What is paroxysmal nocturnal hemoglobinuria (PNH) in a patient with a positive antinuclear antibody (ANA) test, negative antiphospholipid (aPL) antibodies, and a history of Budd-Chiari syndrome?

Paroxysmal Nocturnal Hemoglobinuria (PNH)

Paroxysmal nocturnal hemoglobinuria is a rare, acquired clonal hematopoietic stem cell disorder caused by a somatic mutation in the PIGA gene, resulting in deficiency of glycosylphosphatidylinositol (GPI)-anchored complement regulatory proteins (CD55 and CD59), which leads to complement-mediated intravascular hemolysis, thrombosis, and bone marrow failure. 1, 2

Pathophysiology

• The PIGA gene mutation occurs in a multipotent hematopoietic stem cell, causing defective synthesis of GPI anchors that normally attach complement regulatory proteins to cell membranes 3, 2
• Without CD55 and CD59 surface proteins, red blood cells, granulocytes, monocytes, and platelets become vulnerable to complement-mediated destruction 1, 3
• The mutation leads to clonal expansion of the affected stem cell, with PNH clone size ranging from <1% to 100% of granulocytes 3
• Complement activation causes intravascular hemolysis as the primary manifestation, but also contributes to thrombosis through effects on multiple cell lineages 3, 4

Clinical Manifestations

The classic triad consists of hemolytic anemia, pancytopenia, and thrombosis, making PNH a unique clinical syndrome. 1

Hemolysis

• Chronic intravascular hemolysis with recurrent nocturnal exacerbations (though not all patients experience nocturnal symptoms) 1
• Hemoglobinuria, anemia requiring transfusions, and elevated lactate dehydrogenase 5, 6
• Negative direct antiglobulin test (Coombs test) distinguishes PNH from autoimmune hemolytic anemia 6, 7

Thrombosis

• Venous thrombosis in unusual sites, particularly splanchnic vessels (hepatic, portal, mesenteric veins) 6, 8
• Budd-Chiari syndrome occurs in 9-19% of PNH patients and represents a major cause of mortality 6, 8
• Cerebral venous and less commonly arterial thrombosis can occur 5, 8
• Patients with >60% PNH granulocytes have significantly higher thrombosis risk 6, 7, 8

Bone Marrow Failure

• Frequently associated with aplastic anemia (present in approximately 68% of PNH cases with marrow disorders) and myelodysplastic syndrome 9
• Presents with cytopenias including neutropenia, thrombocytopenia, and anemia 1, 9

Other Complications

• Renal impairment from chronic hemoglobinuria 3
• Pulmonary hypertension 3
• Recurrent infections related to neutropenia 1
• Fatigue and reduced quality of life 10

Diagnostic Approach in Your Clinical Context

Given the patient's positive ANA, negative antiphospholipid antibodies, and history of Budd-Chiari syndrome, PNH testing is mandatory as it accounts for 9-19% of Budd-Chiari cases. 6, 8

Initial Laboratory Evaluation

• Complete blood count with differential and reticulocyte count 6
• Peripheral blood smear examining for schistocytes (indicating intravascular hemolysis) and other hemolysis markers 6, 7
• Hemolysis markers: elevated LDH, reduced haptoglobin, elevated indirect bilirubin, elevated free hemoglobin 5, 6, 7
• Direct antiglobulin test (should be negative in PNH) 6, 7

Confirmatory Testing

• Flow cytometry for PNH clone detection is the gold standard diagnostic test 5, 6
• Assess percentage of PNH granulocytes (>60% indicates higher thrombosis risk) 6, 7, 8
• Renal function tests and coagulation profile 6

Additional Workup for Thrombosis

• JAK2V617F mutation testing to exclude myeloproliferative neoplasms 6
• Thrombophilia screening (though antiphospholipid antibodies already negative) 6
• The positive ANA may indicate concurrent autoimmune disease but does not exclude PNH 6

Bone Marrow Evaluation

• Bone marrow aspiration, biopsy, and cytogenetic analysis if cytopenias are present 5, 6
• Particularly important in young patients with hypoplastic features or normal cytogenetics 6

Treatment Considerations

Complement Inhibitors

• Eculizumab (C5 inhibitor) is FDA-approved as the first effective drug therapy for PNH, reducing hemolysis and preventing thrombosis 10, 1
• Dosing for adults: 600 mg IV weekly for 4 weeks, then 900 mg at week 5, followed by 900 mg every 2 weeks 10
• Meningococcal vaccination (serogroups A, C, W, Y, and B) is mandatory at least 2 weeks before starting therapy due to increased infection risk 10
• Treatment extends survival to match healthy controls and improves quality of life 4

Anticoagulation for Budd-Chiari Syndrome

• Long-term (indefinite) anticoagulation is warranted due to the severity of Budd-Chiari syndrome, even with complement inhibitor therapy 8
• Hepatology consultation for consideration of transjugular intrahepatic portosystemic shunt (TIPS) in selected cases 8

Alternative Therapies

• Approximately 30% of patients on C5 inhibitors develop clinically significant extravascular hemolysis requiring alternative approaches 4
• Upstream complement inhibitors (C3 or factor B inhibitors) address both intravascular and extravascular hemolysis 4
• Allogeneic hematopoietic cell transplantation remains the only cure, with indications including persistent hemolysis despite treatment, persistent thrombosis, and associated marrow failure 9

Critical Pitfalls

• Do not delay PNH testing in patients with Budd-Chiari syndrome—it is present in nearly 1 in 5 cases 6, 8
• The absence of nocturnal symptoms does not exclude PNH; many patients lack this classic feature 1
• A positive ANA does not rule out PNH and may represent concurrent autoimmune disease 6
• Breakthrough hemolysis can occur with any complement inhibitor during strong complement triggers (infections, surgery) 4
• Pregnancy carries high maternal mortality risk in PNH patients and requires specialized management 8