Bleeding symptoms in persons with rare bleeding disorders and a heterozygous genotype: data from the RBiN study.

Background: Limited data exists on persons with rare bleeding disorders (RBDs) possessing a heterozygous genotype, as most studies focus on bi-allelic 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: Explore the incidence of bleeding symptoms and postoperative bleeding in persons with a heterozygous genotype.

Patients/methods: This cross-sectional sub-study 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 bi-allelic genotype. Clinical data and laboratory samples were collected during a single study visit along with questionnaires.

Results: Eighty-six persons with a heterozygous genotype and fifty-five with a bi-allelic 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 bi-allelic genotype (35%; 86/247, p=.926).

Conclusions: In our RBD population, 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.