Paroxysmal Nocturnal Hemoglobinuria

Today we talked about Paroxysmal Nocturnal Hemoglobinuria, an interesting cause of intravascular hemolysis and thrombosis.

1) Pathogenesis:

• Defect in the PIG-A gene that encodes the cell membrane anchor glycophosphatidylinositol (GPI). Glycophosphatidylinositol is necessary for binding proteins to the RBC membrane.
• Defect in the GPI anchor leads to the absence of GPI linked proteins. Two important proteins that are missing include CD55 and CD59, which are involved in the down regulation of the complement system.
• The complement system is part of our innate immunity and is composed of a cascade of enzymatic reactions that culminate in the creation of a membrane attack complex (MAC) that results in cell lysis and destruction. There are two forms of the complement system, the classical pathway that is initiated by IgG/IgM antibodies and the surveillance system that does not require antibodies to become activated. It is this latter system that affects RBCs. 
• CD55 and CD59 act to accelerate decay of the complement system and protect against lysis, respectively, thereby preventing the formation of the deadly MAC. Patients with PNH who lack CD55/CD59 suffer from episodic intravascular hemolysis, the severity of which depends on the degree of absence of GPI linked proteins.
• PNH III: complete absence
• PNH II: partial absence
• PNH I: normal

2) Symptoms

• Hemolysis: Episodic hemolysis, the severity of which depends on the degree of expression of CD55/59. The hemolysis is intravascular and therefore characterized by hemoglobinuria, hemoglobinemia and hemosiderin in the urine. Hemolysis in PNH can happen at any time, not necessary at night as the name implies. However, it is thought that hemolysis increases at night due to intestinal absorption of lipopolysaccharides that enhance the complement system. 
• Nitric Oxide sequestration: Free hemoglobin is a NO scavenger. Nitric Oxide is important in relaxing smooth muscle, therefore depletion of NO as a result of hemolysis results in smooth muscle dysfunction. This manifests as esophageal dysmotility with dysphagia and abdominal cramping.
• Renal dysfunction: Acute hemolysis results in hemoglobinuria that can cause acute kidney injury. Also over time, chronic renal dysfunction occurs due to hemosiderin deposition.
• Prothrombotic state: Patient with PNH have a higher propensity for both venous and, to a lesser extent, arterial thrombosis. The etiology is not well known but thought to be secondary to an abnormal  line of platelets. Patients present with thrombosis of hepatic veins, intra-abdominal veins and even cerebral veins.
• Diminished hematopoiesis: May progress to aplastic anemia
• Hematologic malignancies: May lead to myelodysplastic syndrome and acute leukemia.

3) Treatment

• The treatment of PNH has been revolutionized by the introduction of eculizumab, a humanized monoclonal antibody against C5. This stops terminal complement activation. See this link to the TRIUMPH study a double blind randomized multicenter control study looking at use of eculizumab compared to placebo for PNH. TRIUMPH
• Supportive therapy includes intermittent transfusions as needed and iron/folate supplementation. Be careful of patients developing iron overload due to repeated blood transfusions!
• Anticoagulation is initiated for those with a history of thrombosis. Prophylactic anticoagulation may also be used in those with a large percentage of abnormal granulocyte clones.