Platelet Transfusion Refractoriness

1. Causes of Refractoriness

• Fever or Sepsis: Infection and inflammation can shorten platelet survival ().
• Active Bleeding: Ongoing hemorrhage or consumption (e.g. surgical bleeding) uses up transfused platelets.
• Disseminated Intravascular Coagulation (DIC) or Microangiopathy: Accelerated consumption in conditions like DIC or TTP ().
• Medications: Certain drugs (e.g. amphotericin B, vancomycin, heparin, anti-platelet agents) can either cause platelet destruction or interfere with platelet recovery ().
• Splenomegaly: Enlarged spleen sequesters platelets, reducing post-transfusion counts ().
• Poor Platelet Product Quality: Extended storage or improper handling can reduce platelet viability ().

• Clinical clues: If a patient has no significant bleeding, infection, DIC, etc., yet still has consistently low CCIs, an immune cause is suspected. A history of multiple transfusions or pregnancies (predisposing to alloimmunization) raises suspicion as well () ().
• Laboratory workup: The transfusion service or HLA lab should perform an antibody screen to confirm alloimmune refractoriness. A rapid ELISA or bead assay can detect if the patient’s serum contains anti-HLA or anti-platelet antibodies (). If this screen is positive, further testing to identify specific antibody targets is warranted (discussed below). A negative antibody screen, on the other hand, suggests refractoriness is due to non-immune causes, and HLA-matched platelets would not be indicated ().

2. HLA and HPA Antibodies in Refractoriness (Patient Risk Factors)

• Hematology/Oncology patients: Individuals with acute leukemia, aplastic anemia, myelodysplasia, etc., often require multiple platelet transfusions. Prior to universal leukocyte reduction, up to 50% of heavily transfused patients developed HLA antibodies; leukoreduction has reduced this to ~20–30%, but risk remains () (). For example, multiply transfused thrombocytopenic patients have an ~23% incidence of HLA alloimmunization ().
• Multiparous women: Pregnancy is a potent immunizing event because a mother is exposed to fetal HLA antigens. The risk of developing anti-HLA antibodies rises with each pregnancy – one study showed ~11% after one pregnancy and up to 32% after four or more pregnancies (). Thus, female patients with multiple prior pregnancies (especially those now receiving platelets for oncology treatments or surgical bleeding) are more likely to be alloimmunized.
• Transplant recipients or candidates: Patients awaiting organ transplant (e.g. kidney) are often screened for HLA antibodies, and many have been sensitized by prior transfusions or grafts. Similarly, someone who previously received a transplant may have formed antibodies against the donor HLA antigens. These patients, if they need platelet transfusions (e.g. during peri-transplant period or surgery), have a higher chance of refractoriness due to those antibodies.
• Other multi-transfused patients: Individuals with chronic anemia or other conditions requiring frequent blood transfusions (e.g. sickle cell disease, myelodysplastic syndrome) can also become HLA-sensitized over time, although red cell transfusions are leukoreduced and have less HLA antigen exposure than platelet transfusions.

• Major incompatibility: The patient’s plasma contains antibodies against the donor’s RBC type (e.g. group O patient receiving group A platelets – the patient’s anti-A can bind A antigens on donor platelets). High-titer anti-A or anti-B in the patient can cause rapid clearance of the transfused platelets bearing those antigens (). This immune destruction by ABO isoagglutinins can lead to poor post-transfusion increments, essentially an immune refractoriness mechanism.
• Minor incompatibility: The donor plasma contains anti-A or anti-B that correspond to the patient’s RBCs (e.g. group O donor platelets given to a group A patient contain anti-A). This situation can cause hemolysis of patient red cells in rare cases and is generally more concerning for hemolytic reactions than platelet refractoriness. It typically does not cause platelet destruction (the platelets are not harmed by their donor’s antibodies), though transfusing large volumes of incompatible plasma is avoided.

3. HLA Matching Considerations (HLA-A, B, and C) in Platelet Transfusion

• HLA-A and HLA-B matching: Historically, HLA-matched platelet transfusions aim to match the patient’s HLA-A and B antigens with those of the donor. A “perfect match” in this context is often defined as a 4/4 match (both HLA-A alleles and both HLA-B alleles of donor and recipient are the same) (). Providing such HLA-identical platelets greatly increases the chance of successful platelet increments and can circumvent HLA antibody-mediated destruction. In fact, HLA matching has been shown to produce equivalent clinical success to crossmatch-based selection in refractory patients (). Additionally, using HLA-matched donations reduces the risk of new antibody formation because the patient is not exposed to new foreign HLA antigens ().
• HLA-C considerations: Because platelets express little HLA-C, many transfusion programs do not require matching at HLA-C for platelet support. Anti-HLA-C antibodies are uncommon and often of unclear significance in this setting. There are occasional reports of refractory patients with specific anti-HLA-C who only respond to HLA-C matched platelets, but this is unusual (). In general, matching for HLA-A and B is the priority. If a patient’s antibody screen identifies a strong anti-HLA-C (which is rare), then donors lacking that antigen may be selected on a case-by-case basis.
• Class II HLA (HLA-DR, DQ, DP): Platelets do not express class II HLA, so these are irrelevant for platelet transfusion compatibility. (Class II matching is important in stem cell transplantation but not for platelet support.)

4. Impact of ABO Matching on Platelet Transfusion Success

• ABO-identical platelets yield better increments: Transfusing platelets that are ABO matched (identical) with the patient often results in higher post-transfusion platelet count increments than ABO-mismatched transfusions (). Studies have shown that patients receiving ABO-identical platelet units have superior CCIs and longer platelet survival compared to those receiving non-identical units (). This is because there is no immunologic conflict – the patient’s plasma does not react with the donor platelets, and the donor plasma does not significantly harm the patient’s cells.
• Major ABO incompatibility causes immune destruction: If platelets bearing ABO antigens are transfused into a patient with the corresponding antibodies, the patient's isoagglutinins (anti-A or anti-B) can bind those platelets and lead to their removal from circulation (). For example, a group O patient (who has anti-A and anti-B) may rapidly clear group A platelets. This immune-mediated clearance can contribute to refractoriness. In an extreme case, a very high-titer ABO antibody in the patient could even destroy the transfused platelets almost immediately, much like an HLA antibody would.
• Minor incompatibility and other issues: When the donor is, say, group O and the patient is group A, the donor’s anti-A antibodies can potentially cause hemolysis of the patient’s red cells. This is a transfusion reaction risk and also a reason to prefer ABO-compatible units. Minor incompatibility doesn’t typically destroy the platelets, but if a significant hemolytic reaction occurs, it can indirectly worsen patient condition. Another consideration is that transfusing ABO-incompatible plasma can sometimes trigger mild reactions or endothelial activation. Overall, ABO-compatible or identical units are preferred to avoid any such complications.
• Out-of-group transfusions (ABO non-identical): In practice, due to inventory constraints, perfectly ABO-matched platelets are not always available for every patient. Platelets have a short shelf-life and blood centers must balance supply. It’s reported that only ~55% of platelet transfusions are ABO-identical under current practices (). Transfusing ABO-compatible but not identical platelets is common (e.g. group A platelets to AB patient). This is generally safe, but the increment may be slightly reduced if not identical. ABO-incompatible (major mismatch) platelets are usually avoided in immune refractory patients because they risk immediate platelet loss. If they must be given (in urgent shortage situations), one might expect lower efficacy.
• Mitigation strategies: Some blood services use platelet additive solutions (PAS) to replace a portion of plasma, thereby diluting donor ABO antibodies and reducing reactions. Also, titer screening of donor plasma can allow use of low-titer incompatible platelets with reduced risk. However, these are adjuncts; the simplest approach is to choose ABO-identical or at least ABO-compatible platelets whenever possible, especially in a refractory patient (). For example, guidelines recommend using ABO-matched platelets to maximize increments ().

5. HLA Antibody Testing Methods: SSO, “Real-Time” Assays, and NGS

• Screening ELISA: Many labs start with a quick screening test to confirm the presence of HLA or HPA antibodies. For example, an ELISA-based platelet antibody screen can be done, which will simply indicate if any anti-HLA or anti-HPA antibodies are present in the patient’s serum (). This is rapid (a few hours) and relatively low-cost. If the screen is negative, it suggests immunity is not the cause, potentially saving the effort of more complex analyses (). If positive, further testing is needed to identify specific antibodies.
• Complement-Dependent Cytotoxicity (CDC) Panel (Historical PRA test): In the past, the standard method was a lymphocytotoxicity assay, where the patient’s serum is mixed with a panel of lymphocytes of known HLA types (). If the serum contains HLA antibodies that match a lymphocyte’s HLA, it will bind and, with complement added, cause cell lysis. By testing against a broad panel of donor cells, labs determined the Panel Reactive Antibody (PRA) percentage – the percentage of cells lysed, which reflects how many donors in the population would likely be incompatible. This method was used for decades to gauge sensitization (). While it effectively identified strong antibodies, it had low sensitivity for weak ones and did not precisely identify antibody specificities.
• Solid-Phase Assays (Luminex Single-Antigen Beads): Today, the gold standard for HLA antibody identification is a solid-phase immunoassay, commonly the Luminex single-antigen bead (SAB) test (). In this assay, tiny beads are coated with individual HLA class I glycoproteins (covering a wide array of HLA-A, B, C alleles). The patient’s serum is incubated with the beads; any HLA antibodies will bind to the beads bearing their target antigen. A fluorescent anti-human IgG is then added and detected by the Luminex instrument (a specialized flow cytometry device) (). The result is a list of specific HLA antibodies present in the serum and their strength, reported as mean fluorescence intensity (MFI) (). For example, the assay might show anti-HLA-A2 with MFI 10,000, anti-B44 with MFI 8,000, etc. This level of specificity is extremely useful for choosing compatible donors.
  • Advantages: SAB is very sensitive and can detect even low-level antibodies that CDC might miss. It provides clear specificity information – exactly which HLA antigens are targeted (). It also allows calculation of a calculated PRA (cPRA) based on those specificities (addressed in the next section) ().
  • Challenges: The high sensitivity means it may detect antibodies of unclear clinical significance. Many labs observe that very low-titer antibodies (MFI below a certain cutoff) might not actually cause platelet destruction (). For instance, an anti-HLA with MFI of 500 might be a false positive or too weak to matter. One study showed that weak/moderate HLA antibodies (SAB-positive but CDC-negative) were not associated with clinical refractoriness (). Labs must decide an MFI threshold to call an antibody “positive” – thresholds vary widely (500 to 1,000 or even up to 3,000 MFI) between labs (). Despite this, SAB has become the mainstay for guiding platelet matching.
  • C1q and advanced assays: To better predict clinical relevance, some labs use a C1q binding assay variation – it identifies whether the detected antibodies can bind complement component C1q, which might correlate with more destructive capability (). In transplantation, C1q-positive antibodies correlate with rejection, but in platelet transfusion the data is mixed and not clearly predictive of refractoriness ().
• Solid-Phase Red Cell Adherence (SPRCA) Crossmatch: Another “real-time” assay relevant to platelet support is the platelet crossmatch by SPRCA. In this test, a panel of donor platelets (or specific donor unit platelet samples) is tested against the patient’s serum. If the patient’s antibodies bind to a donor’s platelets, indicator red cells coated with anti-IgG will adhere (a positive result) (). This is essentially a compatibility test, often done on-demand when selecting units (hence we might consider it a real-time assay). SPRCA crossmatching is relatively quick (results within hours) and can directly identify which available donor unit is compatible (). It simultaneously accounts for HLA and HPA antibodies (any antibody that can bind platelets will cause crossmatch failure) (). Many transfusion services use crossmatch-compatible platelets as the first-line strategy for refractory patients due to its speed and simplicity.
• Monoclonal Antibody Immobilization of Platelet Antigens (MAIPA): This is a specialized lab assay to detect antibodies against specific platelet glycoproteins (HPAs). Patient serum is incubated with platelets, then specific monoclonal antibodies are used to capture platelet glycoproteins and any bound human antibodies, which are then detected. MAIPA is sensitive for HPA antibodies and can differentiate, for example, anti-GPIIb/IIIa vs anti-GPIb antibodies. It’s used mostly in reference labs when HPA incompatibility is suspected (such as in neonatal alloimmune thrombocytopenia or unexplained platelet refractoriness with negative HLA antibody tests).
• “Real-time” vs “virtual” crossmatching: The term "real-time assays" might refer to performing actual crossmatches or quick tests at the time of need, as opposed to doing a theoretical (virtual) compatibility assessment using known antibody data. In context, a real-time approach is testing patient serum against donor cells (like an immediate crossmatch), whereas a virtual crossmatch uses the known HLA antibody profile and donor HLA type to predict compatibility without a physical test. Real-time crossmatching (via SPRCA or flow cytometry) is feasible within 24 hours and is very useful if the patient’s antibody specificities are not fully identified or if donor typing information is limited ().

• SSO (Sequence-Specific Oligonucleotide) Probing: Often implemented via reverse SSO on platforms like Luminex for genotyping. In PCR-SSO, the patient’s DNA (or donor’s DNA) is amplified at HLA loci, then hybridized to a panel of probes specific to known HLA allele sequences. Each probe is bound to a bead (or a spot) and corresponds to a particular DNA motif. By detecting which probes bind the sample’s DNA, the lab can determine the HLA allele or at least the antigen group. SSO kits can provide low-to-intermediate resolution typing – for example, they might tell us a patient is HLA-A02:01 or maybe just HLA-A02 (broad antigen level depending on the kit design). SSO typing has been a workhorse in HLA labs for years because it’s relatively fast (results in one day) and can be batch-run for multiple samples. The cost per sample is moderate and the equipment (thermal cycler and Luminex reader) is available in most HLA labs. For platelet matching purposes, SSO typing is usually sufficient, as it identifies the key antigens (A, B) needed for match grading.
• SSP (Sequence-Specific Primers) by real-time PCR: Another approach is PCR-SSP, where a series of specific primers are used in separate PCR reactions targeting particular HLA alleles or allele groups. Traditionally, SSP is done as endpoint PCR with gel electrophoresis. However, newer real-time PCR assays can perform SSP with fluorescent detection, eliminating gels and reducing time. Some HLA labs use real-time PCR kits for rapid low-resolution typing (for example, to quickly confirm a particular allele or type in a few hours). Real-time PCR methods are especially common for HPA genotyping – for instance, typing a patient for HPA-1, -5, -15 alleles using TaqMan probes is quick and helps determine if they lack a certain platelet antigen. The feasibility of real-time PCR is high for targeted questions (it’s fast, but not practical for high-resolution typing of many loci due to the number of reactions needed). Cost is relatively low for a small number of targets, and turnaround can be under 2-3 hours in an urgent scenario. Thus, if an HLA lab needs to urgently genotype a patient for a few HLA antigens, real-time PCR based SSP can be an option.
• NGS (Next-Generation Sequencing) for HLA typing: In the last decade, NGS has emerged as a powerful method for high-resolution HLA typing. Using platforms like Illumina or Ion Torrent, HLA genes can be sequenced in full, determining the exact allele (e.g., HLA-A*02:01:01 vs *02:01:02). NGS provides the most detailed information, which is crucial for stem cell and organ transplantation (where allele differences can be immunogenic). However, for platelet transfusion support, such granularity is usually not required; serologic antigen matching suffices, as discussed. NGS turnaround time is typically longer – it might take 2 days to prepare and run samples and another day to analyze, depending on the lab’s workflow. It is also higher in cost, both for reagents and for the initial investment in sequencers and bioinformatics infrastructure. Many HLA labs do have NGS capability now, but they might not routinely use it for every platelet refractoriness case due to the time/cost. Instead, NGS might be reserved for particularly difficult cases (e.g., a patient with unusual antibodies where allele-specific differences might matter, or to use advanced matching algorithms based on epitopes).
• Comparing feasibility and utility: For an HLA lab consulting on platelet refractoriness, the practical approach is often:
  • Use PCR-SSO or SSP to determine the patient’s HLA-A and B types if not already known (often hematology patients may have HLA typing done if they were transplant candidates).
  • Identify donor HLA types either from an HLA-typed donor registry or by typing potential donors (SSO can be done on donors too, or their previously stored HLA type can be retrieved).
  • High-resolution typing by NGS is generally not needed just to secure platelets, but if the lab has data or needs to resolve ambiguous SSO results, they may deploy NGS. For example, if SSO shows a broad antigen but the lab wants to be sure of any cross-reactive antigens (CREG) or minor epitopes, NGS can clarify. However, this is balanced against urgency; platelets are needed quickly for bleeding patients, so waiting days for NGS is often impractical.
  • Cost considerations: SSO/SSP methods have a lower per-sample cost than NGS and require less specialized analysis. NGS becomes cost-effective when many samples are batched or when high resolution is necessary. For one-off cases of platelet refractoriness, SSO and antibody testing typically cover the clinical need.
  • Turnaround time: SSO typing can be done in 6–8 hours for a single sample (or overnight), whereas NGS might take ~48-72 hours for results. If a patient is actively bleeding and refractory, one cannot wait for NGS; instead, interim support would be provided via crossmatched platelets or known partially matched units. NGS data might be used later to refine donor searches (especially if the refractoriness is prolonged and patient will need many future transfusions).

• For antibody detection: ELISA screens and Luminex single-antigen bead assays are standard, with older CDC assays largely supplanted () (). These have high clinical utility in pinpointing immune causes of refractoriness, guiding donor selection despite some challenges in interpretation of low-level antibodies.
• For HLA typing: PCR-SSO (or SSP) provides timely identification of HLA-A, B, C types for matching. NGS offers detailed allele resolution but is typically more than needed for platelet support; its use may be limited to complex cases or concurrently for transplant planning. The cost and turnaround trade-offs mean that SSO/SSP remains popular for quick typing, whereas NGS is used when the extra detail is worth the wait and expense.

6. Calculated Panel Reactive Antibody (cPRA) and Its Role

• Calculation: Once specific HLA antibody specificities are identified (usually via the Luminex SAB assay), each antibody can be mapped to the frequency of that antigen in the donor population. For example, if a patient has anti-HLA-A2 and anti-HLA-B44, and those antigens are present in, say, 50% and 10% of donors respectively, one can calculate the overall fraction of donors who have any of the antigens the patient reacts to. Modern calculators (often provided by national registries or UNOS) take into account the population frequency of each HLA antigen and whether the antibodies are additive. The result is given as a percentage – e.g., cPRA of 85% means 85% of random donors carry at least one of the HLA antigens that the patient’s serum would react against, leaving only 15% of donors potentially compatible.
• Interpretation: A high cPRA (close to 100%) indicates the patient is broadly sensitized and will be refractory to platelets from most donors (). Such patients are very challenging to support; they will likely need either perfectly HLA-matched donors or a strategy like crossmatching many donors to find those rare compatible units. Conversely, a low cPRA (e.g. 20%) means the patient’s antibodies are limited to a few specific antigens, and a significant portion of donors (80% in this example) would not trigger those antibodies. This could be managed by avoiding donors with those particular antigens – relatively easier.
• Use in decision-making: For HLA lab professionals, cPRA provides a quick summary of sensitization severity. It helps answer the question: How hard will it be to find a good platelet unit?
  • If a patient has cPRA <20-30%, one might try to manage by simply avoiding the specific mismatches (through selective donor choice or crossmatch) without needing a nationwide search.
  • If cPRA is extremely high (>80–90%), it signals the need to engage special resources early – for instance, contacting an HLA-matched donor registry, considering family donors, or even discussing therapies to reduce antibodies. It also means that even HLA-matched platelets could be hard to find because the patient likely has antibodies to common HLA antigens that make finding a match difficult.
  • cPRA can influence whether to pursue HLA matching vs crossmatching. A high cPRA patient may benefit from a calculated approach of identifying any antigen “holes” in their antibody profile and finding donors who fit that narrow window. A moderate cPRA patient might be efficiently managed with crossmatch-compatible random donors (since many donors will be compatible).
• Monitoring and trends: In some cases, serial cPRA measurements can be used to monitor a patient’s sensitization status. For example, after a bone marrow transplant (which might suppress antibody production or change immune status), the cPRA might drop if antibodies wane, potentially broadening donor options over time.
• Limitations: cPRA assumes knowledge of all relevant antibodies. If a patient has an antibody that wasn’t detected or tested for (e.g., a low-incidence antigen or a weak antibody below lab cutoff), the cPRA might underestimate sensitization. Additionally, cPRA is population-dependent; it’s usually calculated based on antigen frequencies in a reference population (often national blood donor demographics). If a patient has a rare HLA type, finding a matched donor could still be hard even with a moderate cPRA, because the pool of identical matches is small. Thus, cPRA is a guide, not an absolute predictor.
• Relation to PRA: Historically, labs reported a PRA % from the CDC assay. cPRA is more precise as it is calculated from specific antibody data rather than empirically measured by cell panel reactivity. For modern usage, cPRA is preferred since it leverages the granular SAB results (). For example, instead of saying “this serum reacts with 80% of a panel (PRA 80%)”, we now say “based on specific antibodies, 98% of donors would express an antigen that this serum reacts with (cPRA 98%)”.

7. Platelet Unit Selection Strategies for Alloimmune Refractoriness

• Pros: Crossmatching is rapid – results can be obtained within hours, often enabling transfusion on the same or next day (). It requires no prior knowledge of the patient’s HLA type or antibody specificities, so it’s useful when antibody identification is incomplete or as an interim measure (). It also inherently addresses all antibody types (HLA, HPA, or even unforeseen antibodies) because any antibody that can bind platelets will cause an incompatible result. Many blood banks prefer to start with crossmatch-compatible units for these reasons.
• Cons: Crossmatch finding suitable donors can become difficult if the patient is highly alloimmunized (high cPRA). If, say, 95% of donors would react, a lot of testing may be needed to find that 1 in 20 who is compatible (). Also, transfusing crossmatch-compatible but not HLA-matched units may expose the patient to new HLA antigens that they don’t yet have antibodies against, risking future alloimmunization on those new specificities (). In other words, crossmatch ensures no current antibodies will destroy the platelets, but it doesn’t prevent the patient from making new antibodies to any mismatched antigens on those platelets. Nonetheless, in an acute setting, getting platelets that survive now is the priority, and crossmatching achieves that in a straightforward way.

• Pros: A 4/4 HLA match virtually guarantees that the patient’s anti-HLA antibodies (if any) will not target the donor platelets, since the donor isn’t providing foreign A or B antigens (). This often results in excellent CCIs and can even help avoid additional sensitization (no new antigen exposure) (). HLA-matched platelets are a very effective solution for patients with anti-HLA antibodies.
• Cons: The challenge is availability. Finding a perfect match depends on donor databases; common HLA types may have many matches available, whereas rare types may have few or none. Smaller centers without an HLA donor pool must specially call donors or import units, causing delays (). Also, if a patient has unusual HLA like certain minority haplotypes, matched donors might be geographically distant. Another limitation: HLA matching doesn’t address platelet-specific antibodies – if the patient has an HPA antibody, an HLA-identical donor could still be incompatible. In practice, though, HPA issues are rare.

• A match: 4/4 (all A and B antigens match).
• B match (B1U, B2U, etc.): One or two mismatches, often within the same cross-reactive groups (CREGs) or one-way mismatches.
• C or D match: Poor matches with multiple mismatches.

• Pros: HLA-compatible selection often yields a larger donor pool than strict matching. Many donors who are not genotype matches may still lack the specific antigens the patient reacts to (). Studies show that this approach is equivalent in efficacy to true HLA matching in terms of patient platelet count responses (). For example, a patient might not find any 4/4 donors, but using ASP they find 10 donors who simply don’t express the 2 antigens that the patient’s antibodies target – those donors’ platelets should survive well (). This method leverages the detailed SAB results and cPRA calculation to broaden options ().
• Cons: An HLA-compatible (but not genotype-identical) unit still carries some mismatch, meaning the patient is being exposed to foreign HLA antigens (just not the ones they currently have antibodies to) (). This means there is a risk the patient could become immunized to those new antigens in the future, especially if they need repeated transfusions (similar to crossmatch-compatible in that sense) (). However, sometimes one can prioritize donors that share as many antigens as possible to minimize this risk. Another consideration is that selecting based on antibodies assumes the lab’s antibody identification is comprehensive. If the patient has an undetected antibody, a supposedly “compatible” unit might still fail – but that is a risk with any method.

• Alternative donor sources: If the regular donor pool fails, consider family donors or directed donations. Sometimes a sibling or parent shares one haplotype fully with the patient and can donate platelets that are a partial match (or even full if a haploidentical match) (). Caution: if the patient is going to receive a related stem cell transplant, using that donor for platelets might cause the patient to develop antibodies to minor antigens that could affect engraftment (). So coordination with the transplant team is needed.
• High-dose or multiple random units: Not usually effective in immune refractoriness – simply giving more mismatched platelets typically doesn’t overcome immune destruction significantly. However, if antibody titers are low, doubling the dose could give a transient bump. This is not a preferred strategy but might be used in resource-limited settings while waiting for matched units.
• IVIg or immunosuppression: There is anecdotal use of IV immunoglobulin to reduce platelet destruction in refractory patients (IVIg can block Fc receptors and might help in ITP or alloimmune thrombocytopenia). Similarly, immunosuppressive drugs (like corticosteroids) might dampen reticuloendothelial clearance. The evidence for routine use is not strong, so these are considered on a case-by-case basis in refractory bleeding patients.
• Complement inhibition: If complement-fixing antibodies are suspected to play a major role, drugs like eculizumab (a C5 inhibitor) have been tried to improve platelet increments in refractory patients (). There are reports of successful increase in CCI with eculizumab in highly refractory cases (), though this is very expensive and not standard therapy.
• “In vivo adsorption” (antibody depletion): An extreme strategy mentioned in the literature is to use platelets as a sink to absorb antibodies. For example, transfuse a platelet unit expressing the target antigen to intentionally soak up the patient’s antibody, and immediately follow with another unit for actual clinical effect (). Essentially, the first unit is sacrificed to neutralize antibody, then the next might survive longer. This has been used for critical bleeding scenarios when no compatible units were readily available (). It’s a risky and last-resort measure due to the obvious wastage and potential reactions.

1. Initial approach: Provide ABO-compatible, crossmatch-compatible platelets to stabilize the patient while HLA antibody identification is ongoing (). Monitor the 10–60 min CCI after these trial transfusions.
2. If crossmatched random platelets fail (low CCIs despite compatibility by crossmatch), escalate to HLA-selected units – either matched or antibody-avoidance strategy (). This suggests the patient’s antibody profile is so broad that even crossmatch finds few options, so a targeted search for specific HLA types is needed.
3. Continuously communicate with the clinical team about inventory – e.g., if no perfect matches exist, they might try next-best compatible donors.
4. Reserve HPA-matched units only if HPA antibodies are proven and HLA-compatible transfusions are inadequate ().
5. Use special interventions (family donors, novel therapies) in exceptional cases.

8. Pooled Donor Platelets vs. HLA-Matched Platelets

• Advantages of pooled units: They are generally readily available and don’t require special donor selection beyond basic ABO/Rh matching. Blood centers can draw from the general donor pool to make pools, which is useful if inventory of single-donor units is low. Pooled platelets are usually leukoreduced and ABO-matched within the pool when possible, but not HLA-selected.
• Disadvantages for refractory patients: Each pool introduces multiple donors’ platelets. For an alloimmunized patient, this means multiple distinct HLA antigen exposures in one transfusion. The chance that all donors in the pool lack the patient’s target antigens is extremely low if the patient has widespread antibodies. If even one donor’s platelets in the pool carry an antigen to which the patient has an antibody, those platelets (and potentially the entire pool, as platelets circulate together) can be rapidly destroyed. Essentially, pooled random platelets are ineffective in the setting of strong HLA antibodies – the patient’s immune system will attack any incompatible subset, and the overall increment will be poor. Additionally, pooling increases the patient’s cumulative exposure to foreign antigens, potentially exacerbating alloimmunization (more unique HLA types per transfusion).
• Use cases: Pooled platelets are fine for non-refractory patients or when refractoriness is due to non-immune factors (in which case any platelet should survive normally once the underlying issue is resolved). But if immune refractoriness is confirmed, continuing to give pooled random platelets is usually futile and wastes resources. Guidelines explicitly advise that patients who are refractory solely due to non-immune causes should not receive HLA-selected products () – which implies that if immune causes are present, one should move away from random pools to selected units. In practice, once refractoriness is identified, clinicians will switch from random pooled (or random apheresis) platelets to special matching strategies.
• Example: A leukemic patient refractory after two random pools (each pool ABO-identical but not HLA-matched) would next be managed with either crossmatch or HLA-matched single donors. Continuing to give random pools would likely result in ongoing CCIs <5k.

• The exposure is to one donor’s HLA profile instead of many, reducing the immediate chance of incompatibility if that donor is well-chosen, and also reducing the risk of new antibody formation (fewer new antigens introduced per transfusion).
• Apheresis platelets from an HLA-matched donor are often high in yield (3×10^11 platelets or more) and can fully support an adult patient. Pooled units also reach that dose but with multiple donors.
• The process of obtaining HLA-matched units can be complex. If an HLA-identical donor is not already on the shelf, the transfusion service might issue an alert to a donor registry. The donor must be available and donate, or an existing frozen HLA-matched product must be located and shipped. This can take time (often >24 hours), during which the patient may need interim support (like ABO-matched random platelets or crossmatched units).
• Efficacy: When a true HLA-matched platelet unit is given to an alloimmunized patient, the increment is often dramatically better than with unmatched pools. It’s not guaranteed (other factors like fever can still dampen increment), but if HLA antibodies were the main issue, matched units solve that by removing the target. Studies and experience have shown that implementing HLA-matched platelet support significantly improves count recovery and reduces bleeding in refractory patients () ().
• Resource intensity: HLA-matched single donor platelets are a scarce resource. They require maintaining HLA typing data on many donors and sometimes directing donors to come in on short notice. This can be costly. There is also more wastage risk if a specific donor is called up and the patient no longer needs the unit or if the unit doesn’t get used before expiration. Because of these factors, guidelines recommend not using HLA-matched platelets unless clearly indicated (i.e., confirmed immune refractoriness) ().

• Random Pooled Platelets:
  • Pros: Immediately available in most blood banks, no special testing needed, can transfuse quickly; good for general use.
  • Cons: Ineffective if patient has HLA/HPA antibodies; high risk of immune destruction in alloimmunized patients; multiple donor exposures per transfusion.
• HLA-Matched Single-Donor Platelets:
  • Pros: Best option for patients with HLA antibodies – highest likelihood of successful increment; minimizes additional immune exposures; necessary for continued support of alloimmunized patients.
  • Cons: Limited supply, requires advance planning/coordination; slower to obtain; higher cost (both in lab resources and donor management).

9. Guidelines and Literature on Managing Platelet Transfusion Refractoriness

• Both American and British guidelines concur that refractoriness should be confirmed with at least two sequential low post-transfusion platelet count increments (typically measured at 10 minutes to 1 hour post-transfusion) (). The accepted definition per BSH (British Society for Haematology) is an increment of <5×10^9/L (i.e., <5,000/µL) above baseline on two occasions despite adequate transfusions (). This is in line with other references that use CCI <5,000 as a benchmark ().
• Once identified, a key guideline principle is to distinguish immune vs non-immune causes. The BSH guidelines and others note that non-immune causes (like sepsis, fever, DIC, medications) are the most common reason (~80%) for poor increments (). Therefore, they recommend addressing those first: e.g., treat infections, stop offending drugs, control bleeding. If refractoriness is solely due to non-immune factors, do not proceed to HLA-matched transfusions (), as these will not fix the issue and waste scarce resources.
• If an immune cause is suspected (especially in bone marrow failure patients with repeated transfusions), guidelines advise performing an antibody screen for HLA (and HPA) antibodies. This aligns with expert reviews that suggest a stepwise workup: confirm refractoriness with CCIs, then initiate antibody testing if no clear non-immune explanation.

• Guidelines endorse using ABO-identical or at least compatible platelets whenever possible. For example, BSH recommends ABO-matched platelets to maximize increments (Grade 2C recommendation) (). However, they also acknowledge that 100% ABO matching is not practical due to inventory constraints (). The decision is often to give ABO-compatible (no major incompatibility) if identical is not available. The emphasis is on avoiding known issues like high-titer mismatches, as supported by literature that ABO-nonidentical transfusions have lower count increments ().

• There has historically been debate on whether HLA-matched platelets or crossmatch-selected platelets are superior. A 2015 systematic review (Pavenski et al.) examined available studies and found no clear randomized trial evidence strongly favoring one over the other; most data were observational (). The consensus is that both approaches are valid and achieve comparable outcomes in many cases ().
• Many guidelines suggest a pragmatic approach: if HLA-matched platelets are readily available (e.g., patient has a common type and the center has an inventory), they can be used early. If not, crossmatching is a good first-line because it’s faster (). The ASFA (Apheresis) guidelines and others also mention platelet crossmatching as an effective method to identify compatible units.
• The BSH 2016 guideline specifically states: For patients refractory with HLA class I antibodies, provide HLA-selected (matched or compatible) platelets (Grade 2C) (). If those patients prove refractory even to HLA-selected transfusions and are found to have HPA antibodies, then use HPA-selected platelets (Grade 2C) (). They also caution not to give HLA-selected platelets to patients who are not refractory (to avoid unnecessary alloimmunization and conserve resources) ().
• US practice (AABB and others) typically recommends leukoreduction for all (to prevent alloimmunization in the first place), then: after two poor increments, investigate and, if immune, switch to either crossmatch-compatible or HLA-matched strategy. The American Red Cross’s Compendium of Transfusion Practice Guidelines similarly outlines checking CCI and moving to HLA-matched or crossmatched support for immune refractoriness.

• Guidelines note that isolated HPA-mediated refractoriness is rare. However, if a patient has HLA-selected transfusions that fail, one should test for HPA antibodies (). If present, providing antigen-negative platelets (e.g., from donors who lack that platelet antigen) is indicated (). For example, a patient with anti-HPA-1a should receive HPA-1a negative platelets. Such donors may be found among family or via national rare donor programs. BSH gives this a 2C grade recommendation, reflecting moderate quality evidence but a consensus that it’s beneficial.

• The literature acknowledges the resource implications of managing refractoriness. HLA-matched programs require donor typing, inventory management, and sometimes shipping of products from far away. There’s also discussion of using platelet additive solution to mitigate minor ABO issues and extend inventory flexibility ().
• A cost-effective approach often advocated is: preventive leukoreduction (to reduce incidence of refractoriness), and early identification of refractoriness to avoid wasting many random units. Once identified, targeted therapy (HLA or crossmatch) should be used so that we’re not throwing “good platelets after bad.”
• The “antibody specificity prediction” method (selecting platelets based on the patient’s antibody profile) is viewed as a resource-efficient way to broaden donor selection (). Instead of insisting on a perfect match which might be impossible, one finds any donor lacking the problematic antigens – increasing chances of finding a unit and getting it to the patient in time (). This has been shown to improve feasibility without compromising patient outcomes ().
• There is also mention in literature that both crossmatching and HLA matching can reduce bleeding events compared to doing nothing in refractory patients, but each transfusion service must consider its logistics. Smaller hospitals may rely on reference labs for HLA testing and thus lean on crossmatch (SPRCA kits), whereas large academic centers may have on-site HLA labs and donor pools, facilitating HLA-matched transfusions.

• Guidelines universally recommend using leukoreduced blood components to prevent HLA alloimmunization (). In regions where this isn’t universal, any patient who might become long-term transfusion dependent should get leukoreduced platelets from the start.
• Some literature also explores newer methods like UVB irradiation of platelets to reduce immunogenicity, but these are experimental. The mainstay remains leukoreduction.
• For patients with known risk (e.g., pregnant women with platelet disorders, or those already having some antibodies), one might consider assigning them ABO-identical and possibly HLA-selected platelets proactively. However, prophylactic HLA matching is not generally recommended due to scarcity – better to see if they become refractory first (), unless they are in a clinical trial or special scenario.

• Guidelines emphasize continued monitoring of CCIs even after implementing matched transfusions. If a chosen strategy (say crossmatch-compatible units) is not giving satisfactory results, escalate to the next step (HLA-matched) (). The iterative approach is important; sometimes initial crossmatch units might work for a while until new antibodies form, then you adjust accordingly.
• Documentation in patient records of refractoriness and antibody status is crucial so that future transfusion episodes (even at other hospitals) can plan appropriately for HLA-matched support.

• Verify true refractoriness with proper increment calculations (Level B/C evidence, consensus) () ().
• Treat or exclude non-immune causes before attributing to alloimmunity (Level B evidence, known percentage of cases) () ().
• If immune, perform HLA antibody testing (Level B, widely practiced) and/or a platelet crossmatch (Level B/C) to guide therapy ().
• Use leukoreduced, ABO-matched platelets to maximize success (Level B/C) () ().
• For HLA antibody-positive patients, provide HLA-matched or HLA-compatible platelets (Level C evidence – observational studies support it) () ().
• Crossmatched platelets are an acceptable alternative to HLA-matched (Level C, expert consensus) and can be first-line due to rapid availability () ().
• Avoid HLA-matched platelets in patients who don’t need them (i.e., not refractory) to conserve resources (Good practice point) ().
• In refractory cases unresponsive to HLA-matched units, investigate HPA antibodies and match for those if found (Level C) () ().
• Engage specialized therapies (IVIg, etc.) only in extreme cases or research settings (expert opinion, case reports) ().

• Cohn CS. Platelet transfusion refractoriness: how do I diagnose and manage? Hematology Am Soc Hematol Educ Program. 2020(1):527-532 () () () () () () () () () () () (). (Overview of immune refractoriness, causes, and management strategies)
• Pavenski K, et al. Clinical practice guidelines on the evaluation and management of platelet refractoriness. (Referenced in BSH 2016) () (). (Systematic review of refractoriness causes and interventions)
• BSH Guidelines (2016). Guidelines for the use of platelet transfusions. Br J Haematol. () (). (Recommends definitions and use of HLA/HPA selected platelets)
• Vitalant Health. Platelet Transfusion Refractoriness – Technical Manual. () (). (Details on calculating CCI/PPR and testing methods)
• Stanworth SJ, et al. Platelet refractoriness – practical approaches and ongoing challenges. Transfus Med Rev. (Discusses strategies like crossmatch vs HLA match)
• Hod E, Schwartz J. Platelet transfusion refractoriness. Brit J Haematol. 2008;142(3):348-60. (Classic review on causes and management of refractoriness)