Paroxysmal Nocturnal Hemoglobinuria Clinical Presentation

A working classification has been developed for paroxysmal nocturnal hemoglobinuria (PNH) that includes all the variations in the presentation, clinical manifestations, and natural history among PNH patients: (1) classic PNH, (2) PNH in the setting of another specified bone marrow disorder (eg, PNH/aplastic anemia or PNH/refractory anemia-myelodysplastic syndrome [MDS]), and (3) subclinical PNH (PNH-sc) in aplastic anemia are now recognized.

Paroxysmal nocturnal hemoglobinuria (PNH) presents in any of the 3 syndromes or sets of symptoms.

• Hemolytic anemia is usually in the form of intravascular hemolysis.

  • The most common presentation is the presence of anemia associated with dark cola-colored urine that is a manifestation of hemoglobinuria. The latter may be confused with hematuria, and erroneous treatment could be given for urosepsis. Hemosiderin is nearly always present in the urine sediment and can accumulate in the kidneys, which shows up on magnetic resonance images (MRI) or computed tomography (CT) scans.
  • Elevated reticulocyte count and serum lactic acid dehydrogenase (LDH) with a low serum haptoglobin in the absence of hepatosplenomegaly are the hallmarks of intravascular hemolysis. The bone marrow is usually markedly erythroid, with decreased or absent iron stores, depending on how long the patient has been losing iron in the urine.
• Thrombosis involves the venous system, and it usually occurs in unusual veins, namely the hepatic, abdominal, cerebral, and subdermal veins.

  • Hepatic vein thrombosis results in Budd-Chiari syndrome, which manifests as a sudden and catastrophic event characterized by jaundice, abdominal pain, a rapidly enlarging liver, and accumulation of ascitic fluid. This syndrome may be severe and lead to vascular collapse and death, or it can be slow and insidious, leading to hepatic failure.
  • Abdominal vein thrombosis presents with upper abdominal pain, or it can occur anywhere in the abdomen, lasting 1-6 days. It can lead to bowel infarction in severe cases.
  • Cerebral vein thrombosis can range from the mildest form to a severe headache, depending on which veins are involved. The sagittal vein is commonly affected, which can give rise to papilledema and pseudotumor cerebri.
  • Dermal vein thrombosis manifests as raised, painful, red nodules in the skin affecting large areas, such as the entire back, which subsides within a few weeks, usually without necrosis. In cases that do result in necrosis, skin grafting may be necessary.
• Deficient hematopoiesis usually presents with anemia despite the presence of an erythroid marrow with suboptimal reticulocytosis. In some cases, neutropenia and thrombocytopenia can occur in a hypoplastic bone marrow similar to aplastic anemia (aplastic episodes).
• Other symptoms of paroxysmal nocturnal hemoglobinuria (PNH) include esophageal spasms that occur in the morning and, like the dark-colored urine, clear up later in the day. In males, impotence can occur concomitant with hemoglobinuria, the cause of which is unknown.

Most commonly, in patients with paroxysmal nocturnal hemoglobinuria (PNH), pallor suggests anemia, fever suggests infections, and bleeding, such as mucosal bleeding, suggests skin ecchymoses in thrombocytopenia similar to aplastic anemia. Other physical examination findings may include the following:

• Hepatomegaly and ascites in the presence of Budd-Chiari syndrome
• Splenomegaly if there is splenic vein thrombosis
• Absent bowel sounds in the presence of bowel necrosis
• Papilledema in the presence of cerebral vein thrombosis
• Skin nodules that are red and painful in the presence of dermal vein thrombosis

Paroxysmal nocturnal hemoglobinuria (PNH) is now known to be a consequence of nonmalignant clonal expansion of one or several hematopoietic stem cells that are deficient in GPI-anchor protein (GPI-AP) acquired through a somatic mutation of PIG-A.

• Recent information has led us to understand that paroxysmal nocturnal hemoglobinuria (PNH) is not a monoclonal disease with a malignant phenotype. Rather, the clinical pathology may actually be an epiphenomenon resulting from an adaptive response to injury, such as an immune attack on the stem cells of hematopoiesis.
• In paroxysmal nocturnal hemoglobinuria (PNH), the peripheral blood and bone marrow is a mosaic composed of GPI-AP+ and GPI-AP- cells; with GPI-AP-, cells can be derived from multiple mutant stem cells. The GPI-AP- mutant cells may appear to dominate hematopoiesis in PNH by providing a proliferative advantage under some pathologic conditions. For example, if damage to stem cells causing bone marrow failure is mediated through a GPI-linked surface molecule, the PNH cells lacking these molecules will survive. The close association with aplastic anemia and MDS suggests that the selection process arises as a consequence of this specific type of bone marrow injury.