Defining Severity for Rare Factor Deficiencies. Insights from the North American Rare Bleeding Disorder Registry(NARBDR).
Authors: Acharya Suchitra S , DiMichele Donna 
Published: April 2020

Abstract
Defining Severity for Rare Factor deficiencies: Insights from the North American Rare Bleeding Disorder Registry (NARBDR)
The NARBDR was published in 2004 compiling data from Hemophilia Treatment Centers across North America using a questionnaire format. The goals of this registry were to establish prevalence, bleeding phenotype, treatment strategies along with disease and treatment related complications of inherited deficiencies of factors(F) FII,VII,X, V, XIII, and fibrinogen disorders. Given the paucity of genotyping data (5.4%), these deficiencies were characterized as homo/heterozygous based on factor activity levels using a previously published hemostatic level cut –off of 0.2u/ml. However, a UK group has published disorder-specific cut off levels of &lt; 0.01–0.16u/ml, while an Italian group utilized a cut off of 0.1u/ml to define severe disease. Thus, it would seem that severity for rare factor deficiencies is not well defined and needs to be established. Defining severity would aid in predicting an individual’s bleeding phenotype for counseling and surgical prophylaxis as well as in future genotype-phenotype analysis. To this end, we re-analyzed our NARBDR data to ascertain the relative utility of two biochemical severity classifications for FII (n=16), VII (n=135), X(n=37) and V(n=35) deficiencies using hemostatic (HC) factor activity levels &lt;0.2u/ml; and the traditional classifications (TC)used for hemophilias ≤ 0.05u/ml) to predict the following clinical parameters of severity: age at first bleed, bleeding triggers (trauma vs spontaneous) and sites/types of bleeding. A p-value&lt;0.05 was considered statistically significant and was calculated using t-tests and ANOVA tests. There was only a weak correlation between age at first bleed and biochemical severity irrespective of classification (R2 = 0.355) for FII, V, X and no corrleation for FVII deficiencies. Table 1 summarizes the analyses. The HC correlated more significantly than TC with overall clinical bleeding severity (defined by non mucocutaneous (MC) hemorrhage) and trauma as a bleed trigger for FII and VII but not for FX. However, when mean life-time MC and musculoskeletal (MS) bleeds, most common bleeding sites, were specifically examined, significant correlation was observed using the TC but not the HC for FII, FVII and FX. For FV, both TC and HC were significantly informative in predicting mean life-time bleeds per patient. This analysis represents the initial attempt to correlate factor levels with parameters of clinical severity for the rare disorders. In this dataset, limited by low survey response rates (26%), incomplete responses to clinical phenotype questions, lack of data source verification, the hemostatic was overall more informative than the traditional severity classification for most of the clinical severity variables examined, however, traditional system tended to better characterize clinical severity based on musculoskeletal bleeding (F II, VII, X). However, differences were noted between the vitamin K and FV deficiencies. These results suggest that rare factor deficiencies may not be amenable to a single classification and underscores the need for establishing national and international prospective databases to further define disease severity.
Table 1
FII FVII FX FV TC&#x2028; HC TC&#x2028; HC TC&#x2028; HC TC&#x2028; HC NS-not statistically significant Clinical Severity &gt;5%&#x2028; 1–19%&#x2028; NS&#x2028; p&lt;0.0001 &gt;5%&#x2028; &gt;20%&#x2028; P&lt;0.0001&#x2028; p&lt;0.0001 NS&#x2028; NS NS&#x2028; NS Bleeding sites (MC vs MS) p=0.02&#x2028; NS P=0.02&#x2028; NS p=0.01&#x2028; NS p=0.003&#x2028; p=0.002 Triggers-traumatic bleeds NS&#x2028; p&lt;0.0001 NS&#x2028; p&lt;0.0001 NS&#x2028; NS NS&#x2028; NS