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cardio.dvt.paroxysmal-nocturnal-hemoglobinuria.v1PRODUCTION
cardio.dvt.paroxysmal-nocturnal-hemoglobinuria.v1

DVT in paroxysmal nocturnal hemoglobinuria (PNH)

cardiologyacuteadult
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Detailed

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

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PNH phenotype framed

Patient inputs (12)

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)

Marks chronic intravascular hemolysis; positive in PNH; supports diagnosis when flow cytometry pending

PNH typically presents in young to middle-aged adults; pediatric PNH is rare; age informs transplant eligibility

PNH affects both sexes equally; pregnancy in PNH is high-risk for both maternal thrombosis and fetal loss; eculizumab is safe in pregnancy

PNH-aplastic anemia overlap is common; transplant consideration if severe aplastic anemia; informs cytoreduction vs immunosuppression decisions

Cardinal symptom of proximal DVT

Initial confirmation of DVT location (proximal vs distal)

Anemia (often normocytic / macrocytic), reticulocytosis, often pancytopenia from aplastic-anemia overlap; smear shows polychromasia, schistocytes uncommon

LDH 5-10× normal + low / undetectable haptoglobin + indirect hyperbilirubinemia define intravascular hemolysis; ferritin paradoxically normal/low (urinary iron loss)

HAS-BLED + GI bleed history drives indefinite-AC eligibility

eGFR for DOAC dosing; PNH can cause renal dysfunction from chronic free-haemoglobin nephrotoxicity

Quadrivalent ACWY conjugate + serogroup B vaccination MANDATORY at least 2 weeks before C5 inhibitor initiation per CDC and FDA REMS

* = hard-required. Engine cannot meaningfully run until these are filled.

Severity triggers (4)

4 need judgement
  • informationallife_threateningmeningococcal_vaccination_compliance_failure_on_c5_inhibitor
    Patient on eculizumab or ravulizumab missed scheduled meningococcal booster (5-year interval) or initiated C5 inhibitor without ACWY plus serogroup B vaccination — high-risk window for invasive Neisseria meningitidis infection
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationallife_threateningsplanchnic_vein_thrombosis_as_index_pnh_event
    Splanchnic vein thrombosis (Budd-Chiari, portal, mesenteric, splenic) or cerebral venous sinus thrombosis as index event — flow cytometry mandatory; PNH diagnosis triggers indefinite AC plus complement inhibition plus vaccination
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationalseverebreakthrough_hemolysis_on_c5_inhibitor_with_new_thrombosis
    Persistent or rising LDH and falling haptoglobin on stable eculizumab or ravulizumab dosing plus new thrombotic event — suggests pharmacokinetic breakthrough or extravascular hemolysis from C3 fragment opsonization
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationalseverepancytopenia_with_transplant_eligibility_in_pnh_aa_overlap
    PNH with severe aplastic-anemia overlap (ANC < 500, platelets < 20, retic < 60 × 10⁹/L) plus thrombosis — transplant evaluation indicated; complement inhibition alone insufficient
    Trigger could not be auto-evaluated — needs clinician judgement.

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Recommended regimen

PNH VTE — acute AC + complement inhibition + meningococcal vaccination + transplant consideration (TRIUMPH; PEGASUS; ASH 2020; ACCP 2021)
axis: pnh_vte_anticoagulation_plus_complement_inhibition
Selected axis "PNH VTE — acute AC + complement inhibition + meningococcal vaccination + transplant consideration (TRIUMPH; PEGASUS; ASH 2020; ACCP 2021)" by default fallback (first axis)
  • apixaban
    first line
    doac_factor_xa_direct
    10 mg BID × 7 d → 5 mg BID full-dose; 2.5 mg BID extended-phase after first 6 mo if continuing indefinite • PO • BID × ≥3 months minimum, indefinite for any thrombotic event in PNH per expert consensus
    triggers: pnh_associated_vte, no_active_bleed, no_triple_positive_aps, egfr_above_25
    AMPLIFY (Agnelli NEJM 2013 PMID 23808982) — apixaban first-line for VTE; AMPLIFY-EXT supports 2.5 mg BID extended-phase; expert consensus accepts DOAC for PNH VTE layered on complement inhibition
    rxcui 1364430
  • rivaroxaban
    first line
    doac_factor_xa_direct
    15 mg BID × 21 d → 20 mg daily; 10 mg daily extended-phase after first 6 mo if continuing indefinite • PO • BID then daily ≥3 months, indefinite per criteria
    triggers: pnh_associated_vte, no_active_bleed, no_triple_positive_aps, egfr_above_30
    EINSTEIN-DVT (Bauersachs NEJM 2010 PMID 21128814)
    rxcui 1114195
  • edoxaban
    first line
    doac_factor_xa_direct
    60 mg PO daily (30 mg if CrCl 15-50, weight ≤60 kg, or with strong P-gp inhibitor) after 5-10 d LMWH bridge • PO • daily × ≥3 months, indefinite per criteria
    triggers: post_lmwh_bridge, doac_alternative
    Hokusai-VTE (Büller NEJM 2013 PMID 23991958)
    rxcui 1599538
  • warfarin
    first line
    vitamin_k_antagonist
    5 mg daily; INR target 2-3 • PO • daily ≥3 months, indefinite per criteria
    triggers: concurrent_aps_triple_positive, severe_renal_impairment_doac_unsafe, patient_preference
    TRAPS (Pengo Blood 2018 PMID 30002145) — warfarin > rivaroxaban in triple-positive APS; preferred when DOAC clearance unpredictable
    rxcui 11289
  • enoxaparin
    first line
    lmwh
    1 mg/kg SC BID; reduce to 1 mg/kg daily if CrCl <30 • SC • BID
    triggers: pregnancy, aps_workup_pending, planned_invasive_procedure, doac_contraindicated
    ASH 2020 (PMID 33007077); ASH 2018 pregnancy (PMID 30482767) — LMWH first-line in pregnancy and as bridge during workup
    rxcui 67108
  • eculizumab
    first line
    complement_c5_inhibitor
    600 mg IV weekly × 4 weeks → 900 mg IV q14d maintenance • IV • weekly × 4 then q14d indefinite
    triggers: pnh_with_thrombosis, classic_pnh_with_significant_hemolysis, meningococcal_vaccinated_at_least_2_weeks_prior
    TRIUMPH (Hillmen NEJM 2006 PMID 16990386); Hillmen Blood 2007 (PMID 17716988) — eculizumab reduces thromboembolic events ~85% in PNH; foundational therapy
    rxcui 591781
  • ravulizumab
    first line
    complement_c5_inhibitor
    2400-3000 mg IV loading weight-based then maintenance q8w • IV • q8w
    triggers: pnh_with_thrombosis, meningococcal_vaccinated, eculizumab_breakthrough_intolerance, patient_preference_for_less_frequent_dosing
    Lee Blood 2019 / Kulasekararaj — ravulizumab non-inferior to eculizumab with less breakthrough hemolysis and longer dosing interval
    rxcui 2107301
  • pegcetacoplan
    second line
    complement_c3_inhibitor
    1080 mg SC twice weekly • SC • twice weekly
    triggers: breakthrough_hemolysis_on_c5_inhibitor, persistent_anemia_despite_eculizumab_or_ravulizumab
    PEGASUS (Hillmen NEJM 2021 PMID 33730455) — pegcetacoplan superior to eculizumab in patients with persistent anemia; addresses extravascular hemolysis on C5 inhibitor
    rxcui 2557372
  • meningococcal-acwy-conjugate-vaccine
    first line
    vaccine
    0.5 mL IM single dose with booster q5y • IM • ≥2 weeks before C5 inhibitor; booster q5y
    triggers: planned_complement_inhibitor_initiation
    CDC ACIP and FDA REMS — Neisseria meningitidis infection risk dramatically increased on C5 inhibitor; vaccination ≥2 weeks before therapy mandatory
  • meningococcal-b-vaccine
    first line
    vaccine
    0.5 mL IM 2-dose series • IM • 0 + 6 months ≥2 weeks before C5 inhibitor
    triggers: planned_complement_inhibitor_initiation
    CDC ACIP — serogroup B coverage required in addition to ACWY conjugate for complement-deficient patients
  • ciprofloxacin
    comorbidity specific
    antibiotic_fluoroquinolone
    500 mg PO daily as prophylaxis if vaccination cannot precede C5 inhibitor by 2 weeks • PO • daily until 2 weeks post-vaccination
    triggers: urgent_c5_inhibitor_initiation_before_vaccine_immunity
    Bridge prophylaxis until meningococcal vaccine immunity develops; expert consensus
    rxcui 2551

outpatient playbook — drug actions (4)

  1. 1. maintenance apixaban
    rxcui 1364430
    apixaban 2.5 mg BID extended-reduced OR 5 mg BID full • PO • BID
    trigger: Per 3-mo decision
    AMPLIFY / AMPLIFY-EXT
  2. 2. continue eculizumab or ravulizumab
    rxcui 591781
    eculizumab 900 mg IV q14d OR ravulizumab 3000 mg IV q8w • IV • q14d / q8w
    trigger: PNH with thrombosis or significant hemolysis
    TRIUMPH / Lee Blood 2019
  3. 3. pegcetacoplan if breakthrough hemolysis persists
    rxcui 2557372
    pegcetacoplan 1080 mg SC twice weekly • SC • twice weekly
    trigger: Persistent anemia / breakthrough
    PEGASUS PMID 33730455
  4. 4. switch to LMWH if pregnancy planned or confirmed; continue eculizumab
    rxcui 67108
    enoxaparin therapeutic 1 mg/kg BID antepartum + 6 weeks postpartum • SC • BID
    trigger: Pregnancy
    ASH 2018 pregnancy PMID 30482767

Auto-drafted A&P note

outpatient

Subjective

- Possible entry pathways: Unilateral leg swelling in patient with dark / cola-colored morning urine, episodic abdominal pain, dysphagia, erectile dysfunction, or fatigue out of proportion — consider PNH; Budd-Chiari, portal, mesenteric, splenic, or cerebral venous sinus thrombosis as index event — flow cytometry for PNH clones is mandatory regardless of CBC; CBC with cytopenias plus elevated LDH 5-10× normal, low haptoglobin, indirect hyperbilirubinemia, urine hemosiderin — classic PNH biochemical profile.

Objective

- No vitals, labs, or imaging entered for this encounter.

Assessment

**DVT in paroxysmal nocturnal hemoglobinuria (PNH)** (cardio.dvt.paroxysmal-nocturnal-hemoglobinuria.v1).
Scope: 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

No severity triggers fired against current inputs.

Plan

Regimen axis: **PNH VTE — acute AC + complement inhibition + meningococcal vaccination + transplant consideration (TRIUMPH; PEGASUS; ASH 2020; ACCP 2021)**.
1. apixaban 10 mg BID × 7 d → 5 mg BID full-dose; 2.5 mg BID extended-phase after first 6 mo if continuing indefinite PO BID × ≥3 months minimum, indefinite for any thrombotic event in PNH per expert consensus (doac_factor_xa_direct, first line) — AMPLIFY (Agnelli NEJM 2013 PMID 23808982) — apixaban first-line for VTE; AMPLIFY-EXT supports 2.5 mg BID extended-phase; expert consensus accepts DOAC for PNH VTE layered on complement inhibition
2. rivaroxaban 15 mg BID × 21 d → 20 mg daily; 10 mg daily extended-phase after first 6 mo if continuing indefinite PO BID then daily ≥3 months, indefinite per criteria (doac_factor_xa_direct, first line) — EINSTEIN-DVT (Bauersachs NEJM 2010 PMID 21128814)
3. edoxaban 60 mg PO daily (30 mg if CrCl 15-50, weight ≤60 kg, or with strong P-gp inhibitor) after 5-10 d LMWH bridge PO daily × ≥3 months, indefinite per criteria (doac_factor_xa_direct, first line) — Hokusai-VTE (Büller NEJM 2013 PMID 23991958)
4. warfarin 5 mg daily; INR target 2-3 PO daily ≥3 months, indefinite per criteria (vitamin_k_antagonist, first line) — TRAPS (Pengo Blood 2018 PMID 30002145) — warfarin > rivaroxaban in triple-positive APS; preferred when DOAC clearance unpredictable
5. enoxaparin 1 mg/kg SC BID; reduce to 1 mg/kg daily if CrCl <30 SC BID (lmwh, first line) — ASH 2020 (PMID 33007077); ASH 2018 pregnancy (PMID 30482767) — LMWH first-line in pregnancy and as bridge during workup
6. eculizumab 600 mg IV weekly × 4 weeks → 900 mg IV q14d maintenance IV weekly × 4 then q14d indefinite (complement_c5_inhibitor, first line) — TRIUMPH (Hillmen NEJM 2006 PMID 16990386); Hillmen Blood 2007 (PMID 17716988) — eculizumab reduces thromboembolic events ~85% in PNH; foundational therapy
7. ravulizumab 2400-3000 mg IV loading weight-based then maintenance q8w IV q8w (complement_c5_inhibitor, first line) — Lee Blood 2019 / Kulasekararaj — ravulizumab non-inferior to eculizumab with less breakthrough hemolysis and longer dosing interval
8. pegcetacoplan 1080 mg SC twice weekly SC twice weekly (complement_c3_inhibitor, second line) — PEGASUS (Hillmen NEJM 2021 PMID 33730455) — pegcetacoplan superior to eculizumab in patients with persistent anemia; addresses extravascular hemolysis on C5 inhibitor
9. meningococcal-acwy-conjugate-vaccine 0.5 mL IM single dose with booster q5y IM ≥2 weeks before C5 inhibitor; booster q5y (vaccine, first line) — CDC ACIP and FDA REMS — Neisseria meningitidis infection risk dramatically increased on C5 inhibitor; vaccination ≥2 weeks before therapy mandatory
10. meningococcal-b-vaccine 0.5 mL IM 2-dose series IM 0 + 6 months ≥2 weeks before C5 inhibitor (vaccine, first line) — CDC ACIP — serogroup B coverage required in addition to ACWY conjugate for complement-deficient patients
11. ciprofloxacin 500 mg PO daily as prophylaxis if vaccination cannot precede C5 inhibitor by 2 weeks PO daily until 2 weeks post-vaccination (antibiotic_fluoroquinolone, comorbidity specific) — Bridge prophylaxis until meningococcal vaccine immunity develops; expert consensus

Setting playbook (outpatient) — Long-term PNH-thrombosis management: indefinite AC for indicated patients with annual reassessment; maintenance complement inhibition with LDH monitoring; vaccination boosters; transformation surveillance (PNH → MDS / AML); pregnancy planning; transplant consideration; cardiovascular risk optimization
12. maintenance apixaban apixaban 2.5 mg BID extended-reduced OR 5 mg BID full PO BID — Per 3-mo decision (AMPLIFY / AMPLIFY-EXT)
13. continue eculizumab or ravulizumab eculizumab 900 mg IV q14d OR ravulizumab 3000 mg IV q8w IV q14d / q8w — PNH with thrombosis or significant hemolysis (TRIUMPH / Lee Blood 2019)
14. pegcetacoplan if breakthrough hemolysis persists pegcetacoplan 1080 mg SC twice weekly SC twice weekly — Persistent anemia / breakthrough (PEGASUS PMID 33730455)
15. switch to LMWH if pregnancy planned or confirmed; continue eculizumab enoxaparin therapeutic 1 mg/kg BID antepartum + 6 weeks postpartum SC BID — Pregnancy (ASH 2018 pregnancy PMID 30482767)

Non-pharmacologic actions:
- Compression stocking 30-40 mmHg if PTS symptoms
- OCP avoidance lifelong if PNH with VTE history
- Pre-procedure AC + complement-inhibitor management plan documented
- MedicAlert ID for complement deficiency
- Annual transformation surveillance with bone marrow if indicated

AVOID / contraindication checks:
- Doac_avoid_active_bleeding (FDA labels)
- Apixaban_avoid_egfr_below_15 (FDA label)
- Rivaroxaban_avoid_egfr_below_30 (FDA label)
- Doac_avoid_triple_positive_aps_use_warfarin (TRAPS 2018; ISTH 2020)
- C5_inhibitor_requires_meningococcal_vaccination_at_least_2_weeks_prior (FDA REMS)
- C5_inhibitor_initiation_requires_acwy_plus_serogroup_B_vaccines (CDC ACIP)
- Warfarin_avoid_pregnancy_use_lmwh (ASH 2018 pregnancy)
- Eculizumab_continuation_in_pregnancy_safe_no_alternative (Kelly 2015 Blood)
- Decision:pnh_with_thrombosis_indefinite_AC (expert consensus; ASH 2018)
- Decision:pnh_with_classic_hemolysis_and_thrombosis_initiate_complement_inhibitor (TRIUMPH)
- Decision:transplant_only_for_severe_AA_overlap_or_eculizumab_refractory_disease (international PNH consensus)

Monitoring

Regimen monitoring:
- ldh q2 weeks during complement inhibitor initiation then monthly (target normalization)
- haptoglobin reticulocyte count cbc monthly (Parker consensus)
- pnh clone size q6 12 mo for disease modification (international PNH registry)
- meningococcal vaccination booster at 5 years (CDC ACIP)
- cbc creatinine at 4 weeks then quarterly during indefinite AC (FDA labels)
- pts villalta at 3 6 12mo (Kahn Lancet 2014)
- annual AC continuation decision with HASBLED reassessment (ACCP 2021)
- inr weekly during warfarin titration then q4 6 weeks (ACCP 2021)
- annual bone marrow if disease progression or transformation suspected (Schrezenmeier registry)

Setting (outpatient) monitoring:
- Quarterly CBC + LDH + haptoglobin + clinical reassessment
- Annual labs + clone size
- Annual PTS Villalta
- Annual HAS-BLED
- 5-year meningococcal booster

Follow-up plan: 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)
- Close-out criterion: long-term plan and transformation surveillance documented

Monitoring phase: 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

Disposition

Current setting: outpatient — Long-term PNH-thrombosis management: indefinite AC for indicated patients with annual reassessment; maintenance complement inhibition with LDH monitoring; vaccination boosters; transformation surveillance (PNH → MDS / AML); pregnancy planning; transplant consideration; cardiovascular risk optimization

Disposition criteria:
- Indefinite annual hematology + AC clinic + PNH registry follow-up

Escalation triggers (move to higher acuity):
- New VTE despite AC + complement inhibitor → reassess adherence + breakthrough hemolysis + consider pegcetacoplan
- Pregnancy → switch to LMWH + continue eculizumab
- Transformation suspicion → urgent bone marrow + transplant evaluation
- Major bleed → reverse, hold, reassess indefinite indication

Earlier-Return Triggers

Return-precaution thresholds (watch for):
- [LIFE_THREATENING] Patient on eculizumab or ravulizumab missed scheduled meningococcal booster (5-year interval) or initiated C5 inhibitor without ACWY plus serogroup B vaccination — high-risk window for invasive Neisseria meningitidis infection
- [LIFE_THREATENING] Splanchnic vein thrombosis (Budd-Chiari, portal, mesenteric, splenic) or cerebral venous sinus thrombosis as index event — flow cytometry mandatory; PNH diagnosis triggers indefinite AC plus complement inhibition plus vaccination
- [SEVERE] Persistent or rising LDH and falling haptoglobin on stable eculizumab or ravulizumab dosing plus new thrombotic event — suggests pharmacokinetic breakthrough or extravascular hemolysis from C3 fragment opsonization

Citations

- TRIUMPH eculizumab in PNH + PEGASUS pegcetacoplan + Schrezenmeier international PNH registry + ASH 2018 thrombophilia + ACCP/CHEST 2021 [PMID:16990386](https://pubmed.ncbi.nlm.nih.gov/16990386/)
- Cited evidence (PMID 17716988) [PMID:17716988](https://pubmed.ncbi.nlm.nih.gov/17716988/)
- Cited evidence (PMID 33730455) [PMID:33730455](https://pubmed.ncbi.nlm.nih.gov/33730455/)
- Cited evidence (PMID 24990947) [PMID:24990947](https://pubmed.ncbi.nlm.nih.gov/24990947/)
- Cited evidence (PMID 17420403) [PMID:17420403](https://pubmed.ncbi.nlm.nih.gov/17420403/)

Last reconciled with current guidelines: 2026-05-15.
References
  • TRIUMPH eculizumab in PNH + PEGASUS pegcetacoplan + Schrezenmeier international PNH registry + ASH 2018 thrombophilia + ACCP/CHEST 2021 — PMID:16990386
  • Cited evidence (PMID 17716988) — PMID:17716988
  • Cited evidence (PMID 33730455) — PMID:33730455
  • Cited evidence (PMID 24990947) — PMID:24990947
  • Cited evidence (PMID 17420403) — PMID:17420403