The occurrence of thrombotic events in patients with congenital bleeding conditions has received considerable attention in recent years. The same is true for asymptomatic defects of factors of the contact phase of blood coagulation, mainly FXII. Anecdotal reports on thrombosis in patients with prekallikrein deficiency have occasionally been reported. These involved both arterial and venous thrombosis. The purpose of the present article is to analyze the stories and the clinical pictures of all 75 cases of prekallikrein deficiency published so far. Among these patients were 9 with thrombosis, 6 arterial (myocardial infarction and ischemic stroke) and 3 venous (deep vein thrombosis with or without pulmonary embolism). In 6 cases acquired thrombosis risk factors were present; in 2 cases no associated risk factors were present and in 1 case no information was supplied in this regard. One patient who presented both a stroke and a pulmonary embolism had a fatal outcome. The article clearly indicates that prekallikrein deficiency does not protect from thrombosis in spite of the severe in vitro coagulation defect.

Girolami A, Ruzzon E, Fabris F, Varvarikis C, Sartori R, Girolami B: Myocardial infarction and other arterial occlusions in hemophilia A patients. A cardiological evaluation of all 42 cases reported in the literature. Acta Haematol 2006;116:120–125.
Girolami A, Randi ML, Ruzzon E, Zanon E, Girolami B: Myocardial infarction, other arterial thrombosis and invasive coronary procedures, in hemaophilia B: a critical evaluation of reported cases. J Thromb Thrombolysis 2005;20:43–46.
Goodnough LT, Saito H, Ratnoff OD: Thrombosis or myocardial infarction in congenital clotting factor abnormalities and chronic thrombocytopenias: a report of 21 patients and a review of 50 previously reported cases. Medicine (Baltimore) 1983;62:248–255.
Girolami A, Scandellari R, Zanon E, Sartori R, Girolami B: Non-catheter associated venous thrombosis in hemophilia A and B. A critical review of all reported cases. J Thromb Thrombolysis 2006;21:279–284.
Girolami A, Tezza F, Scapin M, Vettore S, Casonato A: Arterial and venous thrombosis in patients with von Willebrand’s disease: a critical review of the literature. J Thromb Thrombolysis 2006;21:175–178.
Girolami A, Ruzzon E, Tezza F, Scandellari R, Vettore S, Girolami B: Arterial and venous thrombosis in rare congenital bleeding disorders: a critical review. Haemophilia 2006;12:345–351.
Ratnoff OD, Busse RJ, Sheon RP: The demise of John Hageman. N Engl J Med 1968;279:760–761.
Zeerleder S, Schloesser M, Redondo M, Wuillemin WA, Engel W, Furlan M, Lämmle B: Reevaluation of the incidence of thromboembolic complications in congenital factor XII deficiency – a study on 73 subjects from 14 Swiss families. Thromb Haemost 1999;82:1240–1246.
Girolami A, Morello M, Girolami B, Lombardi AM, Bertolo C: Myocardial infarction and arterial thrombosis in severe (homozygous) FXII deficiency: no apparent causative relation. Clin Appl Thromb Hemost 2005;11:49–53.
Acar K, Yağci M, Sucak GT, Haznedar R: Isolated prolonged activated partial thromboplastin time in an asymptomatic patient: Fletcher factor deficiency. Thromb Res 2006;118:765–766.
Asmis LM, Sulzer I, Furlan M, Lämmle B: Prekallikrein deficiency: the characteristic normalization of the severely prolonged aPTT following increased preincubation time is due to autoactivation of factor XII. Thromb Res 2002;105:463–470.
Aznar JA, España F, Aznar J, Tascon A, Jimenez C. Fletcher factor deficiency: report of a new family. Scand J Haematol 1978;21:94–98.
Bouma BN, Kerbiriou DM, Baker J, Griffin JH: Characterization of a variant prekallikrein, prekallikrein Long Beach, from a family with mixed cross-reacting material-positive and cross-reacting material-negative prekallikrein deficiency. J Clin Invest 1986;78:170–176.
Castaman G, Ruggeri M, Rodeghiero F: A new Italian family with severe prekallikrein deficiency. Desmopressin-induced fibrinolysis and coagulation changes in homozygous and heterozygous members. Ric Clin Lab 1990;20:239–244.
Colla G, Carrea M, Sbaffi A. Fletcher factor deficiency (report of a new case). Ric Clin Lab 1983;13:443–448.
Currimbhoy Z, Vinciguerra V, Palakavongs P, Kuslansky P, Degnan TJ. Fletcher factor deficiency and myocardial infarction. Am J Clin Pathol 1976;65:970–974.
DeLa Cadena RA: Fletcher factor deficiency in a 9-year-old girl: mechanisms of the contact pathway of blood coagulation. Am J Hematol 1995;48:273–277.
De Stefano V, Leone G, Teofili L, De Marinis L, Micalizzi P, Fiumara C, Bizzi B: Association of Graves’ disease and prekallikrein congenital deficiency in a patient belonging to the first CRM+ prekallikrein-deficient Italian family. Thromb Res 1990;60:397–404.
Dietzel H, Lutze G, Kätzel R, Liebscher K: Präkallikrein-(Fletcher-Faktor-)Defekt als Ursache einer präoperativen APTT-Verlängerung. Med Klin (Munich) 2003;98:587–590.
Entes K, LaDuca FM, Tourbaf KD. Fletcher factor deficiency, source of variations of the activated partial thromboplastin time test. Am J Clin Pathol 1981;75:626–628.
Ferrières J, Cambou JP, Ruidavets JB, Pous J: Trends in acute myocardial infarction prognosis and treatment in southwestern France between 1985 and 1990 (the MONICA Project-Toulouse). Am J Cardiol 1995;75:1202–1205.
François D, Trigui N, Leterreux G, Flaujac C, Horellou MH, Mazaux L, Vignon D, Conard J, de Mazancourt P: Severe prekallikrein deficiencies due to homozygous C529Y mutations. Blood Coagul Fibrinolysis 2007;18:283–286.
Girolami A, Marun S, Vettore S, Scaliter G, Molina A, Scarparo P, Tabares A, Lombardi AM: A large family from Argentina with Prekallikrein deficiency due to a compound heterozygosis (T insertion in intron 7 and Asp558Glu in exon 15): Prekallikrein Cordoba. Am J Hematol DOI: 10.1002/ajh21654.
Harris MG, Exner T, Rickard KA, Kronenberg H: Multiple cerebral thrombosis in Fletcher factor (prekallikrein) deficiency: a case report. Am J Hematol 1985;19:387–393.
Hathaway WE, Belhasen LP, Hathaway HS: Evidence for a new plasma thromboplastin factor. I. Case report, coagulation studies and physicochemical properties. Blood 1965;26:521–532.
Hathaway WE, Wuepper KD, Weston WL, Humbert JR, Rivers RP, Genton E, August CS, Montgomery RR, Mass MF: Clinical and physiologic studies of two siblings with prekallikrein (Fletcher factor) deficiency. Am J Med 1976;60:654–664.
Hattersley PG, Hayse D: Fletcher factor deficiency: a report of three unrelated cases. Br J Haematol 1970;18:411–416.
Hess DC, Krauss JS, Rardin D: Stroke in a young adult with Fletcher trait. South Med J 1991;84:507–508.
Isobe J: Prekallikrein deficiency (Fletcher trait) (in Japanese). Ryoikibetsu Shokogun Shirizu 1998;21:468–470.
Joggi J, Stalder M, Knecht H, Hauert J, Bachmann F: Déficience en prékallicréine: à propos de 2 cas. Schweiz Med Wochenschr 1990;120:1942–1944.
Jones DW, Russell G, Allford SL, Burdon K, Hawkins GA, Bowden DW, Minaee S, Mumford AD: Severe prekallikrein deficiency associated with homozygosity for an Arg94Stop nonsense mutation. Br J Haematol 2004;127:220–223.
Katsuda I, Maruyama F, Ezaki K, Sawamura T, Ichihara Y: A new type of plasma prekallikrein deficiency associated with homozygosity for Gly104Arg and Asn124Ser in apple domain 2 of the heavy-chain region. Eur J Haematol 2007;79:59–68.
Kolodie L, Poirot P, Foret C: Un cas de déficit en facteur Fletcher. Nouv Rev Fr 1980;22:89–90.
Kyrle PA, Niessner H, Deutsch E, Lechner K, Korninger C, Mannhalter C: CRM+ severe Fletcher factor deficiency associated with Graves’ disease. Haemostasis 1984;14:302–306.
Lombardi AM, Sartori MT, Cabrio L, Fadin M, Zanon E, Girolami A: Severe prekallikrein (Fletcher factor) deficiency due to a compound heterozygosis (383Trp stop codon and Cys529Tyr). Thromb Haemost 2003;90:1040–1045.
Nagaya S, Morishita E, Takami A, Maruyama K, Sekiya A, Asakura H, Nakao S, Ohtake S: An elderly case of congenital prekallikrein deficiency. Nippon Ronen Igakkai Zasshi 2009;46:348–351.
Odumosu MC, Yoong WC, Fakokunde AF: Fletcher factor deficiency in a woman requiring emergency caesarean section. J Obstet Gynaecol 2009;29:442.
Oram MP, Mumford AD, Morse C, Underwood S: Management of anticoagulation for coronary artery bypass surgery in a patient with severe prekallikrein deficiency. J Cardiothorac Vasc Anesth 2006;20:580–582.
Pasricha SK, Weiss H, Chen A: Spinal anesthesia in a patient with prekallikrein deficiency. Anesth Analg 1996;83:1325–1326.
Poon MC, Moore MR, Castleberry RP, Lurie A, Huang ST, Lehmeyer J: Severe Fletcher factor (plasma prekallikrein) deficiency with partial deficiency of Hageman factor (factor XII): report of a case with observation on in vivo and in vitro leukocyte chemotaxis. Am J Hematol 1982;12:261–270.
Raffoux C, Alexandre P, Perrier P, Briquel ME, Streiff F: HLA typing in a new family with Fletcher factor deficiency. Hum Genet 1982;60:71–73.
Saade M: Fletcher factor deficiency with mildly prolonged activated PTT. South Med J 1980;73:958.
Saito H, Goodnough LT, Soria J, Soria C, Aznar J, España F: Heterogeneity of human prekallikrein deficiency (Fletcher trait): evidence that five of 18 cases are positive for cross-reacting material. N Engl J Med 1981;305:910–914.
Shigekiyo T, Fujino O, Kanagawa Y, Matsumoto T: Prekallikrein (PK) Tokushima: PK deficiency caused by a Gly401→Glu mutation. J Thromb Haemost 2003;1:1314–1316.
Sollo DG, Saleem A: Prekallikrein (Fletcher factor) deficiency. Ann Clin Lab Sci 1985;15:279–285.
Waddell CC, Brown JA, Udden MM: Plasma prekallikrein (Fletcher factor) deficiency in a patient with chronic lymphocytic leukemia. South Med J 1980;73:1653–1655.
Wuillemin WA, Furlan M, von Felten A, Lämmle B: Functional characterization of a variant prekallikrein (PK Zurich). Thromb Haemost 1993;70:427–432.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.