TRANSFUSION REACTIONS

Please Do not Forget: THIS MAYBE A LIFE SAVER OR A LIFE TAKER !!!

Definition of TR:
A transfusion reaction is any unfavourable transfusion-related event occurring in a patient during or after transfusion of a blood component.

Transfusion reactions could be :

Immediate reactions: occurring within minutes or hours of starting transfusion. These maybe hemolytic, febrile, or due to contaminated blood.
Delayed reactions : occurring usually several days, weeks or months following transfusion. These may again hemolytic, post-transfusion purpura, or transmission of diseases.

Immediate Reactions :
- Immediate Hemolytic Tx reaction. - Febrile Non-Hemolytic Tx Reactions (FNHTR). - TRALI. - Bacterially Contaminated blood. - Circulatory overload. - Allergic and Anaphylactoid reactions. - Air embolism. - Microaggregates related reactions. - Massive transfusion related reactions. - Reactions with bleeding.

Causes of Transfusion-Related Deaths in USA (86-95)

Immediate Hemolytic transfusion reaction 50% TRALI 15% Bacterial contamination 16% Delayed Hemolysis 10% Graft vs Host disease 3 %

Immediate Haemolytic Transfusion reaction:

- Is due to rapid destruction of donated red cells, by antibodies in the recipients plasma. - It is most commonly caused by Anti-A or AntiB present in recipient plasma destroying A, B or AB donated cells; or less so, Anti-K, anti-Jka, anti-Fya. - RBC destruction maybe intravascular if the antibodies fix and activate complement to the full; while if the antibody fixes but does not activate complement fully, it will lead to extravascular hemolysis.

Most Dangerous : Mostly Due to Anti-A, Anti-B

Intravascular Hemolysis

HB Hbemia Hburia

RBC stroma

Intracellular enzymes

Activation of complement

Liberation

of

Thromboplastinlike substances

C5a, C5b -Smooth

muscle contraction.

DIC
Renal damage

-Platelets aggregation. -Increase Capillary Permeability -Release vasoactive amines and hydrolases

Clinical findings of Immediate IV hemolytic Tx Reaction: Usually start within first 5-15 minutes after starting transfusion. 1. Fever with or without chills. 2. Hburia. 3. Hypotension, sometimes shock. 4. Facial flushing. 5. Chest pain. 6. Back or flank pain. 7. Dyspnea/wheezing. 8. Nausea and vomiting. 9. Oliguria or anuria. 10. Pain at the transfusion site. 11. Generalized bleeding (DIC).

Immediate IV Hemolytic transfusion reaction :

If the patient anaesthetized : - Generalized oozing of blood from the operative site. - Hypotension or shock, not corrected by transfusion.

Management :

Measures immediately taken :

1. Stop the Tx. 2. Keep IV line open with saline. 4. Perform bedside checks for clerical errors (80%) 5. Return the unit, set and attached solution to the bank. 6. Collect samples in EDTA (for DCT, FBC), and Clotted blood (for evaluation of hemolysis and serological evaluation), optionally Citrated blood for Coagulation studies . 7. the EDTA blood could be centrifuged immediately and if no red colour in plasma this reaction is unlikely!

Specific management of Immediate

IV hemolytic Tx reaction:

The risk of serious sequelae is proportional to the amount of incompatible blood If such a reaction is suspected, then do not wait for confirmation, immediately start to protect the kidneys, and correct bleeding.

Specific management of Immediate

IV hemolytic Tx reaction:

Hypotension is treated by IV fluids and vasoactive drugs, to maintain systolic pressure > 100 mm Hg. Protect the kidney by maintaining Renal diuresis

FFP, cryoppt. and/or platelets, possibly with heparin, are used for DIC. Think of measures to prevent its occurrence, since in most cases it is due to clerical errors, so preventable.

either by Mannitol, in sufficient amount to get urine volume >100 ml/hr. Recent evidence suggest that diuretics (frusamide or ethacrynic acid) maybe more effective.

Immediate Extravascular hemolytic Tx reaction

Signs and symptoms related to this are usually mild and not life threatening; with fever , chills, jaundice , unexpected anaemia, while hburia and Hbemia are not usually encountered.
They are caused by antibodies which do not activate complement to the full (e.g. Anti-K, Anti-Jka, Anti-Fya.)

Immediate Febrile Reactions

Maybe due : 1. Sensitivity to leucocytes. 2. Sensitivity to platelets. 3. Hemolytic reaction. 4. Bacterial Pyrogens. 5. Unidentifiable cause.

Febrile Non-Hemolytic Transfusion reactions (FNHTR)

Most frequent in multiply transfused or previously pregnants. Usually will require at least 7 previous transfusions, in males, non-parous females and children, but 1-2 in multiparious females. Temp. usually starts to rise 30 min 2hrs after starting transfusion, but may occur 1-2 hours after conclusion of transfusion. Then Temperature usually continues to rise 2-6 hrs after cessation of Tx and it may persist for 12 hours thereafter. The temperature rise is 1-2 C > baseline. Shaking chills may occur (look at in caution!)

Febrile Non-Hemolytic Transfusion reactions (FNHTR)

Often caused by antibodies in the recipient to leucocyte antigens present in the donor blood or component. In platelets transfusion the reaction maybe caused by cytokines released by leucocytes during storage (more frequent in manual than apharesis collected bags). Little risk of FFP, cryoppt., factor concentrates, because do not contain leucocytes.

Febrile Non-Hemolytic Transfusion reactions (FNHTR)

Good prognosis, but maybe confused with hemolytic reactions (Draw a sample, centrifuge and look for hemolysis in plasma sample) Confirmation of Diagnosis depends on the demonstration of HLA or non-HLA antibodies to WBC antigens. Antipyretics, start at a slower rate, unless fever becomes more evident, then discontinue.
Most could be prevented by leucocyte filters or leuco-reduced blood.

TRALI (Transfusion-related Acute Lung Injury): 2nd Leading cause of transfusion related death in US.
Overall TRALI occurs in up to 1/300 red cell transfusions.

Almost All products have been implicated, but rarely with cryoppt or immunoglobulins.
It is underdiagnosed .

TRALI (Transfusion-related Acute Lung Injury): 2nd Leading cause of transfusion related death in US.
- It is Caused by at least 2 independent events. The 1st event relates to underlying clinical condition, leading to pulmonary endothelial activation, resulting in the pulmonary sequestration of neutrophils. 2nd event is infusion of Ab against PMN, - Lysophosphotidylcholines accumulating on blood storage, leading to activation of PMN, with consequent endothelial damage, capillary leak, and acute lung injury.

Pathogenesis hypothesis:

Clinical features of TRALI :

Majority present during transfusion or within the first 1-2 hours (but can occur up to 6 hrs). Symptoms include :
Rapid onset of tachypnea. Cyanosis. Dyspnea. Fever

Signs include :

- Diffuse crackles and decreased breath sounds esp. in dependent areas. - Hypotension. - CXR ; Diffuse fluffy infiltrates c/w pulmonary Edema.

Management of TRALI:
Mortality from TRALI is 5-25%. Most patients will recover within 72 hours. Mild forms will require Prompt delivery of supplemental Oxygen only. More severe forms require aggressive respiratory support, including supplemental oxygen and mechanical ventilation.

Prevention of TRALI
1. decrease blood usage. 2. donors implicated in TRALI should be excluded pending investigations. 3. Use of fresher products (Packed RBC<21 d old, Plat conc<3 d) in high risk groups. 4. Washed cells for high risk procedures.

Differential Diagnosis of TRALI

Circulatory overload.
Anaphylactoid reactions. Bacterial contamination.

Circulatory overload
Presents within minutes or hours of transfusion, with respiratory distress with tachypnea, tachycardia, hypertension and cyanosis. Respond to diuresis, ventilatory support.

Anaphylactic Tx reactions:
May occur rapidly during Tx of any type of protein containing blood product (even if small amounts of it-10 mls ! ! ), and present with respiratory distress related to bronchospasm, manifested by tachypnea, wheezing, cyanosis, and severe hypotension, but no fever. In contrast to TRALI, in this reaction laryngeal rather pulmonary edema is present. Facial and truncal edema and urticaria are commonly associated.

 Anaphylactoid reactions can occur in IgA deficient patients, who have formed Anti-IgA

They may also occur as an extreme form of an allergic reaction (Possibly due to transfused proteins or other unidentified agents, but not antibodies to leucocytes or platelets). However, classically allergic reactions are mild, with generalized pruritis, and urticaria. Which could be easily controlled by parenteral antihistamines, however in very severe forms parenteral adrenaline is required promptly.

Bacterial Contamination
This another important DD of TRALI, and presents with fever, hypotension, respiratory collapse, and sometimes but not always with respiratory distress, abdominal pain, vomiting, diarrhea . The reaction may follow shaking chills some 30 or so minutes, after Tx of as little as 10 mls of heavily contaminated product.

Bacterial contamination
Bacterial Contamination is likely to be from cold-growing organisms like pseudomonas, which would utilize citrate as a source of carbon, depleting sometimes the citrate, leading to clotting. Thus visual inspection of the unit may reveal some clots. Recognition of this possibility early is essential, and could be done by taking some sample from the bag or its tubing, obtain plasma, smear on slide, stain by Gram stain, examine by oil emersion lens. Treatment should be immediately instituted, however fatality is 50-80%.
This problem became less with use of plastic disposable

bags, but Packed red cells and platelets (stored at RT) are particularly implicated.

Other immediate reactions :

Air Embolism : Only large volumes are significant. Associated with pain, cough and sudden dyspnea.
Microaggregates in blood: - Consist of Platelets and fibrin. - May cause pul. Insufficiency, esp. if large amount of stored blood is Tx. - Questionable clinical significance.

Reactions related to Massive transfusions

Massive Transfusions are defined as replacement of total blood volume within 24 hours. - Platelets dilution : monitor counts. Give platelets in <100 000/ul, with bleeding or surgical intervention. - Coagulation factor dilution : in blood stored > 14 days. - Metabolic changes :
* Low pH, hypocalcemia, hyperkalemia, low O2carrying capacity (only imp. If blood >21 d old). * Citrate toxicity (significant only with very rapid Tx and infants). * All these changes are exacerbated by cold (leading to cardiac irregularities); so blood warmers and keeping patient warm are quite important in massive Tx.

Bleeding

Is another immediate transfusion reaction, which could either be: - part of DIC, induced by Hemolytic Tx reaction. - Dilution of Platelets or coagulation factors after massive transfusion. - In a surgical patient always remember bleeding from a severed vessel (most common cause of bleeding in such patients).

Physical damage to RBC

Intravascular lysis by hyper or hypotonic solutions or any added drug. Heat damage by blood warmers. Inadvertent freezing by faulty fridges or improper ones. Mechanical damage by blood pumps.

Delayed Reactions :
Delayed Hemolytic reactions : Post-transfusion Purpura. Transmission of Disease. Iron overload. Alloimmunization.

Delayed Hemolytic Transfusion reaction Usually not predictable or preventable. Is due to previous sensitization of the recipient to one or more Ag by previous Transfusion, pregnancy or transplant. Antibody is not usually detectable by routine pre-transfusion screen.

Delayed Hemolytic Transfusion reaction

Transfusion of blood containing the appropriate Ag, will trigger a brisk anamnestic response. Within days (4-14 days) the antibody will rise with E.V. removal of transfused cells and with a triad of fever(with or without chills), hyperbilirubinaemia, and anemia; while Hbemia, Hburia, shock and renal failure are unusual.

Antibodies commonly implicated in DHTR Anti-Jka - Anti-E - Anti-D - Anti-C

-

- Anti-K - Anti-Fya - Anti-M

Managemnet: -Clinical symptoms are often mild, treat only severe cases by maintaining renal function and transfusions if symptomatic anemias. -Thorough history of previous Tx, pregnancy, transplants should be sought. -Type and screen policy helps prevent it. - Always take a fresh sample for cross-matching, if a transfusion has been given> 48 hrs ago.

Post-transfusion Purpura:
Rare. Severe thrombocytopenia suddenly occurs, 7-10 days, after Transfusion. Always in those with history of previous transfusion or pregnancy (so more common in females). Most frequent cause is the presence in the recipient of anti-HPA-1a antibody against platelets specific Ag (HPA-1a)
The condition is self-limiting. In severe cases however, IV Immunoglobulins, or plasma exchange indicated. But Do not give platelets concentrates.

- Transfusion Hemosiderosis:
Long-term complication of BT . Each unit contains ~200 mg of Iron, but Iron excretion is ~ 1 mg/d. Occurs on frequently Tx patients , e.g thalassaemia major individuals. Neocytes Tx may reduce the frequency of Tx and thus Iron overload, but very expensive, and very practical or as effective as expected. Desferroxamine Iron chelator. Symp and Signs are related to defective function of liver, cardiac muscle and endocrine organs; possibly related to the interference with mitochondrial function by excess Iron accumulation.

-Transfusion associated GVHD :

A complication of blood component or BMT. Although it is rare as BMT complication, however associated with remarkable fatality (84%) with a median survival of 3 weeks, in certain at-risk populations with :
- lymphopenia

It is caused by the proliferation of T-cell lymphocytes derived from the donor blood, immunologically responding to major and minor HLA Ag in the patient. This will lead to bone marrow suppression and death from bleeding or overwhelming infection in most.

BM suppression. fetuses receiving IUT. newborns. AIDS patients.

- Alloimmunization :
Alloimmunization results from previous exposure to donor blood components. Even very small amount of donor Ags (esp. on RBC) may elicit a significant alloimmune response. This will lead to difficulty in finding compatible blood, Tx reactions, or refractoriness to platelets.

To detect occurrence of Alloimmunization

- Previous history of Tx, Pregnancy or Transplant may give a clue. - Screening patients serum for Atypical RBC antibodies. - Lymphocytes panels and Lymphocytoxic antiobody procedures can be performed on patients serum to detect HLA antibodies.

Relative occurrence of Transfusion reactions Common : Febrile reactions, alloimmunization, allergic reactions. Less common : Depletion and dilution of coagulation factors and platelets; DHTR; Circulatory overload (TACO). Unusual : Anaphylaxis, Bact. Contamination, IHTR, Iron overload, TRALI, Physical RBC damage, PTP, TA-GVHD.

Investigating a Transfusion reaction :

Immediate action required.

Follow a set of rules strictly set in advance by the blood Transfusion authority. The Questions to be addressed: ** clinical data : - Diagnosis. - History of previous pregnancy, Tx, Transplant. - current medications. - Clinical signs and symptoms of a reaction.

**Questions related to current Tx

How many millilitres of RBC or products were Tx ? How fast and how long was the unit Tx? Were Red cells given warm or cold? What needle size was used? Was a filter used? What type? Any added solutions or drugs at the time of Tx?

** Samples to be sent to BB upon suspicion of Hemolytic Tx reaction ?

1. A properly collected and labeled clotted blood sample. 2. A non-clotted EDTA sample. other samples including a clotted specimen 5-7 hrs post-Tx, First voided urine sample, and others are optional based on the discretion of the blood bank director.

 1. Clerical Checks. 2. Visual inspection : - Observe the pre and post-transfusion samples (compare sera for evidence of evidence of hemolysis); a 5-7 hr post-Tx sample would be useful for bilirubin. - Observe the unit and its attached tubing and the filters for hemolysis from nonimmunological causes. 3. Direct Coombs Test : A negative results is not exclusive.

Immediate Investigation in a suspected HTR:

- If results suggest Hemolysis or if S&S suggest Immune hemolysis then further tests are necessary:

Recipients and donors Pre and posttransfusion ABO Grouping and Rh typing. Compatibility testing using pre and posttransfusion sample. Antibody screen and Alloantibody identification. Elution and specificity determination if Coombs positive. Urine test : for Hb. Bilirubin in 5-7 hr sample. Hct and Hb.

Please Do not Forget: THIS MAYBE A LIFE SAVER OR A LIFE TAKER !!!