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Paroxysmal Nocturnal HemoglobinuriaMANAGEMENT

HEMATOLOGIC AND ONCOLOGIC PRESENTATIONS · 12 SECTIONS

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852 items

☷ Legend

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Cardiovascular Presentations71▾

Respiratory Presentations52▾

Neurological Presentations83▾

Gastrointestinal Presentations74▾

Genitourinary and Reproductive Presentations48▾

Infectious Disease Presentations148▾

Trauma Presentations89▾

Toxicologic Presentations80▾

Psychiatric Presentations26▾

Musculoskeletal and Rheumatologic Presentations96▾

Dermatology Presentations23▾

Environmental and Exposure Presentations27▾

Hematologic and Oncologic Presentations36▾

Acute chest syndrome Acute Hemolytic Transfusion Reaction Anticoagulant reversal (warfarin, DOAC, heparin)Aplastic Anemia (Crisis)Autoimmune Hemolytic Anemia CAR-T and cytokine release syndrome Coagulopathy Delayed Hemolytic Transfusion Reaction Disseminated Intravascular Coagulation (DIC)Essential Thrombocythemia Febrile Non-hemolytic Transfusion Reaction Graft Versus Host Disease (Acute)Hemolytic Uremic Syndrome (HUS)Hemophilia A (Bleeding Crisis)Heparin-Induced Thrombocytopenia (HIT)Hyperviscosity syndrome Immune checkpoint inhibitor toxicity Immune Thrombocytopenic Purpura (ITP)Leukemoid Reaction Leukostasis Massive transfusion protocol Myelofibrosis Neutropenic enterocolitis (typhlitis)Paroxysmal Nocturnal Hemoglobinuria Polycythemia Vera (Crisis)Pure Red Cell Aplasia Sickle Cell (Acute Chest Syndrome)Sickle Cell (Splenic Sequestration)Sickle cell crisis (vaso-occlusive)Symptomatic anemia Thrombocytopenia (severe)Thrombotic Thrombocytopenic Purpura (TTP)Transfusion-Associated Circulatory Overload (TACO)Transfusion-Related Acute Lung Injury (TRALI)Tumor lysis syndrome Von Willebrand Disease (Bleeding)

Pediatric-Specific Presentations19▾

Endocrine and Metabolic Presentations45▾

ENT and Maxillofacial Presentations27▾

Ophthalmologic Presentations19▾

Obstetric Presentations23▾

Systemic and Miscellaneous Presentations17▾

01Approach to the Critical Patient/attcp56

Immediate priorities

›Acute hemolytic crisis recognition

›Hemoglobin drop from baseline

›Dark or cola-colored urine

›LDH markedly elevated often >5x ULN during crisis

›Hemodynamic instability triggers

›SBP < 90 mmHg

›HR > 120 with pallor

›If hemodynamically unstable, initiate aggressive IV hydration and type and screen immediately

›Normal saline bolus 500 ml over 15-30 minutes

›Repeat bolus if MAP < 65 mmHg

›Thrombotic emergency recognition

›Budd-Chiari syndrome

›Right upper quadrant pain with hepatomegaly

›Acute ascites and jaundice

›Cerebral venous thrombosis

›Sudden severe headache

›Focal neurologic deficit or seizure

›Mesenteric thrombosis

›Severe abdominal pain out of proportion to exam

›Peritoneal signs

›If thrombosis suspected, urgent anticoagulation and imaging

›Consult hematology emergently

›CT angiography or Doppler ultrasound based on site

Airway and renal protection

›Renal protection in hemolytic crisis

›Adequate IV hydration to dilute hemoglobin in tubules

›Target urine output 1-2 ml/kg/hr

02History/hx83

Classic presentation

›Cardinal symptom triad

›Hemolytic anemia

›Fatigue and weakness most common presenting complaint

›Exercise intolerance

›Hemoglobinuria

›Dark or cola-colored urine most prominent in morning on waking

›Present at some point in >90% of patients

›Approximately 50% present with this sign at diagnosis

›Thrombophilia

›Venous thrombosis at unusual sites

›Budd-Chiari most frequent thrombotic manifestation

›Smooth muscle dystonia symptoms

›Abdominal pain

›Occurs in approximately 35% during paroxysms

›Due to nitric oxide scavenging by free hemoglobin

›Dysphagia and esophageal spasm

›Approximately 23% incidence

›Distinction from thrombotic cause important

›Erectile dysfunction in males

›Nitric oxide deficiency mechanism

Paroxysm triggers

›Precipitating factors

›Infections

›Any febrile illness can activate complement cascade

›Bacterial and viral infections equally relevant

›Surgery and trauma

›Complement activation by tissue injury

›High perioperative thrombotic risk

›Drugs and physical stressors

›Physical exertion

›Psychological stress

›Pregnancy and postpartum period

›Markedly elevated maternal and fetal risk

›Highest risk period for thrombotic complications

›Hemolytic episode characteristics

›Duration typically 3-7 days per episode

›Can be prolonged without complement inhibition

›Breakthrough hemolysis on C5 inhibitors is shorter but significant

›LDH spike during paroxysms

›Can reach 25x ULN during severe paroxysms

›Most reliable real-time hemolysis marker

Risk factor history

›Bone marrow disorder history

›Prior aplastic anemia

›Strongest association with PNH

›PNH clones found in 12-18% of aplastic anemia patients

›Up to 50% of aplastic anemia patients on long follow-up develop detectable PNH clones

›Myelodysplastic syndromes

›PNH clones detected on screening

›Concurrent cytopenia pattern

›Prior immunosuppressive therapy for bone marrow failure

›Antithymocyte globulin exposure

›Cyclosporine exposure

›PNH clone risk markers

›Large clone size

›Granulocyte clone >=50% correlates with high thrombotic risk

›LDH >=1.5x ULN with >=2 high disease activity criteria

›Unexplained cytopenias

›Coombs-negative hemolytic anemia

›Pancytopenia without clear cause

›Age and epidemiologic context

›Median age of diagnosis 24-41 years

›Young adults most commonly affected

›No familial or inherited pattern

›Estimated prevalence < 10 per million population

Alarm features

›Acute life threats

›Budd-Chiari syndrome signs

›Right upper quadrant pain with hepatomegaly

›Rapid ascites development

›Pulmonary embolism

›Pleuritic chest pain with dyspnea

›Unexplained tachycardia

›Cerebral venous thrombosis

›Headache with neurologic deficit

›Papilledema

›Progression risks

›Acute kidney injury from hemoglobinuria or renal hemosiderosis

›Decreased urine output

›Rising creatinine

›Pulmonary hypertension development

›Progressive dyspnea

›Right heart failure signs

›Transformation to MDS or AML

›Occurs in approximately 5% of patients

›Worsening pancytopenia or dysplasia

03Physical Exam/exam62

Vitals and general appearance

›Hemodynamic assessment

›Tachycardia

›Compensatory response to anemia

›HR > 100 a common finding in hemolytic crisis

›Hypotension

›SBP < 90 mmHg indicates severe hemolytic crisis or sepsis

›Orthostatic changes in compensated state

›Temperature

›Fever may indicate infection triggering hemolysis

›Fever in complement inhibitor patient requires urgent meningococcal assessment

›General appearance

›Pallor

›Conjunctival pallor correlates with severity of anemia

›Skin pallor most evident in palmar creases

›Jaundice and scleral icterus

›Indirect hyperbilirubinemia from hemolysis

›Scleral icterus visible when bilirubin > 34-51 mmol/l

Abdominal exam

›Hepatic findings

›Hepatomegaly

›Budd-Chiari syndrome presentation

›Right upper quadrant tenderness

›Ascites

›Shifting dullness and fluid wave

›Rapid development suggests Budd-Chiari

›Splenomegaly

›Extravascular hemolysis component

04Differential Diagnosis/ddx59

Hemolytic anemias

›Coombs-negative hemolytic anemia differential

›PNH

›ICD-10 D59.5

›FLAER-based flow cytometry diagnostic

›Microangiopathic hemolytic anemia

›TTP or HUS

›Schistocytes on blood smear

›ADAMTS13 activity low in TTP

›G6PD deficiency

›Episodic hemolysis with oxidative triggers

›Enzyme assay diagnostic

›Heinz bodies on smear during crisis

›Coombs-positive hemolytic anemia

›Autoimmune hemolytic anemia

›Direct antiglobulin test positive

›IgG or complement mediated

›Cold agglutinin disease

›C3d positive on DAT

›Cold-triggered symptoms

›Drug-induced hemolysis

›Medication exposure history

›Resolves with drug withdrawal

Thrombosis at unusual sites

›Budd-Chiari from other causes

›Myeloproliferative neoplasms

›JAK2 V617F mutation testing

›Polycythemia vera association

05Laboratory Tests/lt80

Diagnostic confirmation labs

›Flow cytometry for GPI-deficient clones

›FLAER-based assay

›Gold standard diagnostic test for PNH

›Fluorescein-labeled inactive variant of aerolysin binds GPI anchors

›Combined with anti-CD24 for granulocytes and anti-CD14 for monocytes

›GPI-anchored protein panel

›CD55 and CD59 on red blood cells

›CD16 and CD66b on granulocytes

›Type III cells complete GPI deficiency

›Type II cells partial GPI deficiency

›Cell lineage preferences

›Granulocyte and monocyte analysis with FLAER more sensitive than RBC analysis

›RBC clone size underestimates due to selective hemolysis of GPI-deficient cells and transfusion effect

›Report GPI-deficient percentage of granulocytes and red cells separately

Hemolysis markers

›LDH

›Markedly elevated in active hemolysis

›Often >2-3x ULN at baseline in classic PNH

›Can reach 25x ULN during paroxysms

›Most reliable real-time marker of intravascular hemolysis

›Serial trending

›LDH trending down confirms treatment response

›LDH spike heralds breakthrough hemolysis or thrombotic event

›Haptoglobin

›Undetectable or very low in active intravascular hemolysis

›Haptoglobin binds free hemoglobin and is cleared

›Not specific to PNH

›Indirect bilirubin

›Elevated from RBC breakdown

›Correlates with hemolysis severity

›Direct bilirubin rise suggests hepatic involvement

Complete blood count and reticulocytes

›CBC pattern

›Hemoglobin

›Normocytic or macrocytic anemia

›Severity varies from mild to severe transfusion dependence

›White blood cell count

›Leukopenia if concurrent bone marrow failure

›Normal or low neutrophil count

›Platelet count

›Thrombocytopenia in bone marrow failure overlap

›Platelet consumption during acute thrombosis

›Reticulocyte count

›Elevated in active hemolysis without bone marrow failure

›Absolute reticulocyte count >100 x 10^9/l

›Reticulocyte percentage elevated

›Low reticulocyte despite anemia suggests aplastic component

›Bone marrow failure concurrent

›Bone marrow biopsy indicated

Renal and metabolic labs

›Urinalysis

›Hemoglobinuria

›Dipstick positive for blood without RBCs on microscopy

›Dark or cola-colored urine in acute crisis

›Hemosiderinuria

›Iron stain on urine sediment

›Marker of chronic intravascular hemolysis

›Prussian blue stain positive on urine sediment

›Renal function

›Creatinine and BUN

›AKI from hemoglobin tubular toxicity

›Chronic renal insufficiency from hemosiderosis

›Electrolytes

›Hyperkalemia in severe hemolysis from RBC lysis

›Bicarbonate monitoring for acid-base status

›Iron studies

›Serum ferritin and transferrin saturation

›Iron deficiency from chronic urinary iron loss

›Low ferritin and low saturation common

›Iron supplementation monitoring

›Oral iron replacement can trigger reticulocyte release and hemolytic paroxysm

Coagulation and thrombosis workup

›Coagulation panel

›PT, INR, aPTT baseline

›Prior to anticoagulation initiation

›Hepatic function assessment in Budd-Chiari

›D-dimer

›Elevated in acute thrombosis

›Nonspecific in setting of active hemolysis

›Thrombophilia screen

›Concurrent inherited thrombophilia assessment

›Antiphospholipid antibodies

›Factor V Leiden and prothrombin mutation

›Note: protein C and S levels unreliable in acute hemolysis

06Diagnostic Tests/dt88

Scoring Systems

›PNH classification system

›International PNH Interest Group categories

›Classic PNH: large clone, predominant hemolysis, minimal bone marrow failure

›PNH in setting of another bone marrow disorder: PNH-AA or PNH-MDS overlap

›Subclinical PNH: small clone detected on screening, no clinical or laboratory hemolysis

›Clone size thresholds

›Granulocyte clone >=1% clinically significant threshold for monitoring

›Granulocyte clone >=50% associated with high thrombotic risk

›Clone size monitored every 6-12 months by flow cytometry

›High disease activity criteria

›Thrombotic risk stratification

›LDH >=1.5x ULN

›Presence of >=2 high disease activity signs

›High disease activity signs: fatigue, hemoglobinuria, abdominal pain, dysphagia, erectile dysfunction, dyspnea

›Treatment threshold

›Classic hemolytic PNH with symptomatic disease warrants complement inhibitor therapy

›ACEP equivalent Level B consensus recommendation from international PNH registries

MRI

›MRI abdomen indications

›Budd-Chiari syndrome evaluation

›Hepatic vein and IVC patency assessment

›MR venography for hepatic venous outflow obstruction

›Superior to CT for hepatic parenchymal characterization

›Splanchnic vein thrombosis

›Portal and mesenteric vein assessment

›Contrast-enhanced MRA for thrombus extent

›Renal hemosiderosis

›T2-weighted sequences show cortical signal dropout

›Confirms chronic intravascular hemolysis

›MRI brain for cerebral venous thrombosis

›MR venography

›Superior to CT for early cerebral venous thrombosis detection

›Dural sinus and cortical vein assessment

›Parenchymal findings

›Venous infarction pattern

›Hemorrhagic transformation assessment

›Contraindications

›Unstable patient requires CT first

›Incompatible implants

›CT abdomen and pelvis with contrast

›Budd-Chiari syndrome

›Hepatic vein and IVC thrombosis

›Caudate lobe hypertrophy pathognomonic sign

›Ascites and periportal edema

›Mesenteric and portal vein thrombosis

›Bowel ischemia assessment

›Pneumatosis intestinalis if advanced ischemia

›Spleen and liver size

›Splenomegaly from portal hypertension

›Hepatomegaly from congestion or extramedullary hematopoiesis

›CT pulmonary angiography

›Pulmonary embolism diagnosis

›High sensitivity and specificity for segmental and above PE

›Right heart strain markers on CT

›Pulmonary hypertension assessment

›Pulmonary artery diameter >29 mm suggests PAH

›Right ventricular enlargement

›CT head for initial neurologic assessment

›Rapid exclusion of hemorrhage

›Prior to anticoagulation for cerebral venous thrombosis

›Non-contrast CT adequate for hemorrhage screen

›Limitations

›CT venography less sensitive than MRV for early CVT

›Normal CT does not exclude CVT

Ultrasound

›Doppler ultrasound abdomen

›Hepatic vein and IVC assessment

›Absent or reversed hepatic vein flow in Budd-Chiari

›Real-time and color Doppler for flow direction

›First-line imaging for Budd-Chiari when clinically suspected

›Portal vein Doppler

›Portal hypertension assessment

›Thrombus detection in portal system

›Spleen and liver dimensions

›Serial measurement for disease monitoring

›Ascites quantification

›Lower extremity venous Doppler

›DVT assessment

›Compressibility and color flow assessment

›Bilateral study for bilateral symptoms

›Proximal DVT versus calf DVT distinction

›Proximal DVT requires anticoagulation

›Proximal thrombus extension risk monitoring

›Point of care cardiac ultrasound

›Right heart assessment

›RV dilation from pulmonary hypertension

›Tricuspid regurgitation jet velocity for PAP estimation

›Pericardial effusion screen

›Rarely associated with severe hemolytic crisis

›Tamponade physiology assessment if present

07Disposition/dispo61

Admission criteria

›ICU or high-dependency admission

›Hemodynamic instability

›SBP < 90 mmHg despite initial resuscitation

›Lactate >=2 mmol/l with ongoing hemolysis

›Thrombosis at life-threatening site

›Budd-Chiari with acute hepatic failure

›Cerebral venous thrombosis

›Mesenteric ischemia

›Severe acute kidney injury

›Oliguria despite adequate hydration

›Creatinine >2x baseline acutely

›Sepsis or meningococcal infection in complement inhibitor patient

›Immediate isolation and treatment

›ICU-level monitoring

›General ward admission

›Moderate hemolytic crisis with stable vitals

›Hemoglobin <80 g/l requiring transfusion support

›LDH >5x ULN with falling hemoglobin

›New diagnosis requiring urgent workup

›Flow cytometry confirmation

›Complement inhibitor initiation planning

›Breakthrough hemolysis on complement inhibitor

›LDH spike >2x personal baseline

›Hemoglobinuria return after period of control

Discharge criteria

›Clinical stability criteria

›Hemodynamic stability

08Treatment/t110

Acute hemolytic crisis management

›Supportive resuscitation

›Intravenous hydration

›Normal saline 1-2 L bolus for hemodynamic instability

›Maintenance at 150-200 ml/hr to protect renal tubules

›Target urine output 1-2 ml/kg/hr

›Packed red blood cell transfusion

›Leukoreduced and irradiated products mandatory

›Transfuse for Hgb < 70-80 g/l with symptoms

›Washed RBCs historically used but not required in complement inhibitor era

›Precipitant treatment

›Antibiotics for concurrent infection

›Culture-guided therapy

›Folic acid supplementation

›Folic acid 5 mg PO daily

›Chronic hemolysis increases folate demand

›Prevents folate-deficiency megaloblastic change

Complement inhibitor therapy

›Terminal C5 inhibitors (first-line)

›Eculizumab (Soliris)

›600 mg IV weekly for 4 weeks (induction)

›Then 900 mg IV every 14 days (maintenance)

›Controls intravascular hemolysis and virtually eliminates thrombotic risk

›Class I equivalent recommendation based on landmark TRIUMPH and SHEPHERD trials

›Ravulizumab (Ultomiris)

›Long-acting C5 inhibitor dosed every 8 weeks IV

›Weight-based dosing: 2,700-3,000 mg per cycle for 40-<60 kg

›Weight-based dosing: 3,300 mg per cycle for 60-<100 kg

›Preferred for convenience over eculizumab

›Non-inferior to eculizumab for hemolysis control

›Crovalimab (Piasky)

›Subcutaneous anti-C5 antibody

›For patients >=13 years and >=40 kg

›Self-administered subcutaneous dosing after induction

›Proximal complement inhibitors (for extravascular hemolysis)

›Pegcetacoplan (Empaveli)

›C3 inhibitor subcutaneous infusion

›1,080 mg subcutaneous twice weekly

›Addresses extravascular hemolysis not controlled by C5 inhibitors

›Demonstrated hemoglobin improvement vs eculizumab in PEGASUS trial

›Iptacopan (Fabhalta)

›Oral factor B inhibitor

›200 mg PO twice daily

›Only approved oral monotherapy for PNH

›Demonstrated hemoglobin response in APPLY-PNH and APPOINT-PNH trials

›Danicopan (Voydeya)

›Oral factor D inhibitor

›150 mg PO three times daily

›Add-on to eculizumab or ravulizumab for persistent extravascular hemolysis

›ALPHA trial demonstrated efficacy as add-on therapy

Pre-complement inhibitor requirements

›Mandatory vaccination

›Meningococcal ACWY vaccine

›Administer at least 2 weeks before first dose

›Revaccination every 3-5 years during therapy

›Meningococcal B vaccine

›MenB-4C (Bexsero) or MenB-FHbp (Trumenba)

›Two-dose series per current ACIP schedule

›Even vaccinated patients have ~1,000-2,000-fold increased meningococcal risk

›Antibiotic prophylaxis

›Penicillin V 250 mg PO twice daily

›Consider for duration of complement inhibitor therapy

›NCCN and international guidelines recommend prophylaxis

›Penicillin-allergic alternatives

›Ciprofloxacin 500 mg PO daily

›Azithromycin 250 mg PO daily

›Prophylaxis especially important if urgent complement inhibitor initiation required

›When vaccination given < 2 weeks before starting therapy

›Continue until >=2 weeks after vaccination

Anticoagulation

›Acute thrombosis treatment

›Low molecular weight heparin bridge

›Enoxaparin 1 mg/kg SC twice daily (creatinine clearance >30 ml/min)

›Adjust for renal impairment

›Warfarin for long-term anticoagulation

›Target INR 2-3 for venous thrombosis

›INR 2.5-3.5 for mechanical valve if applicable

›Direct oral anticoagulants

›Appear safe and effective in PNH based on observational data

›Rivaroxaban or apixaban preferred based on available evidence

›Avoid in severe renal impairment

›Prophylactic anticoagulation considerations

›High clone size (>=50% granulocytes) without prior thrombosis

›Individualize based on bleeding vs thrombotic risk

›Complement inhibitor therapy substantially reduces thrombotic risk

›Anticoagulation addition may not be required on adequate complement inhibition

›Budd-Chiari anticoagulation

›Anticoagulation regardless of complement inhibitor status

›TIPS or thrombolysis for refractory or recent thrombosis

›Hepatology and IR involvement mandatory

Iron and supportive therapy

›Iron supplementation

›Oral ferrous sulfate 325 mg PO twice to three times daily

›Indicated when ferritin low and transferrin saturation <20%

›Iron repletion can trigger reticulocyte release and hemolytic paroxysm

›Start at low dose and monitor LDH and urine color

›IV iron if unable to tolerate oral or severe deficiency

›Ferric carboxymaltose 750-1,000 mg IV single dose

›Monitor closely for hemolysis in first 1-2 weeks

›Erythropoiesis-stimulating agents

›Epoetin alfa or darbepoetin when concurrent bone marrow failure

›Concurrent iron supplementation required

›Monitor for hypertension and thrombotic risk

Curative therapy

›Allogeneic hematopoietic stem cell transplant

›Indications

›Severe bone marrow failure with aplastic anemia component

›Inadequate response to complement inhibitors

›Transformation to MDS or AML

›Outcomes

›Only potentially curative therapy

›Reserved for patients with severe disease due to transplant-related morbidity and mortality

›Conditioning regimen selection per transplant center protocol

›Pre-transplant management

›Continue complement inhibitor therapy until engraftment established

›Thrombotic prophylaxis during conditioning

09Special Populations/sp81

Pregnancy

›Obstetric risk

›Markedly elevated maternal risk

›Highest thrombotic risk during pregnancy and postpartum period

›Hemolytic crisis risk elevated with hormonal and immune changes

›Fetal outcomes

›Increased spontaneous abortion risk

›Preterm delivery and fetal growth restriction

›Maternal anemia contributing to placental insufficiency

›Maternal mortality

›Historical maternal mortality up to 10% without treatment

›Substantially reduced with complement inhibitor and anticoagulation era

›Treatment in pregnancy

›Eculizumab during pregnancy

›Continued or initiated in pregnancy when benefits outweigh risks

›FDA category C; placental transfer limited

›Published case series support safety in pregnancy

›Anticoagulation

›LMWH preferred throughout pregnancy

›Warfarin and DOACs avoided in first trimester

›Enoxaparin dose adjustment as weight and GFR change

›Monitoring

›Monthly CBC and LDH during pregnancy

›Serial fetal growth ultrasound every 4 weeks

›Multidisciplinary hematology and maternal-fetal medicine co-management

›Delivery planning

›Neuraxial anesthesia feasibility with hematology input

›Platelet and coagulation status assessment

›Timing of LMWH hold prior to neuraxial procedures

›Postpartum thrombotic risk elevation

›Continue anticoagulation for at least 6 weeks postpartum

›Complement inhibitor continuation mandatory

Geriatric

›Age-specific considerations

›Atypical presentation

›Fatigue may be attributed to age rather than hemolysis

›Thrombosis at atypical sites may present with vague symptoms

›Comorbidity interactions

›Renal impairment affecting complement inhibitor and anticoagulation dosing

›Polypharmacy and drug interaction assessment

›Falls and frailty

›Higher bleeding risk with anticoagulation in frail patients

›Falls assessment prior to anticoagulation initiation

›Medication dosing

›Eculizumab and ravulizumab dosing unchanged by age

›Monitor for infusion reactions more carefully in frail patients

›LMWH dose reduction if CrCl < 30 ml/min

›Renal dosing adjustments

›Enoxaparin 0.75 mg/kg SC twice daily if CrCl < 30 ml/min

›Anti-Xa monitoring for LMWH in severe renal impairment

›Antibiotic prophylaxis safety

›Review for QT prolongation risk if using ciprofloxacin

›Drug interaction check with existing cardiac medications

›Monitoring

›LDH and CBC monitoring

›Monthly at minimum during complement inhibitor therapy

›Clone size monitoring every 12 months in stable older patients

Pediatrics

›Pediatric PNH epidemiology

›Rare in children; median age of diagnosis in adults

›PNH in children more often associated with aplastic anemia

›Consider inherited bone marrow failure syndromes in younger children

›Inherited bone marrow failure exclusion

›Fanconi anemia: chromosomal fragility testing

›Diamond-Blackfan anemia: erythroid aplasia pattern

›Dyskeratosis congenita: telomere length testing

›Complement inhibitor dosing in children

›Eculizumab weight-based dosing

›<10 kg: 300 mg every 2 weeks (induction); 300 mg every 2-4 weeks (maintenance)

›10-<20 kg: 600 mg weekly x2 (induction); 300 mg every 2 weeks (maintenance)

›20-<30 kg: 600 mg weekly x2 (induction); 600 mg every 2 weeks (maintenance)

›>=30 kg: adult dosing applies

›Crovalimab approved for >=13 years and >=40 kg

›Ravulizumab approved for >=1 month weight-based

›Meningococcal vaccination schedule in children

›MenACWY at age-appropriate intervals per ACIP schedule

›MenB series based on current ACIP recommendations

›Pediatric monitoring

›Growth and development monitoring

›Chronic anemia impact on growth velocity

›School performance and cognitive impact of chronic disease

›Flow cytometry clone monitoring

›Clone size every 6-12 months

›Bone marrow biopsy if cytopenias worsen

10Background/b90

Epidemiology

›Prevalence and incidence

›Estimated prevalence < 10 cases per million population

›True rare disease classification

›International PNH Registry contains >3,000 patients

›Age distribution

›Median age of diagnosis 24-41 years in published cohorts

›Rare in childhood

›Can occur at any age

›Sex distribution

›Roughly equal male to female distribution

›No racial or ethnic predilection established

›Mortality and morbidity

›Historical mortality

›Median survival ~10 years from diagnosis in pre-complement inhibitor era

›Thrombosis was leading cause of death historically in 40-67% of deaths

›Modern outcomes

›Median survival approaching general population with complement inhibitor therapy

›Complement inhibitors dramatically reduce thrombotic events and transfusion burden

›Complications driving morbidity

›Renal failure from hemosiderosis and AKI

›Pulmonary hypertension from chronic intravascular hemolysis

›Transformation to MDS or AML in ~5% of patients

Pathophysiology

›PIGA gene mutation

›Somatic mutation in X-linked PIGA gene in hematopoietic stem cell

›Acquired mutation; not inherited

›Clonal expansion of PIGA-mutant cells in context of bone marrow failure

›GPI anchor biosynthesis defect

›Glycosylphosphatidylinositol anchor not produced

›All GPI-anchored proteins absent from cell surface

›Loss of CD55 (DAF) and CD59 (MIRL) most clinically relevant

›Complement dysregulation

›Loss of CD55 (decay-accelerating factor)

›Normally inhibits C3 and C5 convertase formation

›GPI-deficient cells cannot control alternative pathway amplification

›Loss of CD59 (membrane inhibitor of reactive lysis)

›Normally inhibits membrane attack complex (MAC) assembly

›Without CD59, MAC forms on RBC surface causing lysis

›Intravascular hemolysis consequences

›Free hemoglobin scavenges nitric oxide

›Nitric oxide deficiency causes smooth muscle dystonia (abdominal pain, dysphagia, erectile dysfunction)

›Free hemoglobin causes renal tubular injury

›Thrombosis mechanisms

›Nitric oxide scavenging

›Impaired platelet inhibition

›Vasoconstriction promoting clot formation

›Platelet activation

›GPI-deficient platelets more susceptible to complement-mediated activation

›Platelet microparticle generation during hemolysis

›Tissue factor pathway upregulation

›Complement activation promotes prothrombotic state

›Endothelial activation from free hemoglobin

Therapeutic Considerations

›Complement inhibition strategy rationale

›Terminal C5 inhibitors

›Block MAC formation preventing intravascular hemolysis

›Virtually eliminate thrombotic risk when hemolysis controlled

›Do not address extravascular hemolysis or bone marrow failure

›C3b opsonization of GPI-deficient cells leads to extravascular hemolysis in some patients

›Proximal complement inhibitors

›Target earlier in complement cascade (C3, factor B, factor D)

›Address both intravascular and extravascular hemolysis

›Higher infection risk theoretically due to broader complement suppression

›Breakthrough hemolysis on C5 inhibitors

›Causes

›Pharmacokinetic breakthrough during infection or complement surge

›Missed infusion or inadequate trough levels

›C3-mediated extravascular hemolysis unaffected by C5 blockade

›Management

›Increase eculizumab dose or frequency during breakthrough

›Switch to or add proximal inhibitor for persistent extravascular hemolysis

›Treat precipitating infection aggressively

›Treatment selection principles

›First complement inhibitor naive patients

›Ravulizumab preferred over eculizumab for convenience

›Iptacopan emerging as oral monotherapy option

›Inadequate response on C5 inhibitor

›Switch to pegcetacoplan or iptacopan monotherapy

›Add danicopan to existing C5 inhibitor

›Transfusion dependence despite C5 inhibitor

›Strongly consider switch to proximal inhibitor

›Hemoglobin response rates higher with proximal inhibitors in studies

›Monitoring principles

›LDH and CBC monitoring

›Monthly during treatment initiation

›Every 3 months when stable on maintenance therapy

›Clone size monitoring

›Flow cytometry every 6-12 months

›Clone expansion or new cytopenias trigger bone marrow biopsy

›Renal function monitoring

›Annual creatinine and urinalysis

›Prussian blue urine sediment stain for hemosiderin every 6-12 months

11Patient Discharge Instructions/pdi34

copy discharge instructions

›Paroxysmal nocturnal hemoglobinuria home care

›Take all medications as prescribed

›Do not miss scheduled complement inhibitor infusions; missed doses can trigger life-threatening rebound hemolysis

›Take folic acid supplement daily as prescribed

›Take antibiotic prophylaxis daily if prescribed before your meningococcal vaccines take full effect

›Stay well hydrated; drink at least 2 liters of water daily

›Avoid infections when possible; wash hands frequently

›Warning signs to return to ER immediately

›Dark brown, cola-colored, or red urine (hemoglobinuria)

›Fever (temperature >38 C or 100.4 F), especially with headache, neck stiffness, or skin rash

›Severe abdominal pain, especially pain in the right upper abdomen

›Sudden severe headache or vision changes

›Weakness, numbness, or trouble speaking

›Chest pain or severe shortness of breath

›Leg swelling or calf pain

›Decreased urine output or no urine output

›Extreme fatigue or pallor that is suddenly worse

›Meningococcal infection warning

›Your complement inhibitor medication greatly increases your risk of serious meningococcal infection

›Fever with rash or neck stiffness is a medical emergency; go to ER or call 911 immediately

›Carry your PNH patient safety card at all times

›Inform all healthcare providers about your PNH diagnosis and complement inhibitor therapy before any procedures

›Ensure meningococcal booster vaccines are kept up to date

›Follow up appointments

›Hematology follow-up within 1-2 weeks

›Blood test (LDH, CBC) scheduled before or at follow-up appointment

›Next complement inhibitor infusion date confirmed before discharge

12References/r48

Guidelines and key sources

›Primary guideline sources

›Brodsky RA. How I Treat Paroxysmal Nocturnal Hemoglobinuria. Blood. 2021

›Comprehensive treatment algorithm for PNH management

›PMID 33512400

›Patriquin CJ et al. How we treat paroxysmal nocturnal hemoglobinuria: Canadian PNH Network consensus. European Journal of Haematology. 2019

›National registry-based consensus statement

›DOI 10.1111/ejh.13176

›International PNH Interest Group classification and management framework

›Three-category PNH classification: classic, PNH-bone marrow disorder, subclinical

›Key clinical trials

›Hillmen P et al. Pegcetacoplan versus Eculizumab in Paroxysmal Nocturnal Hemoglobinuria. NEJM. 2021 (PEGASUS trial)

›Pegcetacoplan superior to eculizumab for hemoglobin response

›DOI 10.1056/NEJMoa2029073

›Peffault de Latour R et al. Oral Iptacopan Monotherapy in PNH. NEJM. 2024 (APPLY-PNH trial)

›Iptacopan demonstrated hemoglobin improvement vs placebo

›DOI 10.1056/NEJMoa2308695

›Lee JW et al. Addition of Danicopan in PNH with Extravascular Hemolysis. Lancet Haematology. 2023 (ALPHA trial)

›Danicopan add-on reduced extravascular hemolysis

›PMID 38030318

›Gurnari C et al. PNH-related thrombosis in the era of novel therapies. Blood. 2024

›2,043 patient-year analysis of thrombosis outcomes

›PMID 38513233

Meningococcal safety references

›Vaccination and infection risk

›McNamara LA et al. High risk for invasive meningococcal disease in patients receiving eculizumab despite vaccination. MMWR. 2017

›Documented ~1,000-2,000-fold risk increase

›PMID 28704351

Learn More: Paroxysmal Nocturnal Hemoglobinuria→

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Reviewed by SymptomDx Medical Team · Last reviewed August 18, 2026

SymptomDx is an educational tool for medical professionals. It does not replace clinical judgment. Verify all clinical data and drug dosages with authoritative sources.