Complications of Blood Transfusion: An Overview Clinical Pathology Conference Dean Fong, DO January 6, 2006

Complications of Blood Transfusion:An Overview

Clinical Pathology ConferenceDean Fong, DOJanuary 6, 2006

Case Presentation 63 y/o male status post AVR 2° to AS on

11/18. Developed fevers, weakness, sternal

erythema, SOB readmitted on 12/3.+ BCEcho vegetations c/w endocarditis

12/10 AMReceived 2U FFP 2° PT and PTT

Case Presentation Approximately 20 minutes after transfusion,

pt. developed…Shaking/rigorsTachycardiaHypoxiaNo change in tempterature during transfusion

Pt. was given benadryl, lasix, intubation and ventilatory support

Pt. improved and was extubated later that afternoon

Case Presentation PMH: AVR S/P AS, endocarditis, left arm

septic thrombophlebitis CXR:

12/9 “fluid overload, unchanged, LLL consolidation, pneumonia R base”

12/10 (AM after transfusion) “bibasilar atelectasis/consolidation”

12/10 (later AM) “↑ pulmonaty edema, unchanged LLL consolidation)

12/11 “no change”

Case Presentation Labs:

HCT 11/20 32.8%12/10 27.6% (16:00)12/10 34.7% (20:00)12/12 34.7%

Haptoglobin 100 mg/dl (30-200 mg/dl) Blood bank:

Pt. is O+, DAT – Backtype on both units FFP – Gram stain -, cultures (after 7 days) – Donor information:

33 y/o female, O+, G2, CMV+ 64 y/o male, O+, CMV+

Case Presentation

DIFFERENTIAL DIAGNOSIS?

Differential Diagnosis

Circulatory overload Pulmonary embolism Anaphylactic reaction TRALI Bacterial/Sepsis

Complications of Transfusion Transfusion reactions occur in 2% of units or

within 24 hours of use. Most common adverse side effects are

usually mild and non-life-threatening Two categories:

Infectious complications i.e HIV and HCV 1 transmission/2 million

transfusion

Non-infectious complications

Non-infectious Complications of Transfusions

Technical Manual Acute (< 24°)

ImmunologicNon-immunologic

Delayed (> 24°) ImmunologicNon-immunologic

Acute (< 24°) Immunologic

Hemolytic Fever/chills, non-hemolytic Urticarial/Allergic Anaphylactic

Acute (< 24°) Non-Immunologic

Hypotension associated with ACE inhibition Transfusion-related acute lung injury (TRALI) Circulatory overload Nonimmune hemolysis Air embolus Hypocalcemia Hypothermia

Delayed (> 24°) Immunologic

Allo-immunizationRBC antigensHLA

Hemolytic Graft-versus-host disease (GVHD) Post-transfusion purpura Immuno-modulation

Delayed (> 24°) Non-Immunologic

Iron overload


HemolyticFever/chills, non-hemolytic

Urticarial/AllergicAnaphylactic

Hemolytic Most severe hemolytic rxns. occur when transfused RBCs

interact w/ preformed aby Transfused aby rxns. w/ recipient’s RBCs rarely cause sxs.

May cause accelerated RBC destruction

Can occur after infusion of as little as 10-15 mL ABO-incompatible blood

Etiology 1:38,000 to 1:70,000 Clerical and other human error most common causes of ABO-

incompatible transfusion CAP survey – 3601 institution

834 HTR over 5 year period w/ 50 (6%) fatality Mortality estimated to be 1:1,000,000 transfusion

Hemolytic

Highly variable in acuity and severity Severe

Fevers and/or chills Hypotension Dyspnea Tachycardia Pain DIC ARF Shock

Hemolytic Pathophysiology

Intravascular hemolysis, opsonization, generation of anaphylotoxins Complement activation classical pathway

IgM and IgG C1q binds to Ig C3 activation cleavage of C3 leads to C3a being released into plasma and C3b

deposition onto RBC membrane C3a proinflammatory effects C3b erythrophagocytosis

C5 cleaved C5a into plasma C5a proinflammatory (100-fold more potent than C3a)

Assembly of remaining components of the MAC then occurs on RBC surface Lysis of RBC

Cytokines activation TNF, IL-1, IL-6, IL-8

Coagulation activation Bradykinin

Hemolytic

Laboratory findingsHemoglobinemiaHemoglobinuria LDHHyperbilirubinemia Haptoglobin BUN, creatinine in ARFDAT +

Hemolytic

Differential diagnosisAIHANonimmune hemolysisMicroangiopathic hemolytic anemiaDrug-induced InfectionsAny causes of hemolysis

Hemolytic Treatment/Prevention

Stop transfusionSupportive care to maintain renal function

Goal of urine O/P 100 mL/hr. in adults for at least 18-24 hours

Low dose dopamineTreatment of DIC

? Heparin – direct anticomplement effect

Prevention of clerical/human errors


Hemolytic

Fever/chills, non-hemolyticUrticarial/Allergic

Anaphylactic

Fevers/chills, non-hemolytic (FNHTR)

Defined as a rise in temperature of 1°C or greater. Incidence

43-75% of all transfusion rxn. PRBCs 0.5-6% Plts 1-38%

Signs/Symptoms Chills/rigor HA Vomitting

Fevers/chills, non-hemolytic (FNHTR)

Etiology Reaction…

Between recipient WBC antibodies (HLA, WBC antigens) against transfused WBC in product

Cytokines that accumulates in blood bag during storage

Differential Diagnosis: Other causes of fever ruled out

Hemolytic Bacterial/Septic

Treatment/Prevention Discontinue transfusion? Acetaminophen/meperidine Leukoreduced blood component



Urticarial/AllergicAnaphylactic

Uritcarial/Allergic Continuum

Mild – urticarial “Anaphylactoid” Severe – anaphylactic

Incidence 1-3% of all transfusion rxn.

Signs/Symptoms Uriticarial/hives – upper trunk and neck Fever Pulmonary signs (10%) – hoarseness, stridor, “lump in throat”,

bronchoconstriction No cutaneous involvement

GI – N/V, abd. pain, diarrhea Circulatory – tachycardia, hypotension

Uritcarial/Allergic Etiology

Circulating aby against soluable material in the blood Proteins in donor plasma

Binds to preformed IgE aby on mast cells Release of histamine

Vasoactive substances C3a, C5a, leukotrienes

Differential Diagnosis: Hemolytic Bacterial TRALI

Treatment/Prevention Discontinue transfusion Antihistamine/steroids Washing of blood products, pretreatment,leukoreduction?



Urticarial/Allergic

Anaphylactic

Anaphylactic Rare Incidence

1:18,000 to 170,000 Plt 1:1598-9630 FFP 1:28,831 RBCs 1:23,148-57,869

Signs/Symptoms In addition to uritcarial/allergic…

Cardiovascular instability Cardiac arrhythmia Shock Cardiac arrest

More pronounced respiratory involvement

Anaphylactic Etiology

IgA aby (IgE, IgG, IgM) in IgA deficiency Serum IgA < 5 mg/dL Estimated 1 in 342 blood donors

C4 aby Aby against nonbiologic origin Haptoglobin deficiency (IgG or IgE anti-haptoglobin) ?

Differential Diagnosis: Hemolytic Bacterial TRALI Circulatory overload

Anaphylactic Treatment/Prevention

Discontinue transfusion Supportive care Epinephrine Antihistamine/steroids In IgA deficient pts. IgA-deficient product, wash blood

product


Hypotension associated with ACE inhibitionTransfusion-related acute lung injury (TRALI)

Circulatory overloadNonimmune hemolysis

Air embolusHypocalcemia

Hypothermia

Hypotension associated with ACE inhibition

Pt. on ACEI receiving albumin during plasma exchange Etiology

Inhibition of bradykinin catabolism by ACEI Bradykinin activation by activator (low level prekallikrein) in albumin

Bradykinin activation by prekallikrein in plasma protein

Differential diagnosis Rule out hemolysis

Treatment/Prevention Withdraw ACEI/supportative care Avoid albumin Avoid bedside leukofiltration


Hypotension associated with ACE inhibition

Transfusion-related acute lung injury (TRALI)Circulatory overload

Nonimmune hemolysisAir embolus

HypocalcemiaHypothermia

Transfusion-related acute lung injury (TRALI) What Is TRALI?

Transfusion related noncardiogenic pulmonary edema Differential Diagnosis

Circulatory overload (TACO) Allergic/Anaphylactic Bacterial Acute hemolytic reaction

Clinical presentation (“classic”, severe form) Acute respiratory distress Pulmonary edema Hypoxemia Hypotension Transfusion usually within 6 hours (majority of cases during

transfusion or within 2 hours of transfusion)

TRALI Clinical criteria

Insidious, acute onset of pulmonary insufficiency Profound hypoxemia PaO2/FiO2 < 300 mmHg CXR b/l fluffy infiltrates c/w pulmonary edema Cardiac PA wedge pressure 18 mmHg No clinical evidence of LA HTN

TRALI Definition

TRALI w/out clinical risk factors for ALI: New ALI temporally related to transfusion Worsening of pre-existing pulmonary insufficiency

temporally related to transfusion

TRALI in pts. w/ clinical risk factor for ALI: New ALI temporally related to transfusion New ALI thought to be mechasnistically related to the

transfusion Worsening of pre-existing pulmonary insufficiency

temporally related to transfusion

TRALI Syndrome of TRALI (Weber KE et. al., Transfusion

Med Rev, 2003) Very common

Dyspnea, hypoxemia, pulmonary edema, hypotension, fever (1-2°C increase)

Common Tachycardia, cyanosis

Uncommon Hypertension

? Leukopenia, hypocomplements, monocytopenia

TRALI Implicated Blood Products

RBCs, FFP, apheresis platelets, platelet concentrates

Rare cases of IVIG, cryo-No cases of albumin reported

TRALI Clinical Course

100% TRALI patients require O2 and 72% require ventilation support

81% resolves within 4 days and 17% resolve within 7 days

Most pts. recover with 72 hours

Mortality rate 6% (subsequent series up to 14-25%) No long term sequela

Treatment Respiratory support No role for treatment w/ steroids or diuretics

TRALI Why Is TRALI Important?

Between 2001 – 2003, FDA report on causes of transfusion related deaths

TRALI 16.3% ABO/Hemolytic transfusion reaction 14.3% Bacterial contamination 14.1%

UK SHOT Data 7 years experience (from 1996) Total 155 cases

32 Deaths

TRALI Why Is TRALI Important? (cont.)

UK SHOT Data 7 years experience (from 1996)Reaction Type 1996/1997 1997/1998 1998/1999 1999/2000 2000/2001 2001/2002 2003

IBCT 81 110 144 201 213 258 (343) 358ATR 27 28 34 34 37 38 (49) 44DTR 27 24 31 28 40 33 (46) 32PTP 11 11 10 5 3 3 (3) 1

TA-GVHD 4 4 4 0 1 0 (0) 0TRALI 11 (6.5%) 16 (8.2%) 16 (6.3%) 19 (6.5%) 15 (4.8%) 26 (7.2%) (32) (6.7%) 37 (7.7%)

TTI 8 3 9 6 6 5 (5) 8Unclassified 0 0 7 0 0 0 0

TOTAL 169 196 255 293 315 363 (478) 480

2001/2002Red cells 2.7 millionPlatelets 250KFresh frozen plasma 385KCryoprecipitate 88KTOTAL 3.4 million

TRALI Pathogenesis

Two current working model hypothesis Both models are directed against increase in pulmonary

microvascular permeability

Pulmonary Microvascular Permeability

Leukocyte AntibodyBioactive Lipids

“Two-Hit” Model

Pulmonary Edema

TRALI UK and SHOT (7 Year Experience)

Data between 1996 to 2003 Define TRALI as “Acute dyspnea, hypoxia, bilateral

pulmonary infiltrates within 24 hours after transfusion with no other apparent causes”

1996 < 10 cases 2003 40 cases Total 155 cases

138 cases examined, others were excluded

32 Deaths 11 Other Demise

4 Partial Recovery

94 Fully Recovered

TRALI UK and SHOT (cont.)

Serological testing Leukocyte antibody investigation 71 cases of leukocyte antibodies

Incomplete samples or not done

2%

Donor and patient

negative 19%

Patient positive

8%

1 or more donors positive

71%

50 HLA Class I or II

5 HLA and HNA

16 HNA

18 Crossmatched

14 Antibody only in donor

18 Multiple antibodies

TRALI UK and SHOT (cont.)

Products implicated 45/139 FFP/Cryo- 34/139 RBCs 27/139 Platelets

Estimation FFP/Platelet 1 in 50-60K RBC/Cryo- 1 in 500-600K Frequency 1 in 1,000-2,500 patients transfused Would expect to see 300-750 cases/year

TRALI UK and SHOT

What UK is doing October 2003 Male donor ONLY for FFP 2004 Import FFP for children April 2004 Previously transfused donors

excludedFuture Considerations

? Male plasma only to suspend platelet pools ? Female apheresis platelet donor for leukocyte antibody ? Effects of decreased plasma (additive solution) in

platelet concentrates/apheresis platelets ? Mild TRALI. Does it exist?





Hypothermia

Circulatory overload Acute pulmonary edema due to volume overload Incidence

One of the most common complications of transfusion Young children and elderly at risk Cardiac and pulmonary compromise Chronic anemia with expanded plasma volume Infusion of 25% albumin

Shifts large volume of extravascular fluid into the vascular space

Signs/Symptoms Dyspnea, cyanosis, orthopnea, severe HA, HTN, CHF

during or soon after transfusion

Circulatory overload Differential diagnosis:

TRALI Allergic rxn. Other causes of CHF

Treatment/Prevention Stop transfusion Supportive care Phlebotomy Diuretic Slow transfusion

Usually 4 hours, can be extended to 6 hours Other strategies



Circulatory overload

Nonimmune hemolysisAir embolus

HypocalcemiaHypothermia

Nonimmune hemolysis Lysis of RBCs as a result of storage, handling, or

transfusion condition Incidence

Rare

Signs/Symptoms Transient hemodynamic Pulmonary impairment Renal impairment Hemoglobinemia and hemoglobinuria Hyperkalemia (renal failure) Fever

Nonimmune hemolysis Differential diagnosis

Hemolytic Autoimmune Bacterial/sepsis PNH, drug-induced, oxidative stress, etc. Diagnosis of exclusion

Treatment/Prevention Stop transfusion Investigation of blood bag and tubing Investigate for hemolytic transfusion rxn. Check serum K Supportive care Maintain urine O/P (except for contraindication…i.e. renal failure)





Hypothermia

Air embolus

Air infusion via line Rare Cough, dyspnea, chest pain, shock If suspected…

Pt. placed on left side with head down Displace air bubble from pulmonary valve

Hypocalcemia

Large volumes of FFP, whole blood, plts. transfused rapidly plasma citrate levels may rise binds iCa+2 Citrate rapidly metabolized manifestations transient Prolonged apheresis

Periorbal/peripheral tingling paresthesias, shivering, lightheadedness, tetanic sxs., hyperventilation, depressed cardiac function

Ca+2 replacement

Hypothermia

Rapid infusion of large volumes of cold blood Ventricular arrhythmias More likely via central catheters Increased toxicity of hypocalcemia and hyperkalemia Impaired hemostasis Increase caloric requirement

Blood warmer


Allo-immunizationHemolytic

Graft-versus-host disease (GVHD)Post-transfusion purpura

Immuno-modulation

Allo-immunization Occurs weeks to months after transfusion Incidence

1-1.6% to RBC antigens 10% to HLA

Signs/Symptoms PRBCs hemolysis Plts. refractoriness

Treatment/Prevention Plts.

Leukoreduction Cross-matched and/or HLA-matched plts.


Allo-immunization

HemolyticGraft-versus-host disease (GVHD)

Post-transfusion purpuraImmuno-modulation

Hemolytic Once allo-immunization has occurred, abys may diminish to

undetectable levels Especially Kidd system (anti-Jka and anti-Jkb) Hemolysis typically extravascular

Anamnestic response W/in hours or days (up to 6 weeks), IgG aby reacts with transfused red

cells Prospective study

58 of 2082 (2.8%) RBC recipients were found to have alloabys (previous undetected) w/in 7 days of transfusion

Incidence Based on above study, only 1 recipient w/ new aby w/in 7 days of

transfusion was shown to have hemolysis Estimated rate

1 in 2082 recipients 1 in 11,328 units

Other reports at 0.02 to 0.009%

Hemolytic Signs/Symptoms

Fever Declining Hb Mild jaundice Hemoglobinuria ARF – uncommon

Check for alloaby in both serum and RBC Treatment/Prevention

Rarely necessary May need to monitor urine O/P, renal function, coagulation

functions IVIG Appropriate units for transfusion




Immuno-modulation

Graft-versus-host disease (GVHD) Fatal complication cause by engraftment and clonal

expansion of donor lymphocytes in susceptible host Attack recipient tissues Immunocompromised pts.

Hematologic malignancies or certain solid tumors receiving chemotherapy radiation

Stem cell transplant Recipients of HLA matched products or familial blood donation Lupus or CLL requiring fludarabine Not reported in AIDS pts.

2-30 days after transfusion Incidence

Rare (0.002-0.005%)

GVHD Signs/Symptoms

Appears w/in 10-12 days of transfusion Skin – whole body erythroderma, desquamation GI N/A, diarrhea Liver BM failure leading to pancytopenia

Treatment/Prevention No effective treatment Gamma irradiation

Render T-cells incapable of replication FDA requirement

Minimum of 2500 cGy target to the midline of the container Minimum of 1500 cGy target to all other part of component



Graft-versus-host disease (GVHD)

Post-transfusion purpuraImmuno-modulation

Post-transfusion Purpura (PTP) Characterized by abrupt onset of severe throbocytopenia

(< 10K) Average of 9 days (range 1-24 days) PRBCs or whole blood Reported in plts., plasma, frozen deglycerolized PRBCs

Incidence Rare Over 200 cases published Male:Female 1:5 Median age 51 years (range 16-83)

Clinical course Usually self-limited, recovery w/in 21 days 10-15% mortality

Intracranial hemorrhage

PTP Signs/Symptoms

Profound thrombocytopenia Purpura Bleeding Fever (reported)

Etiology Plt. specific IgG aby that are auto-aby

All HPA implicated but HPA-1a most common 3 mechanisms

Immune complex – pt. aby and donor antigen Concersion of antigen- autologous plts. to aby targets to antigen in

transfused components Cross-reactivity of pts. autoaby w/ autologous plts.

PTP Differential diagnosis

ITP TTP Alloimmunization Sepsis DIC BM failure Drug-induced

Treatment/Prevention Steroids – controversial Plasma exchange – achieves plts. counts to 20K in 1-2 days (up to 12 days) IGIV – recovery of plts. Counts of 100K w/in 3-5 days

Block aby-mediated clearance Splenectomy – refractory pts., high risk of life-threatening hemorrhage Plts. transfusion not effective Antigen-negative blood product




Immuno-modulation

Immuno-modulation

? Increases risk of recurrent cancer and bacterial infection

WBCs cytokines during storage interfere w/ immune function

Uncertain clinical significance Leukoreduction of blood products

Delayed (> 24°) Non-Immunologic

Iron overload

Iron overload Each unit of PRBC 200-225 mg of Fe Chronic transfusion > 50-100 units of PRBC Storage in RE sites saturation other sites

Heart, liver, endocrine glands (pancreas)

Removal of Fe Desferoxamine – Fe-chelating agent

Chronic transfusion in hemoglobinopathy Prolong intertransfusion interval or PRBC exchange

Case Presentation

Follow-up

Case Presentation Donor FFP from 33 y/o female (G2)

Anti-HLA aby resulted positive for several anti-HLA aby

Recipient Positive anti-HLA aby, HLA Class II antigen, HLA DQ1 But…

Pt. had received 11 units PRBCs and 2 units Plts. Over plast 1 month

Conclusion… ? TRALI

Pt. was transfused with 2 U FFP over a 6 hour period w/out incident ? Other

Recommendation… ? What to do with donor ? What to do with patient

References Brecher ME et. al., Technical Manual, 14th Ed., AABB Press, 2002. Davenport RD, “Pathophysiology of Hemolytic Transfusion Reactions”

Seminars in Hematology 2005; 42: 165-168. Gilstad CW, “Anaphylactic transfusion reactions”, Current Opinion in

Hematology 2003; 10: 419-423. Kuriyan M, Carson JL, “Blood transfusion risks in the intensive care unit”,

Crit Care Clin 2004; 20: 237-253. MacLennan S, Barbara JAJ, “Risks and side effects of therapy with

plasma and plasma fractions”, Best Practice and Research Clinical Haematology 2006; 19(1): 169-189.

Mintz PD, Transfusion Therapy Clinical Principles and Practice, AABB Press, 2005.

Shander A, Popovsky MA, “Understanding the Consequences of Transfusion-Related Acute Lung Injury”, Chest 2005; 128: 598-604.

Silliman CC, McLaughlin NJD, “Transfusion-related acute lung injury”, Blood Reviews 2005; article in press.

Documents

Complications of Blood Transfusion: An Overview Clinical Pathology Conference Dean Fong, DO January 6, 2006