Diagnostic challenges of inherited mild bleeding disorders: a bait for poorly explored clinical and basic research

Abstract

Summary The best‐known inherited mild bleeding disorders (MBDs), i.e. type 1 von Willebrand disease (VWD), platelet function disorders (PFDs), and mild to moderate clotting factor deficiencies, are characterized clinically by mucocutaneous bleeding, and, although they are highly prevalent, still pose difficult diagnostic problems. These include establishing the pathological nature of bleeding, and the uncertainties surrounding the clinical relevance of laboratory results. Furthermore, the high frequency of bleeding symptoms in the normal population and the subjective appraisal of symptoms by patients or parents makes elucidating the pathological nature of bleeding difficult. Standardized bleeding assessment tools and semiquantitative bleeding scores (BSs) help to discriminate normal from abnormal bleeding. However, as most MBDs have similar bleeding patterns, for example, bleeding sites, frequency, and severity, BSs are of little help for diagnosing specific diseases. Global tests of primary hemostasis (bleeding time; PFA‐100/200) lack sensitivity and, like BSs, are not disease‐specific. Problems with the diagnosis of type 1 VWD and PFD include assay standardization, uncertain definition of von Willebrand factor cut‐off levels, and the lack of universal diagnostic criteria for PFD. Regarding clotting factor deficiencies, the bleeding thresholds of some coagulation factors, such as factor VII and FXI, are highly variable, and may lead to misinterpretation of the clinical relevance of mild to moderate deficiencies. Remarkably, a large proportion of MBDs remain undiagnosed even after comprehensive and repeated laboratory testing. These are tentatively considered to represent bleeding of undefined cause, with clinical features indistinguishable from those of classical MBD; the pathogenesis of this is probably multifactorial, and unveiling these mechanisms should constitute a fertile source of translational research.

Investigation of patients with unclassified bleeding disorder and abnormal thrombin generation for physiological coagulation inhibitors reveals multiple abnormalities and a subset of patients with increased tissue factor pathway inhibitor activity

“…Standard laboratory tests have limitations and were normal in our cohort. 27 In our collection, there were some abnormalities in tPA discovered which is in keeping with other reports which have found increased fibrinolytic abnormalities in patients with UBD [1 & 23]. No patients included in this study had a significant variant in these genes via the ThromboGenomic panel.…”

Thrombin‐generating potential, plasma clot formation, and clot lysis are impaired in patients with bleeding of unknown cause

“…Patients with BUC suffer from a clinically relevant bleeding tendency while showing normal test results in all routine coagulation tests . According to our data, parameters of thrombin generation and clot formation and lysis identify patients with BUC.…”

“…Mild to moderate bleeding tendency is a frequent cause for detailed investigations of the plasmatic coagulation system and platelet function. However, in the majority of these patients no underlying bleeding disorder can be identified, leading to the categorization as patients with bleeding of unknown cause (BUC) . Although the bleeding phenotype and severity are not different from patients with a diagnosis of a specific bleeding disorder, the mechanisms underlying the bleeding tendency are unknown in these patients.…”

Characterization of a large cohort of patients with unclassified bleeding disorder; clinical features, management of haemostatic challenges and use of global haemostatic assessment with proposed recommendations for diagnosis and treatment

“…30 Standard laboratory tests carry limitations as they detect common monogenic disorders and do not investigate subtle platelet disorders, collagen defects, fibrinolysis or physiological anticoagulants. 1 The number of patients with abnormalities in TG was higher than in the standard laboratory tests. There are several explanations for this.…”

“…Menorrhagia was symptomatically improved by treatment with TxA and desmopressin, which has been described in a prospective trial in women with menorrhagia and abnormal haemostasis . Standard laboratory tests carry limitations as they detect common monogenic disorders and do not investigate subtle platelet disorders, collagen defects, fibrinolysis or physiological anticoagulants . The number of patients with abnormalities in TG was higher than in the standard laboratory tests.…”