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Long-term safety outcomes of prekallikrein (Fletcher factor) deficiency: A systematic literature review of case reports

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Hereditary prekallikrein (Fletcher factor) deficiency is a rare condition characterized by a prolonged activated partial thromboplastin time. Inhibitors of plasma kallikrein have recently been approved for prophylaxis of hereditary angioedema and are under investigation for use in other indications.


We attempted to conservatively assess the impact of long-term inhibition of this pathway by reviewing reported comorbidities in patients with hereditary prekallikrein deficiency.


We searched several medical literature databases for publications that reported data from patients with hereditary prekallikrein deficiency (<10% of normal and/or shortening of activated partial thromboplastin time on increased incubation time). Data reporting of cardiovascular, bleeding, and autoimmune-related diseases were extracted.


Of 1966 publications screened, 45 publications (which represented 53 patients with prekallikrein deficiency) were included. Among 53 identified patients with prekallikrein deficiency, 25 were explicitly defined as asymptomatic, with no comorbidities mentioned in another three cases. Another 16 of the 53 patients were described as having undergone surgery or dental extractions with no complications. Cardiovascular comorbidities were reported in 19 patients, mainly hypertension (9 patients) and cerebrovascular ischemia or stroke (5 patients). Excessive bleeding episodes after surgery were reported in four patients. Autoimmune-related diseases were reported for three patients (two with Graves disease and one with systemic lupus erythematosus).


This review identified patients with hereditary prekallikrein deficiency who reported a spectrum of health outcomes from asymptomatic to infrequent reports of cardiovascular, bleeding, and autoimmune comorbidities. The majority of the reports did not indicate any association between prekallikrein deficiency and comorbidities; however, additional observation is required to confirm the long-term safety of plasma kallikrein inhibition.

Keywords: C1 esterase inhibitor; Fletcher factor deficiency; Prekallikrein deficiency; activated partial thromboplastin time; autoimmune diseases; cardiovascular diseases; contact system; hereditary angioedema; plasma kallikrein; systematic literature review

Document Type: Research Article

Affiliations: 1: From the Department of Medicine, Padua Medical School, Padua, Italy 2: Excel Medical Affairs, Envision Pharma Group, London, United Kingdom 3: Rare Disease Drug Discovery Unit, Shire, a Takeda company, Lexington, Massachusetts, and 4: Global Clinical Development, Shire (A Takeda company), and 5: Department of Internal Medicine, University of Cincinnati School of Medicine, Cincinnati, Ohio

Publication date: January 1, 2020

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