Overview of Purposes of Hemostasis Testing and Common Sources of Error

Screening to Assess Risk of Hemorrhage in Otherwise Asymptomatic Patients Before an Invasive Procedure

A structured bleeding history is much more powerful than laboratory tests in predicting bleeding risk in patients undergoing invasive procedures. Thus, patients who did not show hemorrhagic tendencies during prior hemostatic stress (e.g., dental procedures, trauma, or childbirth) are unlikely to have a significant congenital bleeding diathesis. The prevalence of such disorders in the general population is low; indiscriminate conventional testing does little to predict hemorrhage because of its relatively low sensitivity and specificity. On the other hand, abnormal tests are frequently predictable based on the clinical history. Nonetheless, prothrombin time (PT), activated partial thromboplastin time (PTT), fibrinogen, and platelet count are often performed. Additional screening tests that assess platelet function, von Willebrand factor (VWF), and (rarely) the fibrinolytic system are occasionally performed. It should be noted that none of the tests have a well-documented value in predicting bleeding in the absence of supportive clinical history. Global hemostasis testing platforms such as thromboelastography/thromboelastometry are occasionally used for presurgical evaluation, but the value of these tests in predicting hemorrhage in this situation is yet to be proven. When abnormalities are found, the screening tests are usually followed up by more specific tests.

Measuring the Effect of Hemostasis System-Modifying Drugs

Physicians have an ever-expanding arsenal of medications that inhibit various components of hemostasis, in an effort to prevent unwanted clot formation or hemorrhage. Some, such as warfarin and unfractionated heparin, have a variable dose response and must be closely monitored to prevent under- and overanticoagulation. Others have a more predictable dose response and need to be measured only in special situations, such as unexpected bleeding or thrombosis while on medication. Unlike many therapeutic drug monitoring tests in other areas of medicine, the drug monitoring in hemostasis is frequently performed by measuring the effect rather than the concentration of a medication. This is done for two major reasons. First, owing to complexity of the coagulation system, some drugs may have large patient-to-patient variation in their effect at similar concentrations. For instance, infants have ∼50% of the adult concentration of antithrombin, which serves as a target for heparin therapy. Thus, infants and others with low antithrombin levels may show less anticoagulation at the same plasma concentration of heparin. Second, measuring the effect of the drug on the coagulation system is frequently more rapid and more accessible than the concentration-based approaches. The simplest tests often provide enough information to monitor drug effect. When the medications have a predictable effect on the factors in the clotting cascade, PT, PTT, and thrombin time–based tests, they offer convenient, inexpensive, and widely available approaches. The tests may not be entirely specific but frequently provide sufficient information. However, for many (mostly newer) drugs, the response of either PT or PTT is not satisfactory, either due to poor dose response or due to presence of interferences. In those cases, specific tests that directly measure the effects of drugs on their physiologic targets with minimal interference from other factors have been developed.

Numerous platforms are now offered to monitor effects of aspirin and ADP-receptor antagonists on platelets. Unfortunately, the lack of agreement between methods in detecting poor response, and the absence of conclusive evidence that such monitoring improves patient outcomes outside of limited circumstances, makes the indications for testing controversial. The field is rapidly evolving, thus it is possible that clear clinical benefit from the platelet-based therapy response determination may be demonstrated in future studies.

Monitoring Hemostasis System Under Stress and Assessing the Need for Replacement Products

Surgery and severe trauma challenge the hemostasis system in numerous ways. Because of the reductive nature of much of the current coagulation testing, no individual standard test can measure the numerous perturbations associated with these challenges. Numerous tests measuring plasma elements (PT, PTT, and fibrinogen), platelet number and function, and occasionally fibrinolysis may be needed to sufficiently assess the status of the hemostasis system under stress. More integrative tests, such as thrombin generation assays that are capable of capturing thrombin activity past the point of clot formation and thromboelastography/thromboelastometry that measure clot formation and stability in whole blood, offer attractive alternatives to the more specific tests. However, the usage of these tests is still evolving and their exact place in the arsenal of testing is yet to be determined. At present, it is not clear whether the global hemostasis tests improve patient outcomes compared with the standard screening tests.

Outside of trauma and surgery, various disease states can have numerous effects on the hemostasis system either as primary manifestation (e.g., heparin-induced thrombocytopenia) or as secondary manifestation (disseminated intravascular coagulation in sepsis). In such cases testing may be targeted to specific suspected abnormalities.

Diagnostic Workup to Assess Risk of Recurrent Thrombosis or Bleeding in Patients With Unexpected Thromboembolic or Hemorrhagic Event

This category of tests is often the most challenging. Although research studies and astute clinical observations have given us a fairly detailed understanding of most of the involved factors and many of their interactions and perturbations, we cannot yet quickly convert much of the knowledge into directly actionable clinical information in the laboratory. Frequently, coagulation workups in search of a lesion involve multistep processes that start with screening tests and proceed to multiple individual tests to pinpoint a lesion. Often, once a potential lesion is localized, it must be confirmed at a separate time point to assess its persistence and to improve diagnostic accuracy.

Such workups may be expensive and slow and should only be undertaken if there is sufficient clinical suspicion. Owing to relative rarity of any individual defect and multiple tests that are frequently required to find them, the rate of false positivity can become unacceptably high if the pretest probability of finding a lesion is similar to that of the general population. Routine, extensive, screening workups for hemorrhagic states or thrombophilia are therefore rarely, if ever, indicated. Use of reflex testing algorithms and rational testing panels clearly improves the diagnostic yield and cost efficiency of complex coagulation testing.

The foregoing makes it clear that knowing when to order tests is frequently just as important as knowing how the test is performed or how to interpret it. Whenever relevant, such indications and interpretive information are listed in the next chapters.