Transfusion Reaction Transfusion Reaction

Mulugeta Melku(BSC, MSC)Mulugeta Melku(BSC, MSC)

Objectives

• At the end At the end Analyse the adverse complication of blood

transfusion Identify the major noninfectious complication of

blood transfusionExplain the mechanisms of complication of blood

transfusion Recognize transfusion transmitted infection

Introduction TransfusionTransfusion• can be autologous or AllogeneicAutologous transfusion:– is an alternative therapy for many patients

anticipating transfusion

Categories: 1.1. Preoperative collection Preoperative collection

blood is drawn and stored before anticipated need

Introduction cont’d 2. Perioperative collection and administrationPerioperative collection and administration

A. Acute normovolemic Hemodilution A. Acute normovolemic Hemodilution blood is collected at the start of surgery and then

infused during or at the end of the procedure

B. Intraoperative collection . Intraoperative collection shed blood is recovered from the surgical field or

circulatory device and then infused

C. Postoperative collection . Postoperative collection blood is collected from drainage devices and re-

infused to the patient

Introduction cont’d

Introduction cont’d • Autologous Blood DonationDisadvantagesDoes not eliminate risk of bacterial

contamination

Does not eliminate risk of incompatibility error

Increased incidence of adverse reactions to autologous donation

Subjects patients to perioperative anemia and increased likelihood of transfusion

Introduction cont’d • Allogeneic transfusion Allogeneic transfusion

Between similar species Between similar species

Disadvantage Disadvantage – the risks of transmissible disease and transfusion

reactions inherent in allogeneic transfusions.– Alloimmunization Alloimmunization – GVHDGVHD– Post transfusion purpuraPost transfusion purpura– Circulatory over load Circulatory over load

Introduction cont’d

Non-Infectious Non-Infectious Complication Complication

of Transfusion of Transfusion

Complication Cont’d

Four broad categories of transfusion reactions:– Acute immunologic– Acute nonimmunologic– Delayed immunologic,– Delayed non-immunologic complications

pathophyiology, prevention and differential criteria

Complication Cont’dManifestation:Manifestation:• one should consider any adverse manifestation

occurring at the time of the transfusionFever with or without chills (rise of 1OC )

Shaking chills (rigors) with or without fever

Pain at the infusion site or in the chest, abdomen

Blood pressure changes

Respiratory distress, including dyspnea, tachypnea, wheezing, or hypoxemia

Complication Cont’dSkin changes, including urticaria, pruritis (itching), flushing, or localized edema

Nausea with or without vomiting

Darkened urine or jaundice

Bleeding or other manifestations of a consumptive coagulopathy

Complication Cont’d

Acute Transfusion Reactions(AHTR)Definition: An AHTR features rapid destruction of RBCs immediately after a transfusion But a hemolytic reaction occurring within 24 hours of the

inciting transfusion is generally considered to be an AHTR

Can be:• Immune-mediated Hemolysis• Non immune-mediated Hemolysis

Complication Cont’d A. Immune-mediated HemolysisA. Immune-mediated HemolysisPathophysiology and ManifestationsPathophysiology and ManifestationsThe most severe hemolytic reactions

Occur when transfused red cells interact with preformed antibodies in the recipient

The interaction of transfused antibodies with the recipient’s red cells rarely causes symptoms. – there may be accelerated red cell destruction, and plasma-containing products with high-titer ABO

antibodies can cause acute hemolysis

Complication Cont’dMechanismsMechanisms– The interaction of antibody with antigen on the red cell

membrane can initiate a sequence of complement activation, cytokine

Classical pathway of C’ activation Classical pathway of C’ activation – IgM bind on RBC Fc binds to complement– Membrane attack complex

Severe symptoms can occur after the infusion of as little as 10 to 15 mL of ABO-incompatible red cells

the initial manifestations of an acute HTR – hemoglobinuria, hypotension, or diffuse bleeding at the surgical

site.

Complication Cont’dCause:Cause:– severe acute HTRs today are usually caused by ABO

incompatibility– occasionally may be caused by antibodies with other specificities

• In contrast, hemolysis of an entire unit of blood can occur in the virtual absence of symptoms and may be a relatively slow process– hemolysis is typically extravascular, without generation

of significant systemic levels of inflammatory mediators

Complication Cont’dComplement Activation

The binding of antibody to blood group antigens may activate complement, depending on the characteristics of both the antibody and the antigeno C3 activation releases the anaphylatoxin C3a

o Red cells coated with C3b are removed by phagocytes with complement receptors, more rapidly than if antibody is present alone

• enzymatic cascade proceeds to completion and a membrane attack complex membrane attack complex is assembled, intravascular hemolysis results production of C5aC5a

Complication Cont’d This sequence is characteristic of ABO incompatibility and causes

the cardinal manifestations of hemoglobinemia hemoglobinemia hemoglobinuriahemoglobinuria.

Anaphylatoxins Anaphylatoxins Interact with a wide variety of cells [[monocytes/macrophages,

granulocytes, platelets, vascular endothelial cells, and smooth muscle cells ]]hypotension and bronchospasm,

cause the release or production of multiple local and systemic mediators [[granule enzymes, histamine

and other vasoactive amines, kinins, oxygen radicals, leukotrienes, nitric oxide, and cytokine]]

mimicking manifestation of allergy mimicking manifestation of allergy

Complication Cont’d• These events cause hypotension,

Vasoconstriction and renal ischemia, and the activation of the coagulation system

Cytokines They mediate some of the effects of alloimmune hemolysis

stimulation of endothelial cells to increase expression of adhesion molecules adhesion molecules and procoagulant procoagulant activity, and recruitment and activation of neutrophils and platelets

Vasodilatation: Hypotension And renal failure

Complication Cont’dCoagulation Activation Several mechanisms may be responsible for

abnormalities of coagulation in HTRs AB-Ag interaction activates intrinsic clotting cascade

by Hageman factor(XII)

activated Hageman factor (Factor XIIa) acts on the kinin system bradykinin

bradykinin: vasoactiveoDilates arterioles, causing a decrease in systemic arterial

pressure

Complication Cont’dactivated C’ cytokines, interleukin may increase the expression of tissue factor by leukocytes and endothelial

cells• Tissue factor activates the “extrinsic”coagulation pathway

DIC– formation of thrombi within the microvasculature and ischemic

damage to tissues and organs

– consumption of fibrinogen, platelets, and other coagulation factors

– activation of the fibrinolytic system and generation of fibrin degradation products

Generalized oozing or uncontrolled bleedinguncontrolled bleeding.

Complication Cont’dHow is could be Diagnosed ?Hypotension Hypotension secondary secondary manifestation of ischemia manifestation of ischemia – Hypotension provokes a compensatory sympathetic sympathetic

nervous system response nervous system response that produces Vasoconstriction in organs and tissues with a vascular bed rich in alpha-adrenergic receptors, renal, splanchnic, pulmonary, and cutaneous capillaries, aggravating ischemia in these sites

Renal failure:Free hemoglobinAB-Ag depositionThrombi formation

Complication Cont’dDifferential Diagnosis Differential Diagnosis patients receiving transfusion therapy can develop a

hemolysis from many sources– it is important to distinguish an AHTR from acute hemolysis of

other causes. Most common cause of hemolysis in transfused patients improper storage of RBCsimproper storage of RBCs

thermal injury, mechanical trauma, inappropriatelymixed with hypotonic solutions or drugs, or contaminatedby bacteria.

Patients with congenital or acquired forms of hemolytic anemia congenital or acquired forms of hemolytic anemia may be incorrectly assumed to have had an AHTR

• hereditary spherocytosis, sickle cell anemia, or RBC enzyme deficiency

• coexistent microangiopathic hemolytic anemia• a patient with thrombotic thrombocytopenic purpura

•

Complication Cont’d• Confirmation of the DiagnosisThe initial suspicious of AHTR

Discontuation of transfusion and initiate lab investigation o Observation of post-transfusion plasma oPerform DAT oInspect the blood bag oRepeat Pretransfusion testing

Complication Cont’d

Complication Cont’dNonimmune-Mediated Hemolysis Nonimmune-Mediated Hemolysis CausesCausesRed cells may undergo in-vitro hemolysis– unit is exposed to improper temperatures– mishandled at the time of administration– Malfunctioning blood warmers, use of microwave

ovens or hot water-baths,– inadvertent freezing may cause temperature-related

damage– pressure infusion pumps, pressure cuffs, or small-

bore needles

Complication Cont’dCauses cont’d Causes cont’d – Osmotic hemolysis in the blood bag or infusion set

– Inadequate deglycerolization of frozen red cells may cause the cells to hemolyze after infusion

– Bacterial growth in blood units

– intrinsic red cell defect of patient or donor has an, such as G-6-DH deficiency

Complication Cont’dFebrile Nonhemolytic transfusion Febrile Nonhemolytic transfusion

Reactions(FNHTR)Reactions(FNHTR)Pathophysiology and ManifestationsPathophysiology and Manifestationsis often defined as:– a temperature increase of >1o C associated with transfusion and without any other explanation.– Such reactions are often associated with chills or

rigorsCause• Non-leukocyte reduced red cell transfusions• Previous opportunities for alloimmunization• After platelet transfusion (1-38%

Complication Cont’d• Many febrile reactions are thought to result from an interaction between

antibodies in the recipient’s plasma and antigens present on transfused lymphocytes, granulocytes, or platelets, most frequently HLA antigens

Complication Cont’dTransfusion-Related Acute Lung Injury (TRALI)Transfusion-Related Acute Lung Injury (TRALI) Pathophysiology and ManifestationsPathophysiology and ManifestationsTransfusion recipient

Experiences acute respiratory insufficiency and/or X-ray findings are consistent with bilateral pulmonary edema but has no other evidence of cardiac failure or a cause for respiratory failure

• Defined acute lung injury (ALI) as a syndrome of: – acute onset; – hypoxemia– bilateral lung infiltrates on a chest x-ray; and – no evidence of circulatory overload.

• New ALI occurring during transfusion or within 6 hours of completion

Complication Cont’d• Mechanisms Mechanisms – Donor antibodies Donor antibodies directed against recipient HLA class

I or II antigens, or neutrophil antigens of the recipient Sequence of events that increase the permeability of the pulmonary microcirculation high-protein fluid enters the interstitium and

alveolar air spaces

– Infrequently, antibodies in the recipient’s antibodies in the recipient’s circulation against HLA or granulocyte antigens initiate the same events

Complication Cont’d suggest that pulmonary edema in TRALI is caused by

neutrophil-mediated endothelial damageneutrophil-mediated endothelial damage, initiated by antibodies activating neutrophils directly or via activation of monocytes, pulmonary macrophages, and/or endothelial cells

Complement activation after granulocyte transfusion

Anaphylatoxins C3a and C5a, aggregation of granulocytes into leukoemboli that lodge in the pulmonary microvasculature

Transfusion of cytokines that have accumulated in stored blood components

Reactive lipid products from donor blood cell membranes

Complication Cont’dCirculatory OverloadCirculatory Overload

Pathophysiology and ManifestationsPathophysiology and Manifestations Transfusion therapy may cause acute pulmonary edema due to volume overload, and this can have

severe consequences, including death

• Rapid increases in blood volume are especially poorly tolerated by patients with compromised cardiac or pulmonary status and/or chronic anemia with expanded plasma volume

Complication Cont’d

The infusion of 25% albumin, which shifts large volumes of extravascular fluid into the vascular space, may also cause circulatory overload.

Hypervolaemia must be considered if dyspnea, cyanosis, severe headache, hypertension, or congestive heart failure occur during or soon after transfusion.

Complication Cont’d Coagulopathy in Massive TransfusionCoagulopathy in Massive Transfusion Pathophysiology • Of greater concern is the occurrence of coagulopathy

during massive transfusion • Classically, this coagulopathy is ascribed – to dilution of platelets and clotting factors, which

occurs as patients lose hemostatically active blood• The lost blood is initially replaced with red cells and fluids

• progressive increase in the incidence of “microvascular microvascular bleeding” bleeding” as a result of multiple transfusion of stored whole blood

Complication Cont’d

Delayed Consequences of Transfusion

Complication Cont’dDELAYED HEMOLYTIC TRANSFUSION REACTIONS PathophysiologyPathophysiology Primary alloimmunization, evidenced by the appearance of

newly formed antibodies to red cell antigens, becomes apparent weeks or months after transfusion

• DHTRs commonly occur in patients who have been immunized to foreign blood group antigens during previous transfusions and/or pregnancies– but the antibody decreases over time and is not detected in

subsequent pretransfusion testing

Transfusion of seemingly compatible blood stimulate Ab intr/extravascular hemolysis

Complication Cont’dDefinition and incidence Definition and incidence accelerated destruction of transfused red cells that begins

only when sufficient antibody has been produced as a result of an immune response induced by the transfusion

most DHTRs share these characteristics– DHTRs generally occur in patients who have been

alloimmunized to RBC antigens by previous transfusions or pregnancies

– implicated antibody is not detected in pretransfusion is not detected in pretransfusion antibody screening or compatibility testing

Complication Cont’dCharacteristics of DHTR

– usually suspected 3 to 10 days after transfusion

– DAT and/or a positive antibody screening test in post-transfusion testing

– Antibodies directed against Rh (CEce) and Kidd (Jka, Jkb) system antigens are the antibodies most commonly implicated in DHTR

Complication Cont’dTransfusion-Associated Graft-versus-Host Disease

• usually fatal immunologic transfusion complication caused by engraftment and proliferation of donor lymphocytes in a susceptible host

• The engrafted lymphocytes mount an immunologic attack against the recipient tissues– hematopoietic cells, leading to refractory pancytopenia with

bleeding and infectious complications

Complication Cont’d Pathophysiology and ManifestationsPathophysiology and ManifestationsComplex and incompletely understood.The overall mechanism includes

– escape of donor T lymphocytes present in cellular blood components from immune clearance in the recipient and

– subsequent proliferation of these cells, which then mount an immune attack on host tissues

Complication Cont’dManifestation Manifestation The rash typically begins as a blanching,

maculopapular erythema of the upper trunk, neck, palms, soles, and earlobes

Factors that determine an individual patient’srisk for TA-GVHD – degree the recipient is immune status – the degree of HLA similarity between donor and

recipient, and – the number and type of T lymphocytes transfused that are capable of multiplication

Complication Cont’dPost-transfusion PurpuraPost-transfusion Purpura Pathophysiology and ManifestationsPathophysiology and Manifestations Uncommon event is characterized by the abrupt onset of severe abrupt onset of severe

thrombocytopeniathrombocytopenia (platelet count usually <10,000/μL) an average of 9 days after transfusion (range, 1-24 days)

Most cases (68%) involve patients whose platelets lack the HPA-1a, HPA-1b and other HPA who form the corresponding antibody

Alloantibodies destruction of patient's own platelet

Complication Cont’dThe reason for destruction of the patient’s own platelets by

platelet alloantibody is controversial• Three mechanisms have been proposed

– formation of immune complexes of patient antibody and antibody and soluble donor antigen soluble donor antigen that bind to Fc receptors on the patient’s platelets and mediate their destruction

– conversion of antigen-negative autologous platelets to antibody targets by soluble antigen in the transfused component

• .

Complication Cont’d

– cross-reactivity of the patient’s antibodies with autologous platelets

othe presence of an autoantibody component

Bleeding after transfusion

Complication Cont’d Iron OverloadIron Overload Every RBC unit contains approximately 200 mg of iron Chronically transfused patients, especially those with

hemoglobinopathies, have progressive and continuous accumulation of iron

no physiologic means of excreting it Storage occurs initially in reticuloendothelial sites– when they are saturated, there is deposition in parenchymal

cells

• clinical damage is lifetime exposure to greater than 50 to 100 RBC units in a non-bleeding person

Complication Cont’d

• Iron deposition interferes with function of the– heart, liver, and endocrine glands (eg, pancreatic

islets, pituitary)

Hepatic failure and cancer, diabetes mellitus, and cardiac toxicity cause most of the morbidity and mortality

Summary

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