Background
Allogeneic blood transfusion is a form of temporary transplantation. This procedure introduces a multitude of foreign antigens and living cells into the recipient that will persist for a variable time. A recipient who is immunocompetent often mounts an immune response to the donor antigens, resulting in a variety of clinical consequences depending on the blood cells and specific antigens involved. The antigens most commonly involved are classified in the following categories: (1) HLAs, class I shared by platelets and leukocytes and class II present on some leukocytes; (2) granulocyte-specific antigens; (3) platelet-specific antigens (human platelet antigen [HPA]); and (4) RBC-specific antigens.
The consequences of alloimmunization to blood include the following clinical manifestations:
- Alloimmunization against RBCs
- Acute intravascular hemolytic transfusion reaction, which is rarely a consequence of alloimmunization
- Delayed hemolytic transfusion reactions (DHTRs)
- Hemolytic disease in newborns (mother's alloimmunization against fetal antigens, most often resulting from previous pregnancies)
- Acute intravascular hemolytic transfusion reaction, which is rarely a consequence of alloimmunization
- Alloimmunization against platelets (platelet-specific or HLA class I antigens)
- Refractoriness to platelet transfusion
- Posttransfusion purpura
- Neonatal alloimmune thrombocytopenia (mother's alloimmunization against fetal antigens, most often resulting from previous pregnancies)
- Refractoriness to platelet transfusion
- Alloimmunization against granulocytes (granulocyte-specific or HLA antigens)
- Refractoriness to granulocyte transfusion
- Febrile nonhemolytic transfusion reactions
- Transfusion-related acute lung injury, ie, a transfusion reaction in which donor HLA antibodies react against recipient antigens
- Refractoriness to granulocyte transfusion
- Transplant rejection
- Alloimmunization against HLA antigens
- Alloimmunization against blood cell antigens (in bone marrow transplantation)
- Alloimmunization against HLA antigens
Hemolytic transfusion reactions, posttransfusion purpura, febrile nonhemolytic transfusion reactions, and transfusion-related acute lung injury are discussed in Transfusion Reactions. Hemolytic disease in newborns and neonatal alloimmune thrombocytopenia are discussed in the Neonatology section of eMedicine. Transplant rejection is discussed in Renal Transplantation (Medical).
DHTR and refractoriness to platelet transfusions are discussed in this article. Refractoriness to granulocyte transfusions involves either anti-HLA or granulocyte-specific antibodies and is similar to platelet refractoriness, except that refractoriness to granulocyte transfusions results in the patient failing to respond to the granulocyte transfusions. Because granulocyte transfusions are rarely used, they are not discussed further in this article.
Pathophysiology
The main mechanism for alloimmunization to antigens present in transfused cells may involve presentation of the donor antigens by donor antigen–presenting cells (APCs), ie, monocytes, macrophages, dendritic cells, B cells, to recipient T cells. Recognition of the MHC class I alloantigens by CD4+ recipient T cells and their subsequent activation requires a co-stimulatory signal from either the donor or recipient APCs. Alloimmunization by non–leukoreduced platelets involves shared donor HLA antigens (HLA-restricted) and live functional donor APCs. The TH2 subset of CD4+ T helper cells secretes interleukin (IL)–4, IL-5, IL-6, and IL-10; activates B cells; and initiates the antibody response.
Leukoreduction of transfused platelets virtually eliminates donor APCs, but 20% of patients still develop alloimmunization. Alloimmunization from leukoreduced platelets involves recognition of the alloantigen and activation of recipient CD4+ T cells by alloantigen-presenting recipient APCs. This process also involves initial recognition of alloantigens by natural killer cells, which secrete interferon-gamma. This cytokine, in turn, is involved in the activation of CD4+ TH2 cells.
After initial activation and development of the primary immune response, T cells become memory cells. Memory T cells do not need co-stimulatory signals to become activated and can recognize signals in the absence of class II HLA molecules. Thus, donor RBCs, platelets, and inactivated APCs can induce restimulation of the immune response. Blood transfusion (mainly through the TH2 subset) can actively suppress the host immune response and induce tolerance to donor antigens. Another mechanism of immunosuppression involves stimulation of CD8+ suppressor T cells, which can recognize MHC class I alloantigens in platelets as well as donor APCs. Primary immunization with blood transfusion reflects the balance between clonal expansion and tolerogenic mechanisms. The secondary response depends on the restimulation of memory cells. Repeated immunization eventually results in sustained clonal expansion and clinically significant antibody production.
Refractoriness to platelet transfusions
The presence of HLA antibodies on the platelet surface is the most common cause of platelet refractoriness. Other non-HLA antigens present on the platelet surface (eg, platelet-specific antigens, HPA) are also involved in a number of cases. Patients not previously sensitized develop antiplatelet antibodies approximately 3-4 weeks (10 d to 26 wk) after the transfusion. Patients previously immunized by transfusion, pregnancy, or organ transplantation develop antiplatelet antibodies as early as 4 days after transfusion. Macrophages in the liver, spleen, and other tissues of the mononuclear phagocyte system phagocytize and destroy antibody-coated platelets.
Risk factors for developing antiplatelet antibodies include the presence of more than 1 million donor leukocytes in transfused products, transfusing ABO-mismatched platelets, the presence of an intact immune system (ie, absence of cytotoxic or immunosuppressive therapy), female sex (approximately 75% of cases), and a history of multiple transfusions (>20).
Delayed hemolytic transfusion reactions
DHTRs occur between 24 hours and 3 months (frequently 2 wk) after transfusion and usually represent a secondary immune response. Anti-RBC antibody titers frequently drop below detectable levels. Patients are transfused with incompatible RBCs, resulting in restimulation of memory cells and an increase in antibody titer. Antibodies bind to the surface of RBCs and, depending on the number of antigen-antibody interactions, activate complement with deposition of C3b. Usually, more than 105 antigenic sites per cell are required for potent complement activation.
Rarely, binding of immunoglobulin M antibodies to RBCs activates the classic complement pathway and leads to intravascular hemolysis. RBCs coated with immunoglobulin G antibodies and/or complement bind to C3b and immunoglobulin Fc receptors present on mononuclear phagocytes and are destroyed by phagocytosis (ie, extravascular hemolysis). Immunoglobulin G antibodies that efficiently activate complement (eg, those in Kidd and Duffy systems) tend to cause more intense extravascular hemolysis compared with antibodies that do not efficiently activate complement (eg, Rh and Kell).
Frequency
United States
Refractoriness to platelet transfusions
With regard to the frequency of alloimmunization, approximately 20-85% of patients who receive multiple transfusions become immunized against platelet antigens (eg, HLA, HPA), and approximately 30% of patients who are alloimmunized develop refractoriness to platelet transfusions.
Platelet refractoriness occurs in approximately 20-70% of patients who receive multiple transfusions. In approximately 66% of these patients, nonimmune factors alone are the cause, whereas alloimmunization may be involved in 33% of refractory patients, often in combination with nonimmune causes.
With regard to the frequency of type of antibody involved in platelet refractoriness, HLA class I antibodies are involved in most alloimmunization cases, whereas platelet-specific antigens (ie, HPA) may be involved in approximately 10-20% of refractory cases. Both types of antibodies are involved in approximately 5% of cases. A single random RBC or platelet transfusion induces anti-HLA antibodies in less than 10% of recipients (most likely related to the tolerogenic effect of blood transfusions). If patients have more than 20 transfusions, they become sensitized in increasing proportions; after 50 transfusions, most (as many as 70%) patients have anti-HLA antibodies.
The presence of HLA antibodies shows better correlation with platelet refractoriness than antibodies directed against platelet-specific antigens. In the minority of cases of platelet refractoriness due to HPA antibodies, HPA-1b, HPA-5b, and HPA-1a antibodies are most commonly involved. Platelet-specific antigen systems are listed in Table 1.Table 1. Human Platelet-Specific Antigen Systems
| Platelet Antigen System | Protein Antigen | Synonyms | Alleles | Antigen Frequency |
|---|---|---|---|---|
| HPA-1 | GPIIIa | PlA,Zw | HPA-1a = PlA1 |
| HPA-1b = PlA2 | 97% |
| 26% | |||
| HPA-2 | GPIb | Ko, Sib | HPA-2A |
| HPA-2b | 99% |
| 14% | |||
| HPA-3 | GPIIb | Bak, Lek | HPA-3a |
| HPA-3b | 85% |
| 66% | |||
| HPA-4 | GPIIa | Pen, Yuk | HPA-4a |
| HPA-4b | >99% |
| <1% | |||
| HPA-5 | GPIa | Br, Hc, Zav | HPA-5a |
| HPA-5b | 99% |
| 20% |
Delayed hemolytic transfusion reactions
Approximately 0.1-2% of patients who receive transfusions develop anti-RBC antibodies. In patients who are transfused regularly (eg, patients with sickle cell disease), the frequency of alloimmunization is much higher, affecting 10-38%. Despite the relatively high frequency of RBC alloimmunization, clinical manifestations of hemolytic transfusion reactions are rare (approximately 0.05% of patients transfused). The most frequent clinically significant RBC antibodies are shown in Table 2.
Table 2. Frequent Clinically Significant Anti-RBC Antibodies
| Antigen | System | Frequency Among All Detected Alloantibodies | Frequency of Antigen |
|---|
| (Whites) | Frequency of Antigen |
|---|
| (Blacks) | Potency* | ||||
|---|---|---|---|---|---|
| E | Rh | 16-40% | 30% | 2% | 4% |
| Kell (Kl) | Kell | 5-40% | 9% | 3% | 9% |
| D | Rh | 8-33% | 85% | 92% | 70% |
| c | Rh | 4-15% | 80% | 99% | 4% |
| Jk(a) | Kidd | 2-13% | 77% | 91% | 0.14% |
| Fy(a) | Duffy | 4-12% | 63% | 10% | 0.46% |
| C | Rh | 2-10% | 70% | 32% | 0.22% |
| e | Rh | 2-3% | 98% | 98% | 1% |
| Jk(b) | Kidd | 2% | 72% | 43% | 0.06% |
| S | MNSs | 1-2% | 55% | 31% | 0.08% |
| s | MNSs | <1% | 89% | 97% | 0.06% |
Mortality/Morbidity
- The risk of death from a DHTR is approximately 1 fatality per 3.85 million units (1 per 1.15 million U in patients who have received transfusions).
- Data regarding the impact of platelet refractoriness on morbidity and mortality for thrombocytopenic patients are inconsistent. Failure to achieve platelet counts greater than 5 X 109/L significantly increases the probability of life-threatening bleeding.
Race
Individuals from ethnic minority groups have an increased risk of alloimmunization from transfusion because notable differences exist in the frequency of blood cell antigens between races. Efforts to increase the blood supply from minority donors are essential to reduce the frequency of alloimmunization in these groups.
Sex
DHTRs and platelet refractoriness are more common in females than in males, possibly because of previous sensitization from pregnancy.
Age
Older patients (ie, >50 y) tend to have reduced immune responsiveness to blood transfusions.
Treatment
Transfusion medicine specialist or hematologistMedical Care
Consultations
Medication
Immunosuppressive agents such as IVIG can be as much as 70% effective in patients with platelet refractoriness resulting from alloimmunization. Consider using cytotoxic agents only in person clearly unresponsive to the other treatment modalities. Only physicians familiar with the use and toxicity of cytotoxic agents should prescribe these drugs because few data support their use for alloimmunization. This indication is considered investigational.
Drug Category: Immunosuppressive agents
Inhibit activity of immune system.
| Drug Name | Immunoglobulin intravenous IVIG (Gamimune, Sandoglobulin, Gammagard) |
|---|---|
| Description | Fractionated human immunoglobulins treated to inactivate viruses and filtered to eliminate high molecular weight complexes. Neutralizes circulating myelin antibodies through antiidiotypic antibodies. Down-regulates proinflammatory cytokines, including INF-gamma. Blocks Fc receptors on macrophages. Suppresses inducer T and B cells and augments suppressor T cells. Blocks complement cascade. Promotes remyelination. May increase CSF IgG (10%). |
| Adult Dose | 400 mg/kg/d IV for 5 d |
| Pediatric Dose | Administer as in adults |
| Contraindications | Documented hypersensitivity; IgA deficiency (except IgA-depleted IVIG) and anti-IgE/IgG antibodies; relatively contraindicated in patients with renal failure and in patients with history of migraines |
| Interactions | Increases toxicity of live virus vaccine (MMR); do not administer within 3 mo of vaccine |
| Pregnancy | C - Safety for use during pregnancy has not been established. |
| Precautions | Ensure that medical emergency resources are immediately available to manage possible rash, dyspnea, hypotension, or anaphylaxis; administer slowly the first time to detect adverse effects and watch for fluid overload in predisposed patients; mild adverse effects (eg, chills, headache, fever, rash, pruritus) can be prevented or modified by oral acetaminophen (15 mg/kg; maximum required dose in adults generally 650 mg) or diphenhydramine (1 mg/kg; maximum required dose in adults generally 50 mg) Consider checking serum IgA before IVIG, use IgA-depleted IVIG (eg, G-Gard-SD) if indicated IVIG may increase serum viscosity and thromboembolic events; reported adverse effects include migraine attacks, 10% increased risk of aseptic meningitis, and increased risk of urticaria, pruritus, or petechiae 2-5 d postinfusion that may last as long as 1 mo; increased risk of renal tubular necrosis in older patients, diabetic patients, volume-depleted patients, and patients with preexisting kidney disease IVIG can lead to the following changes in laboratory values: elevated antiviral or antibacterial antibody titers for 1 mo, 6-fold increased ESR for 2-3 wk, and apparent hyponatremia |
Drug Category: Cytotoxic agents
Inhibit immune cell growth and proliferation.
| Drug Name | Vincristine (Oncovin) |
|---|---|
| Description | Only one report describes effectiveness, in an 18-mo-old child with platelet refractoriness. Several reports, however, describe its use for treating autoimmune thrombocytopenia. Use for platelet alloimmunization remains investigational. |
| Adult Dose | Not established |
| Pediatric Dose | Not established |
| Contraindications | Documented hypersensitivity |
| Interactions | Acute pulmonary reaction may occur when taken concurrently with mitomycin-C |
| Pregnancy | C - Safety for use during pregnancy has not been established. |
| Precautions | Caution in severe cardiopulmonary or hepatic impairment and patients with preexisting neuromuscular disease |
| Drug Name | Cyclosporin A (Sandimmune, Neoral) |
|---|---|
| Description | Two reports describe use in patients with aplastic anemia and platelet refractoriness. Both patients dramatically improved in response to platelet transfusions after treatment. Use for platelet alloimmunization remains investigational. |
| Adult Dose | Not established |
| Pediatric Dose | Not established |
| Contraindications | Documented hypersensitivity; uncontrolled hypertension or malignancies; do not administer concomitantly with PUVA or UVB radiation in psoriasis because may increase risk of cancer |
| Interactions | Carbamazepine, phenytoin, isoniazid, rifampin, and phenobarbital may decrease concentrations; azithromycin, itraconazole, nicardipine, ketoconazole, fluconazole, erythromycin, verapamil, grapefruit juice, diltiazem, aminoglycosides, acyclovir, amphotericin B, and clarithromycin may increase toxicity; acute renal failure, rhabdomyolysis, myositis, and myalgias increase when taken concurrently with lovastatin |
| Pregnancy | C - Safety for use during pregnancy has not been established. |
| Precautions | Evaluate renal and liver functions often by measuring BUN, serum creatinine, serum bilirubin, and liver enzymes; may increase risk of infection and lymphoma; reserve IV use only for those who cannot take PO |
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