Paroxysmal Nocturnal Hemoglobinuria

Also see Aplastic Anemia.

Definition, Etiology, Pathogenesis

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare acquired clonal hematopoietic stem cell disorder characterized by uncontrolled complement activation. PNH is caused by the loss of glycosylphosphatidylinositol (GPI)-anchored proteins due to somatic sequence variations in the PIGA gene, limiting the expression of cell surface proteins (eg, CD55, CD59) that are crucial in regulating complement activity. Absence of these proteins results in complement-mediated destruction of cells. This leads to uncontrolled chronic intravascular hemolysis and often coexists with immune-mediated bone marrow failure, as may be seen in states such as aplastic anemia (AA).

Clinical Features

Symptoms of hemolysis may include fatigue, back and abdominal pain, dyspnea, jaundice, and esophageal spasms or erectile dysfunction in men (due to the uptake of nitric oxide by free hemoglobin). Episodic hemoglobinuria is relatively uncommon but may be seen particularly during an exacerbation.

Patients can present with pancytopenia and features of acquired AA. Iron deficiency from urinary losses and biochemical evidence of hemolysis (anemia, elevated reticulocyte count, elevated lactate dehydrogenase [LDH], bilirubin, decreased haptoglobin and free hemoglobin) may be seen. A direct antiglobulin test (DAT)/direct Coombs test is negative.

Venous and arterial thromboembolic events can be prominent, and a history of recurrent or unusual sites of involvement (intra-abdominal, cerebral) may warrant consideration for PNH testing.

The CATCH acronym (cytopenias, AA/myelodysplasia, thrombosis, Coombs-negative hemolysis, and hemoglobinuria) has been proposed as a method for identifying patients with PNH, but it is not formally validated.

Diagnosis

Laboratory testing suggestive of hemolytic anemia and a clinical history as outlined may raise concern for PNH. Formal diagnosis can be established using high-sensitivity peripheral blood flow cytometry to identify the absence of GPI-linked proteins (eg, CD55 and CD59) on neutrophils, monocytes, and erythrocytes by staining with monoclonal antibodies or using a specific fluorescein-tagged proaerolysin (FLAER) variant.

Cells are characterized as type I, II, or III depending on the level of expression of GPI (type III = total loss), and expressed in percentages. Larger clone sizes may correlate with higher thromboembolic risk. Of note, erythrocytes are susceptible to hemolysis and confounding from transfused samples, and are therefore not reliable as a sole metric of disease activity.

Bone marrow evaluation may be considered to exclude concomitant AA or myelodysplastic syndrome (MDS).

Treatment

The index of suspicion for PNH needs to be high in patients presenting with recurrent or unusual sites of thrombosis, pancytopenia in younger patients, or signs and symptoms of hemolysis. Patients with PNH should be referred to a specialized hematology referral center for assessment and testing, and enrolment in registries and/or clinical trials should be offered given the rarity of this condition.

1. Hemolytic anemia: Screening for iron deficiency, folic acid supplementation, supportive transfusions. Erythropoiesis-stimulating agents (ESAs) can be considered in some cases.

2. Thrombosis: Therapeutic anticoagulation is used for acute treatment. Extended duration of anticoagulation may be considered. Prophylactic anticoagulation is not typically initiated.

3. Complement inhibition: Eculizumab and ravulizumab can improve the disease course, quality of life, and overall survival. Therapy initiation may be considered in the setting of a prominent leukocyte clone, intravascular hemolysis, end-organ damage, thromboembolic history, or pregnancy. Patients on complement inhibitors require meningococcal vaccination and/or antibiotic prophylaxis if initiated emergently. Novel complement inhibitors are under development.

Allogeneic stem cell transplant is considered in cases of refractory disease or underlying bone marrow failure, and is curative albeit high risk.