14 Complement-Related Disorders
- PNH: acquired PIGA mutation → ↓ GPI anchor → ↓ CD55/CD59 → intravascular hemolysis
- Triad: hemolysis, thrombosis, cytopenia
- Dx: flow cytometry (FLAER positive)
- Tx: C5 inhibitors, proximal inhibitors (pegcetacoplan, iptacopan, danicopan)
- Vaccinate meningococcal ≥2 wks before C5i; prophylaxis <2 wks post-vaccination
- TMA: hemolytic anemia, ↓plt, end-organ damage; ADAMTS13 <10% = TTP (PLEX); normal = CM-TMA/ST-TMA
- CM-TMA (aHUS): CFH/CFI/C3/THBD mutations; complement blockade essential
- ST-TMA: E. coli O157:H7 or Shigella; mostly pediatric, self-limited
- Distinguish early: PLEX harmful in CM-TMA; eculizumab ↑ plt count & renal function in aHUS
14.1 Introduction
Complement system (discovered 1896) modulates immunity & inflammation via 3 pathways: - Classical: antibody-mediated (C1q) - Lectin: microbial carbohydrates or MBL-activated - Alternative: spontaneous/microbe-activated - All converge on C3 cleavage → MAC (membrane attack complex) formation → pathogen lysis
Host protection: CD55 (DAF), CD46 (MCP), CD59 (protectin) prevent self-cell complement damage
This chapter covers PNH & TMA (defective complement regulation/activation)
14.2 Paroxysmal Nocturnal Hemoglobinuria
14.2.1 Pathophysiology
PNH: acquired clonal HSC disorder - Mutation: PIGA gene (X chromosome) - Mechanism: disrupts GPI anchor formation → ↓ GPI-linked proteins (>150) including CD55, CD59 - Result: GPI-deficient RBCs exquisitely sensitive to complement-mediated lysis → hemolytic anemia - Occurs in HSCs → can occur w/ aplastic anemia
Cell populations (GPI-linked protein levels): - Type I: normal CD55/CD59 - Type II: markedly ↓ levels - Type III: absent GPI proteins - Clone size & proportion drive severity; <10% clones may be asymptomatic
Hemolysis mechanisms: - IVH (intravascular): MAC-mediated RBC lysis (early); ↓ C3 fragments - EVH (extravascular): C3d opsonization → RES phagocytosis (as clone size ↓, Hct ↓) - Mutations necessary but not sufficient; requires monitoring for clonal evolution, myelodysplasia, aplastic anemia
PIGA mutations → variable clonal evolution. Stable clones vs. progression to MDS/aplastic anemia. Flow cytometry screening in all aplastic anemia or unexplained thrombosis.
14.2.2 Laboratory findings
PNH hemolysis + variable BMF: - DAT-negative IVH: macrocytic anemia, ↑LDH, ↓haptoglobin, ↑reticulocytes - Reticulocytopenia post-hemolysis or w/ ESRD (iron loss in urine)
PBS findings: polychromasia, nucleated RBCs, spherocytes, schistocytes (helps differentiate)
Genetic testing indicated for severity assessment: - PIEZOT variants: hemozygous/compound heterozygous, severe hemolysis, iron overload - KCNV4 variants: transfusion-dependent iron overload
14.2.3 Clinical manifestations
PNH heterogeneous severity; common diagnostic delay
Fatigue: most frequent complaint
Hemolysis severity: mild-chronic to severe (transfusion-dependent) - Cola-colored urine (hemoglobinuria) w/ IVH - Classic triad (BMF, thrombosis, hemoglobinuria) NOT common at presentation
Hemolytic episodes (triggered by infection, surgery, immunization, pregnancy, inflammation): - Back pain, abdominal pain, dyspnea, erectile dysfunction
Thrombosis: leading mortality cause in untreated PNH - Unusual sites: Budd-Chiari, mesenteric veins, cerebral sinuses (VTE >> arterial) - Risk ↑ w/ large clones (>50%): ~10–40% 10-yr thrombosis risk
Unexplained thrombosis in unusual sites (Budd-Chiari, mesenteric, splenic) → flow cytometry for PNH
14.2.4 Treatment
Watchful waiting: asymptomatic patients, small clones (<10%), no hemolysis; periodic monitoring
Allogeneic HCT: only curative; reserved for severe disease - Intractable hemolysis, symptomatic thrombosis refractory to complement inhibition, concurrent BMF w/ cytopenia
14.2.4.1 Complement Inhibitors
C5 Inhibitors (C5i) — block terminal complement, prevent MAC formation: - Eculizumab (IV): 600 mg wkly × 4 wks, then 900 mg wk 5, then 900 mg q2wks - Controls ~70% burden; IVH controlled but not EVH - Ravulizumab (IV, long-acting): weight-based loading → 3-wk maintenance intervals - Pegcetacoplan (IV C3 inhibitor): twice weekly; effective for EVH w/ C5i
Proximal complement inhibitors — block earlier cascade, superior for EVH w/ C5i: - Iptacopan (oral Factor D inhibitor): approved 2023 for PNH monotherapy; ↑Hgb, ↓transfusions - Danicopan (oral FI inhibitor): approved 2024 as add-on to C5i for residual anemia; ↑Hgb, ↓transfusions
Breakthrough hemolysis: despite complement inhibition (pharmacokinetic or pharmacodynamic escape) - Evaluate & escalate: dose adjustment, add proximal inhibitors
14.2.4.2 Vaccination & Anticoagulation
Vaccination: Neisseria meningitidis ≥2 wks before C5i; reduces but not eliminates meningococcal risk - If C5i must start <2 wks: antibiotic prophylaxis; educate patients, provide alert cards
Anticoagulation: - Acute thrombosis: anticoagulation - Prophylaxis: controversial untreated PNH; warfarin ↓ risk in large clones (>50%) - C5i therapy ↓ thrombotic risk; no routine prophylaxis in C5i-treated w/o prior VTE
14.2.5 Prognosis
Pre-C5i era: median survival 10–15 years
Post-C5i era: minimal/no difference vs. age-matched controls
Exceptions: BMF evolution (aplastic anemia, MDS) → ↓ survival; monitor for clonal evolution, down-trending counts despite hemolysis control
14.3 Thrombotic Microangiopathies
TMA encompasses overlapping entities w/ MAHA (schistocytes, ↑LDH, ↓Hgb), thrombocytopenia (<100K), end-organ damage (renal, CNS)
Major categories: - TTP: ADAMTS13-deficient - ST-TMA: Shiga toxin-mediated (E. coli O157:H7, Shigella) - CM-TMA (aHUS): complement-mediated defects
14.3.1 Complement-mediated thrombotic microangiopathy
CM-TMA: hereditary or acquired complement regulation defects
Genetic alterations (~60% identifiable):
| Mechanism | Gene | Prevalence |
|---|---|---|
| Factor H mutations | CFH | ~30% of CM-TMA |
| Factor I mutations | CFI | ~10% |
| C3 mutations | C3 | ~10% |
| Thrombomodulin mutations | THBD | ~5% |
| Factor H-related protein mutations | CFHR1, CFHR3 | Rare |
| Anti-FH antibodies | Anti-FH AB | ~5% of aHUS |
Key point: CM-TMA requires complement blockade; more common in adults than children (~5–10% all TMAs)
14.3.2 Shiga toxin-mediated thrombotic microangiopathy
ST-TMA caused by enteric infection: - E. coli (esp. O157:H7) or Shigella producing Shiga toxins - Accounts for ~95% childhood TMAs
Presentation: - Prodromal bloody diarrhea, self-limited course - Subset (~5–15% childhood) w/ Streptococcus pneumoniae → worse morbidity & long-term sequelae - Sporadic or outbreak transmission
Mechanism: Shiga toxins → endothelial injury → microthrombi; complement activation (↑C3 cleavage, ↓C3) contributes to renal injury
14.3.3 Clinical features
TMA pentad (not all required for diagnosis): - MAHA: schistocytes on smear, ↑LDH, ↓Hgb - Thrombocytopenia - Renal dysfunction: ↑creatinine, proteinuria, hematuria - Neurologic: confusion, seizures, stroke - Fever
Demographics & patterns: - CM-TMA: adults; universal renal involvement - ST-TMA: predominantly children - TTP: neurologic symptoms more common
Complications: hypertensive emergency, AKI requiring dialysis, HTN, pulmonary edema, disseminated microvascular thrombosis
| Feature | CM-TMA/aHUS | ST-TMA | TTP |
|---|---|---|---|
| Diarrhea | Rare | +++ (often bloody) | – |
| Renal involvement | +++ (universal) | +++ | Variable |
| Neurologic symptoms | + | + | +++ (confusion, stroke) |
| Thrombocytopenia severity | Mild–moderate | Mild–moderate | Severe (<20K) |
| ADAMTS13 activity | Normal (>10%) | Normal (>10%) | <10% |
| C3 level | ↓ (variable) | ↓ (variable) | Normal |
| sC5b-9 | ↑ | ↑ | Normal |
14.3.4 Diagnosis
Requires clinical suspicion + lab confirmation:
- ADAMTS13 (activity & inhibitor)
- <10% activity or inhibitor present → TTP
- Normal → CM-TMA or ST-TMA
- Complement markers
- ↓C3, ↓C4, ↑sC5b-9 → suggests CM-TMA
- Peripheral blood smear
- Schistocytes, spherocytes, polychromasia
- Stool/travel history
- Recent bloody diarrhea → consider ST-TMA
- Genetic testing
- CFH, CFI, C3, THBD mutations → CM-TMA; up to 40% identifiable
- Kidney biopsy (refractory cases)
- Thrombotic microvasculopathy
- Rules out lupus, ANCA-vasculitis, C3GN
Get ADAMTS13 immediately. If <10% → TTP, start PLEX. If normal & renal dysfunction prominent → suspect CM-TMA; initiate complement blockade if clinical features support (no PLEX response, persistent thrombocytopenia). Do not delay complement inhibition awaiting genetic testing.
14.3.5 Management
PLEX (plasma exchange): standard for TTP (ADAMTS13 <10%) - Daily until platelet recovery & LDH normalization
Complement blockade for CM-TMA (aHUS): - Eculizumab (C5i): standard; ↑ plt count & renal function within days - Ravulizumab (C5i): longer-acting alternative - Pegcetacoplan or proximal inhibitors: refractory cases or incomplete response
Supportive care: - Blood products cautiously; avoid unnecessary transfusions - Aggressive BP control - RBC transfusion only if Hgb severely reduced
Key principle: Differentiate TTP from CM-TMA early - PLEX ineffective (& potentially harmful) in CM-TMA - Complement inhibition definitive for CM-TMA - Delays in complement blockade → worse renal outcomes & dialysis dependence
14.4 Bibliography
Brodsky RA. How I treat paroxysmal nocturnal hemoglobinuria. Blood. 2021;137(10):1304–1309.
Crabb C. Complement & immunity: complement update. J Clin Immunol. 2021;10(5):948.
Dunn D, Fakhouri F, Scully M, Provost F, et al. Management of thrombotic microangiopathy & complement disorders: an international working group consensus. Blood. 2023;153(9):1271–1273.
Fakhouri F, Schreuder N, Fernandez-Baglioni S. Atypical & Shiga toxin-associated HUS: a disease of the endothelium. Blood. 2023;141(5):1273–1281.
Fremeaux-Bacchi V, Legendre CM. Complement: a therapeutic target in atypical HUS. Clin Immunol. 2021;10(3):230–240.
Kalfa TA. Diagnosis & clinical management of red cell membrane disorders. Hematology Am Soc Hematol Educ Program. 2021;2021(1):331–340.
Scully M, Cataland S, Peyvandi F, et al. Management of thrombotic thrombocytopenic purpura & results from international prospective registry data. Blood. 2023;141(5):1271–1281.
Shammo JM. Complement-related disorders. Hematology Am Soc Hematol Educ Program. 2024; Chapter 14.