Bleeding symptoms in persons with rare bleeding disorders and a heterozygous genotype: data from the Rare Bleeding Disorders in the Netherlands study

Background: Limited data exist on persons with rare bleeding disorders possessing a heterozygous genotype, as most studies focus on biallelic genotypes and more severe coagulation factor deficiencies. A growing body of evidence suggests that persons with a heterozygous genotype experience clinically relevant bleeding symptoms. 

Objectives: This study aimed to explore the incidence of bleeding symptoms and postoperative bleeding in persons with a heterozygous genotype. 

Methods: This cross-sectional substudy of the Rare Bleeding Disorders in the Netherlands study (2017-2019) included persons with rare coagulation factor deficiencies and disorders of fibrinolysis with a heterozygous or biallelic genotype. Clinical data and laboratory samples were collected during a single study visit along with questionnaires. 

Results: In total, 86 persons with a heterozygous genotype and 55 with a biallelic genotype were included. Median factor activity levels in persons with a heterozygous genotype approached 50% with considerable heterogeneity (range, 11%-93%). In 75%, persons with a heterozygous genotype reported bleeding severity of grade II or III. Female-specific bleeding was common. In total, 425 surgical procedures were performed. Persons with a heterozygous genotype were less likely to receive periprocedural treatment, and omission of periprocedural treatment was associated with postoperative bleeding in procedures with intermediate-high bleeding risk. Postoperative bleeding was comparable for persons with a heterozygous genotype (35%; 59/171) and a biallelic genotype (35%; 86/247; P = .926). 

Conclusion: In our population with rare bleeding disorders, the majority of persons possessing a heterozygous genotype exhibited spontaneous bleeding symptoms. Especially in intermediate-high risk procedures, a proactive approach to periprocedural hemostatic treatment in persons with a heterozygous genotype seems beneficial.