Management of Patients Refractory to Platelet Transfusion

Abstract

Refractoriness to infused platelets becomes a major clinical problem for many patients with acute myeloid leukemia (AML). Inadequate post-transfusion platelet count increments can be due to a number of host-related factors such as: spleno-megaly, severe infection with high fever, disseminated intrava-scular coagulation, drug-mediated antibodies and/or alloim-munization, and occasionally by administration of platelets damaged or activated during collection or storage. Lymphocy-totoxic antibody directed against HLA-A orB antigens is an excellent serologic marker for alloimmunization. In one large study, the presence of anti-HLA antibodies was correlated with a poor post-transfusion platelet increase in over 90% of such patients, whereas patients lacking antibodies had satisfactory increments after transfusion 85% of the time. 1 Similar predictive information can be obtained using a variety of anti-platelet antibody tests. Post-transfusion counts obtained at the conclusion of transfusion, at a time that the patient must be seen by the physician or nurse to switch infusion bags, are identical to counts obtained 1 h later and it is therefore relatively simple to assess the results of every platelet transfusion to determine if the expected count increment was achieved. 2 The incidence of alloimmunization appears to be unrelated to the number of transfusions that patients receive. In a series of 114 newly diagnosed AML patients receiving 2-10+ transfusions of pooled non-leukocyte-depleted platelet concentrates (PC) from random donors, there was no relationship between the number of transfusions or donor exposures, and the development of new anti-HLA antibody. 3 At the end of induction therapy, 35-40% of patients had developed anti-body. The majority had persistence of the antibody, but 20% had disappearance of antibody over time. After marrow recovery from the induction therapy, 60% of patients remained anti-body-negative and, indeed, never developed antibody or refractoriness to platelet transfusion despite multiple subsequent red blood cell and platelet transfusions, suggesting that they had become immune tolerant to histocompatibility antigens. These patients continued to be easily supported with random donor transfusions and therefore measurement of lym-phocytotoxic antibody at this time in a patient's treatment course is helpful in predicting and arranging for their future transfusion needs. The traditional management of alloimmune-mediated plate-let refractoriness is by HLA typing of donors and recipients. A significant fraction of HLA 'matched' transfusions do not produce satisfactory increments, however, while some 'mismat-ched' transfusions are successful, and a number of studies have evaluated subtleties of HLA serology to attempt to explain these discrepancies. As one example, there is a high

Platelet transfusion refractoriness responding preferentially to single donor aphaeresis platelets compatible for both ABO and HLA

“…The earliest possible assessment of post‐transfusion increments are most specific to determine immune platelet destruction when increments are low, but the later (18–24‐h) assessments are at least sensitive enough to rule out immune platelet destruction if the increments remain good (Chockalingam & Sacher, 2007; Hod & Schwartz, 2008), as was the case in the most successful transfusions witnessed in this audit. This audit did not, however, support the observation that fresher platelets (<48−h old) provided better increments at 18 h post‐transfusion (Slichter et al , 2005).…”

“…These mechanisms include sequestration because of splenomegaly, and accelerated consumption or decreased production from states such as fever/infection, disseminated intravascular coagulation (DIC), circulating immune complexes, drug‐related antibodies or toxicities, ‘endotheliopathies’ of myelosuppressive/myeloablative therapy, thrombotic microangiopathies, and finally the properties of the platelet transfusion itself (quantity transfused and storage duration) (Stroncek & Rebulla, 2007; Vassallo, 2007; Hod & Schwartz, 2008). Any of these non‐alloimmune insults may manifest with platelet transfusion refractoriness in 50% of patients (Novotny, 1999; Chockalingam & Sacher, 2007).…”

“…Alloimmune mechanisms, on the contrary, consist chiefly of sensitisation to foreign class I A or B human leucocyte antigens (HLA) through transfusion, pregnancy or transplantation. The attack of variably expressed major‐incompatible A, B antigens on donor platelets by pre‐formed recipient ABO‐isogglutinins also plays a role in this category, and least often, sensitisation to polymorphic antigens in the human platelet alloantigen (HPA) system may occur as well or instead (Novotny, 1999; Saito, Ota et al , 2002;Cooling et al , 2005; Chockalingam & Sacher, 2007; Stroncek & Rebulla, 2007; Vassallo, 2007).…”

“…Most implement at least one of several possible strategies, including the administration of the freshest and the highest‐yield platelet products, minimising moot exposures through alternatives to platelet transfusion and prioritising the selection of platelets after a determination of pre‐transfusion compatibility. This in turn may be predicted using either in vitro crossmatching or theoretical models based on the intended recipient's HLA type and expected range of HLA tolerance (Novotny, 1999; Chockalingam & Sacher, 2007; Dzik, 2007; Slichter, 2007; Vassallo, 2007; Hod & Schwartz, 2008). In cases where platelet transfusion matching is impossible or fails to work, alternatives include local haemostatic control, off‐label drugs (intravenous immunoglobulin [IVIG], inhibitors of fibrinolysis, recombinant activated factor 7, thrombopoietin and rituximab), plasma exchange and large bolus or continuous low‐dose infusions of random platelets (Slichter, 2007; Vassallo, 2007).…”

Spontaneous intramural small bowel hematoma in a patient with acute myeloid leukaemia receiving chemotherapy and nilotinib

“…Refractoriness to platelet transfusion can be confirmed by failure of the platelet count to increment by 5×10 9 /L within 1 hour after two sequential ABO-compatible transfusions 12. Non-immune causes (such as fever, sepsis, bleeding, disseminated intravascular coagulation, drugs, infections or splenomegaly) are most likely and should be explored first.…”