Alloimmunization From Transfusions 

Updated: Sep 08, 2017
Author: Douglas Blackall, MD, MPH; Chief Editor: Michael A Kaliner, MD 

Overview

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 persist for a variable time. A recipient who is immunocompetent may mount an immune response to the donor antigens (ie, alloimmunization), resulting in various clinical consequences, depending on the blood cells and specific antigens involved. The antigens most commonly involved can be classified into the following categories: (1) human leukocyte antigens (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 antigens [HPAs]); and (4) RBC-specific antigens.

The consequences of alloimmunization to blood-based antigens include the following clinical manifestations:

  • Alloimmunization against RBCs

    • Acute intravascular hemolytic transfusion reactions (rarely a consequence of alloimmunization and almost always caused by ABO antibodies)[1]

    • Delayed hemolytic transfusion reactions (DHTRs) (hemolysis caused by RBC alloantibodies typically presenting clinically 7–14 days after transfusion)

    • Hemolytic disease of the fetus and newborn (mother's alloimmunization against red blood cell fetal antigens, most often resulting from previous pregnancies)

  • Alloimmunization against platelets (platelet-specific or HLA class I antigens)

    • Refractoriness to platelet transfusion (an increase in the platelet count after platelet transfusion that is significantly lower than expected [eg, < 30% of predicted 10-60 min posttransfusion or < 20% at 18-24 h posttransfusion])

    • Posttransfusion purpura (thrombocytopenia after transfusion of red cells or other platelet-containing products, associated with the presence of platelet alloantibodies)

    • Neonatal alloimmune thrombocytopenia (mother's alloimmunization against fetal  platelet antigens, most often resulting from previous pregnancies but can be seen in a first pregnancy)

  • 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 with recipient white blood cell antigens)

  • Transplant rejection

    • Alloimmunization against HLA antigens

    • Alloimmunization against blood cell antigens in bone marrow transplantation leading to hemolysis and the possibility of delayed engraftment

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 other sections of Medscape Reference. Transplant rejection is discussed in Assessment and Management of the Renal Transplant Patient.

DHTRs and refractoriness to platelet transfusions are discussed in this article. Refractoriness to granulocyte transfusion involves either HLA or granulocyte-specific antibodies and is similar to platelet refractoriness, except that refractoriness to granulocyte transfusion results in the patient failing to respond clinically to the infused granulocytes. Because granulocyte transfusions are rarely used, they are not discussed further in this article.

Pathophysiology

The immunologic mechanism for alloimmunization to antigens present in transfused cells involves 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 II alloantigens by CD4+ recipient T cells and their subsequent activation requires a co-stimulatory signal from either the donor or recipient APCs. The TH 2 subset of CD4+ T helper cells secretes interleukin (IL)–4, IL-5, IL-6, and IL-10, which activates B cells and initiates the antibody response.[2]

Leukocyte reduction of transfused platelets virtually eliminates donor APCs, but patients may still develop alloimmunization. Alloimmunization from leukocyte-reduced cellular blood products requires recognition of the alloantigen by recipient APCs and activation of recipient CD4+ T cells. This process also involves the initial recognition of alloantigens by natural killer cells, which secrete interferon-gamma. This cytokine, in turn, is involved in the activation of CD4+ TH 2 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. Interestingly, blood transfusion (mainly through the TH 2 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 thus reflects a balance between clonal expansion and tolerogenic mechanisms. A secondary immune 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

HLA alloimmunization is the most common cause of platelet refractoriness. The immune response to non-HLA antigens, present on the platelet surface (most importantly, platelet-specific antigens or HPAs) are involved less commonly. Patients not previously sensitized may develop platelet antibodies approximately 3-4 weeks after transfusion. However, patients previously immunized by transfusion, pregnancy, or organ transplantation may develop platelet 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 platelet antibodies include the presence of more than 1 million donor leukocytes in transfused cellular blood products (platelets, red blood cells), 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).[3]

Delayed hemolytic transfusion reactions

DHTRs generally occur 1-2 weeks after transfusion. They represent a secondary immune response in patients previously immunized to a red cell antigen by transfusion or pregnancy.[4] In very rare cases, a brisk primary immune response can result in a DHTR after an initial transfusion. When RBC antibody titers drop below detectable levels (about 50% of the patients with alloimmunization), there is a risk for the transfusion of incompatible units of blood. Transfusion with incompatible RBCs results in restimulation of memory cells and an increase in IgG antibody titer (ie, an anamnestic immune response). Antibodies bind to the surface of RBCs and, depending on the number of antigen-antibody interactions, may activate complement with deposition of C3b. Typically, more than 105 antigenic sites per cell are required for potent complement activation.

RBCs coated with IgG antibodies and/or complement bind to immunoglobulin Fc or C3b receptors present on mononuclear phagocytes and are destroyed by phagocytosis (ie, extravascular hemolysis). IgG antibodies that efficiently activate complement (eg, those in the Kidd blood group system) tend to cause more intense extravascular hemolysis compared to antibodies that do not efficiently activate complement (eg, Rh and Kell system antibodies). Rarely, binding of IgM antibodies to RBCs activates the classic complement pathway and leads to intravascular hemolysis, but this is much more commonly seen in the context of ABO-incompatible transfusions with accompanying acute hemolytic transfusion reactions.

Epidemiology

Frequency

Refractoriness to platelet transfusions

Approximately 20-85% of patients who receive multiple transfusions become immunized to platelet antigens (eg, HLA, HPA), and 30% of patients who are alloimmunized develop refractoriness to platelet transfusions.

Overall, platelet refractoriness occurs in approximately 20-70% of patients who receive multiple transfusions. In two-thirds of these patients, nonimmune factors (see Differentials) alone are the cause, whereas alloimmunization may be involved in one-third of refractory patients, often in combination with nonimmune causes.

HLA class I antibodies are implicated in most alloimmunization cases, while platelet-specific antigens (ie, HPA) may be involved in 10-20% of refractory cases. Combinations of both types of antibodies are seen in approximately 5% of cases. A single random RBC or platelet transfusion induces HLA antibodies in less than 10% of recipients (most likely related to the tolerogenic effect of blood transfusions). However, if patients receive more than 20 transfusions, they become sensitized in increasing proportions. As an example, after 50 transfusions, most patients (as many as 70%) have HLA antibodies. In addition, patients with RBC alloantibodies are more likely to have HLA antibodies.

The presence of HLA antibodies is better correlated with platelet refractoriness than antibodies directed against platelet-specific antigens. In those cases of platelet refractoriness due to HPA antibodies, HPA-1b, HPA-5b, and HPA-1a antibodies are most commonly implicated. The platelet-specific antigen systems are listed in Table 1.

Table 1. Human Platelet-Specific Antigen Systems (Open Table in a new window)

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 red blood cell transfusions develop RBC antibodies. In patients who are transfused regularly or in whom there is a mismatch between donor and recipient red blood cell antigens (eg, patients with sickle cell disease), the frequency of alloimmunization is much higher, affecting 10–38%.[5, 6] Despite the relatively high frequency of RBC alloimmunization, clinical manifestations of hemolytic transfusion reactions are rare (approximately 0.05% of patients transfused), as blood banks routinely detect RBC antibodies and provide antigen-negative units of blood for transfusion. The most frequently detected clinically significant RBC antibodies are shown in Table 2.[32]

Table 2. Frequent Clinically Significant RBC Antibodies (Open Table in a new window)

Antigen

System

Frequency Among All Detected Alloantibodies

Frequency of Antigen

(Whites)

Frequency of Antigen

(Blacks)

Potency*

E

Rh

16-40%

30%

22%

4%

K

Kell

5-40%

9%

2%

9%

D

Rh

8-33%

85%

92%

70%

c

Rh

4-15%

80%

96%

4%

Jk(a)

Kidd

2-13%

77%

92%

0.14%

Fy(a)

Duffy

4-12%

66%

10%

0.46%

C

Rh

2-10%

68%

27%

0.22%

e

Rh

2-3%

98%

98%

1%

Jk(b)

Kidd

2%

74%

49%

0.06%

S

MNSs

1-2%

55%

31%

0.08%

s

MNSs

< 1%

89%

94%

0.06%

*Percentage of antigen-negative recipients who become alloimmunized if transfused with antigen-positive units

Clinically significant DHTRs have been observed in about 1:2500 transfused patients in Germany and 1:3000 transfused patients in the Netherlands.

Mortality/Morbidity

The risk of death from a DHTR is approximately 1 fatality per 3.85 million red blood cell units transfused.

Data regarding the impact of platelet refractoriness on morbidity and mortality for thrombocytopenic patients are inconsistent. However, 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 group 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.

 

Presentation

Physical

Delayed hemolytic transfusion reactions

Hemolysis is usually extravascular, but in rare cases a component of intravascular hemolysis is present.

Most cases manifest during the second week after transfusion, but the reaction can occur from 24 hours to 3 months after the transfusion.

Many patients are asymptomatic, and the condition is oftentimes detected only by laboratory testing.[7]

In some patients, fever and/or chills (50%), jaundice (10%), pain (3%), and dyspnea (1%) can occur.

Rarely, cases may be complicated by renal failure (6%) or disseminated intravascular coagulation (1%).

In patients with sickle cell disease, a DHTR can precipitate a sickling crisis.[8]

Refractoriness to platelet transfusions

Frequently, patients with refractoriness to platelet transfusion are asymptomatic and diagnosed by laboratory methods; however, failure to achieve hemostatic levels of platelets may preclude these patients from important procedures, including bone marrow transplantation. Alloimmunization should be avoided in candidates for bone marrow transplantation.

Preexisting bleeding resulting from thrombocytopenia may persist after transfusion of an appropriate therapeutic dose of platelets.[9] Rarely, spontaneous bleeding may occur after prophylactic transfusion of platelets.

Causes

Alloimmunization to blood antigens occurs after the following:

  • Transfusion

  • Pregnancy

  • Transplantation

  • Sharing intravenous needles (rare)

 

DDx

Diagnostic Considerations

Delayed hemolytic transfusion reactions

Immune hemolysis

  • Paroxysmal nocturnal hemoglobinuria

  • Warm autoimmune hemolytic anemia

  • Cold agglutinin disease

  • Paroxysmal cold hemoglobinuria

Nonimmune hemolysis

  • Sepsis (particularly clostridial species), malaria, babesiosis

  • Mechanical hemolysis (eg, prosthetic valve, left ventricular assist device, small phlebotomy needles, infusion pumps, other devices)

  • Infusion of incompatible solutions together with RBC units

  • Accidental freezing or excessive heating of RBC units

  • Microangiopathic hemolytic anemia

  • Drug-induced hemolysis

  • Congenital hemolytic anemia (eg, glucose-6-phosphate dehydrogenase deficiency, hereditary spherocytosis)

Reabsorption of hematoma (eg, high lactate dehydrogenase or bilirubin, low haptoglobin)

Refractoriness to platelet transfusions

Before attempting to identify the cause of platelet refractoriness, ensure that the patient has been transfused with an adequate dose of ABO-compatible platelets.[10, 11]

Common nonalloimmune causes of inadequate response to an adequate dose of platelets include the following:[12]

  • Active bleeding (even subclinical)

  • Fever[13]

  • Sepsis

  • Splenomegaly[13] (ie, splenic sequestration)

  • Autoimmune thrombocytopenia

  • Disseminated intravascular coagulation

  • Veno-occlusive disease[13]

  • Drug-induced thrombocytopenia (eg, amphotericin B, vancomycin)

  • Circulating immune complexes

  • Thrombotic thrombocytopenic purpura

  • Bone marrow and early post-stem cell transplantation

  • Renal dialysis

  • Platelet age (>3 d) and poorly stored platelet concentrates

Differential Diagnoses

 

Workup

Laboratory Studies

Delayed hemolytic transfusion reactions

The most reliable laboratory finding is a failure to observe the expected posttransfusion increase in blood hemoglobin level (approximately 1 g/dL/U) in the absence of bleeding.

In some cases, the loss of circulating red cells may be higher than would be expected if only antigen-positive cells were cleared. This phenomenon results from bystander hemolysis, which is caused by the deposition of activated complement on both donor and recipient RBCs.

Laboratory signs of hemolysis include elevated lactate dehydrogenase, indirect bilirubin, and reticulocyte levels and decreased hematocrit and haptoglobin levels.

Intravascular hemolysis is characterized by the presence of free plasma hemoglobin, free urine hemoglobin, and possibly hemosiderinuria.

The results of direct and indirect antiglobulin tests (ie, Coombs' tests) are often positive.

Alloantibodies can be eluted from RBCs, and their specificity can be defined. In the setting of hemolysis, sensitive elution techniques should be performed to identify alloantibodies, even if serum antibodies are undetectable and the direct antiglobulin test is only weakly reactive. In 15-20% of cases, patients with DHTRs have multiple antibodies; some may be detectable only by elution.

If possible, type the donor RBCs for the corresponding antigen(s) of interest and re-crossmatch them with the patient's serum, if segments from the transfused units are available.

Refractoriness to platelet transfusions

Refractoriness to platelet transfusions is defined as a repeated failure to achieve the expected increment in platelet count after 2 or more platelet transfusions. The expected increment, also called the corrected count increment (CCI), can be calculated based on the number of platelets transfused and the patient's body surface area (BSA) using the following formula:[31]

CCI = (posttransfusion count – pretransfusion count in platelets/µL) X BSA (in M2) ÷ number of platelets transfused (X 1011)

As an example, if a man with a BSA of 2.0 M2 increases his platelet count from 5,000/ul to 45,000/ul after receiving 4 X 1011 platelets, then his CCI equals 20,000 (ie, (45,000-5,000) X 2.0 ÷ 4.0 = 20,000).

Of note, if the actual number of platelets in a platelet product are unknown, 6 X 1010 platelets can be assumed for each whole blood-derived platelet transfused; an average apheresis unit contains the equivalent of approximately 6 pooled whole blood-derived platelet units or 4 X 1011 platelets.

On the basis of studies in patients receiving prophylactic platelet transfusions and platelet transfusions in healthy volunteers, the expected CCI in a successful transfusion should range between 10,000 and 20,000.

CCIs of less than 7500 at 10-60 minutes posttransfusion indicate a probable platelet transfusion failure. Consistent failure to achieve expected CCIs defines the platelet refractory state.

A simple screen for platelet refractoriness is failure to achieve an increment of >5 X 109/L (5,000/µL) at 20-24 hours after transfusion of a standard platelet dose (1 unit/10 kg of pooled platelets or one single-donor apheresis unit).

Note that many cases of apparent refractoriness result from causes other than alloimmunization (see Differentials).

In general, alloimmunization results in the rapid removal of platelets and in lower counts at 10 minutes to 1 hour posttransfusion, whereas nonimmune causes mostly affect the 4- to 24-hour posttransfusion count. Mild alloimmunization, however, can still be present with 1-hour posttransfusion platelet increments within the expected range.

Microcytotoxicity assays against a panel of 30-60 different lymphocyte cells can demonstrate lymphocytotoxic HLA antibodies. The percentage of cells to which the patient's serum reacts is referred to as the panel-reactive antibody (PRA) level. PRA values greater than 20% indicate significant alloimmunization to HLA antigens and correlate with an increased risk for platelet refractoriness.

The presence of antiplatelet antibodies can be demonstrated by flow cytometry or by immunoassays such as the modified antigen capture enzyme-linked assay, the solid-phase RBC adherence assay, and the monoclonal antibody immobilization of platelet antigens assay. Most of these assays permit screening for HLA and HPA antibodies as well as specific identification of the most commonly involved HPA antigens.

A negative result from platelet antibody screening (HLA and HPA) strongly suggests nonimmune causes of refractoriness.

 

Treatment

Medical Care

Delayed hemolytic transfusion reactions

Most patients tolerate DHTRs well and only require observation and supportive care.

Good communication with the blood bank is essential to provide future transfusion support with antigen-negative RBCs. If these RBCs are not available, weigh the risk of further hemolysis against the indications for transfusion.

If the load of transfused antigen-positive packed RBCs is large (>5 U), exchange transfusion should be considered. In addition, the administration of intravenous human immunoglobulin (IVIG) to block further hemolysis is worth consideration. The IVIG dose is 400 mg/kg, infused slowly, within 24 hours of transfusion.

Refractoriness to platelet transfusions

Avoiding platelet transfusions as much as possible is important in alloimmunized patients. Prophylactic transfusions are not recommended. Measures to minimize the likelihood and extent of bleeding (eg, rapid treatment of infection; avoidance of invasive procedures; correction of coagulation deficiencies, anemia, and renal insufficiency; use of antifibrinolytic agents) should be used extensively.

After diagnosing alloimmune platelet refractoriness, use the sequence of measures that follows, initiating each subsequent intervention if the previous one fails.

  • Rule out nonimmune, autoimmune, and drug-related causes of platelet refractoriness and treat accordingly. Providing immune-compatible platelets is unlikely to be effective in the presence of nonimmune causes of refractoriness.

  • Consider alternatives to platelet transfusion to control bleeding, including the use of antifibrinolytic agents such as alpha-aminocaproic acid or activated recombinant factor VIIa.[14]

  • Transfuse ABO-compatible fresh (aged < 48 h) platelet concentrates. ABO-matched and fresher platelets are associated with higher posttransfusion platelet increments than mismatched and older (age >3 d) platelets.

  • Transfuse with platelets from blood relatives. Obtaining platelets from blood relatives is worthwhile because the chance of matching 2 or more HLA and platelet antigens is high (resulting in good recovery), and relatives are often willing to donate frequently. Irradiation of blood products from relatives is mandatory to prevent transfusion-associated graft-versus-host disease.

  • Select HLA-matched platelets. Perform HLA typing of patients who will receive multiple transfusions before they become pancytopenic (eg, bone marrow transplant recipients). Matching for both private (ie, HLA-A, HLA-B) and public (ie, cross-reacting groups) antigens is best achieved by computerized selection of donors, based on the results of the PRA assay.

  • Select crossmatched platelets. Crossmatch-compatible platelets can significantly improve platelet recovery in approximately 50% of patients who are refractory to random-donor platelets. Selecting crossmatched platelets is especially indicated for patients with high PRA levels or those who do not respond to HLA-matched platelets.

  • The use of HPA1a/5b-negative platelets has been successful in cases of posttransfusion purpura and neonatal platelet alloimmunization. These antigens are involved in most (95%) of these cases, but they account for no more than 10-20% of immune refractoriness to platelet transfusions.

  • Pretreat with IVIG before transfusion. IVIG pretreatment can result in successful increments after platelet transfusion in patients who are alloimmunized. Success rates vary and depend on the degree of alloimmunization. IVIG does not reduce the level of alloantibodies but may decrease platelet-associated immunoglobulins and possibly interferes with platelet destruction mechanisms. IVIG is more effective in improving short-term (1-6 h) recovery of platelets than longer term platelet survival (>24 h).

  • Use high-dose platelet transfusion. Empirical use of high doses of random platelet units (eg, 1 apheresis unit tid or 2-3 apheresis units before invasive procedures) may result in a lower overall titer of the effecting antibody(ies), overwhelming the mononuclear-phagocyte system, and increasing the survival of transfused platelets.

  • Attempt large-volume plasmapheresis. Plasmapheresis (eg, 2 plasma volumes for 1-3 d) before bone marrow transplantation results in beneficial responses in most patients who are alloimmunized to platelets. Perfusion of the plasma through a staphylococcal protein A column is an experimental treatment that has met with some success.

  • Consider administering immunosuppressive drugs. While steroids are not effective, isolated reports suggest that immunosuppressive therapy may be beneficial. As examples, the use of vincristine and cyclosporin A has been successful but require 2-3 weeks to take effect.

Consultations

Transfusion medicine specialist or hematologist

 

Medication

Medication Summary

Immunosuppressive agents such as IVIG can provide short-term benefit in patients with platelet refractoriness resulting from alloimmunization. Consider using cytotoxic agents only in patients clearly unresponsive to all other treatment modalities. Only physicians familiar with the use and toxicity of cytotoxic agents should prescribe these drugs, as there is only anecdotal support for their use in alloimmunization. In other words, this indication is considered investigational.

Immunosuppressive agents

Class Summary

Inhibit activity of the immune system.

Immunoglobulin intravenous IVIG (Gamunex, Iveegam EN, Gammagard)

Fractionated human immunoglobulins treated to inactivate viruses and filtered to eliminate high molecular weight complexes. Neutralizes circulating myelin antibodies through antiidiotypic antibodies. Promotes remyelination. May increase CSF IgG (10%). 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.

Cytotoxic agents

Class Summary

Inhibit immune cell growth and proliferation.

Vincristine (Oncovin)

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.

Cyclosporin A (Sandimmune, Neoral)

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.

 

Follow-up

Further Inpatient Care

Delayed hemolytic transfusion reactions

To assess the effectiveness of RBC transfusions, measure hemoglobin levels 1 and 24 hours posttransfusion.

More than 40% of RBC antibodies become undetectable after the first detection, but these antibodies may cause hemolysis upon restimulation.[15]

Maintain accurate records of the antibodies present and consider notifying patients (eg, with a carry-on card) that they have clinically significant alloantibodies.

Refractoriness to platelet transfusions

To assess the effectiveness of platelet transfusions, obtain platelet counts at 1 and 24 hours posttransfusion.

If the specificity of antibodies is identified, keep a permanent record and consider notifying the patient (eg, with a carry-on card).

Consider planning future platelet transfusions in advance by selecting donors who lack the involved antigens.

Deterrence/Prevention

Delayed hemolytic transfusion reactions

Properly identify blood group alloantibodies prior to transfusion, and select antigen-negative RBCs for transfusion.

Patients with previously identified alloantibodies must be documented in a database, with information shared between institutions, as appropriate. Antigen-negative RBC units should be provided whenever possible, even if corresponding alloantibodies have decreased below detectable levels (to prevent immune restimulation).

Patients with alloantibodies require fully crossmatched (ie, antihuman globulin phase) donor units.

In patients of ethnic minorities who have received multiple transfusions (eg, African-Americans with sickle cell disease), testing for commonly involved antigens (eg, Rh, Kell, Kidd, Duffy) and transfusing antigen-negative units can significantly reduce the frequency of alloimmunization. However, the cost effectiveness of this approach must be considered because most patients who receive multiple transfusions do not form clinically significant alloantibodies. A more cost-effective approach may be to match the ethnic origin of donors and recipients, reserving extensive antigen typing for recipients who have been alloimmunized previously. These patients may also benefit from leukocyte reduced RBCs because leukoreduction appears to decrease the frequency of alloimmunization to RBC antigens, possibly due to decreased stimulation of TH 2 lymphocytes associated with transfusions.[6]

If Rh-positive units (RBCs, platelets, or granulocytes) must be transfused into an Rh-negative recipient, alloimmunization to the D antigen can be prevented by administering intravenous Rh-immunoglobulin (eg, WinRho SD, 10-12 mcg/mL of transfused Rh-positive RBCs). If transfusing a large number of Rh-positive units, the dose of Rh-immunoglobulin may be reduced after removing the antigen load by RBC exchange.[16, 17]

Refractoriness to platelet transfusions

Primary alloimmunization to class I HLA antigens present on platelets requires active donor APCs.

Removing leukocytes by filtration or buffy coat removal or deactivating APCs by ultraviolet-B irradiation reduce the frequency of alloimmunization.

Leukocyte reduction is indicated in all patients who are expected to be transfused repeatedly, especially candidates for bone marrow transplantation. These patients may also benefit from initial HLA typing and transfusions from crossmatched or HLA-matched platelets.[18]

Pooled, random-donor, leukocyte-reduced platelets do not increase the frequency of alloimmunization compared with leukocyte-reduced, single-donor apheresis platelets.[19]

Transfusion of ABO incompatible platelets (ie, donor platelets with A or B antigens reacting with the recipient's A or B antibodies) increases the likelihood of alloimmunization to other platelet antigens and reduces platelet survival. Therefore, ABO-compatible platelets should be provided routinely, as available, to avoid alloimmunization.[20]

Patient Education

Inform patients that they have alloreactive antibodies and educate them about the names of these antibodies (eg, with a wallet carry-on card). Instruct patients to present the carry-on card if they are admitted to a care facility different from that which they usually attend..

 

Questions & Answers

Overview

What is alloimmunization from blood transfusions?

What are the consequences of alloimmunization to blood-based antigens?

What is the pathophysiology of alloimmunization?

What is the pathophysiology of alloimmunized refractoriness to platelet transfusions?

What is the pathophysiology of delayed hemolytic transfusion reactions (DHTR)?

What is the prevalence of delayed hemolytic transfusion reactions (DHTR)?

What is the prevalence of alloimmunized refractoriness to platelet transfusions?

What is the mortality and morbidity associated with alloimmunization from transfusions?

What are the racial predilections of alloimmunization from transfusions?

What are the sexual predilections of alloimmunization from transfusions?

Which age groups have the highest prevalence of alloimmunization from transfusions?

Presentation

Which physical findings are characteristic of delayed hemolytic transfusion reactions (DHTR)?

Which physical findings are characteristic of alloimmunized refractoriness to platelet transfusions?

What causes alloimmunization from transfusions?

DDX

Which conditions are included in the differential diagnoses of delayed hemolytic transfusion reactions (DHTR)?

Which conditions are included in the differential diagnoses of alloimmunized refractoriness to platelet transfusions?

What are the differential diagnoses for Alloimmunization From Transfusions?

Workup

What is the role of lab testing in the workup of delayed hemolytic transfusion reactions (DHTR)?

What is the role of lab testing in the workup of alloimmunized refractoriness to platelet transfusions?

Treatment

How are delayed hemolytic transfusions reactions (DHTR) treated?

How is alloimmunized refractoriness to platelet transfusions treated?

Which specialist consultations are beneficial to patients with alloimmunization from transfusions?

Medications

What is the role of medications in the treatment of alloimmunization from transfusions?

Which medications in the drug class Cytotoxic agents are used in the treatment of Alloimmunization From Transfusions?

Which medications in the drug class Immunosuppressive agents are used in the treatment of Alloimmunization From Transfusions?

Follow-up

When is inpatient care indicated in the treatment of delayed hemolytic transfusion reactions (DHTR)?

When is inpatient care indicated in the treatment of alloimmunized refractoriness to platelet transfusions?

How are delayed hemolytic transfusion reactions (DHTR) prevented?

How is alloimmunized refractoriness to platelet transfusions prevented?

What is included in patient education about alloimmunization from transfusions?