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

Abstract

The investigation of inherited bleeding disorders of secondary hemostasis remains a challenge for most clinical laboratories, especially those that lack experience or specialized personnel. Bleeding can be essentially caused by a variety of acquired or congenital conditions, which impair either primary or secondary hemostasis. Since a universally agreed approach for the diagnostics of hemorrhagic disorders is still unavailable, this article aims to provide an easy guidance for routine clinical laboratories. This pragmatic approach to identifying and diagnosing inherited bleeding disorders of secondary hemostasis entails a multifaceted strategy, based on a collection of personal and family history, the results of first-line tests, which can then be followed by second- or third-line analyses to definitely establish the specific nature and the severity of the bleeding phenotype. Briefly, the presence of profound hemorrhages rather than mucocutaneous bleeding is suggestive of a disorder of secondary hemostasis. Although a positive family history is frequently reported in patients with congenital conditions, the lack of clinically meaningful symptoms in patient's relatives is not absolutely indicative of an acquired disorder. The next step encompasses the assessment of first-line coagulation tests (i.e., prothrombin time, activated partial thromboplastin time, and fibrinogen) if family history is not suggestive of a specific factor deficiency. The emergence of abnormal data of these assays and the variable combination of their results is then helpful to guide the performance of second-line tests, in particular specific factor assays, which will then provide a reasonable basis for a preliminary diagnosis. Third-line tests (namely, immunological assays of clotting factors and molecular biology) are then supportive for a final diagnosis and for identifying the nature of the factor deficiency (i.e., quantitative or functional).

Development and implementation of an expert rule set for automated reflex testing and validation of routine coagulation tests in a large pathology network

“…Routine coagulation tests are among those most frequently ordered by clinicians. These tests may be requested in order to assist with the diagnosis or exclusion of haemostasis defects (eg disseminated intravascular coagulation (DIC), liver disease or factor deficiencies/bleeding disorders), or in many cases to monitor anticoagulant therapy . The routine coagulation assays most commonly performed by laboratories include the prothrombin time (PT), as potentially converted to an international normalized ratio (INR), and the activated partial thromboplastin time (APTT) .…”

“…For example, difficulty arises when attempting to assess “abnormal” coagulation test results, due to lack of clinical information provided by clinicians, such as the presence or absence of anticoagulant therapy and/or type of anticoagulant therapy. Thus, “abnormal” coagulation test results represent a relative term, potentially anticipated due to anticoagulant therapy or potentially unexpected, in which case results may be clinically relevant and follow‐up action would be required . Clinicians similarly face challenges with interpretation of test results, which may require different interpretations based on clinical scenario and test results.…”

What should be the laboratory approach against isolated prolongation of a activated partial thromboplastin time?

“…For instance, despite a lack of clinical bleeding in FXII, prekallikrein or HMWK deficiencies, APTT can be prolonged. Also, sepsis, malignancy, and atherosclerosis are also associated with disturbance in physiological hemostasis and abnormal coagulation test results . These should always be considered when interpreting APTT results.…”

“…Activator's role is to provide a negatively charged surface required for activation of the coagulation factors. Phospholipid content of the reagents is highly variable in terms of both concentration and source . The diversity in concentration and composition of the APTT reagents results in remarkable differences in response to heparin, coagulation factor deficiencies, and LAs.…”

Impact of experimental hypercalcemia on routine haemostasis testing

“…Coagulation tests are usually classified according a conventional hierarchy of complexity, entailing first-line (i.e., screening), second-line (i.e., diagnostic) and third-line tests, the last of which are usually performed to help defining the specific nature and severity of an underlying hemostatic disorder [3]. Due to the crucial role of haemostasis testing in diagnosing and managing hemostasis disturbances, a high degree of accuracy must be assured throughout the total testing process, i.e., from sample collection to testing and clinical interpretation of data [4–7].…”