Hemostasis: Principles of investigation

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CHAPTER 31 Hemostasis

Principles of investigation

Introduction

The hemostatic system, a complex defense against bleeding, is critical to survival. Its integrity is compromised by inherited or acquired failure of its individual components, or by deregulation of the entire system provoked by organ failure, the inflammatory response, or exposure to cancer cell surfaces. Hemostasis also acts (in the wrong place, at the wrong time) as thrombosis. Bleeding is always a threat, while thrombosis increases due to age-related changes in coagulation factors and blood vessels to become the dominant hemostatic risk in later life.

The extreme complexity of hemostasis revealed by scientific scrutiny induces a degree of alienation in many clinicians practicing at the bedside and in the operating theate. The hematologist must be their translator of basic knowledge into clinically useful advice, and guide to the increasing menu of potent drugs and biological agents available for the therapy of bleeding and thrombosis.

To do this work a reliable toolkit of investigational methods is essential. These include a focused approach to the patient’s personal and familial medical history, a set of rapid laboratory tests to indicate the presence and general nature of any hemostatic malfunction, and the ability to extend this inquiry to measurement of specific proteins and analysis of DNA if required. The principle underlying these ‘nested’ methods of investigation is common to all disciplines in clinical pathology: provide data that increases (or decreases) the likelihood that a particular pathologic state – a diagnosis – is present and needs specific therapy or other intervention.

Hemostatic tests retain unique features and problems in interpretation. Even coagulation screening tests (the only commonly requested tests that require explicit coreporting of control experiments) are complex bioassays in miniature. An abnormal value can have diametrically opposed meanings for patient care depending on the clinical context. Expressing clinical pretest probability in an intelligible way and using test results to modify this probability is the best way of avoiding potential confusion and error.1

The application of meta-analysis of randomized studies (‘evidence-based medicine’) to diagnostic laboratory testing has been limited,2 and hemostatic testing is no exception. It is therefore not possible yet to claim evidence-based validation, in its strict sense, for many of the principles discussed below. However, the writings of many expert clinician–scientists over the years are the best guide we have to these principles, and should certainly form a starting-point for further analyses.

Physiology of hemostasis applied to diagnosis

The clinical approach to the patient who may have a hemostatic disorder is informed by knowledge of the physiology of hemostasis. Hemostatic reactions operate in a clock-like sequence, the first two phases being termed ‘primary’ and ‘secondary’ hemostasis.

A careful clinical history and examination (see below) can tentatively locate the potential defect in one of these phases, guiding the selection of initial investigations. The pretest probability of a defect involving primary hemostasis rises if abnormal bleeding follows a ‘mucosal’ pattern (see below), while a history of muscle or joint bleeding increases the likelihood of a coagulation deficiency. Disorders of the regulatory protein C pathway tend to manifest as venous thromboembolism. Abnormalities of the final phase of hemostasis, fibrinolysis, tend to contribute to bleeding in specific clinical settings, for example disseminated intravascular coagulation (DIC) and hepatic failure.

To assist this diagnostic thinking, it helps to keep in mind a simplified map of the hemostatic system, whatever knowledge of its complexity one possesses (or not, as the case may be). These simple maps are caricatures: readers are referred to fuller versions3,4 and to other chapters in this volume.

Secondary hemostasis: generation of fibrin clot by the coagulation pathway (Fig. 31.2)

Unless underpinned by a fibrin net, primary platelet plugs disintegrate under the shear stress of flowing blood. The complex coagulation pathway that generates fibrin can be divided into three substages:

Clot regulation and removal: the protein C and fibrinolytic pathways

Two further systems regulate and eventually remove the clot (in the context of tissue repair and neoangiogenesis) (also see Chapter 28):

The clinical approach to the patient with a possible hemostatic disorder

The question of a possible hemostatic disorder occurs in two main settings. An individual is referred because they have presented with, or self-reported, clinical phenomena suggesting excess bleeding. Investigation can proceed in a structured elective style. In the second case, excess bleeding occurs acutely in a patient undergoing treatment in the hospital, emergency department or surgical theater. The tempo, urgency and completeness of the diagnostic work-up (before recourse to therapeutic action) are then different, but the principles are shared.

Experts writing about the investigation of possible bleeding disorders unanimously stress the importance of a carefully taken history.1012 They also recommend specific questions, answers to which alter the pretest probability of a bleeding disorder. The discussion below draws on this consensus. Similarly, key findings on clinical examination may aid the diagnostic process, although they are less frequent than narrative clues.

It must be conceded that these narrative and clinical signs have not been formally tested, either singly or in clusters, for their relative value in predicting the presence of hemostatic disorders. Such testing has refined and simplified the use of clinical clues in other contexts,13 and may be of future benefit in hemostasis. Until such clarification becomes available, the shared insight of experienced clinicians is our best guide.

Key questions

Surgical challenges

Clinical examination

Skin

The whole skin surface should be inspected for purpura and bruising, documenting the distribution, size and age of lesions and correlating them with the clinical history. Palpation of bruises will detect hematomata, while palpable purpura suggests vasculitis. Close attention should be paid to the ankles, where venous and capillary pressure is highest: petechiae first appear here in thrombocytopenia, and signs of venous or arterial insufficiency may be evident. Large bruises (ecchymoses) typical of hemophilia or anticoagulant overdose may be found tracking into dependent parts of the body such as the scrotum.

The surface of lesions should be inspected. Edema may indicate the urticarial component of anaphylactoid purpura. Lesions of hereditary hemorrhagic telangiectasia may be seen in finger pulps and ear lobes, spreading over the face in later life. Bruises with abrasions or thermal trauma, that follow the outline of a blunt object, or are associated with other signs of abuse or self-harm may indicate non-accidental injury or factitious bruising.

Scars should be examined. Keloid formation might rule out a skin bleeding time. In Ehlers–Danlos syndrome they pucker like tissue paper on sideways compression, and may show central breakdown with fresh exudation. Poor scar quality may also be seen in hypo- or afibrinogenemia.

Non-hemorrhagic lesions mistaken for signs of bleeding include cherry-red Campbell de Morgan spots, stretch marks, livedo reticularis and Majocchi’s purpura or other ‘dermatological’ purpuras.

Screening tests of hemostasis: two warnings

Armed with an estimate of pretest probability, the next step is to perform screening tests of hemostasis to generate further data capable of increasing or decreasing it.

On screening tests

These tests ‘screen’ hemostasis, not people – a source of considerable misunderstanding and futile testing. They do not meet the epidemiological standard of true screening tests because they are not sensitive or specific enough to screen a population for bleeding disorder. They only work in concert with the history and examination as described above.

The 250 ‘clotting screen’ requests typically made every day in a large teaching hospital represent educational failure. This futile attempt to screen the population entering hospital for surgery (or other intervention) for bleeding risk depends partly on misinterpretation of the ambiguous term ‘screen’. Even more misleading – and potentially wasteful – is the lazy application of the term ‘thrombophilia screen’ to detailed testing for inherited and acquired thrombophilia. When the term ‘screen’ is unavoidable, it is used below strictly to refer to tests performed as the result of a clinical history of bleeding or thrombosis.

Initial screening tests, usually applied whatever the pattern of abnormal bleeding, consist of a multiparameter blood count including the platelet count, and coagulation tests: a prothrombin time (PT), activated partial thromboplastin time (APTT), and sometimes a thrombin clotting time (TT).

If the pretest probability of a bleeding disorder is possible or probable, normal results in these initial tests should be followed by a skin bleeding time estimation or whole blood platelet function analysis. The need for further platelet function tests, specific assays of hemostatic proteins or genes, or further clinical tests for systemic disorders depends in part on the results of ‘global’ tests of hemostasis, but should also proceed if the full history is convincing, even if initial tests are normal. Below, tests of primary hemostasis and coagulation are grouped together for coherency, but they are also ranked into ‘screening’ and ‘diagnostic’ categories.