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The screening of patients with bleeding disorders is based on a two-step diagnostic strategy. In step 1, tests of global hemostasis are performed, which help the physician to identify the phase of the hemostatic system that is abnormal. In step 2, specific tests are performed, which study in more detail the phase of hemostasis that is suspected to be abnormal, based on the results of step 1 and, when informative, the type of bleeding history. This strategy aims at limiting the number of specific diagnostic tests to be employed in the diagnostic work-up of the patient, because they are usually complex and expensive. Step-1 screening tests should be simple, relatively inexpensive and sensitive to most known disorders of hemostasis. Traditionally, they include two tests exploring the coagulation system, the prothrombin time (PT) and the activated partial thromboplastin time (APTT), and one test that explores primary hemostasis, the bleeding time (BT). PT and APTT are indeed very effective in helping the diagnosis of patients with abnormalities of the coagulation system, because not only are they accurate and highly reproducible, but they also help to identify the coagulation pathway in which the abnormality is likely to be found. In contrast, the usefulness of BT for the diagnostic work-up of patients with defects of primary hemostasis is questionable, not only because its sensitivity seems unacceptably low, but also because it is of no help in differentiating among the various types of defects of primary hemostasis. As a matter of fact, since BT can be equally prolonged in, for instance, von Willebrand disease (VWD) and platelet function defects, it is of no help in differentiating between these two common disorders of primary hemostasis. In addition, it is an invasive and poorly reproducible test, which is influenced by many variables and should therefore be carried out by experienced personnel.

These last drawbacks created the need for new, in-vitro tests that could substitute for BT in the diagnosis of defects of primary hemostasis. The PFA-100® was proposed as a useful screening test for defects of primary hemostasis, because it is simple, non-invasive, reproducible and does not require specialized personnel [1,2]. The principle of the system is simple: it creates an artificial vessel consisting of a sample reservoir, a capillary and a biologically active membrane with a central aperture, coated with collagen plus adenosine diphosphate or collagen plus epinephrine. The application of a constant negative pressure aspirates the anticoagulated blood of the sample from the reservoir through the capillary (mimicking the resistance of a small artery) and the aperture (mimicking the injured part of the vessel wall). A platelet plug forms that gradually occludes the aperture; as a consequence, the blood flow through the aperture gradually decreases and eventually stops. The time needed to blood flow interruption (‘closure time’) is recorded. In several published studies, PFA-100® proved to be more sensitive than BT to type 1 VWD (VWD-1) [3–6], which usually causes mild abnormalities of primary hemostasis and is associated with mild bleeding diathesis. In contrast to VWD, PFA-100® is not sensitive to platelet secretion defects [7], which represent the vast majority of abnormalities of platelet function [8].

In this issue of the Journal, Quiroga et al. tested the sensitivity of BT and PFA-100® in 148 consecutive patients referred to their Center for personal and family history of mucocutaneous bleedings, suggestive of defects of primary hemostasis [9]. All patients were carefully interviewed by the same physician and only those who had an unequivocal bleeding history were enrolled in the study. Quiroga and her collaborators found that neither BT nor PFA-100® were sufficiently sensitive to the two disorders that were diagnosed in their patients: VWD-1 and primary platelet secretion defects (PSD). As expected, PFA-100® performed slightly better than BT in patients with VWD-1 (sensitivity, 61.5% for PFA-100®, vs. 42% for BT, P = NS), while BT was slightly better than PFA-100® in patients with PSD (24% for PFA-100®, vs. 42% for BT, P = NS). Based on the results of the study by Quiroga et al., it can be concluded that BT and PFA-100® are of no use (and therefore should not be performed) in the diagnostic work-up of patients with a positive personal and family history of mucocutaneous bleedings. Although this is the logical conclusion of a well-performed study that gives negative results, it is my opinion that the same conclusion would have been reached even if the results of the study had been different. As a matter of fact, the presence of a positive personal history of mucocutaneous bleeding is by itself a sufficient indication for screening patients for VWD or platelet abnormalities, independently of the results of global in-vivo or in-vitro tests exploring primary hemostasis. In my opinion, in the setting of patients with a positive history of mucocutaneous bleeding, global tests of primary hemostasis should be withheld, independently of their sensitivity, unless they help distinguish between VWD and platelet function disorders, in order to be able to guide the following diagnostic work-up. Other potential useful applications of global tests of primary hemostasis would be in the diagnosis of patients whose bleeding history is not informative, and in the prediction of the bleeding risk. To this aim, studies should be designed to test their sensitivity and specificity for bleeding history and their correlation with the severity of bleeding.

In conclusion, based on the evidence of Quiroga et al., the use of BT and PFA-100® in the diagnostic work-up of patients with unequivocal mucocutaneous bleeding is not justified. However, further studies are needed to define the diagnostic utility of these tests in other settings.

References

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  2. References
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