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Platelet Refractoriness

Platelet transfusion refractoriness (PTR) is defined as the occurrence of at least two poor incremental platelet counts after transfusion of a standard dose of platelet s. PTR is classified as either immune or nonimmune.  Immune-mediated PTR is caused by alloantibodies or autoantibodies reacting against antigens on donor platelets. Antibody binding is associated with the rapid removal of transfused platelets from the circulation. The most common causes of alloimmune-mediated PTR are recipient antibodies against:

  • HLA Class I antigens HLA-A and HLA-B
  • Human platelet antigens (HPA)
  • A and B blood group antigens on platelets

HLA antibodies form within 2 to 5 weeks after transfusion and persist for a median of 14 weeks after the last transfusion. Seventy percent are undetectable at one year. If HLA antibodies disappear, there is a 50% chance that they will not reappear with subsequent platelet transfusions.

Alloimmunization against histocompatibility antigens occurs in 25 to 35% of patients with acute leukemia who are transfused with multiple random donor platelet transfusions and in 5 to 15% transfused with apheresis platelets. This is the most important long-term complication of platelet transfusions because patients become refractory to future platelet transfusions.

Nonimmune causes for PTR are diverse and include:

  • Fever
  • Sepsis,
  • Splenomegaly
  • Disseminated intravascular coagulation (DIC)
  • Bleeding
  • Stem cell transplant
  • Graft versus host disease
  • Veno-occlusive disease
  • Vasculitis
  • Immune thrombocytopenia
  • Drug induced immune thrombocytopenia (heparin, amphotericin, vancomycin, ciprofloxacin)

An adult patient is considered to be refractory if the 10 to 60 minute post-transfusion platelet count fails to rise more than 2,000/uL per random platelet concentrate or 10,000 to 12,000/uL per apheresis platelet. Children are considered to be refractory if the one hour post-transfusion platelet count fails to rise more than 3,500/uL per random donor platelet concentrate. Because patients may have a poor post-transfusion increment to a single transfusion yet have excellent platelet increments with subsequent transfusions, a diagnosis of refractoriness should only be made when at least two ABO compatible transfusions, stored less than 72 hours, result in poor increments.

Once a patient is shown to be refractory to platelet transfusions, a careful review of the medical history should be undertaken including current medical condition, medications, transfusion history, transplant history, and previous pregnancies. The latter three events increase the likelihood of HLA and HPA alloimmunization.

Nonimmune causes of platelet refractoriness are best managed by treating the underlying condition. Immune mediated PTR is best managed by identifying the responsible antibodies and using this information to guide the selection of suitable units. There is no evidence that alloimmunized patients benefit from continued prophylactic transfusion of incompatible platelets that do not produce an increase in posttransfusion platelet count. 

The diagnosis of immune platelet refractoriness should be confirmed by testing for HLA and HPA antibodies. Approximately 90% of alloimmunized patients have demonstrable platelet antibody. The majority of patients have antibodies to HLA class I antigens. If the platelet antibody screening test is negative, refractoriness is probably due to clinical factors rather than alloimmunization and crossmatched platelets will not be beneficial.

Patients with immune PTR should be transfused with ABO identical platelets that are less than 3 days old while awaiting further testing such as platelet crossmatch,  HLA-A and -B antigen typing, and identification of  HLA-A/B antibodies. This strategy should be repeated for 2 to 3 times to determine if the low post transfusion increment persists. It is important to obtain platelet counts 10 minutes to 1 hour following each transfusion of compatible platelets since a useful but temporary post transfusion increment may occur but be missed if platelet counts are not obtained until the next morning.

Platelet crossmatch allows for rapid selection of compatible platelets for PTR patients with either HLA or HPA alloantibodies. HLA-A and B phenotyping and HLA-A and B antibody identification take longer to complete but assist in providing HLA antigen negative and HLA matched platelets.  Identification of HLA-A/B antibodies includes calculation of the percent reactive antibody (PRA) which corresponds to the expected prevalence of incompatible platelet donors. For example a PRA of 60% means that the patient will be incompatible with 60% of donors. Platelet crossmatching is successful in finding compatible platelet donors for 50 to 90% of patients with a PRA between 20 and 40%. It is more difficult to find crossmatch compatible platelets when PRA exceeds 60%.

Experts have differing opinions about the advantages and disadvantages of  crossmatch compatible, HLA antigen negative and HLA matched platelets. Platelet crossmatch may be less sensitive than tests for HLA antibodies, but it can identify compatible platelet donors much faster than HLA typing. Usually at least 3 days are required to find HLA matched platelets. The likelihood of finding HLA antigen negative platelets depends on the degree of sensitization.One alloimmunized patient may require a pool of 1000 to 3000 HLA typed donors to find compatible platelets. Even with a donor pool of this magnitude only 10% of patients will receive HLA matched platelets. The degree of HLA antigen matching predicts the expected response. A, B1U (3 antigen) and B2U (2 antigen) matches provide the best response. All other HLA matches are partially  incompatible and may stimulate additional antibody formation. Crossmatch compatible platelets are usually just as effective as HLA matched platelets if A and BU matched platelets cannot be obtained.

If 4 crossmatch compatible platelets fail to produce an adequate post transfusion platelet count, a reasonable strategy is to procure HLA matched platelets. Approximately 4% of hematology-oncology patients require HLA matched platelets and approximately 20 to 25% of these patients will achieve a significant increase in post transfusion platelet counts with HLA antigen negative or HLA matched platelets. If 2 transfusions with HLA antigen negative or HLA matched platelets fail to produce a significant rise in post transfusion platelet count, subsequent transfusions should revert back to random apheresis platelets.

Several anecdotal strategies have been reported for controlling bleeding in thrombocytopenic patients when compatible platelet donors cannot be found in a timely manner. Transfusion of RBCs to increase the hematocrit to 30% or higher prior to platelet infusion, increases the likelihood of platelet contact with the endothelial surface of blood vessels (Ho CH, Transfusion 1998;38:1011-14). Some patients may benefit from repeated large boluses of two apheresis platelets. Large numbers of platelets may adsorb much of the circulating platelet antibody (Nagasawa T, Transfusion 1978;18:429-35). Continual platelet infusion of one half unit of apheresis platelet every 4 hours has also been advocated (Narvios A, Am J Hematol 2005;79:80). Concomitant administration of antifibrinolytic medication, such as Amicar, may decrease bleeding (Kalmadi S, Cancer 2006; 107:136-40). Recombinant factor VIIa or thrombopoietin receptor agonists such as romiplostim may also be considered. Intravenous immune globulin and plasma exchanges have not been found to be effective in reducing the refractory state. 

  1. Petz LD, Garratty G, Calhoun L, et al. Selecting donors of platelets for refractory patients on the basis of HLA antibody specificity. Transfusion. 2000; 40: 1446–1456.
  2. Hod E, Schwartz J. Platelet transfusion refractoriness. Br J Haematol. 2008; 142: 348-360.
  3. Schiffer CA. Management of patients refractory to platelet transfusion.  Leukemia.  2001; 15:683-685.
  4. Dzik S. How I do it: platelet support for refractory patients.  Transfusion.  2007; 47:374-378.
  5. Kopko PM, Warner P, Kresie L, Pancoska C. Methods for the selection of platelet products for alloimmune-refractory patients. Transfusion 2015; 55:235-344.
  6. Franchini M. The use of recombinant activated factor VII in platelet disorders: a critical review of the literature. Blood Transfus. 2009; 7 24-8.
  7. Curtis BR, McFarland JG. Platelet immunology and alloimmunization. In: Simon TL, Snyder EL, Stowell CP, et al. eds. Rossi’s Principles of Transfusion Medicine, 4th ed. Wiley-Blackwell, Hoboken, NJ, 2009.
  8. Berthelot-Richer M, Boilard B, Morin A, et al. Romiplostim efficacy in an acute myeloid leukemia patient with transfusion refractory thrombocytopenia. Transfusion. 2012; 52: 739-741.
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