Sage Journals: Discover world-class research

Abstract

Platelet transfusion refractoriness (PTR) is a conditioikb1n where platelet counts fail to increase adequately in several transfusions, often found in hemato-oncological situations. PTR poses life-threatening risks to patients, especially in cases when the platelet is very low, and transfusion is life-saving. It can be differentiated into immune or non-immune causes. While non-immune causes predominate, immune factors, particularly anti-HLA antibodies, are also notable in many cases. Accurately determining if platelet transfusion failure originates from an immune or non-immune cause is vital due to differing treatments, particularly the need for HLA-compatible platelets with immune causes. Yet, a lack of consensus exists regarding the diagnostic methods and treatment modalities. Therefore, this review aims to explore the origins, mechanisms, diagnostic criteria, and management approaches concerning PTR.

PLAIN LANGUAGE SUMMARY TITLE

Platelet Transfusion Failure

PLAIN LANGUAGE SUMMARY

Platelet transfusion refractoriness (PTR) is when platelet levels do not rise enough after several transfusions, often seen in malignancy and blood disorder. It's risky, especially when patients urgently need platelets to survive. PTR can happen because of immune or non-immune reasons. While non-immune causes are more common, immune factors, like anti-HLA antibodies, are also important. Figuring out if PTR is from an immune or non-immune cause is crucial because treatments differ, especially needing matching platelets for immune causes. But, there is still no agreement on how to diagnose and treat PTR. This review looks at why it happens, how to diagnose it, and ways to manage it.

Keywords

Platelet transfusion PTR platelet

Introduction

Platelet transfusion is a commonly utilized treatment in various hemato-oncological situations. It is mostly used for prophylactic purposes to prevent bleeding in patients undergoing thrombocytopenia-induced therapy, such as chemotherapy and hematopoietic cell transplantation. It could also serve a therapeutic purpose as a treatment for patients experiencing acute bleeding due to thrombocytopenia.¹ Since their initial use in 1959, platelet transfusions have significantly reduced the incidence of spontaneous grade 2 or higher bleeding in patients with hematologic malignancies undergoing chemotherapy.^2,3 Additionally, certain conditions like myelodysplastic syndrome (MDS) may require multiple platelet transfusions.⁴ However, in some patients, platelet counts fail to increase adequately on multiple occasions, a condition known as platelet transfusion refractoriness (PTR).⁵ PTR was identified in 7%–14% of hemato-oncological patients, with a notably higher prevalence in certain oncology cases, such as acute myeloid leukemia, where the incidence can reach up to 30.4%.^6–8 PTR causes many burdens for patients, such as longer periods of hospitalization and greater expenses, but more importantly, decreased survival for its life-threatening consequences from increased risk of bleeding.⁹ Management for PTR has advanced significantly in the past few decades with the development of Human Leucocyte Antigen (HLA) biology, which includes HLA typing and HLA antibody detection/identification. However, there is currently no consensus on the exact diagnosis nor the optimal approach for treating PTR, which remains a complex and costly challenge.¹⁰ This review will therefore explore the etiology and mechanisms of PTR in greater depth, including its diagnosis and current management strategies.

Epidemiology

Platelet transfusion refractoriness is commonly observed in patients receiving platelet transfusion, particularly in those with hemato-oncological disorders. Its incidence varies among studies, with rates as low as 7% in hematological diseases and as high as 30%–70% in multi-transfused patients.^6,11 The incidence of refractoriness is high among patients with severe aplastic anemia (34%), patients receiving multiple platelet transfusions (27.6%), and patients with acute myeloid leukemia receiving induction chemotherapy (10%).^12–14 In critical care settings, PTR rates are often high. One study found that more than 50% of patients in the ICU who received at least two platelet transfusions experienced PTR, especially those who were younger, admitted for medical or surgical reasons, and had a larger spleen size, putting them at a higher risk for PTR.¹⁵

Etiology and Risk Factors

Platelet transfusion refractoriness can be broadly categorized into immune or non-immune causes, with most cases attributable to non-immune factors. Identifying the underlying cause is crucial for ensuring patients receive appropriate treatment and care (Table 1).

Table 1.

Immune and Non-Immunological Causes of PTR.¹¹^,²⁷^,²⁹

Non-immunological Cause	Immunological Cause
Systemic cause (fever, infection, sepsis)	Antibodies against HLA Class I
Accelerated platelet consumption (DIC, Microangiopathic hemolytic anemia)	ABO-mismatched platelets
Bleeding	Antibodies against human platelet antigens
Splenic sequestration	Antibodies against drug-platelet glycoprotein complex
Medication (amphotericin B, amoxicillin, cephalosporin, ATG, sulfonamides, heparin)
Graft-versus-host disease

*ATG, Anti-Thymocyte Globulin; DIC, Disseminated Intravascular Coagulation; HLA, Human Leucocyte Antigen.

Immune

Immune-mediated platelet transfusion refractoriness is a condition in which antibodies develop after receiving platelet transfusions from a donor. Several antigens known to cause donor's platelets clearance include (1) HLA, which is also present in other blood cells and tissues, (2) human platelet antigen (HPA), which is specific to platelets, and to a lesser degree, (3) ABO, and (4) CD36.^16‐18 Due to the repeated exposures and genetic polymorphisms of these molecules, transfused platelets can be targeted by antibodies that bind to associated antigens on their surface, removing them from the patient's circulation.^18,19

HLA, the primary cause of immune-mediated PTR, was detected in 67% of cases. Platelets only expressed HLA class I molecules, predominantly as HLA-A and HLA-B.²⁰ These highly polymorphic proteins play a crucial role in the development of alloimmunization of PTR. Upon platelet transfusions, recipients are exposed to the allogeneic donor HLA molecules from contaminated leukocytes in the platelet product or HLA class I antigens from the donor's platelet. Exposure to these allogeneic HLA antigens is thought to be the critical factor in the development of alloimmunization to HLA class I antigens.²¹ This exposure is typically due to previous multiple transfusions, organ transplantation, or maternal-fetal incompatibility during pregnancy.²² It is reported that HLA antibody prevalence in multi-transfused hemato-oncological patients was as high as 25% to 93%.²² In women with a history of one pregnancy, the prevalence rate is 11%, whereas it rises to 23% in those with more than four pregnancies.²³

The primary mechanism in which alloimmunization occurs is through the presentation of donor antigen peptides to the T-cell receptors on recipient CD4+ T-cells. This presentation may occur through two different pathways: direct and indirect allorecognition. In direct allorecognition, donor Class II HLA antigens on donor antigen-presenting cells (APC) are directly identified by recipient CD4+ T-cells, mainly from foreign HLA antigens. This interaction between donor APC and recipient T-cells can cause the recipient's B-cells to produce antibodies against these donor antigens. In the second pathway, called indirect allorecognition, recipient APC needs to take up and process fragments of donor cells before activating T cells that identify these alloantigens, eventually generating alloantibodies.²⁴

However, patients with HLA antibodies do not always manifest as PTR, as only about 30% of patients who develop HLA antibodies become refractory to platelet transfusions.²¹ The attributes of antibodies can play a significant role in identifying those that have the potential to cause the disease. Several factors, such as isotypes, IgG subclass, antibody glycosylation, and antigen specificity, may influence platelet clearance and, thus, the development of PTR.²⁵ Trial to Reduce Alloimmunization to Platelets (TRAP) study involving 530 subjects reported that individuals with high levels of antibodies exhibit a wider range of antibody specificities. Repeated exposure to the same alloantigens not only increases the level of antibodies produced but also enhances their affinity, leading to the production of more potent antibodies. A broad range of specificities increases the likelihood of an antibody reacting against a subsequent new allogeneic donor, leading to platelet rejection and, thus, PTR.²⁶ Additionally, the incidence of alloimmunization does not have a clear dose-response relationship with the number of platelet transfusions received. So, there are unknown factors that determine whether an alloimmunized patient will become refractory to platelet transfusions.¹²

The platelet-specific glycoproteins, known as HPA, may also contribute to PTR. HPA is a less common mechanism of platelet alloimmunization and should only be considered when HLA antibodies are not detected. The HPA system compromises 35 known antigens, exhibiting lower antigenic variability than the HLA system. This is why a significantly lower number of antibodies against HPA are involved in immune-based platelet refractory cases. However, if produced, HPA antibodies can induce rapid clearance of donor platelets through the FcγR-dependent mechanism or activation of the complement pathway.¹⁷ Although refractoriness due to HPA antibodies is rare, it is still observed in clinical practice.²⁷ Alloimmunization to HPA antigens has been reported in 2% to 8% of thrombocytopenic patients who receive multiple transfusions.¹⁸ Furthermore, HPA is also often found to coexist with HLA antibodies.²⁸ Fagundes et al reported that among 75 PTR cases, 19% were found to have HPA antibodies, with 78% of these cases also exhibiting HLA antibodies.²⁹

PTR may also arise from cases where the patient has high levels of anti-A or anti-B antibodies, in which there is a possibility of significant removal of donor platelets that carry matching ABO antigens. Thus, transfusing ABO-identical platelets is recommended since such platelets tend to provide a better increment in platelet count compared to ABO-nonidentical units.^30,31 Other causes may include CD-36 and drug-related platelet antibodies.^32,33 Various drugs such as cephalosporin, penicillin, NSAIDs, L-dopa, and heparin are thought to cause the occurrence of PTR.^34,35

Non-Immune

Approximately two-thirds of all cases of PTR are due to non-immune factors. Some of the factors include conditions like fever, sepsis, splenomegaly, hematopoietic stem cell transplantation (HSCT), and Disseminated Intravascular Coagulation (DIC).^36,37 Fever is the most common cause of non-immune PTR. However, fever can occur due to various underlying conditions such as infection/sepsis, drug allergy, DIC, and HSCT. Thus it is still inconclusive whether fever is an independent cause of PTR.³⁸ In a study conducted by Freireich et al, it was observed that percentage platelet recovery (PPR) post-transfusion was inversely proportional to the patient's body temperature, and those with sepsis showed the worst PPR.³⁹ However, Matsui et al reported that the CCI (corrected count increment) −1 h of patients who experienced post-transfusion fever was similar to those who didn't have any fever before or after transfusion.⁴⁰ This uncertainty highlights that the relationship between fever and platelet refractoriness remains unclear, especially considering that a combination of fever, infection, and antibiotic treatment frequently contribute to platelet transfusion refractoriness in patients with hematological malignancies.⁴¹

Platelet transfusion refractoriness can also result from excessive platelet consumption in patients with DIC, exacerbating their bleeding risks, especially in those with conditions like leukemia, solid cancer, or obstetric complications.^42,43 Another significant non-immune factor of PTR is splenomegaly. The spleen, being a vital component of the reticuloendothelial system, plays a significant role in determining the effectiveness of platelet transfusions, as it is a significant site for platelet storage and destruction. As the spleen enlarges, approximately 50%–90% of the transfused platelets are sequestered in the spleen, leading to a reduction of platelet count in the peripheral blood.⁴⁴ Zobel et al reported that patients with large spleens recover only 26% of platelets from the circulation shortly after transfusion, whereas normal controls can recover up to 59% of platelets.⁴⁵ One study conducted using radio-labeled platelets has revealed that in cases where platelets are transfused to patients with splenomegaly, a significant amount of platelets is sequestered and destructed in the spleen, causing lower platelet survival in the circulation, thereby impeding their hemostatic function in the periphery.⁴⁶ Other causes that may contribute to PTR include platelet product storage duration, with a longer storage period associated with lower CCI.^47,48 As platelets are stored, they undergo morphological and biochemical changes, resulting in the development of platelet storage lesions (PSL) that may directly impact the clinical course and outcome. To counteract this problem and lessen antibody-driven immune responses, platelet additive solutions (PAS) have been introduced. However, Different formulations of PAS may vary in their effectiveness. In particular, Citrate, commonly included in numerous PAS formulations, has been shown to elevate reactive oxygen species (ROS) levels, thereby contributing to the formation of platelet storage lesions (PSL). Conversely, excluding citrate from PAS has been found to reduce these effects.⁴⁹

Diagnosis

In diagnosing platelet transfusion refractoriness, it is important to first confirm if the patient is refractory and then identify whether it was due to immune or non-immune factors. There are three commonly used formulas for measuring PTR, namely post-transfusion increment (PPI), corrected count increment (CCI), and percentage platelet recovery (PPR). These formulas are presented in Table 2. Among the three formulas, CCI and PPR are considered more reliable in determining the actual PTR. This is because both of these formulas incorporate an adjustment factor based on the individual's body surface area and platelet transfused, making them more accurate in reflecting the real response to platelet transfusion.⁴⁷ However, in daily practice, PTR measurement using PPI is commonly preferred since sometimes it is not possible to obtain the exact number of platelets transfused or the body surface area (BSA) needed in CCI and PPR calculation.²⁷ Although the quantity of platelets in donated blood components tends to vary, it can be estimated that platelet concentrates contain approximately 6.3 × 10¹⁰ platelets, while apheresis platelets contain approximately 3.0 × 10¹¹ platelets. Additionally, assuming an average adult body surface area of 2m², a physician can make a rough estimation of the patient's CCI and/or PPR.⁵⁰

Table 2.

Common Equations Used to Diagnose Platelet Transfusion Refractoriness.^52‐55

Measures	Formula	Value of PTR
Post transfusion increment (PPI)	post-transfusion platelet count – pretransfusion platelet count	<10⁴/μl between 1 and 24 h post-transfusion
Corrected count increment (CCI)	$\frac{P P I (/ l) x b o d y s u r f a c e a r e a (m^{2})}{p l a t e l e t s t r a n s f u s e d (10^{11})}$	<5000/μl 1 h after transfusion, or <4500/μl 16–24 h after transfusion
Percentage platelet recovery (PPR)	$\frac{P P I (/ l) x b o d y w e i g h t x 0.075}{p l a t e l e t s t r a n s f u s e d (10^{11})}$ × 100%	<20% at 1 h

*PTR, platelet transfusion refractoriness; PPI, Post transfusion increment.

Previously, American Society of Clinical Oncology (ASCO) guidelines recommended measuring platelet count 10 min after transfusion.⁵¹ However, recent studies suggest platelet count typically increases and reaches its highest level within 10 min to an hour, followed by a gradual decline over the next 72 h.¹¹ Current guideline recommendations from ASCO,⁵² British Society for Haematology (BSH),⁵³ and Japanese Task Force Committee for Platelet Transfusion⁵⁴ all recommend obtaining platelet counts within 10 to 60 min after transfusion for all transfused patients, especially when refractoriness is suspected.

Platelet transfusion is considered successful if the PPI exceeded 10⁴/μL at 1 or 24 h post-transfusion, CCI >7500/μL at 1 h and >4500/μL at 24 h post-transfusion, or PPR reached a minimum of 67%.²⁷ PTR diagnosis is marked by two poor platelet increment transfusions. Currently, most guidelines favor the use of CCI over PPR for determining platelet refractoriness. According to ASCO, PTR is defined by a CCI of <5000/μL within less than 4 h post-transfusion.⁵² The BSH guideline defines PTR with CCI less than 5000/μL within 10 min to 1 h post-transfusion.⁵³ In contrast, the Japanese Task Force guideline defined PTR when the CCI 16–24 h after transfusion is <4500/μL and PTR suspicion if CCI at 10 min to 1-h post-transfusion is <7500/μL.⁵⁴ In cases where the CCI calculation is not feasible due to unknown transfused platelet content, the Singaporean guidelines advise using PPI, defined as an absolute platelet count increment of less than 10,000/μl, measured between 1 and 24 h post-platelet transfusion.⁵⁵

Assessing both the CCI-1 h (10 min to 1 h) and CCI-24 h (16–24 h) is recommended to help distinguish immune and non-immune PTR.⁵⁶ Typically, non-immune PTR present with CCI-1 h levels above 7500/μL and CCI-24 h levels below 4500/μL, which indicate normal platelet recovery but reduced platelet survival. Conversely, typical immune PTR cases occurred with CCI-1 h below 7500/μL and CCI-24 h below 4500/μL, which indicates a diminished platelet recovery that occurs almost immediately after the transfusion.⁵⁷

Upon diagnosing platelet transfusion refractoriness, it is crucial to determine whether it has an immune or non-immune cause. Alloimmunization from immune causes is typically a result of the presence of antibodies against HLA antigens and rarely due to platelet-specific antigens.⁵²

The Complement-dependent cytotoxicity (CDC) assay, also referred to as the lymphocytotoxic test (LCT), is a traditional and widely recognized method for detecting HLA antibodies, introduced initially in 1960.⁵⁸ This technique employs donor lymphocytes to identify complement-dependent antibodies present in the patient's plasma. This method is one of the most cost-effective assays compared to other commercially available HLA detection tests. However, it is heavily dependent on the viability of donor cells, requires long incubation times, and does not detect non-cytotoxic antibodies, resulting in low sensitivity. Due to these limitations, there has been a shift towards methodologies such as flow cytometry assays and solid-phase assays. Flow cytometry assays enable the identification of both class I and class II antibodies and effectively detect low-titer antibodies that the CDC assay cannot identify. However, the standardization of flow cytometry assays has been problematic due to variations in flow cytometers and fluorescence dyes between different institutions.^58,59

Solid-phase assays, such as enzyme-linked immunosorbent assay (ELISA) and fluorescence-based technologies like Luminex, are recognized for their higher sensitivity than cell-based assays.⁵⁹ ELISA is the most common screening method used to identify antibodies in the patient's plasma or serum against platelet antigens and HLA antigens with high sensitivity. However, this test takes around four hours to perform thus mainly only conducted in large medical centers.⁶⁰ Luminex assay is a technique that employs beads coated with individual HLA antigens to identify multiple HLA antibody specificities. The assay works by detecting the binding of antibodies with fluorescently labeled antihuman globulin. The antibody level is characterized through flow cytometry, flow microarrays, or enzyme-linked immunosorbent assay. This technique is useful in identifying HLA antibody specificities that are difficult to pinpoint through cytotoxic assays. The assay result is a list of antibody specificities and their respective avidity strength.¹⁸

Management

Immune

In managing immune-mediated PTR, strategies for selecting platelet components depend on the underlying cause. Identifying patients with HLA or HPA antibodies is crucial, as using HLA-matched or HPA-matched platelets has been shown to improve transfusion outcomes.⁶¹ The two principal approaches for transfusing alloimmunized patients involve matching donor-recipient HLA antigens and cross-matching platelets.

HLA-matched platelet is the current standard approach for PTR. The National Health Service (NHS) guidelines recommend that patients with PTR must be evaluated for their HLA type and HLA-specific antibodies first. Should the test yield a positive result, the recommended management strategy involves administering platelet transfusions from donors matched for HLA-A and HLA-B antigens.⁶² This approach can improve the chances of a successful increment for patients undergoing platelet transfusions. A study by Chan et al involving 147 patients reported success rates up to 84%.⁶³ However, HLA typing is associated with high costs and prolonged turnaround times, which may restrict its utility in certain clinical settings. In addition to these drawbacks, HLA matching also requires the availability of a substantial pool of HLA-matched donors.⁶⁴ In the context of platelet transfusion, HLA is matched specifically at the A and B loci. The matching is evaluated based on the degree of compatibility, categorized into grades A, B1U, B1X, B2U, B2UX, B2X, C, D, and R, arranged from highest to lowest match, respectively. Platelets that exhibit a higher degree of HLA match demonstrate improved survival rates post-transfusion. For instance, grades A, B1U, and B2U are associated with the most significant increases in platelet counts. Conversely, grades B2X, C, and D yield platelet responses comparable to those from random donor platelet transfusions.¹⁶ Thus, securing HLA-matched platelets can be challenging. As a result, alternative strategies have been developed to obtain HLA-compatible, if not fully, HLA-matched platelets.¹⁰

Platelet cross-matching assays represent a cost-effective and expedited alternative to HLA-matched transfusions for managing platelet refractoriness. Cross-matched platelet is the simplest and fastest protocol, which uses cross-reactivity between the patient's serum and the donor's platelet. This protocol detects antibodies against platelet HLA or HPA, using indicator red cells coated with anti-immunoglobulin G, without directly testing donor or patient platelet antigen type. These assays facilitate the identification of potential platelet donors and may be advantageous for patients whose refractoriness results also from HPA alloimmunization. The most common technique is The Solid Phase Immune Adherence Assay (SPRCA), an immunological method where one reactant (antigen or antibody) is fixed on a solid surface to detect the other reactant, using fluorescein, an enzyme, and red cells as indicators.⁶⁵ However, this protocol is not suitable for highly alloimunized patients since there will not be enough platelets available to make compatibility tests. It also poses the risk of further additional alloimmunization in some patients.¹⁸

If the outcomes following HLA-selected platelet transfusion are suboptimal, it may be necessary to conduct testing for HPA-specific antibodies.⁶² PTR caused by HPA antibodies is rare. Thus, it is not recommended as a routine investigation. If the antibodies for HPA exist, International Collaboration for Transfusion Medicine (ICTMG) guideline recommends an HPA-selected or crossmatch-selected platelet transfusion. However, it is to be noted that patients who are refractory due solely to non-immune factors should avoid HLA-selected or crossmatch-selected platelet transfusion.⁶⁶

Intravenous immunoglobulin (IVIg) has also been used to address the immune response in immune-mediated PTR. However, a study has reported that administering IVIg with PLT components did not show any significant improvement in the 24-h CCI, despite a slight improvement in the 1-h CCI. Therefore, this approach is currently not recommended due to a lack of demonstrable clinical benefits.⁶⁷

Non-Immune

Non-immunological causes account for approximately two-thirds of PTR cases.³⁶ Typically, PTR arises from conditions such as sepsis, splenomegaly, DIC, and fever. To manage these reactions effectively, it is essential to identify and treat the underlying causes. Additionally, it is important to adjust platelet transfusion practices based on the patient's clinical status. This may involve modifying platelet dosages or discontinuing prophylactic transfusions to avoid unnecessary exposure and minimize potential complications.⁶²

Potential Future Research

A potential future approach to managing platelet transfusion refractoriness is to use human leukocyte antigen-depleted platelets. There has been research into reducing or removing HLA antigens on the surface of donor platelets to decrease their potential to trigger an immune response while maintaining their normal physiological function. While there have been limited successful cases, the findings suggest that HLA-stripped platelets hold promise as a viable option.⁶⁸ Citric acid treatment has been shown to denature HLA Class I complexes without causing substantial damage to the platelets. Platelets treated with citric acid maintain their functional capacity and effectively survive when transfused in PTR patients. A study by Mirlashari et al reported that acid treatment can reduce the expression of HLA Class I by 70.6%.⁶⁸ It has also been shown to reduce the HLA antibody-mediated phagocytosis pathway in removing antibody-coated platelets. Although classical HLA Class I antigens are effectively removed, it remains possible that the acid treatment could unveil neoantigens on the platelets, potentially eliciting antibodies specific to the acid-treated HLA.⁶⁹ There is a need for further evidence to validate the routine use of HLA-depleted platelets in clinical practice.

Additionally, eculizumab, a monoclonal antibody that inhibits the C5 complement, was used in a pilot study in combination with platelet transfusion to PTR patient with detectable anti-HLA A and/or B antibodies. It showed promising results by improving the platelet CCI in 4 out of 10 patients. However, there are still limited data to interpret this finding. Currently, ongoing research is being conducted to evaluate the balance between benefits and risks.⁷⁰

Prevention

There are some strategies to prevent platelet transfusion refractoriness, particularly in cases with immunological causes. The first recommendation is to transfuse ABO-matched platelets to maximize platelet increments, as incompatible ABO has been associated with an increased risk of transfusion reactions and early platelet refractoriness. A study involving over 13,000 platelet transfusions found that ABO-incompatible platelets are 1.5 to 2 times more likely to be associated with a transfusion reaction.^53,71,72 By prioritizing ABO compatibility, healthcare providers can significantly reduce the incidence of these reactions and enhance the overall efficacy of platelet transfusions.

Modified platelet products, such as leukoreduced platelets and UV-B irradiated platelet products, as well as single-donor apheresis platelets, have been shown to reduce the occurrence of refractoriness compared to unmodified pooled platelet concentrates from random donors. However, there is still a possibility of patients developing alloantibodies when receiving repeated transfusions of treated platelet products, such as UV-B irradiated or filtered platelet products.¹⁴ The rate of platelet transfusion also appears to be a contributing factor to refractory thrombocytopenia. Administering platelet concentrate slowly over 6 h using multiple transfusion pumps has been shown to result in a more significant increase in platelet increment.⁷³

Conclusion

Platelet transfusion refractoriness is a frequent yet challenging condition, especially in hemato-oncological patients who receive multiple transfusions. Platelet count should be ordered between 10 to 60 min and 16–24 h after platelet transfusion to evaluate the platelet increments and to identify any refractoriness using PPI, CCI, or PPR formula. Differentiating immune or non-immune causes is fundamental for further management plan. Management includes using cross-matched platelets, HLA-matched type platelets, HPA-matched platelets, HLA depletion, and immunosuppressants. PTR risk can be minimized by transfusing ABO-matched platelets, using modified platelets, and slow transfusion. Ongoing research in the field of platelet transfusion refractoriness is exploring new ways to manage and prevent this condition. However, more conclusive evidence is required to support these advancements.

Footnotes

Acknowledgment

We made this review by ourselves with no help of other parties.

Author Contribution(s)

Anna Mira Lubis: Conceptualization;Data curation;Formal analysis;Investigation;Methodology;Project administration;Supervision;Validation;Visualization;Writing – original draft;Writing – review & editing.

Muhammad Orri Baskoro: Conceptualization;Data curation;Formal analysis;Investigation;Methodology;Project administration;Validation;Visualization;Writing – original draft.

Amirah Yasmin: Methodology;Project administration;Visualization;Writing – original draft.

Availability of Data and Materials

Not applicable.

Funding

The author(s) received no financial support for the research,authorship,and/or publication of this article.

DECLARATION OF CONFLICTING INTEREST

The author(s) declared no potential conflicts of interest with respect to the research,authorship,and/or publication of this article.

Consent for Publication

Not applicable.

Ethical Approval

This study is a review;therefore,no ethical approval was required.

ORCID iDs

Anna Mira Lubis

Muhammad Orri Baskoro

References

Prodger

Rampotas

Estcourt

, et al. Platelet transfusion: alloimmunization and refractoriness. Semin Hematol. 2020;57(2):92‐99.

Stanworth

Estcourt

Powter

, et al. A No-prophylaxis platelet-transfusion strategy for hematologic cancers. N Engl J Med. 2013;368(19):1771‐1780.

Wandt

Schaefer-Eckart

Wendelin

, et al. Therapeutic platelet transfusion versus routine prophylactic transfusion in patients with haematological malignancies: an open-label, multicentre, randomised study. Lancet. 2012;380(9850):1309‐1316.

Godeau

Fromont

Seror

, et al. Platelet alloimmunization after multiple transfusions: A prospective study of 50 patients. Br J Haematol. 1992;81(3):395‐400.

Youk

H-J

Hwang

S-H

H-B

, et al. Evaluation and management of platelet transfusion refractoriness. Blood Res. 2022;57(S1):S6‐S10.

Bub

Gonçalez

Barjas-Castro

, et al. Prospective evaluation of platelet refractoriness in haematological patients in a single Brazilian institution. ISBT Sci Ser. 2021;16(1):2‐11.

Hess

Trachtenberg

Assmann

, et al. Clinical and laboratory correlates of platelet alloimmunization and refractoriness in the PLADO trial. Vox Sang. 2016;111(3):281‐291.

Cai

Zheng

, et al. Clinical and immunological features of platelet transfusion refractoriness in young patients with de novo acute myeloid leukemia. Cancer Med. 2020;9(14):4941‐4948.

Meehan

Matias

Rathore

, et al. Platelet transfusions: Utilization and associated costs in a tertiary care hospital. Am J Hematol. 2000;64(4):251‐256.

10.

Blandin

Dougé

Fayard

, et al. Platelet transfusion refractoriness and anti-HLA immunization. Transfusion. 2021;61(6):1700‐1704.

11.

Hagino

Sato

Tsuno

, et al. Incidence and management of non-immune platelet transfusion refractoriness: a narrative review. Annals of Blood. 2021;6, (September 30, 2021): Annals of Blood, https://aob.amegroups.org/article/view/6483 (2021, accessed 1 January 2021).

12.

Legler

Fischer

Dittmann

, et al. Frequency and causes of refractoriness in multiply transfused patients. Ann Hematol. 1997;74(4):185‐189.

13.

Klingemann

Self

Banaji

, et al. Refractoriness to random donor platelet transfusions in patients with aplastic anaemia: A multivariate analysis of data from 264 cases. Br J Haematol. 1987;66(1):115‐121.

14.

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;337(26):1861‐1870.

15.

Arabi

Almahayni

Alomair

, et al. Prevalence, risk factors, and outcomes of platelet transfusion refractoriness in critically ill patients: A retrospective cohort study. Crit Care Res Pract. 2021;2021:1‐11.

16.

Schmidt

Refaai

Coppage

. HLA-Mediated Platelet refractoriness. Am J Clin Pathol. 2019;151(4):353‐363.

17.

Van Osch

TLJ

Oosterhoff

Bentlage

AEH

, et al. Fc galactosylation of anti-platelet human IgG1 alloantibodies enhances complement activation on platelets. haematol. 2022;107(10):2432‐2444.

18.

Cohn

. Platelet transfusion refractoriness: How do I diagnose and manage? Hematology Am Soc Hematol Educ Program. 2020;2020(1):527‐532.

19.

Neffati

Sellami

Bellali

, et al. Polymorphisme des antigènes plaquettaires humains dans la population tunisienne: Intérêt clinique et anthropologique. Transfus Clin Biol. 2019;26(4):266‐272.

20.

Wang

You

, et al. Simultaneous genotyping for human platelet antigen systems and HLA-A and HLA-B loci by targeted next-generation sequencing. Front Immunol. 2022;13:945994.

21.

Saris

Pavenski

. Human leukocyte antigen alloimmunization and alloimmune platelet refractoriness. Transfus Med Rev. 2020;34(4):250‐257.

22.

Kumawat

Sharma

Malhotra

, et al. Prevalence of risk factors for platelet transfusion refractoriness in multitransfused hemato-oncological patients at tertiary care center in north India. Asian J Transfus Sci. 2015;9(1):61‐64.

23.

Triulzi

Kleinman

Kakaiya

, et al. The effect of previous pregnancy and transfusion on HLA alloimmunization in blood donors: Implications for a transfusion-related acute lung injury risk reduction strategy. Transfusion. 2009;49(9):1825‐1835.

24.

Adane

Enawgaw

. Human leukocyte antigen alloimmunization prevention mechanisms in blood transfusion. Asian J Transfus Sci. 2023;17(2):264.

25.

Couvidou

Rojas-Jiménez

Dupuis

, et al. Anti-HLA class I alloantibodies in platelet transfusion refractoriness: From mechanisms and determinants to therapeutic prospects. Front Immunol. 2023;14:1125367.

26.

Jackman

Lee

Pei

, et al. C1 q -binding anti- HLA antibodies do not predict platelet transfusion failure in T rial to R educe A lloimmunization to P latelets study participants. Transfusion. 2016;56(6):1442‐1450.

27.

Stanworth

Navarrete

Estcourt

, et al. Platelet refractoriness – practical approaches and ongoing dilemmas in patient management. Br J Haematol. 2015;171(3):297‐305.

28.

Kurz

Greinix

HÖcker

, et al. Specificities of anti-platelet antibodies in multitransfused patients with haemato-oncological disorders. Br J Haematol. 1996;95(3):564‐569.

29.

Fagundes

Franz

Jobim

, et al. Diagnosis and treatment of immunological platelet refractoriness by histocompatibility. Hum Immunol. 2020;81(5):197‐201.

30.

Pavenski

Warkentin

Shen

, et al. Posttransfusion platelet count increments after ABO-compatible versus ABO-incompatible platelet transfusions in noncancer patients: An observational study. Transfusion. 2010;50(7):1552‐1560.

31.

Shehata

Tinmouth

Naglie

, et al. ABO-Identical versus nonidentical platelet transfusion: A systematic review. Transfusion. 2009;49(11):2442‐2453.

32.

Liu

Zhang

Chen

, et al. Current Status of and global trends in platelet transfusion refractoriness from 2004 to 2021: A bibliometric analysis. Front Med. 2022;9:873500.

33.

Zhou

, et al. Platelet immunology in China: Research and clinical applications. Transfus Med Rev. 2017;31(2):118‐125.

34.

Aster

Curtis

McFarland

, et al. Drug-induced immune thrombocytopenia: Pathogenesis, diagnosis, and management. J Thromb Haemostasis. 2009;7(6):911‐918.

35.

Tinmouth

Semple

Shehata

, et al. Platelet immunopathology and therapy: A Canadian blood services research and development symposium. Transfus Med Rev. 2006;20(4):294‐314.

36.

Hod

Schwartz

. Platelet transfusion refractoriness. Br J Haematol. 2008;142(3):348‐360.

37.

Sacher

Kickler

Schiffer

, et al. Management of patients refractory to platelet transfusion. Arch Pathol Lab Med. 2003;127(4):409‐414.

38.

Murphy

. Managing the platelet refractory patient. ISBT Sci Ser. 2014;9(1):234‐238.

39.

Freireich

. Response to repeated platelet transfusion from the same donor. Ann Intern Med. 1963;59(3):277.

40.

Matsui

Hagino

Tsuno

, et al.

Does time of CCI measurement affect the evaluation of platelet transfusion effectiveness?

Transfus Apher Sci. 2021;60(3):103123.

41.

Doughty

Murphy

Metcalfe

, et al. Relative importance of immune and non-immune causes of platelet refractoriness. Vox Sang. 1994;66(3):200‐205.

42.

Bishop

Matthews

Yuen

, et al. The definition of refractoriness to platelet transfusions. Transfus Med. 1992;2(1):35‐41.

43.

Asakura

. Classifying types of disseminated intravascular coagulation: Clinical and animal models. J Intensive Care. 2014;2(1):20.

44.

Lau

, et al. Hypersplenism: History and current status. Exp Ther Med. 2016;12(4):2377‐2382.

45.

Hill-Zobel

McCandless

Kang

, et al. Organ distribution and fate of human platelets: Studies of asplenic and splenomegalic patients. American J Hematol. 1986;23(3):231‐238.

46.

Aster

Jandl

. Platelet sequestration in man. II. Immunological and clinical studies. J Clin Invest. 1964;43(5):856‐869.

47.

Slichter

. Factors affecting posttransfusion platelet increments, platelet refractoriness, and platelet transfusion intervals in thrombocytopenic patients. Blood. 2005;105(10):4106‐4114.

48.

Nellis

Spinella

Tucci

, et al. Effect of platelet storage duration on clinical outcomes and incremental platelet change in critically ill children. Transfusion. 2020;60(12):2849‐2858.

49.

Shea

Thomas

Spinella

. The effect of platelet storage temperature on haemostatic, immune, and endothelial function: Potential for personalised medicine. Blood Transfusion. 2019;17(4):321‐330.

50.

Korean Centers for Disease Control and Prevention. Transfusion guideline. 4th ed. Korean Centers for Disease Control and Prevention; 2016.

51.

Schiffer

Anderson

Bennett

, et al. Platelet transfusion for patients with cancer: Clinical practice guidelines of the American society of clinical oncology*. JCO. 2001;19(5):1519‐1538.

52.

Schiffer

Bohlke

Delaney

, et al. Platelet transfusion for patients with cancer: American society of clinical oncology clinical practice guideline update. JCO. 2018;36(3):283‐299.

53.

Estcourt

Birchall

Allard

, et al. Guidelines for the use of platelet transfusions. Br J Haematol. 2017;176(3):365‐394.

54.

Takami

Matsushita

Ogata

, et al. Guideline for the use of platelet transfusion concentrates based on scientific evidence: Update 2019. JJTC. 2019;65(3):544‐561.

55.

Health Science Authority. National guidelines on clinical transfusion [Internet]. Singapore: HSA; 2023, https://www.hsa.gov.sg/docs/default-source/bsg/national-guidelines-on-clinical-transfusion.pdf .

56.

McFarland

Anderson

Slighter

. Factors influencing the transfusion response to HLA-selected apheresis donor platelets in patients refractory to random platelet concentrates. Br J Haematol. 1989;73(3):380‐386.

57.

Pavenski

Freedman

Semple

. HLA Alloimmunization against platelet transfusions: Pathophysiology, significance, prevention and management. Tissue Antigens. 2012;79(4):237‐245.

58.

Weinstock

Schnaidt

. Human leucocyte antigen sensitisation and its impact on transfusion practice. Transfus Med Hemother. 2019;46(5):356‐369.

59.

Takahashi

Nakajima

Tsuno

. Human leukocyte antigen antibody detection technologies in platelet transfusion refractoriness, with special emphasis on functional test. Ann Blood. 2018;3:42‐42.

60.

Swinkels

Rijkers

Voorberg

, et al. Emerging concepts in immune thrombocytopenia. Front Immunol. 2018;9:880.

61.

Zhang

J-C

L-H

, et al. Related donor platelet transfusion improves platelet transfusion refractoriness in hematological patients. Front Med. 2023;10:983644.

62.

National Health Services. Guidelines for the management of platelet transfusion refractoriness [Internet]. National Health Services; 2021. Available from: https://nhsbtdbe.blob.core.windows.net/umbraco-assets-corp/24204/inf139-v2-guidelines-for-the-management-of-platelet-transfusion-refractoriness.pdf.

63.

Chan

LKL

Tam

KWK

Wong

, et al. Provision of human leukocyte antigen (HLA) selected platelets: 10-year experience of a regional blood centre. Ann Blood. 2023;8:22.

64.

Salama

Aladl

El Ghannam

, et al. Evaluation of platelet cross-matching in the management of patients refractory to platelet transfusions. Blood Transfusion. 2014;12(2):187-194.

65.

Ching

. Solid phase red cell adherence assay: A tubeless method for pretransfusion testing and other applications in transfusion science. Transfus Apher Sci. 2012;46(3):287‐291.

66.

Nahirniak

Slichter

Tanael

, et al. Guidance on platelet transfusion for patients with hypoproliferative thrombocytopenia. Transfus Med Rev. 2015;29(1):3‐13.

67.

Kickler

Braine

Piantadosi

, et al. A randomized, placebo-controlled trial of intravenous gammaglobulin in alloimmunized thrombocytopenic patients. Blood. 1990;75(1):313‐316.

68.

Mirlashari

Vetlesen

Nissen-Meyer

LSH

, et al. HLA Class I depletion by citric acid, and irradiation of apheresis platelets for transfusion of refractory patients. Transfusion. 2021;61(4):1222‐1234.

69.

Meinke

Sandgren

Mörtberg

, et al. Platelets made HLA deficient by acid treatment aggregate normally and escape destruction by complement and phagocytes in the presence of HLA antibodies. Transfusion. 2016;56(2):370‐382.

70.

Purev

West

, et al. A pilot trial of complement inhibition using eculizumab to overcome platelet transfusion refractoriness in human leukocyte antigen allo-immunized patients. Br J Haematol. 2020;189(3):551‐558.

71.

Malvik

Leon

Schlueter

, et al. ABO-Incompatible platelets are associated with increased transfusion reaction rates. Transfusion. 2020;60(2):285‐293.

72.

Carr

Hutton

Jenkins

, et al. Transfusion of ABO-mismatched platelets leads to early platelet refractoriness. Br J Haematol. 1990;75(3):408‐413.

73.

Habibi

Esfandbod

Ghafari

, et al. Platelet kinetics after slow versus standard transfusions: A pilot study. Upsala J Med Sci. 2011;116(3):212‐215.