|
 
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| REVIEW ARTICLE |
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| Year : 2019 | Volume
: 4
| Issue : 2 | Page : 140-147 |
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Platelet refractoriness
B Sunil Rajadhyaksha, D Priti Desai, A Anisha Navkudkar
Department of Transfusion Medicine, Tata Memorial Hospital, HBNI, Mumbai, Maharashtra, India
| Date of Submission | 02-Aug-2019 |
| Date of Acceptance | 31-Aug-2019 |
| Date of Web Publication | 17-Oct-2019 |
Correspondence Address:
Dr. B Sunil Rajadhyaksha
Department of Transfusion Medicine, Tata Memorial Hospital, HBNI, Mumbai, Maharashtra
India
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/GJTM.GJTM_45_19
Platelet transfusion support is extensively required for hemato-oncology patients who are multiply transfused. Platelet refractoriness can represent a significant clinical condition that complicates the platelet transfusion support in such patients. It remains a challenge associated with an increased bleeding risk, longer hospital stays, and increased morbidity and mortality. Causes for refractoriness are broadly divided into nonimmune and immune causes. Approximately two-thirds of refractory episodes are due to nonimmune factors while one-third are due to immune factors. Common formulae to assess platelet refractoriness include corrected count increment (CCI), posttransfusion platelet increment, and percentage platelet recovery. Measurement of CCI is one of the best parameters to differentiate between immune and nonimmune causes. In nonimmune factors which are associated with increased platelet consumption, treating the underlying cause and increasing the frequency of transfusion should be considered. However, in immune factors which are due to increased destruction of platelets owing to alloimmunization, other strategies such as ABO-identical/ABO-compatible fresh platelets, human leukocyte antigen-matched platelets, and crossmatched platelet transfusions should be considered. The newer approach includes epitope-matched platelet transfusion which is still in amateur stage. The strategies in the prevention of alloimmunization include leukoreduction of blood components, reducing donor exposure by providing single-donor platelets, and providing ABO-compatible platelets from the beginning of the treatment. This review will address the causes of platelet refractoriness and practical approach to the diagnosis, management, and its prevention.
Keywords: Alloimmunization, corrected count increment, platelet refractoriness, platelet transfusions
How to cite this article:
Rajadhyaksha B S, Desai D P, Navkudkar A A. Platelet refractoriness. Glob J Transfus Med 2019;4:140-7 |
| Introduction | |  |
Platelets are discoid-shaped cells, anucleate, 3–5 μ in diameter with a normal circulating count of 150–400 × 109 platelets/L. The hemostatic response of platelets at sites of vascular injury involves platelet shape change, adherence to the site, platelet plug formation, scaffolding, and cytokines secretion that are essential for repair.[1] Thus, platelets are a crucial component for maintaining vascular integrity. Thrombocytopenia (low circulating platelets) can lead to bleeding symptoms such as bruising, petechia, nose bleed, bleeding gums, intracranial hemorrhage, and death. The maximum platelet life span of 10.5 days and a fixed requirement for 7.1 platelets per microliter of blood per day or about 18% of the normal rate of platelet turnover is required to maintain vascular integrity.[2] Hence, larger proportion of the platelet pool is required to support vascular integrity for thrombocytopenic patients. Many patients have an adequate platelet count increment after platelet transfusions, but unsatisfactory posttransfusion platelet increment (PPI) can be observed in about 30% of patients.[3],[4],[5] Historically, it has been described in 20%–60% of patients who have received multiple platelet transfusions.[6] This inadequate response to platelet transfusion leads to an increased risk of morbidity and mortality, as well as increased hospital stays.
Data acquisition
Data for the study was obtained by extensively searching for the key words in google and Pubmed databases and the citations in relevant studies.
| Definition | | |
Platelet refractoriness is simply defined as less than expected posttransfusion platelet count increment and is due to the shortened survival of the transfused platelets in the recipient's circulation. It is also defined as a lack of adequate response in PPIs after two or more consecutive platelet transfusions of an adequate dose of allogeneic platelets.[7]
[Table 1] mentions the different formulae used to assess platelet refractoriness; however, the 1-h corrected count increment (CCI) is predominantly used as the objective measure of whether a patient is refractory to platelet transfusion.[8]
The pattern of response to PPI is shown in [Figure 1].[13]
Two patterns can be seen in refractory patients. A normal increment at 1 h following transfusion with return to the baseline count within 24 h is typical of the shortening of platelet survival seen with nonimmune causes. The second pattern consists of little or no increment in platelet count, even within 1 h of transfusion; this pattern is seen with immune cause of platelet refractoriness, i.e., alloimmunization.
| Etiology | | |
The causes of platelet refractoriness are often multifactorial and can be grouped into nonimmune and immune causes[10],[12],[14] [Figure 2].
Nonimmune causes
Approximately two-thirds of refractory episodes are due to nonimmune causes which include:
Clinical conditions
Sepsis
Association of sepsis with thrombocytopenia is well known.[15] Few of the following reasons are contributory to refractoriness in sepsis:
- Up to 30% of critically ill thrombocytopenic patients have nonspecific platelet-associated antibodies causing thrombocytopenia[16]
- Hemophagocytosis is common in bone marrow of septic patients which can cause thrombocytopenia[17]
- Platelets can be sequestered at the level of activated endothelium, playing an important role in response of a recipient to sepsis.[18],[19]
Fever
In hematological malignancy cases, the triad of fever, infections, and medications is the most common cause of refractoriness.[20]
Disseminated intravascular coagulation
It is characterized by consumptive coagulopathy leading to fibrin deposition in small vessels.[1] In patients with acute promyelocytic leukemia, due to chemotherapy-induced or spontaneous release of tissue factor from granules of leukemic cells, patients may present with disseminated intravascular coagulation.[21] Consumptive coagulopathy activates and immobilizes platelets leading to poor CCIs following platelet transfusion.[22]
Bleeding
Persistent external or internal bleeding after platelet transfusions can be considered as a potential indicator of platelet refractoriness.[23]
Splenomegaly
As spleen is the major site of platelet destruction, it is the major factor affecting platelet count increment.[5] Spleen sequesters a large proportion of platelet pool, and larger spleens are associated with more sequestration. Furthermore, hypersplenism is associated with reduced time interval until next transfusion.
Hematopoietic stem cell transplantation, graft-versus-host disease, and veno-occlusive disease
Patients undergoing hematopoietic stem cell transplantation (HSCT) receive multiple platelet transfusions, and hence, they are prone to alloimmunization. HSCT may or may not be an independent risk factor for the development of platelet refractoriness.[24] A study by Jones et al. found that patients undergoing HSCT found no difference in the incidence of refractoriness between patients with and without veno-occlusive disease (56% and 60%, respectively).[25] Graft-versus-host disease (GVHD) is a risk factor in HSCT patients, and there is an increased incidence of autoantibodies to platelets in patients with acute or chronic GVHD.[26],[27]
Drugs
Thrombocytopenia caused by drugs is relatively common, with many drugs implicated in this process [Table 2].[28],[29]
Platelet characteristics
Platelet dose/platelet quality
Some patients require proportionally more platelets to achieve adequate increments, and hence, it must be adjusted to the patient's blood volume. Other factors that may adversely affect the quality of the platelets during storage include incorrect storage temperature, improper mode of agitation, and pH (lower than 6.2).[7]
Platelet age
The possible advantage of fresher platelets (<48–72 h) in improving platelet transfusion response in patients with nonimmune refractoriness has been attributed to activation of platelets during storage.[30] An analysis observed in the TRAP study found that platelets stored ≤ 48 hours were associated with significantly higher increments and longer intervals between transfusions.[31]
Leukocyte reduction
The incidence of platelet refractoriness has been decreased with the use of leukocyte-reduced blood components. A significant decrease in the alloimmunization rate leukocyte-reduced platelets was transfused as compared to nonleukocyte-reduced platelet components, which was noted by TRAP study (7%–8% vs. 16%).[11] Leukoreduction does not appear to affect the rate of alloimmunization to platelet-specific antigens.
ABO compatibility
It is a common and acceptable practice to transfuse ABO-nonidentical platelets to patients, especially when ABO-identical platelets are not available. Platelet increments following transfusion of ABO-nonidentical platelets demonstrate a weak response compared with transfusion of ABO-identical platelets with decreased recovery but adequate survival.[32],[33],[34],[35],[36]
Leukocyte content of platelet unit and ABO blood group are platelet unit related factors. However, both these can affect platelet response through the immune mechanism and hence can also be considered an immune cause of platelet refractoriness.
Immune causes
Approximately one-third of refractory episodes are due to immune causes. Immune causes include human leukocyte antigen (HLA) alloimmunization and/or human platelet antigen (HPA) alloimmunization due to prior exposure from pregnancy, transfusion, or transplantation. Other causes include ABO incompatibility, platelet autoantibodies (e.g., autoantibody to platelet glycoprotein), and drug-related platelet antibodies.
Human leukocyte antigen alloimmunization
It is a major risk factor for refractoriness to platelet transfusions. HLA alloimmunization is more common than HPA antibodies and is believed to be the primary cause of immune refractoriness.[37],[38] Although platelets express only HLA Class I antigens, HLA Class II antigens present on leukocytes may be essential for the development of alloimmunization to HLA Class I antigens which may occur through prior transfusion or pregnancy. HLA-A and HLA-B antigens are the predominant HLA antigens expressed on platelets. The risk of HLA antibody formation may be increased in patients who are multiply transfused. Primary HLA alloimmunization occurs at a median of 3–4 weeks (2–56 weeks) after the first transfusion in a recipient of multiple transfusions.[39] Patients with previous HLA antigenic exposure are at high risk to develop alloimmunization and platelet refractoriness.[40] The frequency of HLA alloimmunization also varies with a patient's underlying diagnosis, previous history of pregnancy, and transfusion. The majority of clinically relevant HLA antibodies are directed against epitopes of Class I HLA and are shown to be immunoglobulin G (IgG).[41] The process of indirect allorecognition in the spleen involves host's ability to generate an IgG response to transfused platelets.[14] Thus, HLA antibodies account for the majority of cases of immune platelet refractoriness, with platelet-specific antibodies being much less common.
Human platelet antigen alloimmunization
While alloimmune platelet refractoriness almost always results from the production of antibodies to HLA Class I antigens on the platelet surface, antibodies to platelet-specific antigens (HPA) have also been discussed as a cause for refractoriness to platelet transfusion. In various studies of multitransfused hematology patients, specific HPA antibodies occur at a frequency of 8% to 25%.[11],[20] Usually, they are found in combination with HLA antibodies, but they may also occur in isolation.[14],[42]
ABO incompatibility
Platelets express ABH antigens but not Rhesus antigens on its surface. The ABH antigens expressed are a result of intrinsic molecules due to endogenous synthesis and extrinsic molecules, as a result of adsorption of soluble antigens found in plasma.[43] Earlier, it was common to transfuse ABO-mismatched platelets; however, it became obvious that ABO incompatibility in platelet transfusion affects the efficacy of transfusion.[44] Different studies mention that the patients receiving platelet transfusions with major ABO incompatibility require transfusions at smaller intervals compared to ABO-identical platelets.[45],[46],[47]
Other causes
Other immune causes include platelet autoantibodies (e.g., platelet refractoriness related to an autoantibody to platelet glycoprotein) and drug-related platelet antibodies.[42]
| Diagnostic Approach | | |
- Measuring response to platelet transfusion with the help of formulae given in [Table 1]. One of the best parameters is a measurement of CCI, and platelet refractoriness due to immune cause is defined as a CCI <7500/μL for at least two sequential platelet transfusions[10]
- Determining the cause of refractoriness, i.e., immune or nonimmune cause of platelet refractoriness and treating the underlying condition accordingly
- Panel reactive antibody (PRA): It determines the percentage of recipient antibodies directed against the HLA antigens. PRA of >20%–30% suggests probable HLA alloimmunization[42],[48]
- Platelet antibody screening assay: Antibody screen to HLA Class I and platelet-specific antibodies can be detected by solid-phase red cell adherence assay (SPRCA) and enzyme-linked immunosorbent assay (ELISA), monoclonal antibody-specific immobilization of platelet antigen, platelet immunofluorescence test, flow cytometry, etc.
- Platelet crossmatch: Donor platelets with recipient serum/plasma can be tested by SPRCA, ELISA, and flow cytometry crossmatch. Incompatible crossmatch indicates the presence of antibodies and hence platelet refractoriness.
| Management of the Alloimmunized Patient | | |
In cases of nonimmune platelet refractoriness, the underlying illness must be treated. In cases of immune-mediated refractoriness, there are several strategies to consider when selecting platelets for these patients: provision of HLA-matched platelets or HLA “compatible” (antigen-negative) platelets, platelets selected by crossmatch tests, and methods to reduce alloimmunization.
Furthermore, given the transient nature of antibody production, patients diagnosed with refractoriness need to be regularly reassessed (approximately monthly) for the presence/specificity of antibodies in order to assure the provision of compatible platelet units and avoid unnecessary use of more expensive and difficult to obtain compatible units.
Platelet selection
Once antibodies to HLA or HPA are identified, compatible platelet products need to be made available.
ABO-matched platelets
The initial approach of managing platelet refractory patients should be to select ABO-identical/ABO-compatible fresher platelet units.[49],[50]
Human leukocyte antigen-matched platelets
The traditional management of patients with HLA antibodies is to provide platelets from donors HLA matched for the HLA-A and HLA-B loci. HLA-matched donors can be found either among family members or via a registry of HLA-typed unrelated individuals if available.[51],[52],[53] The degree of match, based on the traditional classification system, can predict the success of posttransfusion platelet count increments. Grade A and BU (B1U or B2U) HLA-matched platelets are associated with the best increases in platelet count.[54]
Cross-reactive group-matched platelets
Selection of platelet donors with antigens in the same “cross-reactive groups” (CREGs) as the patient's antigens has been demonstrated to be nearly as successful in supporting alloimmune platelet refractoriness as HLA-matched transfusions. Expanding the available number of units with the use of CREGs can significantly increase the pool of potential “compatible” donors. HLA-matched donors are frequently unavailable for many patients, particularly those who are highly alloimmunized. Under these circumstances, transfusion of platelets from partially mismatched donors may provide adequate responses.[49],[55]
Crossmatch-compatible platelets
Another possible approach is to identify aphaeresis platelet units compatible by crossmatching with the patient's plasma. The SPRCA test is the most widely used method for platelet crossmatching.[50] Compared with HLA matching strategies, crossmatching can be both more convenient and economical. Crossmatching allows for a quick and effective selection of units from the available inventory and can be performed in a few hours as opposed to the days it may take to perform patient testing and to identify, recruit, collect, and test an appropriate HLA-matched donor. It is also of benefit to patients with uncommon HLA types where it would be very difficult to find an HLA-matched donor.[56] In addition, it avoids the exclusion of HLA mismatched but otherwise compatible donors, thereby increasing the number of potentially compatible units. This method is feasible in resource-limited nations.
Epitope-matched platelets
Alternative computerized matching techniques are now emerging; for example, the HLA matchmaker is a software algorithm that predicts HLA compatibility including acceptable mismatched options. Eplets are considered as essential components of HLA epitopes recognized by antibodies. Therefore, the eplet version of HLA matchmaker represents a more complete collection of HLA epitopes and provides an elaborate assessment of HLA compatibility. HLA epitope matching approach in immune refractory patients can have impressive 1-h CCI results.[57] This technique requires HLA-typed voluntary platelet donor registry to make the eplet-matched platelets available whenever required and hence not feasible in resource constraint countries.
[Table 3] mentions the advantages and disadvantages of different methods to support platelet transfusions in refractory patients. [Figure 3] mentions the algorithm for the diagnosis and management of platelet refractoriness. | Table 3: Advantages and disadvantages of different methods to support platelet transfusions in refractory patients
Click here to view |
 | Figure 3: Algorithm for diagnosis and management of platelet refractoriness
Click here to view |
Other treatment aspects in platelet refractoriness include immunosuppression, rituximab, intravenous immunoglobulin, plasma exchange, antifibrinolytic agents, and recombinant factor VIIa.
| Prevention of Platelet Refractoriness | | |
Leukocyte depletion
Studies observed that leukocyte depletion below 5 × 106 per transfusion is effective in the prevention of primary HLA alloimmunization and results in <5% HLA antibody formation.[40],[58]
Reduction of donor exposure
Primary HLA alloimmunization occurs at a median of 3–4 weeks after the first transfusion in a recipient of multiple transfusions.[39] Reduction of donor exposure by the use of apheresis single-donor platelets showed that alloimmunization was postponed.[59]
Providing ABO-identical or ABO-compatible platelets
A reduction in posttransfusion platelet count increments has been demonstrated with transfusion of ABO-nonidentical platelets as compared to transfusion of ABO-identical platelets.[60] The transfusion of only ABO-identical platelets to patients requiring ongoing platelet support yields better increments, a reduction of overall platelet requirement, and a decrease in platelet refractoriness.[61],[62]
| Summary | | |
Major advances have occurred in the management of patients with hemato-oncological disorders. Platelet transfusion support plays a vital role in its management as these patients are multiply transfused. Moreover, platelet refractoriness once developed poses a challenge to cater to the platelet transfusion needs of such patients. Hence, understanding the etiology, treating the underlying conditions and prevention of development of refractoriness forms the pillars of its management.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3]
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