVII:C varied indirectly with PT (r= -0.76, P<0.001) and time to maximal amplitude in the CloFAL assay (r= -0.51, P=0.01), and directly with CloFAL coagulation index (r= 0.47, P=0.03). FVII:C was also negatively correlated with maximal velocity (Vmax) of plasmin generation (r= -0.67, P<0.001). Bleeding manifestations were severe (bleeding score >/= 3) in all three homozygotes/compound heterozygotes; moderate in 1/21 heterozygotes; mild in 13/21; and absent in the remaining 7 heterozygotes. Among heterozygotes, while there was no significant correlation between bleeding score and FVII:C or PT, there was a significant negative correlation with CloFAL area under the curve (AUC); i.e., as bleeding score increased, AUC decreased. CloFAL AUC explained 19% of variability in bleeding score among heterozygotes (P=0.047). Considering all subjects, CloFAL AUC was significantly higher among those without, versus with, a prior history of bleeding (P=0.046) (Table 1). CloFAL AUC also demonstrated a significant negative correlation with bleeding score (P=0.02) (Table 2). STP values did not correlate with history of bleed or bleeding score.

Conclusion:
These findings indicate that the CloFAL assay is unique in explaining considerable phenotypic variability in congenital FVII deficiency. Larger prospective studies are warranted to evaluate the capacity of the CloFAL assay to predict bleeding severity in this disease and guide prophylactic replacement therapy during episodes of hemostatic stress.

Disclosures:
Grunzke: NHF/Baxter Clinical Fellowship Award 2008–2010: Research Funding.