What are the diagnostic and treatment approaches for a patient suspected of having Marchiafava-Micheli disease (Paroxysmal Nocturnal Hemoglobinuria, PNH)?

Marchiafava-Micheli Disease (Paroxysmal Nocturnal Hemoglobinuria)

Diagnostic Approach

Flow cytometry on peripheral blood is the gold standard diagnostic test for PNH and should be performed immediately in any patient with unexplained intravascular hemolysis, thrombosis in unusual sites (especially splanchnic veins), or cytopenias with bone marrow failure. 1, 2

Clinical Presentations Requiring PNH Testing

• Unexplained intravascular hemolysis with evidence on peripheral smear and negative direct antiglobulin test warrants immediate PNH testing 1
• Venous thrombosis in unusual sites, particularly splanchnic vein thrombosis or Budd-Chiari syndrome (9-19% have underlying PNH), is a critical indication for testing 3, 1
• Cytopenias associated with bone marrow failure syndromes, including aplastic anemia or hypoplastic myelodysplastic syndrome with normal cytogenetics in young patients 1
• Hemolytic anemia with elevated LDH and low or inappropriately normal reticulocyte count suggests intramedullary hemolysis and requires PNH evaluation 4

Initial Laboratory Evaluation

• Complete blood count with differential and reticulocyte count 1
• Peripheral blood smear examination for hemolysis evidence 1
• Hemolysis markers: LDH (markedly elevated), haptoglobin (low), indirect bilirubin (elevated), and free hemoglobin 1, 5
• Renal function tests and coagulation profile 1
• Direct antiglobulin test (Coombs) to exclude autoimmune hemolysis 4

Definitive Diagnostic Testing

• High-sensitivity flow cytometry on peripheral blood to detect GPI-anchored protein deficiency (CD55/CD59 deficiency) is mandatory and superior to older methods 1, 6, 2
• Modern flow cytometry can detect PNH clones as small as <1% of hematopoiesis 6
• Bone marrow aspiration and biopsy with cytogenetics are essential for patients presenting with cytopenias to evaluate for associated bone marrow failure syndromes (aplastic anemia, MDS) 1, 7
• JAK2V617F mutation testing and thrombophilia screening for patients presenting with thrombosis 3

Interpretation of Results

• Patients with >60% PNH granulocytes have significantly higher thrombosis risk and require aggressive management 3
• PNH frequently coexists with aplastic anemia or myelodysplastic syndromes; small clones may be clinically significant in these contexts 1, 6
• All patients with Budd-Chiari syndrome should be routinely tested for PNH 3, 1

Treatment Approach

Complement C5 inhibitors (eculizumab or ravulizumab) are the treatment of choice for patients with PNH and should be initiated in all patients with thrombosis, significant hemolysis, or symptomatic disease. 8, 9, 5

Complement Inhibitor Therapy

• Eculizumab (anti-C5 monoclonal antibody) is FDA-approved and highly effective for reducing hemolysis and preventing thrombosis 10, 5, 11
• Ravulizumab (long-acting C5 inhibitor) is FDA-approved for PNH in patients ≥1 month of age and offers less frequent dosing 8
• Both agents revolutionized PNH care by reducing morbidity and mortality 9, 5
• C5 inhibitors provide excellent prophylaxis against thrombotic events 9

Critical Pre-Treatment Requirements

• Meningococcal vaccination must be completed or updated at least 2 weeks before initiating complement inhibitors, unless the risk of delaying treatment outweighs infection risk 8
• Comply with current ACIP recommendations for meningococcal vaccination in patients receiving complement inhibitors 8
• Patients remain at increased risk for invasive Neisseria meningitidis infection even after vaccination 8
• Both eculizumab and ravulizumab are available only through restricted REMS programs 8

Anticoagulation Management

• Anticoagulation with warfarin or low-molecular-weight heparin should be used in combination with C5 inhibitors in patients who develop thrombotic events 9
• Direct oral anticoagulants (DOACs) may be considered in selected cases 9
• Long-term anticoagulation is warranted for PNH patients with thrombosis given the severity and recurrence risk 3

Alternative and Curative Options

• Allogeneic bone marrow transplantation remains the only curative option but should be reserved for patients with suboptimal response to complement inhibitors or severe bone marrow failure 5, 11
• Novel complement inhibitors targeting different points in the cascade are emerging for patients with extravascular or breakthrough hemolysis on C5 inhibitors 9, 6

Supportive Care

• Blood transfusions for symptomatic anemia 2
• Folic acid supplementation for chronic hemolysis 2
• Monitor for early signs of meningococcal infection and evaluate immediately if suspected 8

Critical Pitfalls to Avoid

• Do not delay flow cytometry testing in patients with unexplained hemolysis or unusual site thrombosis; early diagnosis is essential for improved outcomes 1, 2
• Do not initiate complement inhibitors in patients with unresolved serious Neisseria meningitidis infection (absolute contraindication) 8
• Do not overlook associated bone marrow failure syndromes; perform bone marrow examination in patients with cytopenias 1, 7
• Do not assume small PNH clones are clinically insignificant; they may be relevant in bone marrow failure contexts 6