Paroxysmal nocturnal hemoglobinuria (PNH) is one of those “blink and you miss it” Step topics—until a vignette drops dark morning urine + thrombosis and suddenly it’s free points. This is your one-page, quick-hit cheat sheet to recognize PNH fast, explain it in one line, and pick the right tests and treatment.
The 1-liner (memorize this)
PNH = acquired PIGA mutation → loss of GPI anchors (CD55/CD59) → complement-mediated intravascular hemolysis + thrombosis (hepatic/portal/cerebral) ± aplastic anemia.
Visual / mnemonic device (sticky + shareable)
“Night shift security got fired”
Imagine RBCs working the night shift. Normally they have two security guards that keep complement from attacking:
- CD55 = “DAF” (Decay-Accelerating Factor) → breaks up complement convertases
- CD59 = “MAC stopper” → prevents membrane attack complex (C5–C9)
In PNH, a PIGA mutation means RBCs can’t attach these guards (no GPI anchor), so complement “breaks in” and lyses the cell—often noticed as dark urine in the morning.
Mnemonic: “PIGA Piggybacked off the GPI anchor”
No GPI anchor → no CD55/CD59 → complement lysis.
Core pathophysiology (Step 1 → Step 2 bridge)
What’s mutated?
- PIGA gene (acquired somatic mutation) in hematopoietic stem cells
- Leads to deficiency of GPI-anchored proteins
What’s missing and why it matters
| Missing protein | Nickname | Normal job | What happens in PNH |
|---|---|---|---|
| CD55 (DAF) | “Convertase breaker” | Disrupts C3/C5 convertases | More complement activation on RBC surface |
| CD59 | “MAC blocker” | Prevents C5b-9 MAC insertion | Intravascular hemolysis via MAC |
Why “nocturnal”?
Not truly “only at night,” but hemolysis can be more noticeable in the morning:
- Mild respiratory acidosis during sleep may favor complement activity
- Overnight hemoglobin concentrates in urine → dark/cola urine on first void
High-yield clinical triad (what vignettes are testing)
1) Intravascular hemolysis
- Hemoglobinuria (dark urine; classically morning)
- Low haptoglobin, ↑ LDH, ↑ indirect bilirubin
- Reticulocytosis (unless concurrent marrow failure)
Pearl: Because it’s intravascular, you’ll see free hemoglobin, not just jaundice.
2) Thrombosis (biggest killer)
PNH is notorious for unusual site thrombosis:
- Hepatic vein thrombosis (Budd–Chiari) = classic board favorite
- Portal, mesenteric, splenic veins
- Cerebral venous sinus thrombosis
Mechanism (high-yield concept): Complement activation + free hemoglobin scavenging nitric oxide → endothelial dysfunction, platelet activation, smooth muscle spasm → thrombosis risk skyrockets.
3) Bone marrow failure association
PNH overlaps with:
- Aplastic anemia
- Myelodysplastic syndromes
So you may see pancytopenia in addition to hemolysis.
How to diagnose (what to pick on multiple-choice)
Best test: Flow cytometry
- Shows decreased CD55/CD59 on RBCs and/or WBCs
- Often reported as FLAER test (binds GPI anchors directly)
Why WBCs too? RBCs can be selectively destroyed—WBC analysis can better reflect clone size.
Classic older test (historical)
- Sucrose hemolysis test / Ham test (acidified serum)
You might see it referenced, but flow cytometry is the modern answer.
Key lab pattern (rapid recognition)
| Finding | Direction | Why |
|---|---|---|
| LDH | ↑↑ | cell lysis |
| Haptoglobin | ↓ | binds free Hb (gets consumed) |
| Indirect bilirubin | ↑ | heme breakdown |
| Urine hemosiderin | + | chronic intravascular hemolysis |
| Coombs (DAT) | Negative | not antibody-mediated |
High-yield contrast: DAT negative hemolysis + thrombosis at odd sites → think PNH.
DDx you’ll see nearby (and how to separate fast)
| Condition | Key clue | Coombs | Hemolysis type |
|---|---|---|---|
| PNH | Budd–Chiari + dark urine | Negative | Intravascular |
| Warm AIHA | Spherocytes, autoimmune disease | Positive (IgG) | Extravascular (mostly) |
| Cold agglutinin | Mycoplasma/EBV, acrocyanosis | Positive (C3) | Extravascular ± intravascular |
| G6PD deficiency | Bite cells/Heinz bodies, oxidative trigger | Negative | Intra + extra |
| MAHA (TTP/HUS/DIC) | Schistocytes, thrombocytopenia | Negative | Intravascular (mechanical) |
Treatment (Step 2 clinical decision-making)
Targeted therapy: Complement inhibition
- Eculizumab (anti-C5 monoclonal Ab)
- Ravulizumab (anti-C5; longer acting)
Board logic: If you block C5, you prevent MAC formation → reduces intravascular hemolysis and thrombosis risk.
Supportive / preventive
- Folate and iron (due to chronic hemolysis/hemoglobinuria)
- Transfusions as needed
- Anticoagulation may be considered in high-risk patients or after thrombosis (patient-specific)
Curative option
- Allogeneic hematopoietic stem cell transplant (selected cases, especially severe marrow failure)
Must-know safety step
Vaccinate against encapsulated organisms—especially meningococcus—before starting C5 inhibitors.
Complement blockade increases risk for Neisseria infections.
Rapid-fire “USMLE favorite” facts
- Acquired, not inherited (somatic mutation in stem cells)
- Complement-mediated intravascular hemolysis
- DAT (Coombs) negative
- Thrombosis in unusual locations is the hallmark “danger sign”
- Flow cytometry (CD55/CD59 or FLAER) is the diagnostic go-to
- Eculizumab/ravulizumab = main targeted therapy + meningococcal vaccination
10-second vignette translator (how to spot it instantly)
If you see:
- Fatigue + hemolysis labs AND
- Dark urine (especially morning) OR
- Budd–Chiari / portal vein thrombosis / cerebral venous thrombosis
→ PNH until proven otherwise → confirm with flow cytometry for CD55/CD59 and treat with C5 inhibition.