Blanca Muñoz

Template bleeding time and PFA-100 have low sensitivity to screen patients with hereditary mucocutaneous hemorrhages: comparative study in 148 patients.

Summary.  Objectives and patients: We compared the template bleeding time (BT) and closure time (CT) in the PFA‐100® as screening tests in 148 consecutive patients with unequivocal mucocutaneous bleeding and positive family history. Exclusion criteria: drug intake, concomitant diseases including minor infections, low platelet count, diseases of secondary hemostasis.Results: Type 1 von Willebrand disease (VWD‐1) was diagnosed in 26 patients, primary platelet secretion defect (PSD) in 33, VWD‐1 + PSD in nine, whereas 80 patients did not comply with the criteria for known hemostatic disorders (UD, unknown diagnosis). BT and CT were prolonged in 35.8% and 29.7% of all the patients, respectively (P = 0.23). Sensitivity increased to 48% if an abnormality of BT and/or CT was considered. Same comparisons for BT and CT in each diagnostic category were, respectively: 42 vs. 61.5% in VWD‐1 (P = 0.18), 42 vs. 24% in platelet secretion defects (P = 0.11), 67 vs. 89% in VWD‐1 + PSD (P = 0.50), and 27.5 vs. 15% in UD (P = 0.06). Conclusion: Both tests were relatively insensitive and not significantly different in detecting incoming patients with mucocutaneous hemorrhages. In patients with VWD‐1, the PFA‐100® performed slightly better, whereas the opposite occurred in those patients with platelet secretion defects. In the UD group, both tests lost sensitivity, but the BT detected 1.8 times more patients than the PFA‐100®. Given the large proportion of undiagnosed bleeders and the overall low sensitivity of these tests, clinical decisions still rely on the medical history and etiological diagnosis of the bleeding disorder.

Endothelial cell markers in chronic uremia: relationship with hemostatic defects and severity of renal failure.

Plasma von Willebrand factor antigen, soluble thrombomodulin, and tissue factor were increased in 31 patients with severe chronic renal failure (creatinine clearance <20 ml/min) under conservative treatment, whereas plasminogen activator inhibitor antigen did not differ significantly from healthy controls. No correlation among plasma levels of these proteins was found. Three patterns of relationship between endothelial cell markers and hemostatic defects were identified: 1) Plasma thrombomodulin, a marker of endothelium damage, was found an independent predictor of bleeding time and platelet aggregation, and secretion defects, and was also related to the severity of renal failure; 2) von Willebrand factor antigen, an index of endothelial cell activation and secretion, was significantly correlated with intravascular markers of thrombin and plasmin generation and with platelet adenosine triphosphate content, but not with plasma creatinine levels; and 3) tissue factor and plasminogen activator inhibitor antigen levels were not statistically correlated with the diverse hemostatic defects. Activation of coagulation and fibrinolysis, secondary to endothelial cell activation, appearing early during the evolution of chronic renal failure, is pathogenically related to the platelet dysfunction, and probably to development of atherosclerosis and thrombotic events in this disease. The progression of chronic renal failure, through endothelial cell damage, would lead to aggravation of the platelet functional defect potentiating the hemorrhagic risk.

Thrombin Generation in Platelet-Poor Plasma Is Normal in Patients with Hereditary Mucocutaneous Haemorrhages

Mild hereditary bleeding disorders presenting with mucocutaneous haemorrhages are usually difficult to diagnose. We measured thrombin generation in platelet-poor plasma (TG-PPP) in 206 patients with a clinically unequivocal bleeding tendency: 45 with von Willebrand disease (vWD), 49 with platelet aggregation/secretion defects (PASD), 10 with a combination of both and 102 who did not fit the diagnostic criteria for any known haemostatic disorder. TG-PPP was not significantly different from controls in all patient groups, indicating that an abnormality in the plasmatic clotting system is unlikely to contribute to the bleeding in patients with type 1 vWD and PASD. In patients with undiagnosed mild hereditary bleeding disorders, there must be other mechanisms which explain the abnormal haemorrhagic tendency, most likely as yet unrecognized defects in platelet-vessel wall interaction. As a next step we plan to investigate thrombin generation in PRP.