TransfusionTherapy and Biology¶
Chapter 118 | Harrison's 22e · Part 4 – Oncology: Hematologic Malignancies · Chapter 118
Key Clinical Points¶
- Alloimmunization occurs with transfusion of RBCs, platelets, or neutrophils due to allogeneic determinants.
- Anti-RBC IgG/IgM antibodies cause hemolysis; anti-HLA/HPA antibodies lead to TRALI; anti-HNA antibodies lead to platelet refractoriness.
- ABO (carbohydrate) and Rh (protein) are the primary blood group systems.
- TRALI occurs in ~1% of transfusions involving anti-HLA or anti-HNA antibodies.
- Leukocyte reduction (<1–5x10^6 leukocytes) reduces FNHTR, alloimmunization, and CMV transmission.
- Acute hemolysis is driven by IgM/complement activation; Delayed hemolysis by IgG/macrophage opsonization.
- Platelet transfusion thresholds: <20x10^9/L (bleeding) or <50x10^9/L (surgery).
- Plasma transfusion volume: 10–15 mL/kg for coagulopathy.
- Irradiation prevents GVHD in immunocompromised patients.
- Pathogen reduction reduces TTIs by >99%.
1. DEFINITION & OVERVIEW¶
• Transfusion Therapy: Administration of blood components (BCs) including RBC concentrates, platelet concentrates, and plasma. • Alloimmunization: Development of recipient antibodies against donor antigens. • Immune Mechanisms: ◦ Anti-RBC IgG → extravascular hemolysis via complement activation and ADCC ◦ Anti-HLA/HPA → TRALI via neutrophil activation ◦ Anti-HNA → platelet refractoriness ◦ Warm autoAbs (IgG) → target Rh antigens ◦ Cold autoAbs (IgM) → target ABO, I, i antigens • Blood Group Classification: ◦ Carbohydrate Systems: ABO, H, Lewis ◦ Protein Systems: Rh, Kell, Duffy, Kidd
1.1 Blood Group Systems¶
• ABO System: Based on A/B antigens; O allele is recessive. • H Antigen: Serves as the precursor for A/B antigens. • Rh System: Contains 56 antigens; D antigen is most clinically significant. • Other Systems: Kell (K1/K2), Duffy (Fy(a+b-)), and Kidd (Jka/Jkb) are linked to HDFN. • Table 118-2 (ABO Compatibility): ◦ Type A (A/A or A/O) → Anti-B antibodies; compatible with A or O. ◦ Type B (B/B or B/O) → Anti-A antibodies; compatible with B or O. ◦ Type AB (A/B) → No antibodies; compatible with A, B, or O. ◦ Type O (O/O) → Anti-A and Anti-B; compatible with O only. • Table 118-3 (RBC Group Systems): ◦ ABO: 4 antigens; associated with immediate/delayed hemolysis. ◦ MNS: 49 antigens (M, N, S, U). ◦ P1PK: 3 antigens (P1, Pk, P). ◦ Rh: 55 antigens (D, C, E, c, e); linked to HDFN. ◦ Kell: 36 antigens (K); linked to HDFN. ◦ Duffy: 5 antigens (Fya, Fyb, Fy3, Fy5). ◦ Kidd: 3 antigens (Jka, Jkb, Jk3). ◦ H: 1 antigen (H/Bombay); rare phenotype.
2. ETIOLOGY & PATHOPHYSIOLOGY¶
• Hemolytic Reaction Mechanisms (Figure 118-1): ◦ Acute Response (Panel A): Preexisting antibodies (mostly IgM) → complement activation (C3b, C5–C9) → MAC formation → intravascular hemolysis → release of free hemoglobin → potential renal failure and DIC. ◦ Delayed Response (Panels B & C): Neoformed allogeneic IgG or IgM → opsonization → macrophage-mediated phagocytosis → extravascular hemolysis → conjugated bilirubin production. • Cellular Products: Membrane degradation results in spherocytes and microangiocytes. • Transfusion-Related Acute Lung Injury (TRALI): ◦ Incidence: ~1% of transfusions with anti-HLA or anti-HNA antibodies. ◦ Pathophysiology: Anti-HLA antibodies → neutrophil activation → pulmonary edema and endothelial injury.
3. COMPLICATIONS & PROGNOSIS¶
• Hemolytic Reactions: ◦ Acute: Immediate intravascular lysis; risk of renal failure from hemoglobinuria. ◦ Delayed: Extravascular hemolysis over days/weeks; primary symptoms are anemia and jaundice. • Pulmonary Complications: ◦ TRALI: Respiratory distress within 6 hours of transfusion (immune-mediated). ◦ TACO: Pulmonary edema within 12 hours of transfusion (non-immune). ◦ Severe Allergy: Rapid onset (<4h) with respiratory distress. • Table 118-5 (Adverse Reactions): ◦ Fever ≥38°C (+1–2°C within 4 h) → FNHTR or infection. ◦ Fever (+1–2°C within 15 min) → bacterial infection. ◦ Fever (>2°C) → bacterial infection. ◦ Dyspnea: Differentiates TRALI (<6h), TACO (<12h), and Severe allergy (<4h). ◦ Rash: <2/3 of body (minor); >2/3 of body (severe); >2/3 within 5 min with shock (anaphylaxis). • Table 118-6 (Infectious Events): ◦ Bacterial: Pyogenic bacteria; risk of sepsis. ◦ Viral: HIV, HBV, HCV, HTLV, HEV, CMV, Parvovirus B19, West Nile. ◦ Parasitic: Plasmodium (malaria), Babesia, Trypanosoma cruzi.
4. MANAGEMENT & TREATMENT¶
• Blood Component Processing (Table 118-1): 1. Leukocyte Reduction: → Target <1–5x10^6 leukocytes per unit; reduces fever, chills, and risk of CMV. 2. Irradiation: → X-ray or gamma (25–35 Gy); prevents GVHD in immunocompromised patients. 3. Pathogen Reduction: → Nucleic acid cross-linker/UV; reduces TTIs by 99%. 4. Plasma Reduction: → Prevents allergic reactions in sensitive patients. 5. Cryopreservation: → Glycerol or DMSO used to ensure availability of rare blood groups or platelets. • Clinical Transfusion Guidelines: 1. RBC Transfusion: ◦ Threshold: Hemoglobin <7 g/dL or symptomatic anemia. ◦ Volume: 250–300 mL (including additive solution, max 40–50 mL plasma). ◦ Quality: Hb 22–40 g/dL; Hct 50–70%; Hemolysis ≤0.8%. 2. Platelet Transfusion: ◦ Threshold: <20x10^9/L with bleeding or <50x10^9/L for surgery. ◦ Volume: 100–700 mL; ≥2x10^11 platelets; pH ≥6.4. 3. Plasma Transfusion: ◦ Dose: 10–15 mL/kg for coagulopathy. ◦ Volume: 200–300 mL; fibrinogen ≥2 g/L, factor VIII ≥0.5 IU/mL.
KEY PEARLS & HIGH-YIELD POINTS¶
• Immune Distinction: IgM → Acute hemolysis (complement); IgG → Delayed hemolysis (opsonization). • TRALI vs TACO: TRALI is immune-mediated (anti-HLA, <6h); TACO is non-immune (<12h). • Leukoreduction: Essential for reducing FNHTR and CMV transmission. • Rh Significance: D antigen is the primary concern in Rh system compatibility. • Safety: Pathogen reduction is critical for preventing HIV, HBV, and HCV.
Reference Tables¶
TABLE 118-1 Blood Components: Collection and Manufacturing Processes¶
Harrison's 22e, p.902
| BLOOD OR APHERESIS COLLECTION AND INITIAL PROCESSING |
BLOOD COMPONENT |
ADDITIONAL COMPONENT PROCESSING (OPTIONAL TO MANDATORY) |
RATIONALE | VOLUME AND CONTENT |
STORAGE CONDITIONS AND DURATION |
|---|---|---|---|---|---|
| Whole blood collection: Separation into RBCC and platelet-rich plasma (PRP) by slow centrifugation, followed by high-speed centrifugation of the PRP to yield one unit of platelets (most often subsequently pooled) and one unit of plasma. or |
RBCC from whole blood or from apheresis |
Leukocyte reduction Deleukocytation to <1–5.106 leukocytes per unit (highly recommended): initial whole blood filtration or RBC elective filtration (highly recommended) Irradiation: X-ray or gamma, ~25–35 Gy; most often units not older than 28 days after collection |
Reduction of fever and chills Reduction of intracellular pathogens (including CMV) Reduction of alloimmunization GVHD prevention in immunosuppressed patients or intrafamily transfusions |
250–300 mL (including additive solution, no more than 40–50 mL of plasma) Hemoglobin: 22–40 g/dL Hematocrit: 50–70% Hemolysis ≤0.8% at issuing |
4 +/– 2°C Duration depends on the additive solution: 25–42 days After irradiation: 24 h After plasma reduction: 24 h to 10 days depending on reduction methodology |
| Separation into a RBCC, a plasma, and a “buffy coat” containing leukocytes and platelets by high-speed centrifugation, followed by pooling and slow-speed centrifugation of the buffy coat to produce a pooled platelet unit. Alternatively, the buffy coat may undergo high-speed centrifugation to produce a granulocyte unit that will be subsequently pooled. Apheresis collection: Various apheresis devices allow for the collection of BCs either as individual BCs such as plasma or PC (possibly double, such as double RBCC) or combined BCs, such as PC and plasma, or RBCC, platelets, and plasma. |
|||||
| Plasma reduction | Prevention of allergic reactions in patients with prior severe transfusion reactions |
Lesser volume, 10% reduction in RBC content |
|||
| Pediatric preparation | Adjustment to low-weight recipients |
Adjusted content | |||
| Cryopreservation (glycerol) |
Most often to ensure availability of RBCCs with a rare blood group for immunized “public-negative” recipients or recipients with complex alloimmunizationsa |
Same Hb content Hematocrit: 40–80% Glycerol ≤1 g |
N2 or –80°C electric freeze drying N2: unlimited; –80°C: 30 years 7 days after thawing in suitable additive solutions, 24 h without additive solution |
||
| PC from whole blood (individual units or pools of 4–6 units of ABO identical units) or from apheresis |
Suspension in a platelet additive solution (PAS). PAS contains ingredients such as acetate, potassium, phosphate, and magnesium to sustain platelet storage |
Reduction of fever and chills Plasma orientation toward fractionation |
From 100 to 700 mL ≥2.1011 platelets pH ≥6.4 |
At 20–24°C and under permanent motion: 3–7 days or At 4°C without motion: up to 14–21 days If irradiated: <24 h |
|
| Leukocyte reduction (<1–5.106 leukocytes per unit) (highly recommended): initial whole blood filtration or PC elective filtration |
Reduction of fever and chills Reduction of intracellular pathogens (including CMV infections) Reduction of alloimmunization |
||||
| Pathogen reduction: Most often nucleic acid cross-linker and/or UV illumination |
Reduction of transfusion- transmitted infections Prevention of GVHD |
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| Volume reduction | Prevention of allergic reactions in patients with prior severe reactions |
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| Irradiation: X-ray or gamma, ~25–35 Gy; in general, on bags no older than 3 days after collection |
Prevention of GVHD | ||||
| Pediatric | Volume and content adjustment | ||||
| Cryopreservation (DMSO) | To ensure continuous availability in remote locations To ensure availability of platelets with rare HPA groups |
6 h after thawing (depending on cryopreservation procedure, may be resuspended in plasma) |
|||
| Plasma from whole blood or from apheresis |
Cryopreservation at –18°C (most often) |
Shelf-life extension | 200–300 mL Coagulation factors, including fibrinogen (≥2 g/L), factor VIII (≥0.5 IU/mL), protein C and S, antithrombin |
1–2 years if cryopreserved Up to 28 days if kept unfrozen |
TABLE 118-2 ABO Blood Groups and Antibodies: Transfusion Compatibility GENOTYPE(S) A/A or A/O B/B or B/O A/B O/O a…¶
Harrison's 22e, p.903
| GENOTYPE(S) | ENZYME(S)/IMMUNODOMINANT SUGAR(S) | PHENOTYPE | NATURAL ANTIBODIES |
TRANSFUSION COMPATIBILITY REQUIREMENTS | ||
|---|---|---|---|---|---|---|
| RBCC | PCa | PLASMA | ||||
| A/A or A/O | “A” transferase/N-acetylgalactosamine (GalNac) |
A | Anti-B | A or O | A, 0b, Bb, or ABb | A or A,B |
| “B” transferase/galactose (Gal) | B | Anti-A | B or O | B, O, Ab, or ABb | ||
| A/B | “A” transferase and “B” transferase GalNac and Gal |
A,B | None | A,B or A or B or O | A,B, Ob, or Ab or Bb | A,B |
| Inactive Unconverted H antigen |
O | Anti-A and Anti-B | O | 0, A, B, or A,B |
TABLE 118-3 Red Blood Cell Group Systems and Antibodies: Clinical Significance and Transfusion Recommendations ISBT NO.¶
Harrison's 22e, p.904
| ISBT NO./ SYSTEM |
SYMBOL/GENE(S) | ANTIGENS (NO.) |
MAIN ANTIBODIES (ANTI-) |
HEMOLYSIS CHARACTERISTICS | RBCC TRANSFUSION RECOMMENDATIONS |
|
|---|---|---|---|---|---|---|
| TRANSFUSION | HDFN | |||||
| 1/ABO | ABO/ABO | 4 | A, B | None to severe; immediate and/or delayed |
None to moderate (rarely severe) |
Ab-negative RBCC |
| MNS/GYPA, GYPB, (GYPE) |
49 | M N S, s U |
None (except in extremely rare cases if active at 37°C) None (may be clinically significant in the case of the rare N–S–s–U– phenotype) None to moderate (rare) Mild to severe |
None (except in extremely rare cases if active at 37°C) None None to severe (rare) Mild to severe (one reported case requiring an intrauterine transfusion) |
||
| 3/P1PK | P1PK/A4GALT | 3 | P1 | None to moderate; delayed (rare) |
None | Compatible RBCC (negative IAT at 37°C) |
| P1, Pk, P (Tja) | None to severe | None to severe | Ag-negative RBCC | |||
| RH/RHD, RHCE | 55 | D, C, E, c, e | Mild to severe; immediate or delayed |
Mild to severe | ||
| 6 /Kell | KEL/KEL | 36 | K | Mild to severe; delayed | Mild to severe (rare) | Ag-negative RBCC |
| LE/FUT3 | 6 | Lea, Leb | None (rare cases of hemolytic reactions) |
None | ||
| 8/Duffy | FY/ACKR1 | 5 | Fya, Fyb | Mild to severe (rare); immediate/delayed |
Mild to severe (rare) | Ag-negative RBCC |
| Fy3, Fy5 | Mild to moderate; immediate (rare)/delayed |
Mild (rare) (no data for anti-Fy5) |
Ag-negative RBCC | |||
| JK/SLC14A1 | 3 | Jka, Jkb Jk3 |
None to severe; immediate or delayed None to severe; immediate or delayed |
Mild to moderate (rare) None to mild |
||
| 18/H | H/FUT1 | 1 | H (Bombay) | None to severe; immediate/ delayed |
Not none | Ag-negative RBCC |
| GLOB/B3GALNT1 | 2 | P | None to severe | None to mild |
TABLE 118-5 Transfusion Adverse Reactions: Main Warning Signs Fever (≥38°C)¶
Harrison's 22e, p.908
| Fever (≥38°C) | +1–2°C within 4 h | FNHTR Anti-HLA immunization and cognate Ag in the blood product TRALI (with dyspnea at the forefront) |
|---|---|---|
| +1–2°C within 15 min +/–: • Chills • Dyspnea • Hypotension • Digestive disorders • Disseminated intravascular coagulation • Hemoglobinuria |
Transfusion-transmitted bacterial infection Hemolysis |
|
| >2°C | Transfusion-transmitted bacterial infection | |
| Dyspnea | TRALI (within 6 h of transfusion) TACO (within 12 h of transfusion) Severe allergy (immediate; within 4 h) |
|
| Rash | <2/3 of the body within 2–3 h | Minor allergy |
| >2/3 of the body during or within 2–3 h | Severe allergy | |
| >2/3 of the body within 5 min Associated with dyspnea and shock |
Anaphylaxis | |
| New alloantibody | Alloimmunization | |
| Gum bleeding, purpura 5–12 days after transfusion | Posttransfusion purpura | |
| Top-down investigation after a blood donor is subsequently found to be infected | Transfusion-transmitted infection | |
| Bottom-up investigation after another recipient of a same blood donation is found to be infected |
||
| Infectious symptoms within 6 months |
TABLE 118-6 Infectious Transfusion Adverse Events PATHOGEN Bacteria¶
Harrison's 22e, p.913
| PATHOGEN | DONATION PREVALENCE (/104 BLOOD DONATIONS) |
PREVENTION MEASURES (IN ADDITION TO DONOR DEFERRAL) |
INFECTION PREVALENCE IN RECIPIENTS (/106 BLOOD PRODUCTS TRANSFUSED) |
|
|---|---|---|---|---|
| Bacteria | Pyogenic bacteria | PC: 10–20 | Venipuncture sepsis, diversion of the initial 10–30 mL of blood, bacterial detection, pathogen reduction (for PC) |
Sepsis: PC: 5–30; with bacterial detection: <1 to 10; with pathogen reduction: <1 RBCC: <0.2 |
| Treponema pallidum (syphilis) |
~1a | Serologyb,c | <0.01 | |
| HIV-1/2 HBV HCV HTLV-1/2 HEV CMV Parvovirus B19 West Nile virus |
~0.1 ~0.5 0.2–1.2 0.05–0.1a 0–10 (in endemic regions) Undetermined ~0.5 with viral DNA >106 IU/mL,e up to 100 overall Up to 3 in high season endemic regionsa |
Serology, NAT (+/– p24 Ag)b,c Serology, NATb,c Serology, NATb,c Serology, BC leukocyte reduction b,c NAT Serology, BC leukocyte reductionb,c NAT NATb |
||
| Parasitef | Plasmodium (malaria) | ~4 (40–>50 in donors from endemic regions)a |
Serology (NAT soon available) | <0.1 in nonendemic regions |
| Babesia | ~90 (in endemic regions)a | Serology (NAT implementation underway) |
ND (0.04% donors may be within the serology window period) |
|
| Trypanosoma cruzi (Chagas disease) |
~0.14 in donors/mothers from endemic regionsa |
Serology, leukocyte reduction | ND |