Diagnosis and Discussion - Case 1120

Final Diagnosis

Immune-mediated Platelet Refractoriness

Discussion

In a healthy adult individual, platelets circulate at 150,000-400,000 / µL. Thrombocytopenia can result from either decreased production or increased destruction of platelets. The decision to transfuse platelets is a combination of the patient’s critical condition, platelet function, cause of thrombocytopenia and platelet count. Current guidelines recommend a threshold of less than or equal to 10 x 109/L for prophylactic platelet transfusions in a nonbleeding patient1. The recommendations for prophylaxis for invasive procedures is different and depends on the planned procedure.

Platelet products may either be whole-blood derived or apheresis platelets. In the United States, most platelets are collected by apheresis. A unit of apheresis platelets provides 3-4 x 1011 platelets, which is the equivalent of four to six units of platelets derived from whole blood2. A unit of apheresis platelets has an expected platelet increment of 35-45,000/µL.

Platelet refractoriness is suspected when posttransfusion platelet increments are lower than expected on more than one occasion. The corrected count increment (CCI) is the most commonly used equation for tracking platelet increments based on dosage and size of the patient. The Trial to Reduce Alloimmunization to Platelets (TRAP) study published these calculations as shown below; CCI uses body surface3.  A CCI of >7500 to 10,000 within 1-hour post transfusion is considered appropriate and is not suggestive of refractory4.

The post-transfusion platelet count should be obtained within an hour after transfusion, though in busy care centers, it may be obtained within 10 minutes after transfusion.  The timing of the count can give insight to the reason for the refractoriness. A low 1-hour CCI may suggest an immune-mediated cause (immune refractoriness); low 24-hour CCI following a normal 1-hour CCI may suggest non-immune reasons (clinical refractoriness).

Figure 1

Causes of Platelet Refractoriness

A low posttransfusion platelet increment can be the result of non-immune or immune-mediated causes. Clinical refractoriness/non-immune mediated causes are the most common, happening in 60-80% of refractory cases5. Even in patients where alloimmunization is clearly a causative factor, many of these patients also have other non-immune factors compounding the poor response to platelet transfusion6. Regardless, effort should be made to determine the cause so that treatment may be attempted.  Bleeding, splenomegaly, fever, sepsis, DIC are some of the causes of clinical refractory to platelet transfusions.

Immune refractory to platelet transfusion is mostly associated with HLA antibodies. HLA antibodies can develop from previous transfusions, pregnancy, and transplantations. Platelets do not express Rh antigens on their surface, but they do express ABO and HLA class 1 antigens. Class I consists of HLA-A, HLA-B, and HLA-C antigens, though platelets predominantly display HLA-A and HLA-B. Though significantly less common, human platelet antigen (HPA) antibodies have also been implicated though in only 2-8% of cases where patients had a history of multiple transfusions3. ABO incompatibility is associated with a reduced intravascular recovery but not to the degree that would contraindicate ABO-mismatched platelets a normal patient. Certain drugs, such as heparin or amphotericin, are associated with decreased posttransfusion platelet responses2. There are also drugs implicated in drug-induced antibody development that affect platelet increment levels7. These drugs are thought to interact with platelet membrane glycoproteins causing antibody development.

Management Strategies

In the management of patients experiencing platelet refractoriness, underlying non-immune clinical conditions should be addressed such as treatment for sepsis, fever, and/or bleeding.

Factors related to the platelet concentrate should also be considered. Platelets stored at 20-24C with continuous agitation have a shelf-life of 5-7 days. The intravascular recovery of stored platelets is significantly decreased at the end of the storage period2. In instances where refractoriness is suspected, the freshest platelets should be used.  Most institutions have a policy to avoid the use of ABO-mismatched platelets but in cases where refractoriness is being assessed, care should be taken to confirm ABO-matched products. 

If after a transfusion trial of ABO-matched platelets less than 48-hours-old, the platelet increment is still not satisfactory then immune-mediated causes need to be addressed. When immune-mediated causes are suspected, evaluation for HLA or HPA antibodies should be performed. If positive antibodies are found, there are several strategies that can be explored5.

1. Using HLA-matched platelets: 

HLA-matching reduces the risk of further alloimmunization8 but it also limits the available donor pool since it’s difficult to get a 4/4 match. HLA-matched platelets do not help in cases where HPA-antibodies are the culprit.

2. Crossmatching:

Crossmatching takes the patient’s serum and compares it to a panel of patient platelets to see what is compatible. Unlike with HLA-matched platelets, this method is fast since it does not require HLA-testing. Crossmatching also allows for assessment of HPA-antibodies. The downside of crossmatching is that it can further advance alloimmunization and it may be difficult to find a compatible match with patients that already have high alloimmunization.

3. Antibody specificity prediction (HLA compatible):

The use of HLA-matched platelets became practical when it was shown that partially matched donors still shown acceptable platelet recovery responses9. This method compares the patient’s known HLA-antibodies to a select pool of donors and selects donors that do not react. This method does not require a 4/4 HLA match so it increases the donor pool and still reduces the risk of further alloimmunization. The HLA compatible method does not help with HPA antibodies and requires HLA antibody testing.

Summary

Diagnosis and management of refractoriness to platelet transfusion is complex and requires frequent reassessment of the patient’s clinical scenario. As discussed, patients frequently have more than one causative factor for their platelet refractoriness, as with our patient experiencing sepsis with a history of myelodysplastic syndrome and a history of multiple transfusions.

Ideally, the best practice is to use fresh and ABO-matched platelets. This is not always achievable due to availability and platelet management systems, such as a last-in-first-out policy most blood banks practice to avoid waste.

Once non-immune mediated causes have been addressed, the CCI equation can be used to assess the platelet count increment. The best practice is to check the platelet count 10 minutes to 1 hour post-transfusion on two separate occasions.  A CCI of >7500 to 10,000 within 1-hour post transfusion is considered appropriate and is not suggestive of refractory.

If immune mediated causes have been confirmed, there are three main strategies that can be utilized in treatment management, each with its own advantages and disadvantages. These options are using HLA-matched platelets, Crossmatching, and using Antibody Specificity Prediction.

References

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  3. Trial to Reduce Alloimmunization to Platelets Study Group. Leukocyte reduction and ultraviolet B irradiation of platelets to prevent alloimmunization and refractoriness to platelet transfusions. N Engl J Med. 1997 Dec 25;337(26):1861-9. doi: 10.1056/NEJM199712253372601. PMID: 9417523.
  4. Blood Transfusion Therapy. 13th Edition, AABB, 2020.
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  6. Doughty HA, Murphy MF, Metcalfe P, Rohatiner AZ, Lister TA, Waters AH. Relative importance of immune and non-immune causes of platelet refractoriness. Vox Sang. 1994;66(3):200-5. doi: 10.1111/j.1423-0410.1994.tb00310.x. PMID: 8036790.
  7. Aster RH, Bougie DW. Drug-induced immune thrombocytopenia. N Engl J Med. 2007 Aug 9;357(6):580-7. doi: 10.1056/NEJMra066469. PMID: 17687133.
  8. Seftel MD, Growe GH, Petraszko T, Benny WB, Le A, Lee CY, Spinelli JJ, Sutherland HJ, Tsang P, Hogge DE. Universal prestorage leukoreduction in Canada decreases platelet alloimmunization and refractoriness. Blood. 2004 Jan 1;103(1):333-9. doi: 10.1182/blood-2003-03-0940. Epub 2003 Sep 4. PMID: 12958065.
  9. McCullough, J. (2012). Chapter 11 Clinical Uses of Blood Components. In Transfusion medicine (3rd ed., pp. 259–275)., John Wiley & Sons, Inc.