Ryan Thomas, MD
Sarah Barnhard, MD

Platelet transfusions have become a mainstay of treatment that are invaluable in the management of patients with hematologic and oncologic disorders, significantly reducing the incidence of hemorrhagic complications in these patients.1,2 It has been shown that 25% to 70% of patients with hematologic disease and cancer experience at least one inadequate increment in platelet count after transfusion during the course of treatment.3

Definition

“A post-transfusion platelet increment that is less than expected” is a simple and unembellished (and nevertheless accurate) definition for the rather complex entity known as platelet refractoriness. In order to make an accurate diagnosis a more precise definition was needed, which led to the development of multiple formulae used to define specific thresholds at which platelet refractoriness can be diagnosed. The most recommended and the most commonly used of these formulae (and the one we use at UC Davis) is the 1-hour corrected count increment (CCI).1,4

The CCI should be calculated using a post-transfusion platelet count collected no more than 60 minutes after transfusion. The number of platelets transfused can be approximated knowing that 1 apheresis platelet unit contains about 3.0 x 1011 platelets.

A formal and specific definition for platelet refractoriness using the CCI was outlined in the Trial to Reduce Alloimmunization to Platelets (TRAP) study.4,5

Platelet Refractoriness = A poor response to platelet transfusions on at least two separate sequential occasions using ABO identical platelet units that are less than 72 hours old, with a “poor response” defined as a CCI of less than 5,000/uL calculated 15 minutes to 60 minutes post-transfusion.

Etiology

The causes of platelet refractoriness can be separated into non-immune and immune categories.1,4 Non-immune causes are more common than immune causes, and include the following:

FeverVeno-occlusive diseaseSepsisGraft vs host disease (GvHD)SplenomegalyMedicationsDisseminated intravascular coagulation (DIC)ABO incompatibilityBleedingInadequate storage of platelet units

 

Immune causes include alloimmunization to common blood cell antigens such as human leukocyte antigen (HLA) epitopes or platelet specific antigens such as those in the human platelet antigen (HPA) system. Alloimmunization can occur due to exposure from pregnancy, transfusions, or transplantations.

Sensitization to HLA system and HPA system antigens results from contamination of the donor product with donor lymphocytes, leading to alloimmunization via the direct pathway (i.e. host lymphocytes recognize foreign antigens presented on foreign HLA molecules by donor antigen-presenting cells) and the indirect pathway (i.e. host antigen-presenting cells process foreign donor antigens and present them to host lymphocytes). Since the adoption of near-universal leukoreduction of blood products (all UC Davis blood products are leukocyte-reduced) there has been a significant reduction in the incidence of platelet refractoriness due to removal of donor lymphocytes and antigen presenting cells from the blood products.4,5 However, leukoreduction has no impact on alloimmunization via the indirect pathway of antigen presentation.

Of note, only a fraction of patients with risk factors for alloimmunization will develop HLA and/or HPA antibodies, and in the patients that do develop antibodies, approximately 50% will manifest with platelet refractoriness. In other words, not all detectible alloantibodies are clinically significant.

Our Practice

Testing for immune causes of platelet refractoriness and providing HLA matched units is expensive (approximately 2x the cost of random platelet transfusions) and should only be considered in patients with high suspicion for platelet alloimmunization. For these reasons, when platelet refractoriness is suspected, it is important to consider the following:

1. Is the patient actively bleeding or at high risk of bleeding?

In actively-bleeding patients with a platelet count less than 30,000/uL or patients at high risk of bleeding with a platelet count less than 10,000/uL, a slow platelet infusion (one half-apheresis unit of platelets transfused over 3-4 hours) can be considered, even if the patient has suspected platelet refractoriness. The slow infusion of platelets may improve hemostasis even when the patient is rapidly consuming all transfusions (DIC, acute leukemia, active bleeding, post-surgical, etc). Waiting for results of laboratory testing should not delay patient care.

2. Does the patient likely have a non-immune cause of platelet refractoriness?

Non-immune causes are the most common causes of platelet refractoriness. The patient should be evaluated and treated for any potential non-immune causes.as first line.

3. Is the patient refractory to platelet transfusion?

At least two separate 15-minute to 60-minute post-transfusion CCI values should be calculated on patients who are suspected to be refractory to transfusion. The platelets transfused should be ABO compatible.

If the patient is platelet refractory and there is high suspicion for antibody mediated platelet refractoriness, a platelet refractory investigation should be initiated. All investigations require Transfusion Services guidance. In general, the first step of testing should be screening for anti-HLA and anti-HPA antibodies. The screen requires send-out testing to the blood supplier reference laboratories. If the screen is positive for anti-HLA antibodies, the patient's HLA type can be determined with additional send-out testing. Platelet donors matched to the patient's HLA type can be recruited or supplied by the blood supplier. In some patient populations (eg stem cell/solid organ transplant), the patient's HLA type may have been included as part of a transplant work-up and can be communicated to transfusion services without additional testing.

In cases with severe thrombocytopenia (<10K/uL) who are high risk of bleeding or actively bleeding, or in cases of patients with anti-HPA or anti-glycoprotein antibodies, a platelet crossmatch (Capture-P, Immucor) can be considered. The platelet crossmatch is a send-out test performed at the blood supplier immunohematology reference lab and has a high rate of false positivity due to interference with medications and acute phase reactants.

Management Algorithm

Below is an algorithm slightly modified from one proposed by Hod and Shwartz1 to reflect our practice at UC Davis regarding management of suspected platelet refractoriness.

References:

  1. Hod, E., & Schwartz, J. (2008). Platelet transfusion refractoriness. British Journal Of Haematology, 142(3), 348-360. doi: 10.1111/j.1365-2141.2008.07189.x
  2. Bayer, W., Bodensteiner, D., Tilzer, L., & Adams, M. (1992). Use of Platelets and Other Transfusion Products in Patients with Malignancy. Seminars In Thrombosis And Hemostasis, 18(04), 380-391. doi: 10.1055/s-2007-1002577
  3. Vassallo, R., & Norris, P. (2016). Can we “terminate” alloimmune platelet transfusion refractoriness?. Transfusion, 56(1), 19-22. doi: 10.1111/trf.13411
  4. Stanworth, S., Navarrete, C., Estcourt, L., & Marsh, J. (2015). Platelet refractoriness – practical approaches and ongoing dilemmas in patient management. British Journal Of Haematology, 171(3), 297-305. doi: 10.1111/bjh.13597
  5. Leukocyte Reduction and Ultraviolet B Irradiation of Platelets to Prevent Alloimmunization and Refractoriness to Platelet Transfusions. (1997). New England Journal Of Medicine, 337(26), 1861-1870. doi: 10.1056/nejm199712253372601
  6. Manis, J., & Silberstein, L. (2016). Platelet refractoriness: it's not the B-all and end-all. Blood, 127(14), 1740-1741. doi: 10.1182/blood-2016-02-695437
  7. Slichter, S. (2005). Factors affecting posttransfusion platelet increments, platelet refractoriness, and platelet transfusion intervals in thrombocytopenic patients. Blood, 105(10), 4106-4114. doi: 10.1182/blood-2003-08-2724