Transfusion medicine

Transfusion reactions & complications

Platelet refractoriness

Last author update: 11 May 2023
Last staff update: 11 May 2023

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PubMed Search: Platelet refractoriness

Adeyemi Sofoluwe, M.D.
Reggie Thomasson, M.S., M.D.
Page views in 2022: 335
Page views in 2023 to date: 388
Cite this page: Sofoluwe A, Choksi S, Elsadawi M, Thomasson R. Platelet refractoriness. website. Accessed September 21st, 2023.
Definition / general
  • Defined as a suboptimal platelet count response after multiple platelet transfusions
  • Often clinically assessed using the corrected count increment (CCI) calculation, which adjusts for the transfused platelet dose and the recipient's body size
  • Majority of cases are due to nonimmune factors (e.g., fever, infection, bleeding) compared to immune mediated factors (e.g., anti-HLA antibodies)
  • Poor platelet count response at 10 - 60 minutes may indicate immune mediated refractoriness and laboratory based testing is usually indicated (see Laboratory section), while poor response at 24 hours usually indicates nonimmune causes
Essential features
  • Suboptimal response of platelet counts following 2 or more transfusions with CCI of < 5,000/μL (or < 7,500/μL) when assessed within 1 hour after transfusion
  • Management and treatment vary based on etiology
    • Nonimmune: treat underlying condition
    • Immune: HLA, HPA and ABO matched platelets
  • Increased HLA alloimmunization prevalence in
    • Patients with hematologic malignancy or hematopoietic stem cell transplantation (HSCT)
    • Females with history of pregnancy (compared to males and females who have never been pregnant)
  • Leukoreduction of blood products has been shown to lower frequency of HLA alloimmunization and platelet refractoriness
  • PI: platelet increment
  • CCI: corrected count increment
  • PPR: percentage platelet recovery
  • HSCT: hematopoietic stem cell transplant
  • HLA: human leukocyte antigen
  • HPA: human platelet specific antigen
  • BSA: body surface area
  • PD: platelet dose
  • PRA: panel reactive antibody
  • TXA: tranexamic acid
  • Nonimmune mediated (≤ 80% of cases): usually from rapid consumption or sequestration (Blood 2005;105:4106)
    • Sepsis / infection, fever (temperature > 38.4 °C), bleeding, hypersplenism, disseminated intravascular coagulation (DIC)
    • Medications can have both nonimmune and immune mechanisms (e.g., vancomycin, amphotericin B and heparin)
    • Other possible causes include hepatic sinusoidal obstruction syndrome and graft versus host disease (GVHD) in HSCT patients
  • Immune mediated (≤ 20% of cases)
    • Prior antigenic exposure via transfusion, pregnancy or transplantation leads to alloimmunization against
      • Epitopes of class I HLA (A and B)
      • Human platelet specific antigens (HPA), although rarely implicated
    • ABO antigens are weakly expressed on platelets; therefore, incompatible platelet transfusion can reduce platelet survival (Br J Haematol 2015;171:297)
    • Drug dependent antibodies
    • Other immunogenic antigens implicated include CD36 (glycoprotein IV) due to anti-CD36 antibodies in CD36 deficiency recipients (Transfusion 2021;61:1932)
Clinical features and adverse effects
Screening / evaluation
  • Obtain platelet count within 10 - 60 minutes and at 24 hours posttransfusion on 2 separate occasions
  • A single apheresis platelet transfusion should increase the platelet count by ~30K - 50K/μL in an average sized recipient
  • Calculations used to assess platelet count response:
    • Posttransfusion increment (PI):
      • Simplest calculation, commonly used in routine clinical practice
        • PI = posttransfusion platelet count - pretransfusion platelet count (K/μL)
        • PI > 10,000/μL is considered a good response
    • Corrected count increment (CCI):
      • Calculated using the PI, the patient's body surface area (BSA) and the transfused platelet dose (PD)
        • CCI =
          PI x BSA (m2)
          PD (x 1011)
        • CCI > 5,000 (or > 7,500/μL) at 1 hour is considered an adequate response (Transfus Med Rev 2000;14:180)
        • TRAP study defined platelet refractoriness as a 1 hour CCI of < 5,000/μL on 2 sequential occasions, when transfusing ABO identical fresh platelets (N Engl J Med 1997;337:1861)
    • Percentage platelet recovery (PPR):
      • Calculated using the PI, the patient's total blood volume (TBV) and the PD
        • PPR =
           TBV x PI 
          PD (x 1011)
          x 100
        • PPR > 30% at 1 hour posttransfusion and > 20% at 20 - 24 h is considered a good response (Transfus Med 1993;3:91)
  • In nonimmune platelet refractoriness, the posttransfusion platelet count may be adequate; however, return to pretransfusion levels on repeat 24 hour testing
  • HLA testing is highly complex and is usually performed at reference labs
    • HLA genotyping (PCR)
    • HLA antibody analysis
      • Panel reactive antibody (PRA)
        • Historical method using a lymphocytotoxicity assay in which serum is reacted with a panel of HLA typed lymphocytes
          • Antibody binding to specific HLA antigens induces complement mediated cell death and dye uptake which is visible on fluoroscopy as red cells indicating a positive reaction
          • With negative reactions, the cells survive and dye is excluded, appearing green on fluoroscopy
        • PRA > 20% suggests probable HLA alloimmunization
      • Multiplex flow cytometric bead based assay
        • Beads coated with individual HLA antigens
        • Binding detected by staining with fluorescently labeled antihuman globulin
        • Antibody level determined by flow cytometry, flow microarrays or enzyme linked immunosorbent assay (ELISA)
    • HPA testing can be done concurrently with HLA testing or subsequently if HLA antibody testing is negative and patient continues to be refractory
    • Reference: Virchows Arch 2019;474:139
Case reports
  • 31 year old man with acute myeloid leukemia who developed platelet refractoriness (Asian J Transfus Sci 2021;15:90)
  • 64 year old woman with resolution of platelet refractoriness with secondary acute myeloid leukemia after allogenic bone marrow transplantation (Haematologica 2019;104:e121)
  • 69 year old woman who developed platelet refractoriness following atorvastatin use (Cureus 2021;13:e12502)
  • 74 year old man who developed refractory thrombocytopenia within 1 day of receiving the Moderna SARS-CoV-2 vaccine (J Blood Med 2021;12:221)
  • Nonimmune mediated platelet refractoriness:
    • Treat underlying condition (e.g., discontinue medication, treat infection, treat cause of DIC)
  • Immune mediated platelet refractoriness:
    • ABO identical platelets, stored < 48 hours
    • Crossmatch compatible platelets
      • Can detect incompatibility due to HLA or HPA antibodies
      • Further alloimmunization possible
      • Can be more convenient and less expensive than HLA based strategies depending on institution
    • HLA matched platelets
      • Molecular HLA typing and single antigen testing have supplanted the use of the antigen match grade system (e.g., A, BU, B2U, BX, C matches, etc.)
      • Large HLA typed donor population required to find a match
      • Potentially compatible platelets may be excluded even though not an HLA match
      • Computer based matching algorithms help predict compatibility based on defined epitopes (Hum Immunol 2007;68:12)
    • HLA antigen exclusion platelet units
      • Lack the antigen for which the patient has specific antibodies
      • Not indicated when the PRA is low (< 20%)
      • Further alloimmunization possible
    • HPA matched platelets if anti-HPA antibodies are detected
    • Return to random platelets if patient continues to have poor posttransfusion increments with the strategies listed above
  • Immunosuppressive therapy (e.g., IVIG, rituximab) with or without therapeutic plasma exchange may be considered in extenuating circumstances (limited data)
  • For management of bleeding, consider
    • Antifibrinolytic agents (lysine derivatives), e.g. tranexamic acid (TXA) and minocaproic acid
    • Continued platelet transfusions (may provide some hemostatic benefit) (Br J Haematol 2015;171:297)
  • Prevention:
    • Leukoreduction reduces the exposure to multiple HLA class I and HPA antigens
    • ABO matched platelets (limited data)
Sample assessment & plan
  • Assessment: Jane Doe is a 55 year old woman with a recent diagnosis of acute myeloid leukemia (AML) admitted for induction chemotherapy. Her course was significant for severe thrombocytopenia (platelet count of 15,000/μL), diffuse petechiae and minor nose bleeds. Despite multiple platelet transfusions, the patient continues to have low counts and lower than expected platelet increments. The CCIs for the next 2 successive platelet transfusions were both < 5,000/μL. Transfusion medicine service was consulted for assistance in transfusion management.
  • Plan: The patient's clinical history, current presentation and preliminary screening workup are all suggestive of immune mediated platelet refractoriness.
    • Order reference lab workup for HLA / HPA antibody screen
    • In the meantime, provide crossmatch compatible platelets (continue if adequate platelet response and compatible platelets are available)
    • Depending on lab screening results, consider use of either HLA / HPA antigen matched and HLA antigen exclusion in order to optimize platelet availability
    • If the strategies listed above fail, return to continued transfusion of random platelets to offer some hemostatic benefit
    • Consider use of antifibrinolytics if bleeding continues
Differential diagnosis
Board review style question #1
A 56 year old woman with myelodysplastic syndrome (MDS) requiring weekly transfusions, presented to the Emergency Department with pancytopenia and bright red blood per rectum. Platelet count at presentation was 15K/uL. She received two units of RBCs and one apheresis platelet. A CBC obtained within an hour of platelet transfusion revealed a platelet count of 18K/uL and her hemoglobin increased from 5.6 g/dl to 8.0 g/dl. Despite repeated platelet transfusions, the CCI never went above 3K/uL when assessed within an hour after transfusion. What is the most probable cause of this patient’s refractoriness and the best initial step in management?

  1. Alloimmunization and stop platelet transfusions until HLA typing and antibody screen is resulted
  2. Alloimmunization and transfuse ABO matched platelets
  3. Immune thrombocytopenia (ITP) and start steroids
  4. Progression of MDS and start chemotherapy
Board review style answer #1
B. Alloimmunization and transfuse ABO matched platelets

This patient is currently bleeding, so it is important to continue providing therapeutic hemostatic support with platelet transfusion. The patient is in platelet refractory state as demonstrated by the failure to achieve an expected platelet count increment within an hour of transfusion on multiple occasions. As such, transfusion of ABO matched platelets as a first step is indicated, while evaluating for other causes of platelet refractories including the presence of anti-HLA antibodies. Patient’s MDS associated pancytopenia requires significant blood product transfusions, predisposing patient to multiple antigens and hence alloimmunization. Progression of her MDS would not necessarily have a suboptimal CCI, thus chemotherapy would not be the best initial step in management. ITP is a diagnosis of exclusion characterized by an acquired thrombocytopenia due to autoantibodies directed against platelet antigens. ITP does not affect multiple hematopoietic cell lineages; therefore, pancytopenia is not observed.

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Reference: Platelet refractoriness
Board review style question #2
A 39 year old woman with AML has become refractory to platelet transfusions, evidenced by multiple suboptimal platelet count increments assessed within 1 hour of transfusion. She has recently developed minor bleeding from her nasal mucosa as well as petechiae on her lower extremities. Which of the following HLA antigen typings would be the most useful to optimize her platelet transfusion response?

  1. HLA-A and HLA-B antigens
  2. HLA-A and HLA-C antigens
  3. HLA-A and HLA-DR antigens
  4. HLA-B and HLA-C antigens
Board review style answer #2
A. HLA-A and HLA-B antigens

Platelets express a variety of antigens on their surface, including HLA Class I, ABO and HPAs. Antibodies directed against HLA Class I (HLA-A and HLA-B) are associated with platelet refractoriness but rarely HLA-C antibodies. ABO identical / compatible platelets may help improve the platelet response in certain cases. Antibodies directed towards HPAs can be considered in cases where there is persistent high suspicion for immune mediated refractoriness while the HLA antibody screen is negative. HLA Class II antigens (HLA-DR, HLA-DQ, and HLA-DP) are not found on platelets.

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Reference: Platelet refractoriness
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