Long-term Safety Outcomes of Prekallikrein Deficiency: A Systematic Literature Review

RATIONALE: Hereditary prekallikrein (Fletcher Factor) deficiency is a rare, usually asymptomatic, disorder identified clinically by a prolonged activated partial thromboplastin time (aPTT). Due to the rarity of the condition, any associations between prekallikrein and comorbidities have been difficult to confirm. As medications that target plasma kallikrein are in development for treatment of hereditary angioedema; this systematic literature review (SLR) was conducted to compile and assess reported comorbidities in patients with hereditary prekallikrein deficiency.

METHODS: An SLR using Embase, MEDLINE, Cochrane and PubMed databases identified publications reporting data from patients with confirmed hereditary prekallikrein deficiency (defined as <10% of normal and/or shortening of aPTT on increased incubation time). Data reporting cardiovascular, bleeding and autoimmune-related diseases were extracted from included publications.

RESULTS: Of 1966 publications screened, 77 reported potential prekallikrein deficiency cases. Of these, 45 publications (representing 53 patients with prekallikrein deficiency) met inclusion criteria for hereditary prekallikrein deficiency and were assessed. The health status of 3 patients (5.7%) was not reported, 25 patients (47.1%) were asymptomatic, 18 patients (34.0%) had cardiovascular comorbidities, mainly hypertension (8 patients [15.1%]) and cerebrovascular ischemia/stroke (5 patients [9.4%]). Bleeding episodes were reported for 4 patients (7.5%). Autoimmune-related diseases were reported for 3 patients; 2 (3.8%) had Grave’s disease and 1 (1.9%) had systemic lupus erythematosus.

CONCLUSIONS: This review identified patients with hereditary prekallikrein deficiency reporting a spectrum of health outcomes from asymptomatic to reports of cardiovascular, bleeding and autoimmune comorbidities. No associations between prekallikrein deficiency and comorbidities frequently found in the general population could be determined from this review.