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cardio.dvt.paroxysmal-nocturnal-hemoglobinuria.v1

DVT in paroxysmal nocturnal hemoglobinuria (PNH)

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Start encounter →Print handoutPRODUCTION

Phase E variant of cardio.dvt.core.v1 — narrowed to thrombosis in paroxysmal nocturnal hemoglobinuria (PNH; acquired PIGA mutation; loss of GPI-anchored CD55 / CD59 → complement-mediated intravascular hemolysis and prothrombotic state). Inherits diagnostic arc from parent via routing; specializes for the complement-inhibitor-anchored, meningococcal-vaccination-mandated, transplant-consideration long-term plan. Manifest pointer reuses cardio.dvt.core.v1 manifest. Design-brief pointer reuses parent (PNH-specific differences documented inline). Distinguishing features vs generic DVT: thrombosis is the leading cause of death in PNH; complement inhibition with ECULIZUMAB (TRIUMPH PMID 16990386 — reduces thromboembolic events ~85% per Hillmen Blood 2007 PMID 17716988), RAVULIZUMAB (long-acting q8w C5 inhibitor; non-inferior to eculizumab), or PEGCETACOPLAN (C3 inhibitor for breakthrough hemolysis on C5 inhibitor; PEGASUS PMID 33730455) is mandatory; MENINGOCOCCAL VACCINATION (quadrivalent ACWY conjugate plus serogroup B) is FDA REMS-mandated ≥ 2 weeks before C5 inhibitor with bridge ciprofloxacin if cannot wait; standard AC layered on top (DOAC or LMWH or warfarin per substrate); allogeneic stem-cell transplant only for severe aplastic-anemia overlap, MDS / AML transformation, or eculizumab-refractory life-threatening disease. Splanchnic vein thrombosis and cerebral venous sinus thrombosis are classical PNH presentations and mandate flow cytometry regardless of CBC. Status INTEGRATED. Authored 2026-05-15 by shard-06-cardio-acute as paroxysmal nocturnal hemoglobinuria DVT variant.

Entry points (4)

  • symptom
    Unilateral leg swelling in patient with dark / cola-colored morning urine, episodic abdominal pain, dysphagia, erectile dysfunction, or fatigue out of proportion — consider PNH
    unilateral_leg_swelling_with_dark_urine_or_hemolysis
  • history
    Budd-Chiari, portal, mesenteric, splenic, or cerebral venous sinus thrombosis as index event — flow cytometry for PNH clones is mandatory regardless of CBC
    splanchnic_or_cerebral_venous_sinus_thrombosis_index_event
  • lab_abnormality
    CBC with cytopenias plus elevated LDH 5-10× normal, low haptoglobin, indirect hyperbilirubinemia, urine hemosiderin — classic PNH biochemical profile
    pancytopenia_with_intravascular_hemolysis_pattern
  • history
    Patient with known aplastic anemia or low-risk MDS who develops new venous thrombosis — repeat PNH flow cytometry; PNH clones evolve in 30-50% of aplastic anemia
    aplastic_anemia_or_mds_with_new_thrombosis

Required inputs (12)

  • agerequired
    demographic • used at CONTEXT
    PNH typically presents in young to middle-aged adults; pediatric PNH is rare; age informs transplant eligibility
  • sexrequired
    demographic • used at CONTEXT
    PNH affects both sexes equally; pregnancy in PNH is high-risk for both maternal thrombosis and fetal loss; eculizumab is safe in pregnancy
  • prior_aplastic_anemia_or_mdsrequired
    history • used at CONTEXT
    PNH-aplastic anemia overlap is common; transplant consideration if severe aplastic anemia; informs cytoreduction vs immunosuppression decisions
  • leg_swellingrequired
    symptom • used at ENTRY
    Cardinal symptom of proximal DVT
  • compression_usrequired
    imaging • used at INITIAL_WORKUP
    Initial confirmation of DVT location (proximal vs distal)
  • cbc_with_smearrequired
    lab • used at INITIAL_WORKUP
    Anemia (often normocytic / macrocytic), reticulocytosis, often pancytopenia from aplastic-anemia overlap; smear shows polychromasia, schistocytes uncommon
  • ldh_haptoglobin_bilirubinrequired
    lab • used at INITIAL_WORKUP
    LDH 5-10× normal + low / undetectable haptoglobin + indirect hyperbilirubinemia define intravascular hemolysis; ferritin paradoxically normal/low (urinary iron loss)
  • pnh_flow_cytometryrequired
    lab • used at BRANCHING_WORKUP
    PNH flow cytometry on RBCs (CD55 / CD59) AND granulocytes / monocytes (FLAER + CD157 / CD24) — gold standard; granulocyte clone size more reliable than RBC clone (RBC clone underestimated by hemolysis and transfusion)
  • urine_hemosiderinrequired
    lab • used at BRANCHING_WORKUP
    Marks chronic intravascular hemolysis; positive in PNH; supports diagnosis when flow cytometry pending
  • creatininerequired
    lab • used at TREATMENT
    eGFR for DOAC dosing; PNH can cause renal dysfunction from chronic free-haemoglobin nephrotoxicity
  • meningococcal_vaccination_statusrequired
    history • used at TREATMENT
    Quadrivalent ACWY conjugate + serogroup B vaccination MANDATORY at least 2 weeks before C5 inhibitor initiation per CDC and FDA REMS
  • bleed_riskrequired
    history • used at RED_FLAGS
    HAS-BLED + GI bleed history drives indefinite-AC eligibility

12-phase flow (11)

  1. 1FRAME
    PNH = acquired clonal PIGA mutation → loss of GPI-anchored CD55 / CD59 → complement-mediated intravascular hemolysis + prothrombotic state. Thrombosis is leading cause of death untreated. Acute AC matches parent; complement inhibition + meningococcal vaccination + transplant consideration define the PNH-specific arc
    inputs: leg_swelling
    advance: PNH phenotype framed
  2. 2ENTRY
    Wells DVT score + compression US; document hemolysis history (dark urine, episodic abdominal pain, dysphagia, erectile dysfunction, fatigue), prior aplastic anemia or MDS, prior thrombosis history, family history (rare familial)
    inputs: prior_aplastic_anemia_or_mds, age
    advance: pretest probability + PNH context documented
  3. 3CONTEXT
    Allergies; OCP / hormone use; pregnancy plans; current cytopenias; transfusion history; meningococcal vaccination status; current immunosuppression for aplastic-anemia overlap
    inputs: sex, meningococcal_vaccination_status
    advance: context complete
  4. 4RED_FLAGS
    Concurrent PE; phlegmasia; absolute AC contraindication; ICH; splanchnic vein thrombosis with hepatic decompensation; cerebral venous sinus thrombosis with intracranial hypertension; severe aplastic anemia with profound cytopenias; meningococcal infection on or pending C5 inhibitor
    inputs: bleed_risk
    actions: pe_full, thrombocytopenia
    advance: critical features screened
  5. 5INITIAL_WORKUP
    Compression US (proximal vs distal); CBC with smear + reticulocyte count; BMP; LFTs; LDH (5-10× normal in PNH); haptoglobin; total + indirect bilirubin; urinalysis with hemosiderin; D-dimer if pretest probability borderline; coagulation panel; type and screen
    inputs: compression_us, cbc_with_smear, ldh_haptoglobin_bilirubin, creatinine
    actions: panel.cardiac, panel.renal, panel.coag
    advance: imaging confirms DVT and hemolysis pattern documented
  6. 6BRANCHING_WORKUP
    PNH flow cytometry on RBCs and granulocytes (FLAER) — gold standard; bone marrow biopsy if pancytopenia or aplastic-anemia overlap suspected; abdominal Doppler / MR venogram if splanchnic vein thrombosis suspected; MR venogram if cerebral venous sinus thrombosis suspected; thrombophilia panel sent BEFORE first AC dose if practical
    inputs: pnh_flow_cytometry, urine_hemosiderin
    advance: PNH clone size + AA overlap status documented
  7. 7RISK_STRATIFICATION
    Wells DVT, HAS-BLED, eGFR; PNH clone size > 50% granulocyte clone with hemolysis = classic PNH (high thrombosis risk); subclinical PNH (clone < 10% no hemolysis) = surveillance only; integrate prior thrombosis + clone size + symptom burden into complement-inhibitor decision
    inputs: bleed_risk
    actions: calc.wells_dvt, calc.has_bled
    advance: AC duration + complement-inhibitor plan documented
  8. 8TREATMENT
    Acute AC: DOAC first-line (apixaban 10/7/5 or rivaroxaban 15/21/20 or edoxaban after LMWH bridge); LMWH bridge if pregnancy or pending workup; WARFARIN if concurrent triple-positive APS or severe renal impairment. COMPLEMENT INHIBITION mandatory for PNH thrombosis: eculizumab 600 mg IV weekly × 4 → 900 mg q14d (long-track-record), OR ravulizumab 2400-3000 mg IV loading then maintenance q8w (long-acting C5 inhibitor; non-inferior to eculizumab; less breakthrough hemolysis), OR pegcetacoplan 1080 mg SC twice weekly (C3 inhibitor for breakthrough hemolysis on C5 inhibitor; PEGASUS PMID 33730455). MENINGOCOCCAL VACCINATION (quadrivalent ACWY conjugate + serogroup B) mandatory ≥ 2 weeks before C5 inhibitor; if cannot wait, prophylactic ciprofloxacin or penicillin until vaccination effective. Allogeneic transplant only for severe aplastic-anemia overlap, MDS / AML transformation, or eculizumab-refractory life-threatening disease
    inputs: creatinine, bleed_risk, meningococcal_vaccination_status
    advance: acute AC + complement-inhibitor + vaccination plan documented
  9. 9DISPOSITION
    Inpatient admission for new PNH thrombosis to allow vaccination + complement-inhibitor initiation under monitoring; outpatient maintenance once stable on therapy; admit if splanchnic / cerebral venous sinus thrombosis with end-organ dysfunction, severe aplastic anemia, or transplant evaluation
    advance: disposition documented
  10. 10MONITORING
    LDH q2 weeks during complement-inhibitor initiation then monthly (target normalization); haptoglobin; reticulocyte count; CBC; creatinine; PNH clone size q6-12 mo to track disease modification; meningococcal vaccination booster at 5 years per ACIP; CBC + creatinine at 4 weeks then quarterly during indefinite AC; bleed surveillance; PTS Villalta at 3 / 6 / 12 mo
    actions: panel.cardiac
    advance: monitoring schedule documented
  11. 11FOLLOWUP
    Long-term hematology + thrombosis clinic co-management; annual bone marrow if disease progression suspected; pregnancy planning (eculizumab safe; LMWH preferred over DOAC / warfarin for thrombosis); transplant evaluation if severe aplastic anemia; PNH transformation to MDS / AML surveillance; cardiovascular risk factor optimisation; education on breakthrough hemolysis recognition and meningococcal infection symptoms (fever / headache / petechiae / neck stiffness → ED immediately)
    advance: long-term plan and transformation surveillance documented