Detection of mild inherited disorders of blood coagulation: current options and personal recommendations

Abstract

Although assessment of prior personal and familial bleeding history is an important aspect of the diagnosis of bleeding disorders, patients with mild inherited bleeding disorders are sometimes clinically asymptomatic until presented with a hemostatic challenge. However, bleeding may occur after incursion of trauma or surgery, so detection of these conditions reflects an important facet of clinical and laboratory practice. Mild bleeding disorders may be detected as a result of family studies or following identification of abnormal values in first-line screening tests such as activated partial thromboplastin time, prothrombin time, fibrinogen and global platelet function screen testing, such as the platelet function analyzer. Following determination of abnormal screening tests, subsequent investigation should follow a systematic approach that targets specific diagnostic tests, and including factor assays, full platelet function assays and more extensive specialized hemostasis testing. The current report provides a personal overview on inherited disorders of blood coagulation and their detection.

Postanalytical considerations that may improve the diagnosis or exclusion of haemophilia and von Willebrand disease

“…These tests can then be either manually or automatically activated (eg by adopting specific rules in the software of the analyzers) within the laboratory, on the same plasma sample used for routine analyses, should this be permitted in a given jurisdiction or by the local health care provider. On the other hand, normal routine coagulation tests do not necessarily exclude a bleeding disorder, and abnormal test results do not necessarily reflect a bleeding disorder . Indeed, most “abnormal” coagulation tests in normal laboratory practice probably reflect either anticoagulation therapy (heparin, vitamin K antagonists and increasingly the direct anti‐thrombin or anti‐Xa anticoagulants), or “benign” deficiencies of FXII, or other nonhaemorrhagic conditions such as lupus anticoagulants .…”

“…Normal screening test results will not necessarily exclude a bleeding disorder, and abnormal screening test results will not necessarily confirm a bleeding disorder. Screening tests are not sensitive to all bleeding disorders (FXIII deficiency is probably the most paradigmatic example), and abnormal test results may result as such for a variety of reasons …”

“…Screening tests are not sensitive to all bleeding disorders (FXIII deficiency is probably the most paradigmatic example), 51 and abnormal test results may result as such for a variety of reasons. 6,7,41,[47][48][49][50] Mixing tests are useful for initial investigation of abnormal routine coagulation tests. 52,53 A "correction" in the clotting time of the mixture towards the normal test result suggests a factor deficiency, and "non-correction" suggests some type of inhibitor.…”

“…Individual clotting factors (eg FVIII and FIX) have discrete activities, typically activation of other clotting factors in the "blood coagulation cascade", thereby leading to fibrinogen to fibrin conversion, and formation of a clot within the conceptual framework of "secondary hemostasis". 6,7 Analytically, assessment of such factors entails specific assays using either one-stage clotting assays and/or chromogenic assays, depending on the reason for testing and the type of laboratory performing the tests (eg haemophilia and specialized centres are likely to offer both types of assays). 8,9 In contrast, VWF expresses a multitude of functional properties, which helps explain the heterogeneity of clinical symptoms and bleeding risk in affected VWD patients, as well as diagnostic challenges.…”

Diagnostics of Inherited Bleeding Disorders of Secondary Hemostasis: An Easy Guide for Routine Clinical Laboratories

“…The essential function of these proteins is to prevent undue (or excess) activation of hemostasis, so that deficiencies of these natural anticoagulants are now clearly recognized as powerful risk factors for venous thrombosis. 5 FVIII deficiency (i.e., hemophilia A) and FIX deficiency (i.e., hemophilia B) are the most prevalent inherited disorders of secondary hemostasis (i.e., $1:5,000 and $1:50,000, respectively), whereas other coagulation factor deficiencies are conventionally called "rare disorders" since they usually affect fewer than 200,000 subjects, 6 with the exception of von Willebrand disease (VWD), exhibiting an overall frequency close to that of hemophilia A (i.e., $1:10,000). 7 The activity of VWF cannot be clearly confined within the boundaries of primary or secondary hemostasis (VWF promotes platelet aggregation, a primary hemostasis mechanism, but also effectively protects FVIII from degradation in vivo, thereby supporting secondary hemostasis).…”