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New Treatments for Qualitative Platelet Defects and Antiplatelet Therapy

Congenital or inherited platelet function disorders are characterized by lifelong cutaneous manifestations. Glanzmann’s thrombasthenia causes large periorbital hematomas. So cutaneous bleeding and mucosal bleeding are the hallmarks of platelet function disorders and the mucosal bleeding can take the form of epistaxis, GI bleeds, menometrorrhagia and so on. Inherited disorders of platelet function can be classified on the basis of some of their functional components. The first group are defects of platelet vessel wall interaction. I might add that this classification is shown. Here the defect is in the interaction of the platelets and vessel wall, and there are two entities; the von Willebrand disease and the Bernard-Soulier syndrome. Platelet adhesion to the subendothelium is mediated by von Willebrand factor.

Treatment of these two diseases will be different. In von Willebrand’s disease the impetus is to increase von Willebrand factor in plasma, either through DDAVP or by providing it as a blood product. In Barnard-Soulier syndrome the treatment would be largely through platelet transfusions. This shows representative aggregation tracings in these two entities. The N is the normal control as a patient responds to ADP, collagen and to ristocetin. In von Willebrand disease and Barnard-Soulier syndrome responses to ADP and collagen.

The second group are defects in platelet-platelet interaction, or aggregation. Here again are two entities; congenital A5 afibrinogenemia and Glanzmann’s thrombasthenia. Schematically, aggregation which is platelet-platelet interaction, requires small amounts of fibrinogen. Fibrinogen binds to a complex consisting of two glycoproteins; glycoproteins 2B and 3A. If that be the basic mechanism of aggregation - and I might add, this is somewhat oversimplification.

The third group are disorders of secretion and signal transduction; often called secretion defects. There are three major ways that we recognize. One are defects in the granules, per se. That is, that the granules are deficient. Second are the secretion defects, primary secretion defects.

In storage deficiency there are the granule defects. They don’t secrete because the granules are deficient. In the second group there is a defect in all of the activation mechanisms, so that even if they do have the granules they are unable to secrete.

When one looks at aggregation tracings in these diseases with ADP one does see the primary wave. Both with ADP and with collagen. This is in contrast with thrombasthenia where even the primary wave is absent. One can look at dense granule secretion directly as well, and show that secretion is also impaired when examined directly. Disorders of granules, storage deficiency implies the defect is in the granules, and this could be in the dense granules - which is called delta storage deficiency - or in the alpha granules which is also called the gray platelet syndrome.

Going to the next category, which is the signal transduction defects, or activation defects; this has been an area of intense interest in my laboratory for the last 20 years and there is now evidence from our lab, as well as many others, that patients may have defects in signaling participants. For example, there have been patients described with a defect at the level of the receptors. Defects have been described at the level of the thromboxane A2 receptor, ADP receptor, epinephrine.

I want to make a couple of comments about the relative frequency. Thrombasthenia, Barnard-Soulier syndrome are extremely rare entities. In our experience and those of others as well, the more common ones are those that fall under this rather heterogeneous group.

Switching to management of these patients; needs to be individualized based on clinical features. There is a wide spectrum of clinical intensity. Platelet transfusions are indicated in the management of bleeding episodes or surgical procedures. Transfusions run the risk of leading to the development of specific antiplatelet antibodies. Patients with thrombasthenia can develop antibodies against GP2B3A so that when they are subsequently transfused with platelets.

This is about 18 patients with well-characterized inherited platelet function defects. That’s the effect of placebo, that’s the effect of the drug infusion, indicating that there is a shortening of the bleeding time that occurs after the infusion of DDAVP. But I want to caution that not everybody responds to DDAVP. From literature it is clear that some patients with certain kinds of defects do not respond. Just to highlight that, this is from our study again, these are patients with storage deficiency - placebo and DDAVP - there was no shortening of bleeding time. These are patients with so-called secretion defects that respond very well. So to summarize the findings.

I’m going to switch gears to talk about the acquired disorders of platelet function. These are by far much more common than the inherited varieties. Again, the analogy is that the inherited coagulation defects are just factor VIII, hemophilia or factor IX, Christmas disease, are far more rare than liver disease or DIC which are coagulopathies on an acquired basis.

The other group that cause inhibition or alteration of platelet function are the antibiotics, particularly penicillins and cephalosporins, the so-called beta lactam antibiotics. This effect is dose and duration related. Generally occurs in large doses. It also occurs largely in the context of intensive care units where patients are sick and have other multiple problems. The mechanism seems to be that they associate with the membrane and inhibit interaction of platelet receptors with agonists. So it’s a membrane phenomenon leading to inhibition of platelet function.

I think there are some caveats. If you are going to assess platelet function in somebody you need to take them off as many if not all of the drugs as possible before you test them. Second, for many of these agents that are now reported in literature as affecting platelet function, the effect has been shown in vitro and not in vivo. In some cases even though there is an effect in vivo.

Chronic renal failure is another place where there is abnormal platelet function on an acquired basis. These patients truly have a hemostatic defect. Serious spontaneous hemorrhage is less common than previously considered, because they are dialyzed earlier, their overall care is much better. GI hemorrhage is a common complication.