If the patient is transfused with platelet alloimmunization might happen, including alloimmunization due to RhD antigens or non-histocompatibility. And the patient might develop refractoriness to platelet transfusion.

RhD Antigen-Induced Alloimmunization

Platelets do not express Rh antigens on their surface, but quantity or RBCs in platelet preparations is sufficient to induce Rh sensitization, even in immunosuppressed cancer patients. Different studies have documented that anti-D antibodies can be detected in 7.8% to 19% of heterogeneous groups of RhD-negative cancer patients exposed to RhD antigens via transfusion.

Two small studies have demonstrated that RhD immunoprophylaxis can prevent the development of anti-D in this setting. Thus, if platelets from an Rh-positive donor or platelets from a donor of unknown Rh phenotype are given to an Rh-negative recipient, administration of Rh immunoproplylaxis should be considered, especially for younger female patients who might become pregnant after successful treatment. Because of the thrombocytopenia, it is preferable to use a preparation of anti-D that can be administered intravenously (IV).

The amount of anti-D immunoglobulin necessary to prevent sensitization depends on the number of contaminating RBCs in the PCs. Generally, a dose of 25 μg (125 IU) of anti-D immunoglobulin will protect against 1 mL of RBCs. If possible, the immunoglobulin should be given before or immediately after the transfusion, although, as in the obstetrical setting, it may still be efficacious if given within 72 hours of exposure to the RhD-positive RBCs.

Alloimmunization Against Histocompatibility Agtigens

Besides RhD antigen alloimmunizaton due to non-histocompatibility is a problem when the patients with cancer needs multiple platelet transfusions. Alloimmunization against histocompatibility antigens ocurs in many recipients of multiple random donor platelet transfusions and is the most important long-term complication of platelet transfusion. Recent experience suggests that between 25% and 35% of newly diagnosed patients with AML will produce lymphocytotoxic antibody and become alloimmunized and refractory to nonhistocompatible platelet transfusions. However, as many as 40% to 60% of apparently histocompatible platelet transfusion administered to alloimmunized patients are unsuccessful and when histocompatible donors are not available, the management of alloimmunized patients is difficult.

As a result, the elimination of alloimmunization would greatly simplify platelet transfusion therapy. Vitro and animal studies suggest that the leukocytes contaminating platelet preparations are the primary stimulus for alloimmunization. It seems that presentation of class I and class II antigens by intact leukocytes is required for initial processing by the immune system. Because platelets do not express class II histocompatibility antigens, it is likely that it is the leukocyte that serves as the costimulus.

To reduce the incidence of alloimmunization by leukocytes, different methods exist secondary to filtration of leukocytes or modification of the antigen presenting capacity of leukocytes. Filtration of platelets before transfusion can make 3 to 4 log reduction in leukocyte contamination platelets that obtained either by apheresis or PCs. It has been shown that ultraviolet B (UVB) irradiation can abolish reactivity in mixed lymphocyte reactions and that doses of UVB irradiation can be identified that do not affect platelet function in vitro. However, two recently published small trials failed to show benefit from leukocyte filtration, and as a result of the filtration up to 25% ~ 35% of platelets will be lost.

To help address these concerns, a large, randomized multi-institutional trial (the TRAP trial) was recently completed. In the trial 603 patients with newly diagnosed AML receiving initial induction therapy were randomized to receive the following approaches: pooled PC (control group); filtered PC (leukoreduced); single donor, filtered platelets collected by apheresis; or pooled PC that had been UVB irradiated. All manipulations were performed at blood bank, not at the patient bedside. All RBC transfusions were also leukodepleted by filtration. The target level  of leukocytes is less than 5 × 106 per transfusion. Compared with the control group (45%), there was a statistically significant reduction (17% to 21%) in the formation of lymphocytotoxic antibody (anti-HLA antibody) in all three groups receiving modified platelets.

Thus, the conclusions is that it is appropriate to provide leukoreduced RBC and platelet products to newly diagnosed patients with AML and probably other types of acute leukemia. Although randomized trials have not been conducted in other patients groups, it is likely that alloimmunization can also be decreased in patients with other cancers receiving chemotherapy. For patients not receiving chemotherapy and need multiple platelet transfusions, there  are not data yet. But we would favor this approach in these patients as well.

Of note, this approach should be used only for patients expected to require multiple platelet transfusions during their treatment courses and is not indicated for patients with cancer receiving RBCs or therapies that do not produce significant and sustained thrombocytopenia. It should also be noted that only a subfraction of patients benefit from any successful approach to reduce the rate of alloimmunization. Why? Because only 30% to 40% of patients become alloimmunized without leukocyte-reduced procedure and not all of these 30% to 40% of patients achieve CR and receive intensive postremission therapy. This is of importance because there was only a modest reduction in the incidence of refractoriness to transfusion in the TRAP trial. And aslo since the antibodies often developed after 3 to 4 weeks in the TRAP trial, at a time when the patients may no longer required platelet transfusion. So these reasons make that only a subfraction of patients benefit from the prevention of alloimmunization.

Diagnosis, Evaluation and Treatment of Refractoriness to Platelet Transfusion

If the patient have a poor increment after two ABO-compatible platelet transfusions which stored less than 72 hours, it is suggested that the most likely reason is alloimmunization. To confirm, lymphocytotoxicity assays or platelet antibody testing may be useful since approximately 90% of patients with platelet transfusion alloimmunization will have alloantibody. Of note that other reasons including drug-related antibodies, hypersplenism, severe DIC, shock, and massive hemorrhage may also result in poor platelet increments.

The method to evaluate the platelet recovery due to transfusion is called “CCI” formula which based on estimated blood volume or body-surface size of the patient as well as the number of platelets in the infused product. The TRAP trial use the following formula to evaluate: CCI = absolute increment (μL)× body-surface area (m2)/number of platelets transfused × 1011. For instance, if transfusion of 4 × 1011 platelets produced an increment of 40,000/μL (40 × 109/L) in a 2-m2 recipient, the CCI = 40,000 (μL) × 2 (m2)/4 = 20,000. If the CCI ≥ 5,000 means a satisfactory response to the platelet transfusion(s). While the platelet increment is determined by subtracting the pretransfusion platelet count from the count determined 1 hour after transfusion, however, identical results are obtained by using a 10-minute posttransfusion count, which is simple to obtain because the patient must be seen when the transfusion is completed to switch the IV bags. Although it would be desirable to obtain immediate posttransfusion increments after all platelet transfusions, it is reasonable to obtain such increments in nonbleeding hospitalized patients if the day-to-day increments are not satisfactory and after all transfusions to outpatients.

Patients with alloimmune refractory thrombocytopenia, as defined above, are best managed with platelet transfusions from donors who are HLA-A and HLA-B antigen selected. For patients whose HLA type cannot be determined, who have uncommon HLA types for which suitable donors cannot be identified, or who do not respond to HLA matched platelets, histocompatible platelet donors can often be identified using platelet cross-matching techniques (besides HLA matching technique, there is another way called cross-matching to identify the histocompatibility. These two techniques are complementary). Note that there is no evidence that alloimmunized patients benefit from nonmatched prophylactic platelet transfusions that do not produce posttransfusion increments, and we recommend such patients be transfused only for hemorrhagic events.