title: Abnormal plasma clot structure and stability distinguish bleeding risk in patients with severe factor XI deficiency.
abstract: BACKGROUND
  Factor XI (FXI) deficiency is a rare autosomal recessive disorder. Many patients with even very low FXI levels (< 20 IU dL(-1) ) are asymptomatic or exhibit only mild bleeding, whereas others experience severe bleeding, usually following trauma. Neither FXI antigen nor activity predicts the risk of bleeding in FXI-deficient patients.
  
  
  OBJECTIVE
  (i) Characterize the formation, structure and stability of plasma clots from patients with severe FXI deficiency and (ii) determine whether these assays can distinguish asymptomatic patients ('non-bleeders') from those with a history of bleeding ('bleeders').
  
  
  METHODS
  Platelet-poor plasmas were prepared from 16 severe FXI-deficient patients who were divided into bleeders or non-bleeders, based on bleeding associated with at least two tooth extractions without prophylaxis. Clot formation was triggered by recalcification and addition of tissue factor and phospholipids in the absence or presence of tissue plasminogen activator and/or thrombomodulin. Clot formation and fibrinolysis were measured by turbidity and fibrin network structure by laser scanning confocal microscopy.
  
  
  RESULTS
  Non-bleeders and bleeders had similarly low FXI levels, normal prothrombin times, normal levels of fibrinogen, factor VIII, von Willebrand factor and factor XIII, and normal platelet number and function. Compared with non-bleeders, bleeders exhibited lower fibrin network density and lower clot stability in the presence of tissue plasminogen activator. In the presence of thrombomodulin, seven of eight bleeders failed to form a clot, whereas only three of eight non-bleeders did not clot.
  
  
  CONCLUSIONS
  Plasma clot structure and stability assays distinguished non-bleeders from bleeders. These assays may reveal hemostatic mechanisms in FXI-deficient patients and have clinical utility for assessing the risk of bleeding.
authors.affiliation: Thrombosis and Hemostasis Unit, Amalia Biron Research Institute of Thrombosis and Hemostasis, Sheba Medical Center, Tel Hashomer and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: M
authors.initials: M
authors.lastname: Zucker
authors.forename: U
authors.initials: U
authors.lastname: Seligsohn
authors.forename: O
authors.initials: O
authors.lastname: Salomon
authors.forename: A S
authors.initials: AS
authors.lastname: Wolberg
mesh_terms: D000328:Adult; D000368:Aged; D001777:Blood Coagulation; D015331:Cohort Studies; D005172:Factor XI / Q000378:metabolism; D005173:Factor XI Deficiency / Q000097:blood / Q000175:diagnosis*; D005176:Factor XIII / Q000378:metabolism; D005260:Female; D005342:Fibrinolysis; D006470:Hemorrhage / Q000175:diagnosis*; D006801:Humans; D008297:Male; D018613:Microscopy, Confocal; D008875:Middle Aged; D010743:Phospholipids / Q000737:chemistry; D010949:Plasma / Q000378:metabolism; D012307:Risk Factors; D013917:Thrombin / Q000737:chemistry; D014841:von Willebrand Factor / Q000378:metabolism
chemical_list: D010743:Phospholipids; D014841:von Willebrand Factor; D005172:Factor XI; D005176:Factor XIII; D013917:Thrombin
keywords: bleeding; factor XI; factor XI deficiency; fibrin clot lysis time; plasma clot lysis time