Paroxysmal Nocturnal Hemoglobinuria (PNH)

A 38 year old male presents to the primary care physician with complaints of dark colored urine over the past few months. He also reports fatigue, generalized weakness, shortness of breath, and intermittent abdominal pain. He has a history of recurrent unexplained anemia requiring blood transfusions and a prior episode of deep venous thrombosis. On examination, he has pallor. Vital signs are stable. Laboratory studies show hemoglobin 8.0 g/dL, MCV 100 fL, reticulocytosis, markedly elevated LDH, elevated indirect bilirubin, and low haptoglobin. Direct antiglobulin test (Coombs test) is negative. Flow cytometry with FLAER demonstrates deficiency of GPI-anchored proteins, including CD55 and CD59. Diagnosis?

Diagnosis is Paroxysmal Nocturnal Hemoglobinuria (PNH).

1. Definition

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 proteins and leading to complement-mediated intravascular hemolysis, thrombosis, and bone marrow failure.

2. Pathophysiology

1. Mutation in the X-linked PIGA gene impairs synthesis of the GPI anchor
2. Leads to absence of CD55 and CD59, which normally inhibit complement
3. Results in uncontrolled complement activation and chronic intravascular hemolysis
4. Free hemoglobin binds and depletes nitric oxide
5. Nitric oxide depletion causes smooth muscle dystonia, leading to abdominal pain, dysphagia, and erectile dysfunction
6. Complement activation, platelet activation, and impaired fibrinolysis contribute to thrombosis

3. Clinical Features

3.1 Hemolysis

1. Hemoglobinuria causing dark urine
2. Fatigue, pallor, and dyspnea
3. Coombs negative intravascular hemolytic anemia

3.2 Thrombosis

1. Venous thrombosis is most common
2. Occurs in unusual sites
3. Common sites include hepatic veins, portal veins, and cerebral veins

3.3 Bone Marrow Dysfunction

1. Cytopenias
2. Association with aplastic anemia or other marrow disorders

3.4 Other Features

1. Abdominal pain
2. Dysphagia or esophageal spasm
3. Renal impairment
4. Pulmonary hypertension
5. Erectile dysfunction

4. Laboratory Findings

1. Anemia
2. Reticulocytosis
3. Markedly elevated LDH
4. Unconjugated hyperbilirubinemia
5. Low haptoglobin
6. Negative Coombs test
7. Possible hemoglobinuria and hemosiderinuria
8. May show leukopenia or thrombocytopenia

5. Diagnosis

1. Flow cytometry with FLAER is the gold standard
2. Demonstrates deficiency of GPI-anchored proteins such as CD55 and CD59
3. Should evaluate erythrocytes, granulocytes, and monocytes
4. Older tests such as the Ham test and sucrose lysis test are obsolete

6. Complications

1. Thrombosis, the leading cause of death
2. Acute and chronic kidney disease
3. Bone marrow failure
4. Pulmonary hypertension
5. Progression to aplastic anemia or myelodysplastic syndrome

7. Management

7.1 Supportive Care

1. Blood transfusions
2. Folate and iron supplementation
3. Anticoagulation for thrombosis

7.2 Disease-Modifying Therapy

1. Eculizumab, a C5 inhibitor, reduces complement-mediated hemolysis
2. Ravulizumab, a longer-acting C5 inhibitor
3. Both increase susceptibility to Neisseria infections
4. Meningococcal vaccination is required prior to therapy

7.3 Curative Therapy

1. Allogeneic hematopoietic stem cell transplantation

8. Key Clinical Insight

Coombs negative intravascular hemolytic anemia + hemoglobinuria + thrombosis + absence of CD55/CD59 = PNH

9. Exam Level Pearls

1. Flow cytometry with FLAER is diagnostic
2. Thrombosis is the most serious complication and leading cause of death
3. Hepatic vein thrombosis is classic
4. Nitric oxide depletion explains smooth muscle symptoms
5. Eculizumab and ravulizumab are first-line therapies
6. Hemoglobinuria may not always be nocturnal
7. PNH can overlap with aplastic anemia