Alloimmunization From Transfusions

historical past

Allogeneic blood transfusion is a type of brief transplantation. This procedure introduces a mess of overseas antigens and dwelling cells into the recipient that persist for a variable time. A recipient who's immunocompetent continuously mounts an immune response to the donor antigens, resulting in more than a few medical consequences, relying on the blood cells and particular antigens involved. The antigens most recurrently involved are categorized in the following categories: (1) human leukocyte antigens (HLAs), classification I shared through platelets and leukocytes and class II current on some leukocytes; (2) granulocyte-explicit antigens; (3) platelet-explicit antigens (human platelet antigen [HPA]); and (4) RBC-particular antigens.

the consequences of alloimmunization to blood embody the next scientific manifestations:

Alloimmunization in opposition to RBCs Acute intravascular hemolytic transfusion reactions (infrequently a final result of alloimmunization and almost all the time as a result of ABO antibodies)[1] Delayed hemolytic transfusion reactions (DHTRs) (hemolysis because of RBC alloantibodies at the least 24 hours posttransfusion)Hemolytic illness in newborns (mom's alloimmunization against fetal antigens, most ceaselessly as a consequence of previous pregnancies)Alloimmunization against platelets (platelet-explicit or HLA classification I antigens) Refractoriness to platelet transfusion (an increase within the platelet count after platelet transfusion that is significantly lower than expected [eg, Posttransfusion purpura (thrombocytopenia after transfusion of pink cells or other platelet-containing merchandise, related to presence of platelet alloantibodies) Neonatal alloimmune thrombocytopenia (mother's alloimmunization against fetal antigens, most ceaselessly as a result of previous pregnancies) Alloimmunization towards granulocytes (granulocyte-particular or HLA antigens)Refractoriness to granulocyte transfusion Febrile nonhemolytic transfusion reactionsTransfusion-related acute lung injury (ie, a transfusion response during which donor HLA antibodies react against recipient antigens)Transplant rejection Alloimmunization against HLA antigensAlloimmunization in opposition to blood cell antigens (in bone marrow transplantation)

Hemolytic transfusion reactions, posttransfusion purpura, febrile nonhemolytic transfusion reactions, and transfusion-related acute lung harm are discussed in Transfusion Reactions. Hemolytic illness in newborns and neonatal alloimmune thrombocytopenia are mentioned in other sections of Medscape Reference. Transplant rejection is discussed in review and administration of the Renal Transplant affected person.

DHTR and refractoriness to platelet transfusions are discussed on this article. Refractoriness to granulocyte transfusions involves either anti-HLA or granulocyte-explicit antibodies and is much like platelet refractoriness, with the exception of that refractoriness to granulocyte transfusions leads to the patient failing to answer the granulocyte transfusions. as a result of granulocyte transfusions are hardly ever used, they don't seem to be mentioned further in this article.

NextPathophysiology

the primary mechanism for alloimmunization to antigens existing in transfused cells may contain presentation of the donor antigens by way of donor antigen–presenting cells (APCs), ie, monocytes, macrophages, dendritic cells, B cells, to recipient T cells. popularity of the MHC class I alloantigens by CD4+ recipient T cells and their subsequent activation requires a co-stimulatory signal from both the donor or recipient APCs. Alloimmunization by means of non–leukoreduced platelets involves shared donor HLA antigens (HLA-restricted) and are living purposeful donor APCs. The TH 2 subset of CD4+ T helper cells secretes interleukin (IL)–four, IL-5, IL-6, and IL-10; activates B cells; and initiates the antibody response.[2]

Leukoreduction of transfused platelets nearly eliminates donor APCs, however 20% of patients nonetheless enhance alloimmunization. Alloimmunization from leukoreduced platelets involves attractiveness of the alloantigen and activation of recipient CD4+ T cells by means of alloantigen-offering recipient APCs. This process additionally includes initial popularity of alloantigens via natural killer cells, which secrete interferon-gamma. This cytokine, in turn, is concerned in the activation of CD4+ TH 2 cells.

After preliminary activation and building of the primary immune response, T cells change into memory cells. memory T cells shouldn't have co-stimulatory alerts to turn into activated and may recognize alerts within the absence of class II HLA molecules. for that reason, donor RBCs, platelets, and inactivated APCs can result in restimulation of the immune response. Blood transfusion (mainly through the TH 2 subset) can actively suppress the host immune response and set off tolerance to donor antigens. every other mechanism of immunosuppression entails stimulation of CD8+ suppressor T cells, which is able to acknowledge MHC class I alloantigens in platelets as well as donor APCs. primary immunization with blood transfusion reflects the steadiness between clonal enlargement and tolerogenic mechanisms. The secondary response is dependent upon the restimulation of memory cells. Repeated immunization eventually results in sustained clonal expansion and clinically significant antibody manufacturing.

Refractoriness to platelet transfusions

The presence of HLA antibodies on the platelet floor is the most typical cause of platelet refractoriness. other non-HLA antigens present on the platelet floor (eg, platelet-particular antigens, HPA) are also keen on a variety of instances. patients no longer previously sensitized strengthen antiplatelet antibodies roughly 3-4 weeks (10-26 d) after the transfusion. sufferers prior to now immunized by transfusion, being pregnant, 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 machine phagocytize and wreck antibody-coated platelets.

chance components for growing antiplatelet antibodies embody the presence of more than 1 million donor leukocytes in transfused products, transfusing ABO-mismatched platelets, the presence of an intact immune device (ie, absence of cytotoxic or immunosuppressive remedy), female sex (roughly 75% of instances), and a historical past of a couple of transfusions (>20).

Delayed hemolytic transfusion reactions

DHTRs happen between 24 hours and 3 months (steadily 2 wk) after transfusion and regularly characterize a secondary immune response in sufferers up to now immunized by way of transfusion or pregnancy. In very rare instances, brisk major immune response may end up in DHTR after an preliminary transfusion. Anti-RBC antibody titers frequently (about 50% of the patients with alloimmunization) drop beneath detectable levels, permitting incompatible gadgets to be transfused. Transfusion with incompatible RBCs leads to restimulation of reminiscence cells and an increase in antibody titer. Antibodies bind to the skin of RBCs and, relying on the selection of antigen-antibody interactions, activate complement with deposition of C3b. regularly, more than a hundred and five antigenic sites per cell are required for amazing complement activation.

rarely, binding of immunoglobulin M antibodies to RBCs activates the classic complement pathway and results in intravascular hemolysis. RBCs lined with immunoglobulin G antibodies and/or complement bind to C3b and immunoglobulin Fc receptors current on mononuclear phagocytes and are destroyed by means of phagocytosis (ie, extravascular hemolysis). Immunoglobulin G antibodies that effectively set off complement (eg, these in Kidd and Duffy techniques) are inclined to lead to more intense extravascular hemolysis compared with antibodies that do not efficiently set off complement (eg, Rh and Kell).

PreviousNextEpidemiologyFrequencyUnited StatesRefractoriness to platelet transfusions

with regard to the frequency of alloimmunization, roughly 20-eighty five% of patients who receive more than one transfusions change into immunized towards platelet antigens (eg, HLA, HPA), and approximately 30% of patients who are alloimmunized advance refractoriness to platelet transfusions.

Platelet refractoriness occurs in approximately 20-70% of sufferers who obtain multiple transfusions. In roughly 66% of those patients, nonimmune components (see Differentials) on my own are the lead to, whereas alloimmunization could also be eager about 33% of refractory patients, incessantly in combination with nonimmune causes.

with regard to the frequency of type of antibody serious about platelet refractoriness, HLA type I antibodies are keen on most alloimmunization cases, whereas platelet-explicit antigens (ie, HPA) is also occupied with roughly 10-20% of refractory cases. combinations of both kinds of antibodies are concerned about roughly 5% of cases. A single random RBC or platelet transfusion induces anti-HLA antibodies in not up to 10% of recipients (possibly associated to the tolerogenic effect of blood transfusions). If sufferers have greater than 20 transfusions, they grow to be sensitized in growing proportions; after 50 transfusions, most (as many as 70%) patients have anti-HLA antibodies. patients with RBC alloantibodies are more likely to have anti-HLA antibodies.

The presence of HLA antibodies displays higher correlation with platelet refractoriness than antibodies directed towards platelet-explicit antigens. in the minority of circumstances of platelet refractoriness due to HPA antibodies, HPA-1b, HPA-5b, and HPA-1a antibodies are most commonly concerned. Platelet-particular antigen methods are listed in desk 1.

table 1. Human Platelet-specific Antigen systems (Open desk in a brand new window)

Platelet Antigen SystemProtein AntigenSynonymsAllelesAntigen FrequencyHPA-1GPIIIaPlA,ZwHPA-1a = PlA1

HPA-1b = PlA2

97%

26%

HPA-2GPIbKo, SibHPA-2A

HPA-2b

ninety nine%

14%

HPA-3GPIIbBak, LekHPA-3a

HPA-3b

85%

sixty six%

HPA-4GPIIaPen, YukHPA-4a

HPA-4b

>99%

HPA-5GPIaBr, Hc, ZavHPA-5a

HPA-5b

99%

20%

Delayed hemolytic transfusion reactions

approximately zero.1-2% of sufferers who receive transfusions strengthen anti-RBC antibodies. In sufferers who are transfused frequently (eg, sufferers with sickle cell illness), the frequency of alloimmunization is much better, affecting 10-38%.[3, 4] regardless of the quite high frequency of RBC alloimmunization, scientific manifestations of hemolytic transfusion reactions are uncommon (roughly zero.05% of sufferers transfused). the most time-honored clinically vital RBC antibodies are proven in table 2.

table 2. commonplace Clinically significant Anti-RBC Antibodies (Open table in a brand new window)

AntigenSystemFrequency among All Detected AlloantibodiesFrequency of Antigen

(Whites)

Frequency of Antigen

(Blacks)

efficiency*ERh16-40percent30p.c2p.c4percentKell (Kl)Kell5-40%9%3percent9p.cDRh8-33p.c85p.c92percent70p.ccRh4-15p.c80p.c99%4percentJk(a)Kidd2-13%77percent91%0.14%Fy(a)Duffy4-12p.c63%10p.c0.46%CRh2-10%70p.c32percent0.22percenteRh2-3%98percent98percent1p.cJk(b)Kidd2%72%43%0.06%SMNSs1-2%55%31percent0.08%sMNSs89percent97%0.06%*proportion of antigen-terrible recipients who turn into alloimmunized if transfused with antigen-positive unitsInternational

Clinically important DHTR has been noticed in about 1:2500 cases in Germany and 1:3000 cases within the Netherlands.

Mortality/MorbidityThe risk of death from a DHTR is roughly 1 fatality per three.85 million devices (1 per 1.15 million U in patients who have got transfusions). data regarding the influence of platelet refractoriness on morbidity and mortality for thrombocytopenic sufferers are inconsistent. Failure to succeed in platelet counts better than 5 X 109/L significantly increases the likelihood of lifestyles-threatening bleeding. Race

folks from ethnic minority teams have an elevated possibility of alloimmunization from transfusion because outstanding differences exist within the frequency of blood cell antigens between races. Efforts to extend the blood supply from minority donors are crucial to reduce the frequency of alloimmunization in these groups.

sex

DHTRs and platelet refractoriness are extra standard in females than in males, possibly as a result of earlier sensitization from being pregnant.

Age

Older patients (ie, >50 y) are inclined to have decreased immune responsiveness to blood transfusions.

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