Diagnostic Assessment of Patients with Inherited Mucocutaneous Hemorrhages (IMCH): Opening a Pandora Box?.

Diagnosis of patients with IMCH is plagued with difficulties: 1. Type 1 VWD (VWD-1) and platelet function disorders (PFD), the best characterized disorders of primary hemostasis, present inherent diagnostic difficulties. 2. Bleeding may be present in healthy individuals and may be absent in patients with diagnosed diseases. 3. An unknown proportion of bleeders do not have an identifiable haemostatic disorder. We studied prospectively 280 consecutive patients (age = 14.5±9.5, range 4–48 years) with family bleeding history who had a high probability of being pathological bleeders, based on an objective bleeding score. Only one physician interviewed the patients and the non-bleeder matched controls, (n=299, age 12.2±6.5, range 4–44 years). Exclusion criteria: age <4 and >50 years; platelet count <100.000/μL; other concurrent diseases, drug intake and C-reactive protein >1mg/dL. VWD was diagnosed when at least two tests (VWF:Ag, VWF:RCo, VWF:CB) had values <percentil 2.5 of the controls, without considering ABO type. PFD were diagnosed by PRP aggregation and ¹⁴C-5-HT secretion using pre-established criteria and reference values obtained in the 299 controls. Only 66 (23.6%) of the patients had prolonged bleeding time (BT). Frequency of diseases: 38 (13.6%) patients had VWD-1; 1 (0.35%) had type 2A VWD; 52 (18.6%) had PFD; 8 (2.9%) had concomitant VWD-1 + PFD; 7 patients (2.5%) had mild coagulation factor deficiencies (CFD, 4 with ↓FVIII:C; 2 with ↓ FIX:C; 1 with ↓ FXI:C); and 3 (1.1%) had concomitant VWD-1 + CFD; 171 bleeders (61.1%) had an unknown disorder (UD); in this UD group, 29 (17%) patients had prolonged BT, but all the other hemostatic tests were within the normal range. No distinctive bleeding pattern/severity was found among the above diagnostic categories. One patient with type 2B VWD was excluded because of thrombocytopenia and no patients with type 2N VWD were found. Patients with PFD had a secretion defect, but only 2 of them had typical storage pool disease (↓platelet 5-HT and ADP and ↓ADP/ATP ratio). No phenotypic patterns of Glanzmann or Bernard-Soulier diseases, arachidonate metabolism, or of absent ADP, collagen and TxA2 receptors were observed among the patients with PFD. Interestingly, the 170 patients with UD and the controls had almost the same mean values and distribution of VWF and platelet function variables; so we expect that very few patients with UD would qualify as VWD or PFD in repeated studies. Conclusions: 1. Prevalence of platelet secretion defects is higher than that of type 1 VWD-1 in our population. 2. Types 2 and 3 VWD, as well as paradigmatic platelet disorders (i.e., Glanzmann′s thrombasthenia, Bernard Soulier syndrome) were not detected in this study; they are of very low frequency and they are likely diagnosed at earlier age. 3. Bleeding time lacks sensitivity as a global test of primary haemostasis defects and should be omitted as a diagnostic tool. 4. After a first complete lab workup, 60% of the population with IMCH remains undiagnosed. The overwhelming majority of patients with UD probably constitute a heterogeneous group, independent of VWD or PFD, with a bleeding pattern similar to that of other disorders of primary hemostasis. Hypothetically, structural vascular defects or substances derived from the vascular wall which interfere with the normal platelet-vessel wall interaction could be involved in the pathogenesis of the hemorrhages.