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June / July, 2001

Evaluation and Management of Platelet Refractoriness

Ileana Lopez-Plaza, M.D.
                                                                                                           

INTRODUCTION

Platelet transfusions are used for the treatment and/or prevention of bleeding in patients with a decreased number or function of platelets. Prophylactic platelet transfusion is the standard of care for malignancy or chemotherapy/radiation-induced thrombocytopenia. Therapeutic platelet transfusions are commonly used in the postoperative period after bypass heart surgery for platelet dysfunction and in thrombocytopenia associated with consumption coagulopathy (i.e., disseminated intravascular coagulopathy (DIC)).

 

BACKGROUND

Pooled platelets are random donor platelet concentrates obtained from units of whole blood that are pooled at the time of transfusion. Single donor platelets are collected by apheresis using a cell separator. This technique allows the simultaneous collection of several units of platelets during a single donation. An average single donor platelet collected by apheresis will contain an equivalent of 6-7 units of random donor platelets. The recommended platelet transfusion dose is 1 unit per 10 kilograms of body weight when using random pooled platelets1 or one unit of single donor platelets per transfusion episode. The recommended dose is targeted to elevate the platelet count to adequate hemostatic levels (40,000-50,000/μL). Occasionally ABO antibodies can reduce platelet survival. Clinical factors such as fever, sepsis, splenomegaly, active bleeding, use of amphotericin, veno-occlusive disease, DIC, early post hematopoietic stem cell transplant period and some dialysis procedures are associated with decreased survival of transfused platelets2,3,4.  Immune refractoriness, caused by allo- or auto-antibodies with specificities to the HLA or rarely, HPA antigens, can also complicate platelet transfusion support2,3,4.  

 

DIAGNOSIS

The expected platelet count increment after a platelet transfusion is 5,000-10,000/mL per unit of platelet concentrate transfused or 40,000-50,000/mL after the transfusion of pooled platelets based on 1 unit/10 kg of bodyweight or a single donor platelet. The patientís size and the number of platelets transfused influence the post-transfusion platelet increment. A formula (Figure 1)5 taking into account these two factors is the corrected platelet count increment, which provides a more accurate assessment of the platelet transfusion response. Most often, the post-transfusion platelet response is assessed clinically or by obtaining a 1-hour or 24-hour post-transfusion platelet count.  A poor 24-hour post-transfusion platelet count with an adequate 1-hour post-transfusion platelet count is most often associated with clinical refractoriness due to an increased utilization of platelets. Immune refractoriness, caused mainly by HLA antibodies, is associated with rapid clearance of the transfused platelets resulting in a poor 1-hour post-transfusion platelet count. Active bleeding and splenomegaly can also result in a poor 1-hour response. In the setting of a poor 1-hour post transfusion platelet count, an HLA antibody screen should be ordered to identify the presence of HLA antibodies. A positive HLA antibody screen in this setting strongly suggests the presence of immune refractoriness. Because management interventions are different, attempts to identify the etiology of the platelet refractoriness (clinical versus immune) must be made in order to provide appropriate management.

 

MANAGEMENT

The first step toward management of platelet refractoriness is to ensure that the patient has been transfused with ABO compatible platelets and an adequate dose for the patient's weight. A fixed number of platelets (approximately 10,000/mL per day) are consumed in the maintenance of vascular integrity, irrespective of the patient's baseline platelet count. Therefore, the proportion of platelets needed for this function will increase as the baseline platelet count decreases2.  The best treatment for clinical refractoriness is to treat the underlying clinical condition causing the refractoriness. If the patient is stable and there is no evidence of bleeding, prophylactic transfusions should be limited to platelet counts less than 10,000/mL. High risk patients or unstable patients should be transfused at 20,000/mL. If a patient with clinical refractoriness is to undergo an invasive procedure, a higher dose of platelets is recommended (1.5-2 units/10 kg of body weight) prior to the procedure. If a patient with clinical refractoriness is bleeding, an adequate therapeutic dose might require both a higher dose and an increase in the frequency of platelets transfusions (every 6-, 8- or 12-hours as opposed to once a day). The goal of this therapeutic approach is not solely to increase the platelet count but also to decrease or stop the bleeding. HLA-matched platelets are unlikely to provide any additional benefit to patients with clinical refractoriness unless alloimmunization is also present.  The indications for prophylactic and therapeutic platelet transfusions in patients with immune refractoriness are similar to those with clinical refractoriness. However, the transfusion of HLA-matched or crossmatch compatible platelets are required for an adequate transfusion response. The response of a matched platelet transfusion will depend on the degree of HLA matching as well as the specificities of the patient's antibodies3,4,5. A 1-hour post-transfusion platelet count will be needed to assess the response to the matched platelet transfusion. For patients with both clinical and immune refractoriness and life-threatening bleeding, numerous strategies have been used. For this infrequent clinical occurrence, the patient should be transfused with the best HLA-matched or crossmatched platelet available or with a higher dose of random pooled platelets (2-3 units/10 kg). Platelet transfusion support should be continued every 6-8 hours until bleeding is controlled.  If more intensive platelet support is unsuccessful, IVIG (1gm/kg X 2 days) may be given when short-term control of bleeding is required.   If necessary, the correction of abnormalities in the other components of the coagulation system should be pursued. If not contraindicated, the patient may be started on an antifibrinolytic agent (i.e., ε-aminocaproic acid). Epsilon aminocaproic acid appears to be useful in controlling bleeding in patients with thrombocytopenia due to bone marrow hypoplasia.

 

PREVENTION

In preparation for an expected long-term period of platelet transfusion support, previous platelet transfusion responses should be evaluated to assess platelet transfusion response.  A patient with previous platelet refractoriness may need HLA-matched or crossmatched platelets for transfusion support.   An HLA antibody screen should be obtained as part of the pre-transfusion evaluation. If ABO incompatibility has been identified during prior platelet transfusions, ABO-compatible platelets should be used. For an expected long-term period of platelet transfusion support, the transfusion of leukoreduced blood products6 (red cells and platelets) decreases the risk of becoming HLA alloimmunized. In patients with thrombocytopenia and minimal oral bleeding, the use of local antifibrinolytic agents (mouth rinse) might reduce the need for platelet transfusion support.

 

Figure 1.

Corrected Count Increment (CCI)1 =

Platelet count post - Platelet count pre x BSA (m2)
___________________________________________

Number of units transfused 
CCI < 5000/μL suggests platelet refractoriness  

 

REFERENCES

  1. Platelet Transfusion Therapy Consensus Conference.  JAMA 257:1777-80, 1987.  

  2. Slichter  SJ. Platelet Transfusion Therapy. Hematol Oncol Clin North Am 4:291-311, 1991.  

  3. Kickler TS. The Challenge of Platelet Alloimmunization: Management and Prevention.Transf Med Reviews 4:8-18, 1990.  

  4. Delaflor-Weiss E and Mintz PD. The Evaluation and Management of Platelet Refractoriness and Alloimmunization. Transf. Med Reviews 2:180-96, 2000.  

  5. Vengelen-Tyler V (ed): AABB Technical Manual, 13th ed., American Association of Blood Banks, Bethesda MD, 1999.  

  6. The Trial to Reduce Alloimmunization to Platelets Study Group; Leukocyte reduction and ultraviolet B irradiation of platelets to prevent alloimmunization and refractoriness to platelet transfusions. NEJM 337:1861-69, 1997.  

                                                                                                                                                                             

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