Paroxysmal Nocturnal Hemoglobinuria Clinical Presentation

Updated: Jun 29, 2016
  • Author: Emmanuel C Besa, MD; Chief Editor: Koyamangalath Krishnan, MD, FRCP, FACP  more...
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Presentation

History

The classic manifestation of paroxysmal nocturnal hemoglobinuria (PNH) is dark urine during the night with partial clearing during the day (see image below); however, hemoglobinuria may occur every day in severe cases; more frequently, in episodes lasting 3-10 days; or, in some cases, not at all.

This series of containers holds urine of a patient This series of containers holds urine of a patient with paroxysmal nocturnal hemoglobinuria, showing the episodic nature of the dark urine (hemoglobinuria) during intravascular hemolysis, usually occurring at night. Early morning urine is cola-colored. This may occur at different times of the day and vary from patient to patient. Permission to use this image has been granted by the American Society of Hematology Slide Bank, 3rd edition.

A working classification has been developed for PNH that includes all the variations in the presentation, clinical manifestations, and natural history among PNH patients. PNH can present as any of the following three syndromes or sets of symptoms:

  • Classic PNH
  • PNH in the setting of another specified bone marrow disorder (eg, PNH/aplastic anemia or PNH/refractory anemia- myelodysplastic syndrome [MDS])
  • Subclinical PNH (PNH-sc)

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 lactate dehydrogenase (LDH) level with a low serum haptoglobin level 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 typically occurs in unusual veins, namely the hepatic, abdominal, cerebral, and subdermal veins. The tendency of patients with PNH to suffer thrombosis has been recognized as a major part of the syndrome and interpreted as a very bad prognostic sign and the most common cause of death in PNH. About 30-40% of patients of European origin have serious thrombosis at some time; for unexplained reasons, only 5-10% of patients of East Asian (Chinese, Japanese, and Thai) or Mexican origin develop this complication. [17, 18]

The reason for this propensity is not entirely clear. Intravascular hemolysis may provide altered membrane surfaces upon which coagulation may be initiated. More likely, it is the effect of the activation of complement on platelets and perhaps endothelial cells. In platelets, the deposition of C9 complexes on the surface stimulates their removal by vesiculation; these vesicles are very thrombogenic. Because PNH platelets lack the mechanism for down-regulating C9 deposition (ie, CD59), even a minimal stimulus from activated complement results in a greatly increased production of these vesicles. [19]

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 pseudotumorcerebri.

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 PNH include esophageal spasms that occur in the morning and, like the dark-colored urine, clear up later in the day. In males, erectile dysfunction can occur concomitant with hemoglobinuria, the cause of which is unknown.

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Physical

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

  • Hepatomegaly and ascites in the presence of Budd-Chiari syndrome
  • Splenomegaly in the presence of 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
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