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عدد الاوراق (8)

24-10-2012

Adverse Effects of Blood Transfusion

Haemolytic transfusion reactions
Nonhaemolytic adverse effects of transfusion

Haemolytic Transfusion Reactions

Immunological HTR
Immediate Intravascular Haemolysis
Usually ABO mix-up
Complement activating Ab
Destruction of transfused RBC
Immediate Extravascular Haemolysis
Attachment of Ab to RBC (usually complement activating IgG )
Rapid destruction of coated RBC in RES


Delayed Haemolysis
Nearly always extravascular
Attachment of rapidly developing IgG Ab to donor RBC
Effects of donor's Ab on recipient's RBC
Nearly always group O plasma with high titered Anti-A &/or Anti-B
Development of positive DAT in the recipient

Non Immunological HTR

Physical damage to transfused cells
Overheating
Incompatible fluid
Excessive pressure during infusion
Physical damage to recipient's cells
Infusion of hypotonic solutions
Entrance of irrigating fluids to blood steam

Damage to cells by microbial agents

Gram-negative bacteria in blood or platelets
Clostridial sepsis preexisting in recipient
Damage to patient's intrinsically abnormal RBC
G6PD deficiency
PNH
Sickle cell disease in crisis


Nonhaemolytic adverse effects of transfusion
Allergic reactions (Urticaria, Anaphylaxis)
Febrile reactions
Volume overload (Acute systemic hypertension, Pulmonary edema)
Disease transmission (Hepatitis, HIV, CMV, EBV, Malaria, Syphilis or CJD )
Immunization to blood borne Ag (RBC Ag, HLA Ag, Granulocytes Ag, Platelets Ag or IgA)
Noncardiogenic Pulmonary events (leukoagglutinin reactions, Complement induced granulocyte aggregation, ARDS)
Haemostatic effects
Dilutional thrombocytopenia after massive transfusion
Citrate toxicity, with massive transfusion & depressed liver function
Hypothermia (occurs with massive transfusion, in patients impaired thermal control)
Graft versus host disease
Transfusional haemosiderosis (after years of transfusion to patients with chronic severe haemolysis)
Bacterial contamination

Relative Frequency of Adverse Effects
Very common: Follow 1% or more of transfusions
Febrile Reactions
Allergic reactions
Hepatitis ( C, non A non B ) !!!!
Immunization to RBC,WBC, Platelets or protein Ag


Somewhat common:
Circulatory overload
Dilutional thrombocytopenia
Delayed haemolytic reaction
Hepatitis B ( becoming less common)

Rare:

Intravascular haemolysis (ABO)
Extravascular haemolysis (other blood groups)
Symptomatic CMV transmission
Noncardiac pulmonary reactions
Malaria transmission
Hypothermia
Physical damage to transfused cells
Transfusional hemosiderosis

Very rare:

Anaphylactic reactions
Graft versus host disease
Bacterial contamination
Citrate toxicity
HIV transmission


Relative Significance of Adverse Effects
Serious, potentially life threatening
Intravascular haemolysis (ABO)
Extravascular haemolysis (if severe)
Hepatitis B, C
HIV transmission
Anaphylactoid reaction
Bacterial contamination
Noncardiac pulmonary reaction
GVHD

Serious, but rarely life threatening

Extravascular haemolysis (most)
Delayed haemolytic reactions (if severe)
Coagulation problems
Transfusional hemosiderosis (except in thalassaemia major)
Non A, non B hepatitis
CMV transmission in infants
Malaria

Rarely cause major clinical problems
Febrile reactions
Allergic reactions
Delayed haemolytic reactions (most)
Immunization to blood borne Ags (except immunization to high incidence RBC Ags & development of refractory state to platelet transfusion)
CMV transmission in adults


Haemolytic Transfusion Reaction
Consequences of Ag Ab Interaction Involving RBC

Initial Events

Ab attaches to cell surface Ag sites
C1 attachment occurs with IgM, or 2 IgG
Factor XII (Hageman Factor) activation

Consequences of Complement Activation

Cell lysis, if entire cascade is activated Generation of anaphylatoxic cleavage fragments;  - increased vascular permeability - release of vasoactive mediators - activation of platelets ??? Coating RBC with C3b if cascade is interrupted; - Interaction with receptors on macrophages causes RBC
destruction -Conversion to C3d by inhibitor, leaving unharmed cells
with positive DAT

Consequences of Factor XII Activation

Prekallikrein is activated, ultimately generating bradykinin;
- Increase in vascular permeability
- Relaxation of arterioles
- Bronchospasm
- Pain at infusion site, chest, back
Clotting cascade is activated;
- Platelets undergo activation. Release vasoactive
substances
- Capillary microthrombi may obstruct capillaries &
reduce perfusion
- Activation of thromboplastic & fibrinolytic systems may produce DIC


Consequences of Vasomotor Events
Relaxation of arterioles lessens peripheral resistances, causing hypotension
Increased permeability causes reduced cardiac return, reduced arterial pressure
Platelet activation & slowed capillary flow predispose to microthrombi
Hypotension stimulates norepinephrine release, causing renal & splanchnic ischaemia
Reduced renal perfusion, systemic hypotension, & subsequent arteriolar constriction cause renal tubular ischaemia & subsequent renal failure

Factors affecting clinical consequences of haemolytic reaction of RBC

Concentration of Ab in circulation
Avidity of Ab interaction with Ag
Immunoglobulin class & thermal reactivity of Ab
Density & surface topography of Ag on RBC membrane
Number of incompatible RBC infused
Complement activating property of Ab
Concentration of circulating complement components
Rate of activation & inhibition of coagulation cascade
Adaptability of CVS to altered volume & pressure
Reactivity of macrophages of RES

Clinical Events in HTR
Mild Immediate Reactions
Common
Fever
Chills
Tachycardia
Transient blood pressure changes
Variable
Skin flushing
Anxiety
Nausea
Severe Immediate Reactions
Common
Fever with chills
Pronounced blood pressure drop
Chest & /or back pain
Haemoglobinaemia / haemoglobinuria
Variable
Reflex blood pressure elevation
Oliguria
Haemorrhagic diathesis
Delayed Reactions
Common
Otherwise unexplained fever
Positive DAT
Variable
Fall in PCV
Haemoglobinuria
Oliguria


If Transfusion Reaction is suspected
Stop the infusion of blood or component. Save the container & the infusion set
Check the identifying information on container label & the patient's data
Keep the IV line open
Draw a posttransfusion blood sample.
Send the following items to the transfusion service lab:
Blood container with the infusion set clamped but still attached
Clinical notes
Posttransfusion blood sample ( EDTA + clotted)
Record patient's urine output for the next 6 12 hours. Save the first urine sample voided after reaction is suspected. Send the sample to lab with notation suspected HTR

Urticarial reaction:

Hives & itching occur frequently
Have little significance except to the patient
Histamine mediated skin symptoms are thought to reflect an immunological reaction between some soluble material in the transfused unit & Ab in the patient's circulation
Many patients who had urticarial reactions have Abs against IgA allotypes but similar Abs exists in recipients who do not have reactions
Tend to recur in susceptible patients & are more frequent in those who have had multiple transfusions

Anaphylactic Reactions:

Probably the result of massive release of vasoactive & smooth muscle reactive mediators after Ag Ab interaction.
Start with sudden onset of flushing & hypertension followed by hypotension, wide spread edema, respiratory distress, &, sometimes, nausea, vomiting & diarrhoea.
Abs reactive with the entire class of IgA proteins have been found in 45 60 % of hospitalized patients with IgA deficiency & in 17 % of healthy persons who are IgA deficient.


Febrile Non-Haemolytic Reaction:
Temperature rise of 1C occurring during or within an hour or so after transfusion in a patient with no other reason for acute temperature elevation
Chills & subjective malaise may accompany the fever but other signs or symptoms rarely occur
Usually attributed to reactions between recipient Ab & WBC elements in the transfused components
It's rarely possible to test the reactor's serum against cell preparation from specific donor
Mild reactions can effectively be treated with antipyretics
Febrile reactions are often recurrent
A patient who repeatedly experiences febrile reactions should receive components that are as free as possible from intact or disintegrating WBC

Transfusion Related Acute Lung Injury:
Commonly presents as severe respiratory distress of sudden onset, caused by a syndrome of noncardiogenic pulmonary edema resembling the ARDS.
Chills, fever, chest pain, hypotension, & cyanosis, as well as the usual features of respiratory edema may be seen
Chest X ray shows florid pulmonary edema
The reaction may occur within several hours of the transfusion; it may be severe initially but generally subsides within 48 to 96 hr with respiratory support without residual effects
These reactions are thought to be caused by transfusion of Ab in the donor plasma that are reactive with the recipient WBC. Such Ab may react with HLA or granulocyte specific Ag
It has been suggested that agglutination Ag granulocytes & complement activation occur in the pulmonary vascular bed, leading to capillary endothelial damage with consequent fluid leak into alveoli
Management includes supportive measures for the pulmonary edema & hypoxia, including ventilatory support if required.
Haemodynamic monitoring may be required to determine whether fluid overload is a factor; if not, diuretics are of no value. Very high doses of corticosteroids may be of benefit, probably by blocking granulocyte aggregation and consequent vascular damage
It would be reasonable to avoid further transfusion of plasma containing products from donors who are found to have anti- HLA or antigranulocyte Ab ( many of them are multiparous females)
Posttransfusional Purpura
Development of life threatening thrombocytopenia 5 10 days after transfusion
This rare complication is caused by the development of allo-Ab directed against platelet specific Ag ( anti HPA 1a is usually implicated)
Management includes high dose IVIG; corticosteroids may be of value.


Transfusion related Immunomodulation: TRIM
Allogenic blood transfusion results in the transfer of not only RBCs, but also significant amounts of potential immune effector cells, their products (as cytokines), & various substances that may be seen by the host immune system as foreign Ag
Although possible beneficial immunomodulatory effects have been reported in renal transplant patients receiving transfusion before surgery by mechanisms that are not well understood, TRIM is generally considered to have a number of deleterious effects
A large number ( > 150) of clinical studies have been performed over the last two decades specifically addressing two potential harmful TRIM associated effects: cancer recurrence & postoperative bacterial infections
To date, no definitive association or causal relationship has been proven

Graft Versus Host Disease: (TAGVHD)
Most cellular blood products, including RBC, platelet, & granulocyte products, contain viable, immunocompetent T lymphocytes
When transfused into immunoincompetent recipients, these donor lymphocytes may proliferate in the patient & lead to the clinical syndrome of TA GVHD
TA GVHD has also been reported in immunocompetent patients, especially those who receive transfusions from family members or from random donors who share HLA Ag

High Risk

Bone marrow transplant
Intrauterine transfusions
HLA matched platelet transfusion
Transfusion from blood relatives
Severe congenital immunodeficiency
Hodgkin disease

Moderate risk

Haematoogic malignancies ( ALL,AML, NHL)
Patients treated with purine analog drugs ( CLL)
Malignancies treated with intensive chemo- / radiotherapy
Solid organ transplant recipients
Preterm infants
Newborns receiving exchange transfusion


Low / Theoretical Risk
Human Immunodeficiency Virus / AIDS
Healthy term newborns

Clinical Features:

Fever
Typical erythematous, macularpapular rash that begins centrally & spread peripherally to hands & feet
Hepatic function abnormalities
Nausea, vomiting & bloody diarrhoea
Leucopenia followed by pancytopenia due to BM failure & is seen most often 2 3 wk after the onset of symptoms

Diagnosis:

Based on the clinical picture & can be confirmed histologically by skin biopsy
Lab confirmation that GVHD is transfusion induced can be made by demonstrating the presence of donor lymphocytes in the patient
HLA typing of patient & donor cells
Cytogenetic analysis
DNA micro satellite polymorphism
Variable number tandem repeats

Treatment & Prognosis:

Severe systemic infections are the most common cause of death
Despite aggressive treatment, fatality rate is significantly higher than that associated with BM transplantation & has been reported to be > 90 %
Corticosteroids, ATG, Cyclosporine & growth factors with minimal success


Prevention:
Because of lack of effective treatment, TA GVHD should prevented by pretransfusional irradiation of all blood products administered to patient at risk
Irradiation inhibits proliferation of donor lymphocytes but no adverse effects on RBC, platelets or granulocyte function
The recommended dose for irradiation of blood & it's products is 2500 cGy at the centre of the irradiation field with minimum dose of 1500 cGy at any point in the field

Infectious Complications

Hepatitis B,C, delta, others
HIV
HTLV
CMV
EBV
Syphilis
Bacterial contamination
Parasites malaria, Babesia
Other organisms

Transfusion Associated hepatitis:

Hepatitis B Virus;
DNA virus
Transmitted parenterally, sexually or perinatally from infected mothers
Incubation period ranges from 1 6 months
Only approximately 25 to 40 % of hepatitis B infections are associated with jaundice
Fulminant infection, with high mortality rate, occurs in 0.2 to 0.5 %of cases
Most individuals experience transient hepatitis detectable only by laboratory tests
Although it is often stated that 5 to 10%of infected adults go on to become chronic HBsAg carriers, more recent studies suggest that the development of chronic infection is far less common, approximately 1%
Of these, approximately 25% develop chronic hepatitis that may resolve after many years or may lead eventually to fatal cirrhosis or hepatocellular carcinoma


Serological sequence:
HBs Ag is detectable during the late incubation period with an average of 59 days after exposure
Anti-HBc Ab (IgM) is almost always detectable at the time of illness & persists for 6 12 months, with IgG anti-HBc persisting indefinitely
HBe Ag is detectable in acute hepatitis & in patients who are in the process of becoming chronic HBs Ag carrier. It's presence correlates with high levels of virus, therefore, indicates recent or ongoing infection & infectivity. HBe Ag generally disappears from the serum before HBs Ag & is followed by the development of anti-HBe AB
HBs Ag usually becomes undetectable by 12 weeks after the onset of illness, followed by the appearance of anti-HBs Ab
Patients developing the chronic carrier state usually exhibit high levels of HBs Ag & anti-HBc Ab, but not anti-HBs Ab
All people carrying HBs Ag must be considered infectious, but they vary in degree of infectivity. In an HBs Ag positive person, the presence of HBe Ag correlates with high infectivity, whereas the HBe Ag negative state is less infectious.

Hepatitis C Virus;

RNA virus
Is known to be the cause of approximately 90% of NANB hepatitis
In 1988 the genome of HCV was cloned
Diagnosis can be made either serologically by the detection of Ab to HCV ( anti-HCV) or by the identification of viral genomic material using nucleic acid testing technology
The prevalence of HCV in USA is estimated to be 1.8%.
Half of cases are related to parenteral drug use, but the mode of transmission for the rest remains largely unknown
Most studies of long term sexual partners have indicated very low rates of transmission by this route
The rate of perinatal transmission of HCV is low (average of 5 6%), but is higher in the presence of co-infection with HIV
Window period is 10 days
The average incubation period for HCV is 6 to 7 wk
60 to 70% of infections are asymptomatic
10 to 20% of cases are associated with nonspecific symptoms, & jaundice occurs in only 2o to 30% of cases
Even icteric patients usually have a mild acute illness, although immunocompromised patients may develop severe infections
Fulminant hepatitis is rare
The most important aspect of HCV infection is it's chronicity
Only 15 to 25% of individuals clear the virus, the rest remain chronically infected
60 to 70% of chronically infected patients show biochemical evidence of chronic hepatitis
It is estimated that cirrhosis develops in 10 to 20% of chronically infected patients, and hepatocellular carcinoma develops in 1 to 5%
Treatment with Interferon & Ribavirin suppresses viral replication in some patients, although only a minority achieves a sustained response


Hepatitis D Virus;
Has a hybrid structure consisting of HBs Ag enclosing a minute RNA genome that is incomplete & therefore, incapable of survival without helper function by HBV
This agent may be transmitted with blood products in an association with HBV, resulting in an episode of acute viral hepatitis
In HDV infections in people who are already HBV carriers, the resulting illness is particularly severe
Because HDV can be transmitted only with HBV, testing all blood donations for HBV excludes virtually all transmission of HDV.
Hepatitis A Virus;
RNA virus
Spread by fecal oral route
Incubation period ranges from 15 to 45 days
Viraemia occurs during prodromal phase & last for only a few days before symptoms appear
Transfusion transmitted infection occurs only if blood is collected during the brief asymptomatic viraemic phase.
Hepatitis E Virus
HEV is responsible for waterborne outbreaks
It's spread is similar to HAV in that it is enterically transmitted
To date there is no evidence of chronic carrier state
Therefore, does not appear to present a risk of transmission by transfusion.
Non-A-E Hepatitis;
Approximately 10% of cases of chronic NANB hepatitis are not due to HCV
Despite much effort, the cause of most of these cases remains unidentified
Attempts to isolate viruses from the blood of individuals with chronic NANB hepatitis led to the discovery of several new agents including GB virus, HGV, SEN virus & TT virus
However, there is currently no convincing evidence that any of these agent causes hepatitis
HIV
RNA virus
It is transmitted parenterally, sexually or perinatally
Window period is 11 days
2 to 3 wk after exposure to HIV, the patient often develops an acute flu- or mononucleosis- like illness
The infection then enters a clinically latent stage during which viral replication continues
Untreated patients remain asymptomatic for an average of 10 years
Ultimately the patients CD4+T cells become depleted, and the patient develops severe immunodeficiency, resulting in opportunistic infections, neoplasms, or both, and death
Treatment of infected individuals with highly active antiretroviral therapy has dramatically reduced HIV- related morbidity and mortality in USA, although the development of drug resistance and side effects limits the effectiveness of therapy.









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