TRRF And ISBT Proposed

Standard Definitions

Presented by:

Rayaz Ahmad Bhat

Jammu and Kashmir

Student:

M.Pharm Pharmacy PracticeNational Institute Of Pharmaceutical Education And

Research,Guwahati, Assam

Email: reyazrab@gmail.com

Mentor Institute: National Institute Of Biologicals , Noida , Delhi

Mentor:

Dr. Akanksha Bisht

Officer Incharge – HvPI & Scientist Grade-III

Transfusion Reaction Reporting Form

(TRRF)

Structure of TRRF

A. Patient Information

B. Transfusion Reaction Details

C. Transfusion Product(s) Details

D. Investigations

E. Nature of Adverse Reaction(s)

F. Imputability Assessment

Monthly Denominator Reporting Form

A. Patient Information

• Hospital Code No.

• Patient Initials

• Gender

• Hospital Admission no.

• Age/Date of Birth

• Primary Diagnosis

• Medical History

B. Transfusion Reaction Details

• Anaesthesia: General/Spinal/Local

• Pre-transfusion Vitals

• Vitals at the time of Reaction

Vital signs are measurement of body’s most basic

functions , include( as per TRRF):

Temperature: Normal-36.5 oC to 37.2 oC

Pulse: Normal 60-100 beats/minute

Blood Pressure: Normal Bp – 120/80

Respiratory Rate: Normal- 12-16 breaths/minute

SpO2: Normal blood oxygen saturation 95-100%

Signs and Symptoms of Transfusion Reactions as

per TRRF

• Generalized

• Pain

• Respiratory

• Renal

• Circulatory

• Other

Generalized

• Fever with or without chills: Most common

feature in any transfusion reaction

• Rigors: episodes of shivering

• Nausea with or without vomiting

• Urticaria: Commonly known as hives –

characterized by itchy rash caused by tiny

amounts of fluid that leak from the blood vessels

just under the skin in response to an immune

reaction.

• Flushing: Characterised by redness of skin with

a sensation of warmth or burning of face, neck

and less frequently upper trunk and abdomen.

• Restlessness

• Anxiety: Feeling of uneasiness such as worry, concern or fear, that can be mild or severe.

• Pruritus: itching

• Edema: Accumulation of fluid

• Jaundice: Characterised as yellowing of skin and sclera due to abnormally high levels of bile pigments.

• Other symtoms

Pain

• Chest Pain: Can be due to acute intravascular

haemolysis.

• Abdominal pain

• Back/Flank pain

• Pain at infusion site : due to local injury or in

more adverse conditions due to bacterial

contamination

• Pain at other sites

Respiratory Signs and Symptoms

• Dyspnoea: Shortness of breath

• Wheeze: Breathing with a whistling or rattling sound

in the chest

• Cough : Respiratory reflex

• Hypoxemia: Abnormally low levels of oxygen in blood

• Bilateral infiltrates on chest X-ray

• Other

Renal Signs and Symptoms

• Haematuria: Blood in urine

• Haemoglobinuria: excretion of free haemoglobin

in urine

• Oliguria: Low urine output

• Other

Circulatory

• Tachycardia: Increased heart rate

• Hypertension: Increased blood pressure above

normal values

• Hypotension: Decrease in blood pressure below

normal

• Raised JVP(Jugular Venous Pressure)

• Arrhythmias: Irregular heart beating

• Other

C. Transfusion Product Details

This section contains blood component details about:

• Type of Blood Component

• Indication

• Date and Time of issue of Blood Product

• Date and Time of Transfusion

• Unit Id (Transfused)

• Blood Group

• Volume Transfused(ml)

• Expiry Date of Blood Component

• Manufacturer of Blood Bag

• Batch/ Lot. No. of Blood Bag

• Transfusion record : Ist time or Repeat

Whole Blood

• Whole blood is the donor blood mixed with

anticoagulant preservative solution.

• Whole blood is now considered as a raw

material rather than a transfusion medium .

• Indications:

• The main indication of whole blood is to provide

both oxygen carrying capacity and increase in

blood volume in an actively bleeding patient

with blood loss greater than 25%.

• Exchange transfusion (Blood should be less

than 5 days old)

Storage and Shelf-life

• Storage:

• 1-6 o C

• 2-8 o C during transportation .

• Shelf-life:

• ACD/CPD/CP2D-21 days

• CPDA-1: 35 days

• A unit of whole blood ( approximately 350ml) will increase haemoglobin by about 0.75g/dl while a unit of 450 ml by 1g/dl in an adult patient of about 60-70 kg who is not actively bleeding.

• In pediatric patients the transfusion of 8ml/kg of red cells will increase the haemoglobin by approx. 1g/dl

Blood Components

• Modern blood transfusion envisages the optimal

use of every blood donation by a way of blood

component therapy.

• The development of plastic blood collection bags

with integral tubing, high speed refrigerated

centrifuge, deep freezers, and cell separator

machines have made blood component

preparation easier and practical.

• With more advanced techniques such as Plasma

fractionation various plasma derivatives are now

available , treating multiples of health conditions.

Advantages of Component Therapy

• It maximizes the use of one unit of blood.

• The shelf-life of the components is longer than the

whole blood.

• Better patient care without danger of overloading

or side effects due to other components.

• Cost-effective

• Reduced adverse drug reactions , reduced

alloimmunization.

• With blood component therapy , it is possible to

benefit four different types of patients with one unit

of blood:

• Red cell concentrate for Anemic patients

• Fresh Frozen Plasma(FFP) for bleeding due

coagulation factor deficiencies.

• Platelet concentrate(PC) for bleeding due to

thrombocytopenia .

• Cryoprecipitate(CP) for Haemophilia, Fibrinogen

deficiency.

Packed Red Blood Cells

• Red Blood Cells are prepared by removing

approximately 200 to 250 ml of plasma from

a unit of 450 ml of whole blood or 150 to 175

ml of plasma from a unit of 350 ml of whole

blood.

Indications

• Severe anemia to reduce circulatory

overload.

• Haemolytic anemia especially in aplastic

crisis

• Various hypoplastic anemias

• Various aplastic anemias

• Anemia accompanying chronic renal disease

Transfusion Guidelines for PRBCs as per

American College of Anaesthology

• Haemoglobin concentration less than 6 g/dl:-

– Transfusion indicated

• Hb concentration greater than 10 g/dl:-

– Transfusion unnecessary

• Hb concentration between 6-10 g/dl:-

– Individualize treatment based upon clinical condition

Storage, Shelf-life and DoseCategory Storage Shelf-life

PRBC 1-6o C ACD/CPD/CP2D- 21

days

CPDA-1: 35 days

RBC + Additive solution 1-6o C 42 days

RBC Washed 1-6o C 24 hours

Leucoreduced RBCs 1-6o C ACD/CPD/CP2D-21

days

CPDA-1: 35 days

RBCs Open System 1-6o C 24 hours

RBCs Frozen Liquid

Nitrogen < - 120o C

10 years

Dose: as of whole human blood

Leukoreduced RBCs

• The leukoreduced red cells imply the removal of at least 70% of the leukocytes with the loss of less than 20% of red cells.

• Leukocytes are responsible for many of the adverse effects of transfusion including febrile non-hemolytic transfusion reactions, HLA alloimmunization, and transmission to leukotropic viruses.

• The average content of leukocytes collected in whole blood unit is roughly 2-3 × 109 leukocytes.

Contd…

• The usual levels of leukodepletion to prevent

FNHTR is 0.5 × 108 i.e. 1 log reduction called

Critical Antigenic Leukocytic Load(CAL) and can

be achieved by removing the buffy coat.

• For prevention of HLA immunization to HLA

antigens or preventing the transmission of

leukotropic virus like CMV , the level of residual

leukocytes should not be more than 5 × 106 , called

Critical Immunogenic Leukocyte Load( CIL).

• FDA has defined leukoreduced blood component as

the one with residual leikocyte count of < 5 × 106

per container.

Methods of Leukoreduction

• Centrifugation:

• Washing using saline

• Freezing and Deglycerolization

• Filtration using 3rd generation leukofilters

• Buffy coat removal using automated component

extractor

Now-a-days , mostly filtration and buffy coat removal

techniques are used for the preparation of

leukodepleted Red cells.

Platelets• Random Donor Platelets:

Obtained from whole blood

Supplied as either:

Single donor unit or

Multiple donor pooled unit: Prepared from 4-6 single

donor units pooled into one pack .

One Single donor PC contains 5.5 × 1010 Platelets

in 50-60 ml plasma

Multiple donor pooled unit contains 3 × 1010 platelets

in 150-200 ml plasma.

Contd…

• Apheresis Platelets: Obtained by apheresis.

• One apheresis platelet concentrate is equivalent

to 6 random donor platelet concentrates and

hence the number of donor exposures is

reduced.

• Apheresis platelets contain 3 × 1011 platelets in

150-300 ml of plasma

Dose

• Random Donor Platelets:

• Adult: 1 unit/10 kg body weight ( minimum 6 units)

• 1 unit raises 5000-10,000 platelets/ul

• Child: 1 unit/10 kg body weight

1 unit raises 20,000 platelets/ul

• Neonate: 1 unit/2.5 kg body weight

• 1 unit raises 75,000-1,00,000 platelets/ul

• Apheresis platelets:

• Adult: 1 unit , raises 25000-30,000 platelets/ul

Indications

• Amegakaryocytic thrombocytopenia

– Leukemia

– Chemotherapy

– Bone marrow transplantation

– Drug or radiation induced hypoplasia

• Functional platelet abnormalties

• Vral diseases associated with thrombocytopenia e.g. Dengue

• Disseminated intravascular coagulation

Corrected Count Increment(CCI)

• To assess the efficiency of platelet transfusion, should be done at 1 hour and 24 hours post-transfusion.

CCI = Post transfusion - Pre-transfusion

Platelet count platelet count × Body surface area(m2 )

No. of Platelets transfused × ( 1011 )

Fresh Frozen Plasma

• Plasma separated from whole blood , frozen

within 6-8 hours of collection and stored at

-20o C and below.

• Fresh frozen plasma from a standard donation

of whole blood (450 ml) usually measures 175-

250 ml, containing 70-80 units/dl of factor VIII.

Factor IX, vWF and other clotting factors.

Fibrinogen 200-400 mg

• Shelf-life of 1 year at or below -20o C

Dosage

• The accepted dose of FFP for infusion is 12-

15 ml/kg, however the actual dose depends

on the underlying clinical condition.

• Post-transfusion assessment of patient’s

coagulation parameters like PT, PTT or

specific factor assay is important for

monitoring the efffectiveness of FFP.

Indications

• Active bleeding due to multiple clotting factor

deficiencies in:

– Liver diseases

– DIC

– Coagulopathies in massive transfusion

• Familial factor V deficiency

• Reversal of coumarin drug effect

• Open heart surgery

• Immunodeficiency syndromes

PT/PTT > 1.5 × Normal

Cryoprecipitate

• Precipitated proteins of plasma , rich in factor VIII

and fibrinogen, obtained from FFP , prepared by

thawing FFP at 4-6 o C and removal of supernant,

within 6-8 hours of collection

• Cryoprecipitate ( 1 Pack) Contents:

Constituents Amount

Volume 10-20 ml

Factor VIII 80 – 120 IU

Fibrinogen 150 – 250 mg

Von-Willebrand Factor 40 – 70 % 0f original FFP

Fibronectin 55 mg

Factor XIII 20 – 30 % 0f original

Storage, Shelf-life and Dosage

Storage: - 20o C

Shelf-life:

Frozen- 1 Year

Thawed- 6 hours

Dosage: Depend on severity of deficiency and bleeding.

Each unit of Cryo raises Factor VIII by 2%, therefore to achieve plasma factor VIII rise of 20%, 10units/kg have to be infused

Indications

• Haemophilia A

• Von-Willebrand disease

• Congenital or acquired fibrinogen deficiency

• Factor XIII deficiency

• Also used in local haemostatic agents as a

source of fibrin

Granulocyte concentrates

• Available as:

• Buffy coat granulocyte concentrates

• Content: 0.6 × 109 / L in 15-20ml plasma

• Apheresis granulocytes

• Contents: 1 × 1010 /L granulocytes in 200-400 ml

plasma

Storage , Shelf-life and Dosage

Storage:

20 – 24 o C for 24 hours

• Dosage:

• Adult: 1 apheresis unit or 18-20 buffy coats daily

• Neonates: 0.5-0.6 × 1010 /L granulocytes daily or

8-10 buffy coats or half unit of apheresis

granulocytes daily.

Indications

• Chronic Granulomatous

Disease(Congenital Neutrophil defects)

• Chemotherapy induced Neutropenia

• Treatment of infection

• Infection prophylaxis

• Aplastic Anaemia

• Neonatal Sepsis

Cryoprecipitate Poor Plasma

• Byproduct of Cryoprecipitate preparation

• Lacks factor V , VIII and Fibrinogen

• Indications:

• Coagulopathies due to deficiency of other

stable clotting factors, drugs etc.

• Dose: Same as FFP

D. Investigations as per TRRF

• Clerical Check:

Clerical Check must be performed to ensure that right blood was administered to the right pateint.

1. Check on the cross match label and on the blood bag: Blood bag number and blood group

2. Check on the cross match label and the patient’s file: Patient’s name and CR No.

• Repeat Blood Grouping:

To Re-Confirm Blood Type

• Repeat Crossmatch:

To Re-confirm Compatibility

• Repeat Antibody Screen:

To detect the presence of unexpected

antibodies

• Antibody identification

To detect type of antibody involved.

Direct Antiglobulin Test

• To detect invivo sensitization ( coating) of

red cells with immune antibody IgG or the

compliment component generally C3d.

• Principle:

Red cells coated with incomplete

antibody (IgG) or C3 component of the

complement , will be agglutinated by the

antihuman globulin (AHG) reagent.

Other Tests

• Haemoglobulin test

• Plasma Haemoglobulin test

• Urine haemoglobulin test

• Bilirubin(Total/Conjugated) test

• Platelet count

• Prothrombin time

• Blood culture of patient and blood bag

• Chest x-ray in case of suspected TRALI

General Definitions of Adverse Events

• Adverse event is an undesirable and

unintended occurrence before, during or after

transfusion of blood or blood component which

may be related to the administration of the blood

or component. It may be the result of an error or

an incident and it may or not result in a reaction

in a recipient.

• Incident is a case where the patient istransfused with a blood component which didnot meet all the requirements for a suitabletransfusion for that patient, or that wasintended for another patient. It thuscomprises transfusion errors and deviationsfrom standard operating procedures orhospital policies that have lead tomistransfusions. It may or may not lead to anadverse reaction.

• Near miss is an error or deviation from

standard procedures or policies that is

discovered before the start of the transfusion

and that could have led to a wrongful transfusion

or a reaction in a recipient.

• Adverse reaction is an undesirable response

or effect in a patient temporally associated with

the administration of blood or blood component.

It may, but need not, be the result of an incident.

Adverse Event

Adverse ReactionNear Miss

Incident

Transfusion Reactions

• Any unfavourable transfusion related event(Adverse Event) occurring in a patient during or after transfusion of blood or blood components.

• Depending upon the time of occurrence, transfusion reactions are divided into:

– Acute/immediate: within < 24 hrs

– Delyaed : >24 hrs

Based upon Onset of Reaction

Based upon severity:

• Grade 1 (Non-Severe):

- the recipient may have required medical

intervention (e.g. Symptomatic treatment) but

lack of such would not result in permanent

damage or impairment of a body function.

• Grade 2 (Severe):

• the recipient required in-patient hospitalization

or prolongation of hospitalization directly

attributable to the event; and/or

• the adverse event resulted in persistent or

significant disability or incapacity; or

• the adverse event necessitated medical or

surgical intervention to preclude permanent

damage or impairment of a body function.

• Grade 3 (Life-threatening):

The recipient required major intervention following the transfusion (vasopressors, intubation, transfer to intensive care) to prevent death.

• Grade 4 (Death):

The recipient died following an adverse transfusion reaction.

Grade 4 should be used only if death is possibly, probably or definitely related to transfusion. If the patient died of another cause, the severity of the reaction should be graded as 1, 2 or 3.

Based upon EtiopathogenesisA. Immune Mediated TRs

I. Immediate TR II. Delayed TR

1. Acute hemolytic TR(AHTR)

2. Febrile Non-Hemolytic TR (FNHTR)

3. Allergic TR

4. Anaphylactic TR

5. Transfusion Related Acute Lung

Injury(TRALI)

1. Delayed hemolytic TR (DHTR)

2. Alloimmunization

3. Post-transfusion Purpura

4. Transfusion related Graft versus

host disease(GvHD)

5. Immunomodulation

B. Non-immune mediated TRs

I. Immediate TR II. Delayed TR

1. Hemolytic –Physical/chemical damage to

RBCs

2. Bacterial contamination

3. Circulatory overload

4. Coagulopathy: Depletion/dilution of

coagulation factors or platelets

5. Air embolism

6. Metabolic citrate toxity, hyperkalemia,

hypokalemia

1. Transfusion associated

infections

2. Iron overload

E. Based Upon Nature of Transfusion Reaction

• Hemolytic Transfusion Reactions– Most severe type of transfusion reactions

A hemolytic transfusion reaction is one in which

symptoms and clinical or laboratory signs of

increased red cell destruction are produced by

transfusion. Hemolysis can occur intravascularly or

extravascularly and can be immediate (acute) or

delayed.

HTRs

• Acute HTRs

• Delayed HTRs

• Intravascular TR

• Extravascular TR

Acute Hemolytic Transfusion Reaction(AHTR)

An AHTR has its onset within 24 hours of transfusion.

Common signs of AHTR are:

• · Fever• · Chills/rigors• · Facial flushing• · Hypotension• · Pallor• · Jaundice• · Oligoanuria• · Diffuse bleeding

• Chest pain• Abdominal pain• Back/flank pain• Nausea/vomiting• Diarrhea• Dark urine

• Common laboratory features are:

– · Hemoglobinemia

– · Hemoglobinuria

– · Decreased serum haptoglobin

– · Unconjugated hyperbilirubinemia

– · Increased LDH an AST levels

– · Decreased hemoglobin levels

Not all clinical or laboratory features are

present in cases of AHTR.

• Blood group serology usually shows

abnormal results but absence of

immunological findings does not exclude

AHTR. AHTR may also be due to

erythrocyte auto-antibodies in the recipient

or to non immunological factors like

mechanical factors inducing hemolysis

(malfunction of a pump of a blood warmer,

use of hypotonic solutions, etc.).

• Delayed hemolytic transfusion reaction

(DHTR)

A DHTR usually manifests between 24 hours

and 28 days after a transfusion and clinical or

laboratory features of hemolysis are present.

Signs and symptoms are similar to AHTR but are

usually less severe. DHTR may sometimes

manifests as an inadequate rise of post -

transfusion hemoglobin level or unexplained fall

in hemoglobin after a transfusion. Blood group

serology usually shows abnormal results.

Hemolysis• Immunological

ABO Incompatibility, Alloimmunization

• Non-immune-mediated hemolytic transfusion reactions

• These are generally related to improper storage and handling of blood leading to hemolysis in vitro prior or during transfusion:

• Thermal injury: During re-warming of the blood if temperatures reach more than 42°C

• Cold injury: Inappropriate storage with exposure to ice or temperatures less than 6°C

• Mechanical injury: Lysis during transfusion through small-bore catheters.

• Infection

• Concomitant drug-induced hemolysis

Concomitant administration of hypotonic solutions (D5%W, hypotonic saline) leading to osmotic injury.

Intravascular Transfusion Reaction

• In Intravascular Transfusion Reaction, the

hemolysis of red blood cells takes place within the

circulatory system. This type of hemolysis is mainly

due to IgM antibodies, mediated by rapid activation

of complement and is usually associated with ABO

incompatibility. The clinical effects of an

intravascular transfusion reaction are immediate,

usually within minutes after starting the transfusion

, thus also called Acute Hemolytic Transfusion

Reaction(AHTR). This is the most severe and life

threatening reaction.

• Extravascular transfusion reactions are rarely

severe and occur mainly due to IgG antibodies eg.

Rh, Kell, Duffy system. These antibodies bring

about the destruction of red cells by the

macrophages in the spleen or liver.

• Clinical evidence of reaction is somewhat slower

and in some cases may be delayed up to two

weeks or more after transfusion, thus also called

Delayed Haemolytic Transfusion Reaction which

could be due to

Primary alloimmunization

Anamnestic or secondary response

Extravascular Transfusion Reaction

• In primary alloimmunization , the patient develops

an antibody after couple of weeks after transfusion

and is mostly due to incompatibility of Rh or Kell

system.

• Anamnestic or secondary response occurs in

patients, previously sensitized to red cell antigens,

but the level of circulating antibody to transfused

RBC is so low that they cant be detected in the

cross-match procedure, but since the patient is

immunized , there is increase in antibody

production(anamnestic response) resulting in red

cell destruction.This type of reaction is usually mild

to moderate and the signs and symptoms include

fever, anema, jaundice, and rarely haemoglobinuria.

Causes of Haemolytic Transfusion Reactions

• Clerical Errors

Majority of haemolytic transfusion reactions

are due to clerical errors and are mainly due

to:

Inadequate or incorrect labelling of blood i.e.

Recipient’s pre-transfusion sample, blood

bag or pilot tube.

Improper identification of patient either at the

time of sample collection or trabsfusion of

blood.

• Technical Errors

• Error in blood grouping of recipient or donor

• Incompatibility not detected in cross matching

procedure due to improper technique.

• Destruction of recipients RBCs by donor

antibodies, due to indiscriminate use of group

‘O’ blood.

• Failure to detect weak antibodies.

ABO Incompatibility

• The A and B antigens are the most immunogenic; hence transfusion of an ABO incompatible unit causes the recipient antibodies to interact with the donor RBC surface antigens, triggering complement activation and resulting in the acute intravascular hemolysis of the transfused donor RBCs.

•Complement activation causes various pro-inflammatory effects via release of active C3a and C5a subcomponents. These are anaphylatoxins which cause histamine and serotonin release from mast cells, increase vascular permeability causing a capillary leak syndrome and stimulate smooth muscle contraction. These translate clinically into the classical symptoms of flushing, hypotension and bronchospasm, respectively.

• Experimental evidence supports a central role for cytokines in the pathophysiology of hemolytictransfusion reactions. Tumor necrosis factor (TNF) appears to be the most commonly identified mediator of intravascular coagulation and end-organ injury although other cytokines have been implicated including interleukin (IL)-8, monocyte chemoattractantprotein, and IL-1 receptor antagonist.

•Ultimately, the complement cascade terminates with activation of the membrane attack complex (MAC) leading to cytolysis. The released hemoglobintetramers complex with haptoglobin and are removed by the liver, causing haptoglobin depletion. Residual free hemoglobin circulates in the plasma or gets converted to oxidized methemoglobin in the blood, imparting a reddish or brownish color, respectively.

• Small, unbound hemoglobin dimers are also filtered by

the glomerulus which causes hemoglobinuria. This

heme pigment causes acute kidney injury directly or

via tubular obstruction or vasoconstriction. In practice,

this heme-induced acute tubular necrosis requires a

secondary factor like dehydration, nephrotoxin use or

sepsis to translate into significant renal insufficiency.

•

The hemoglobin is taken up by the renal tubular cells,

degraded and the iron is stored as hemosiderin. When

these renal tubular cells are sloughed in the urine 3-10

days later, hemosiderinuria becomes detectable.

• Delayed serologic reaction (DSTR)

There is a DSTR when, after a transfusion, there

is demonstration of clinically significant

antibodies against red blood cells which were

previously absent (as far as is known) and when

there are no clinical or laboratory features of

hemolysis. This term is synonymous with

alloimmunization.

Non-Haemolytic Transfusion Reactions

• Febrile non hemolytic transfusion reaction (FNHTR)

• Allergic reaction

• Anaphylaxis

• Transfusion associated graft-versus-host disease (TA-GVHD)

• Post transfusion purpura (PTP)

• Transfusion-related acute lung injury (TRALI)

• Transfusion associated dyspnea (TAD)

• Transfusion associated circulatory overload (TACO)

• Hypotensive transfusion reaction

• Transfusion transmitted infections

Febrile non-hemolytic transfusion reaction

(FNHTR)• There is a FNHTR in the presence of one or more of:

Fever (≥38oC oral or equivalent and a change of ≥1oC

from pretransfusion value), chills/rigors

• This may be accompanied by headache and nausea.

• Occurring during or within four hours following transfusion

without any other cause such as hemolytic transfusion

reaction, bacterial contamination or underlying condition.

• FNHTR could be present in absence of fever (if chills or

rigors without fever).

• FOR THE PURPOSE OF INTERNATIONAL

COMPARISONS ONLY THE MOST SERIOUS CASES

OF FNHTR SHOULD BE ACCOUNTED FOR:

• Fever (≥39oC oral or equivalent and a change of ≥2oC

from pretransfusion value) and chills/rigors

Contd..

• FNHTRs result from the patient’s reaction to

donor white blood cells or to biological response

modifiers in the component.4

• Pre-storage leukoreduction reduces the rate of

FNHTRs.5

• Patients may present with either mild, moderate or severe reactions.6

• Allergic reaction

• An allergic reaction may present only with mucocutaneous signs and symptoms:– · Morbilliform rash with pruritus

– · Urticaria (hives)

– · Localized angioedema

– · Edema of lips, tongue and uvula

– · Periorbital pruritus, erythema and edema

– · Conjunctival edema

• occurring during or within 4 hours of transfusion. In this form it usually presents no immediate risk to life of patient and responds quickly to symptomatic treatment like antihistamine or steroid medications. This type of allergic reaction is called ‘minor allergic reaction’ in many hemovigilance systems.

• For the purpose of classification this type of allergic reaction would be graded as 1, i.e. non-severe.

• Anaphylaxis

• An allergic reaction can also involve respiratory and/or

cardiovascular systems and present like an anaphylactic

reaction. There is anaphylaxis when, in addition to

mucocutaneous systems there is airway compromise or

severe hypotension requiring vasopressor treatment (or

associated symptoms like hypotonia, syncope). The

respiratory signs and symptoms may be laryngeal (tightness

in the throat, dysphagia, dysphonia, hoarseness, stridor) or

pulmonary (dyspnea, cough, wheezing/bronchospasm,

hypoxemia). Such a reaction usually occurs occurring during

or very shortly after transfusion.

• For the purpose of classification this type of allergic reaction would be graded as 2 (severe), 3 (life-threatening) or 4 (death) depending on the course and outcome of the reaction.

• An allergic reaction classically results from

the interaction of an allergen and preformed

antibodies. A rise of mast cell tryptase can

support the diagnosis of an allergic

reaction. IgA deficiency and/or anti-IgA in

the recipient has been associated with

severe allergic reactions but is only one

infrequent cause out of many others.

Transfusion associated graft-versus-host

disease (TA-GVHD)

• TA-GVHD is a clinical syndrome characterised by

symptoms of fever, rash, liver dysfunction,

diarrhea, pancytopenia and findings of

characteristic histological appearances on biopsy

occurring 1-6 weeks following transfusion with no

other apparent cause.

• The diagnosis of TA-GVHD is further supported by

the presence of chimerism.

Graft versus Host Disease

• Graft versus host disease is a rare complication following

transfusion but has been reported in a variety of

conditions in which the immune system is depressed. It

is caused by the donor’s lymphocytes engrafting in the

recipient and reacting against host antigen. Patients with

congenital immunodeficiency syndrome , lymphomas

(especially Hodgkin's disease) and post chemotherapy

patients are at risk.

• GVHD occurs in three phases:

– The presentation of host protein by host’s antigen

presenting cells to donor T cells.

– Activation , proliferation , and migration of donor-T

cells.

– Damage of host target tissue.

Post Transfusion Purpura (PTP)

• PTP is characterized by thrombocytopenia arising 5-12

days following transfusion of cellular blood components

with findings of antibodies in the patient directed against

the Human Platelet Antigen (HPA) system.

• PTP is caused by platelet-specific antibodies in a patient

who has been previously exposed to platelet antigens

through pregnancy or transfusion. The most frequently

identified antibody is Anti-PLA1, which reacts with platelet

antigen HPA-1a. The platelet antibody binds to the platelet

surface, which allows for extravascular removal through the

liver or the spleen. The patient's own platelets are

destroyed as well, thus aggravating the thrombocytopenia.4

• Treatment with intravenous immunoglobulin,corticosteroids,

exchange transfusion, and plasmapheresis has been

reported with variable success.5

Transfusion-related acute lung injury

(TRALI)• TRALI is defined as noncardiogenic pulmonary oedema

following blood transfusion. Although all blood components have been implicated in TRALI, frozen plasma is the most common.2

• In patients with no evidence of acute lung injury (ALI) prior to transfusion, TRALI is diagnosed if a new ALI is present.

• Features:

– Acute onset

– Hypoxemia

– Pa02 / Fi02 < 300 mm Hg or

– Oxygen saturation is < 90% on room air or

– Other clinical evidence

– Bilateral infiltrates on frontal chest radiograph

– No evidence of left atrial hypertension (i.e. circulatory overload)

– No temporal relationship to an alternative risk factor for ALI during or within 6 hours of completion of transfusion .

Alternate risk factors for ALI are:

• Direct Lung Injury– Aspiration

– Pneumonia

– Toxic inhalation

– Lung contusion

– Near drowning

• Indirect Lung Injury– Severe sepsis

– Shock

– Multiple trauma

– Burn injury

– Acute pancreatitis

– Cardiopulmonary bypass

– Drug overdose

Contd...

• It has been suggested by the Toronto TRALI

Consensus Panel to add a category of possible

TRALI that would have the same definition as

TRALI except for the presence of a temporal

relationship to an alternative risk factor for ALI (as

described above). In such a circumstance TRALI

should be indicated with a possible imputability to

transfusion.

• TRALI is therefore a clinical syndrome and

neither presence of anti-HLA or anti-HNA

antibodies in donor(s) nor confirmation of cognate

antigens in recipient are required for diagnosis.

Mechanism

• ALI results from capillary endothelial leak that causes fluid to pass from the pulmonary vessels first into the interstitial space and then into the alveolar space causing pulmonary edema.

• It has now been established that neutrophills play a central role in the occurrence of lung damage through the release of granular enzymes, proteins, and reactive oxygen species after being activated.

• Neutrophills may either be directly activated by one strong stimulus, or are more commonly first primed and then activated.

• It is the activation of neutrophills and their interaction with the endothelium that leads to endothelial damage and capilarry leakage

Contd.....

Various stimuli causing priming and activation of

neutrophills and endothelium

• Antibodies: these antibodies are present in transfused

blood products and TRALI is most commonly associated

with transfusion of plasma products. Antibodies may be:

• Leukocyte antibodies ; When transfused with plasma

products from multi transfused individual or multiparous

women. HLA-II antibodies are more commonly

implicated than HLA-I antibodies.

• Anti-neutrophill antibpdies (HNA): particularly notorious are

antibodies of specificity HNA-2a, HNA-3a,HNA-4a which are

capable of directly activating neutrophills and causing TRALI

Clinical Features of TRALI

• Sudden deterioration in lung function

• Tightness in the chest

• Shortness of breath

• Dry cough

• Nausea and dizziness

• Fever and rigors

• Hypoxia, hypotension, tachycardia, and tachypnoea

• Chest auscultation: widespread crepitations.

• Hallmark finding: Copious frothy tracheal exudates

in intubated patients.

• Chest X-ray : bat’s wing pattern of pulmonary

edema

• BNP< 250 pg/ml

Transfusion associated dyspnea (TAD)

• TAD is characterized by respiratory distress within

24 hours of transfusion that does not meet the

criteria of TRALI, TACO, or allergic reaction.

Respiratory distress should be the most prominent

clinical feature and should not be explained by the

patient’s underlying condition or any other known

cause.

Transfusion associated circulatory overload

(TACO)

• TACO is characterized by any 4 of the following:

– Acute respiratory distress

– Tachycardia

– Increased blood pressure

– Acute or worsening pulmonary edema on frontal chest radiograph

– Evidence of positive fluid balance

– Occurring within 6 hours of completion of transfusion.

– An elevated BNP is supportive of TACO.

TACO is a condition characterised by left ventricular

failure and pulmonary oedema due to fluid overload.

This occurs either during transfusion or within the

following six hours, in transfusions with a rapid

infusion rate or a high volume of transfused products.

Risk factors include extremes of age (patients >60

years or <3 years), pre-existing cardiac and/or renal

dysfunction, transfusions after an acute myocardial

infarction, plasma transfusions, pre-existing positive

fluid balances in the 24 hours prior to the transfusion

and large-volume transfusions.2

Contd...

Patients present with acute respiratory distress,

dyspnoea, cyanosis, orthopnea, hypoxia, increase in

systolic blood pressure (>20 mmHg above the baseline)

and signs of cardiac overload (jugular venous pressure

elevation and bilateral crepitation).1 Patients tend to

respond to diuretics and worsen with fluid boluses. A

CXR will show pulmonary oedema and cardiomegaly

and an echocardiogram will be abnormal. There is

some evidence suggesting that B-type natriuretic

peptide (BNP) is a sensitive and specific marker of

TACO. Until further evidence is available, BNP levels

should be used as an adjunct marker to other features

of volume overload in confirming the diagnosis of

TACO.2

Hypotensive transfusion reaction

• This reaction is characterized by hypotension defined as

a drop in systolic blood pressure of ≥30 mm Hg

occurring during or within one hour of completing

transfusion and a systolic blood pressure ≤ 80 mm Hg.

• Most reactions do occur very rapidly after the start of the

transfusion (within minutes).

• This reaction responds rapidly to cessation of transfusion

and supportive treatment. This type of reaction appears

to occur more frequently in patients on ACE inhibitors.

• Hypotension is usually the sole manifestation but facial

flushing and gastrointestinal symptoms may occur.

• All other categories of adverse reactions presenting with

hypotension, especially allergic reactions, must have

been excluded. The underlying condition of the patient

must also have been excluded as a possible explanation for the hypotension.

Transfusion transmitted Bacterial infectionsBacterial contamination of a blood component can

occur either at the time of donation (due to subclinical

donor bacteremia or non-adherence to aseptic

techniques during the phlebotomy) or during blood

component preparation, storage or handling. This can

cause a septic ATR when the component is tranfused to

a recipient. Both Gram-negative and -positive bacteria

have been implicated. Although these reactions

can occur with any blood component, platelets are

the most commonly implicated since they are stored

at room temperature which allows faster bacterial

growth. When the implicated unit is transfused, the

patient rapidly develops acute manifestations.

Contd...

• Bacterial contamination should be considered if

the patient presents with a moderate or severe fever defined as a temperature ≥39 °C or a temperature rise of ≥2 °C from baseline.

• Bacterial contamination should also be suspected if any fever is accompanied with systemic symptoms such as chills, rigors, severe hypotension, shock, dyspnoea, myalgia, nausea or vomiting.

• Symptoms may develop rapidly or within four hours of the transfusion.

• The severity of the reaction is influenced by the type of bacteria involved, bacterial load and the recipient’s clinical status.

• Shock and disseminated intravascular coagulation

(DIC) can occur if a Gram-negative bacterially

infected unit with high levels of endotoxin was

transfused.

• There should be increased caution in patients

receiving blood transfusions while under

anaesthesia (where manifestations may be

masked) in patients with underlying fevers and in

those who have been pre-medicated with

antipyretics, as they may not develop a high-grade

temperature as a warning sign.

Transfusion Transmitted Parasitic Infections6

• Although the incidence of blood transfusion-transmitted parasitic infections (TTPI) is lower in comparison to that of bacterial and viral infections, these organisms pose a considerable risk of illness, especially in immunocompromised individuals.

• As we know, bacterial contamination can occur at numerous points during the collection and the transfusion process but the TTPI are always donor derived. The most common parasitic organisms implicated in transfusion-transmitted infections are Plasmodium spp., Trypanosoma cruzi, Babesia microti, Toxoplasma gondii, Leishmania spp. etc.

• Of the major transfusion-transmitted diseases, malaria is a major cause of TTIP in tropical countries whereas babesiosis and Chagas’ disease pose the greatest threat to donors in the USA In both cases, this is due to the increased number of potentially infected donors.

Other transfusion reactionsa) Haemosiderosis

Transfusion-associated haemosiderosis is being defined as a blood ferritin level of 1000 micrograms/l, with or without organ dysfunction in the setting of repeated RBC transfusions.

b) Hyperkalemia

Any abnormally high potassium level (> 5 mml/l, or 1.5 mml/l net increase) within an hour of transfusion can be classified as a transfusion- associated hyperkaliemia.

c) Unclassifiable Complication of Transfusion (UCT)

Occurrence of an adverse effect or reaction temporally related to transfusion, which cannot be classified according to an already defined ATR and with no risk factor other than transfusion and no other explaining cause.

F. Imputability AssessmentThis is, once the investigation of the adverse transfusion event is completed,

the assessment of the strength of relation to the transfusion of the ATE.

• Definite (certain):

when there is conclusive evidence beyond reasonable doubt that the adverse

event can be attributed to the transfusion

• Probable (likely):

when the evidence is clearly in favor of attributing the adverse event to the

transfusion

• Possible:

when the evidence is indeterminate for attributing the adverse event to the

transfusion or an alternate cause

• Unlikely (doubtful):

when the evidence is clearly in favor of attributing the adverse eventto causes

other than the transfusion

• Excluded:

when there is conclusive evidence beyond reasonable doubt that the adverse

event can be attributed to causes other than the transfusion

References 1.Proposed standard definitions for surveillance of non infectious adverse

transfusion reactions by International society of blood transfusion(ISBT), july

2011

2.Recognition, Investigation and Management of Acute Transfusion Reactions

by *Arwa Z. Al-Riyami,1 Sabria Al-Hashmi,2 Zainab Al-Arimi,3 Louis D.

Wadsworth,4 Abdulhakim Al-Rawas,5 Murtadha Al-Khabori,1 Shahina Daar6

3.Hemolytic transfusion reactions (ABO incompatibility) by Kristen Kipps : The

journal of family practice

4.Pathophysiology, Treatment, and Prevention of Post-Transfusion Purpura

(PTP): LabCE Online laboratory continuing education for clinical laboratories

and med techs

5.Post-transfusion purpura: case report. Kumar R, Ghali A, Ekaldious AW,

Mahmoud OI Al-Lumai AS

6. Transfusion-transmitted parasitic infections Gagandeep Singh and Rakesh

Sehgal: Department of Parasitology, PGIMER, Chandigarh-160012, India:

Asian Journal Of Transfusion Science

Principles & Practice of Transfusion Medicine by Dr. (Prof) R. N. Makroo, Ist

edition ,2014