Patients with classic PNH will present with dark urine or symptoms of anemia and features of intravascular hemolysis: an elevated LDH and reticulocyte count, anemia, a positive urine hemosiderin stain, with low or absent haptoglobin. The chronic loss of hemoglobin in the urine can result in iron deficiency. The patient will often report that the urine is darkest in the morning; it is unclear if this is due to increased hemolysis at night, as once thought, or increased concentration of the urine due to nocturnal fasting. To clarify what patients mean by “dark urine” it is helpful to ask them to compare the color to some familiar liquid. Patients will often describe their darkest urine as appearing as cola, black ink, soy sauce—or appearing red. This may depend upon the oxidation status of the iron in the free hemoglobin. Bouts of darkened urine are interspersed with periods of time with apparently normal appearing urine, as per the term “paroxysmal,” sometimes with upward swings of a chronically elevated LDH and an exacerbation of anemia.

Patients will sometimes have had extensive urologic evaluations prior to referral to a hematologist: while a dipstick that is positive for “blood” in the absence of red cells on a microscopic examination will be a clue that the problem is not hematuria, some patients with PNH will actually have microscopic hematuria as well. In contrast, jaundice, hyperbilirubinemia, dark gallstones, and iron over load are features of extravascular hemolysis not typically seen on presentation—but are seen commonly in patients on C5 inhibitors. In untreated patients, free hemoglobin in the plasma can scavenge nitrous oxide and result in symptoms of smooth muscle dysfunction: abdominal pains, esophageal spasms, and male erectile dysfunction. Pulmonary arterial hypertension and renal dysfunction can occur, but this is usually subclinical. Sometimes a darkening of the kidneys is picked up on magnetic resonance images (MRI) as an incidental finding, a result of hemosiderin deposition. Attacks of hemolysis can be triggered by infection and fever, and due to abdominal discomfort, it may be difficult for patients to follow the typical instructions to keep well-hydrated. This can require a visit to the emergency room (ER) or infusion center for intravenous fluids, even if transfusions are not required at the time.

Patients with classic PNH can also present with thrombosis (with or without symptomatic hemolysis), typically involving unusual sites, such as the cerebral dural venous sinuses, the portal or hepatic veins, or other intra-abdominal veins, such as the inferior vena cava, the renal veins, splenic veins, or inferior or superior mesenteric veins. Thromboses in most of these sites can be detected by a sonogram with Doppler or a contrast computed tomography (CT), but mesenteric vein thrombosis can be detected only on an MR Venogram, which is also sensitive enough to identify thromboses in smaller branches of the hepatic veins as well. Splenic vein and mesenteric vein thromboses are particularly dangerous because they can lead to splenic rupture and bowel infarction respectively: both are surgical emergencies. Patients with thrombosis and secondary gastrointestinal hemorrhage (or central nervous system hemorrhage due to extensive cerebral vein thrombosis) also represent a particular challenge. Hypersplenism or marrow failure can result in thrombocytopenia, and PNH is therefore one of the conditions where the difficult combination of thrombocytopenia and thrombosis can occur. While the aspartate aminotransferase (AST) can be elevated simply due to hemolysis, an elevated alanine transaminase (ALT) in patients with PNH must be taken as a sign of Budd-Chiari syn drome until proven otherwise. Dermal venous thrombosis has been reported56 and can be complicated by necrosis. More familiar sites of thrombosis such as extremity deep venous thrombosis, pulmonary emboli, arterial cerebral vascular accidents (CVAs), and myocardial infarction can also occur in patients with PNH.

Patients presenting with AA/PNH fall along a spectrum, where they can resemble patients with aplastic anemia, or classic PNH, or both. As mentioned above, patients with AA/PNH can have thrombosis and thrombocytopenia at the same time due to marrow failure, resulting in a situation where anticoagulation would be dangerous.

In AA/PNH, the reticulocyte count and neutrophil count can be decreased as well. Aplastic anemia can precede the diagnosis of PNH, or can occur later. A fall in blood counts in a patient with PNH who has been previously stable should prompt a bone marrow biopsy and aspirate to rule out progression to MDS or AML.

The peripheral smear findings will often show various red cell abnormalities, but none is specific to PNH. However, the smear will be useful to rule out findings suggestive of competing causes of intravascular hemolysis and can indicate concurrent iron deficiency. In those with an adequate erythropoietic response and an elevated reticulocyte count, the most prominent feature on the smear can be polychromasia. The mean corpuscular volume (MCV) is usually elevated, even in the absence of reticulocytosis, as occurs in aplastic anemia.

The bone marrow in patients with classic PNH is typically hyper cellular with an erythroid hyperplasia, as can be seen in any patient with reticulocytosis (see Fig. 1). However, the marrow can range from hypocellular to hypercellular, and there is often a patchy distribution of the marrow. A normocellular or even hypercellular mar row does not rule out AA/PNH, and cytopenias may still respond to immune suppression. An increase in mast cells is sometimes noted. Almost a quarter of patients with PNH will have a cytogenetic abnormality, which is sometimes transient and by itself does not make a diagnosis of myelodysplasia (MDS). Likewise, morphological abnormalities can often be seen in PNH that overlap with those seen in MDS. However, excess blasts and complex cytogenetic abnormalities are diagnostic of MDS and are an indication for referral for stem cell transplantation—as may be the case for abnormalities of chromosome 7, which is associated with a poor prognosis when seen in aplastic anemia. Elevated platelets, white blood cell counts, or fibrosis are rare findings but can be seen in the PNH/MPN overlap syndrome and should prompt testing for mutations in JAK2 as well as BCR ABL fusions.

Fig1. THE MARROW CAN HAVE A WIDELY VARIABLE APPEARANCE IN PAROXYSMAL NOCTURNAL HEMOGLOBINURIA. (A) Hypercellularity with erythroid hyperplasia (Wright stain, aspirate), as might be seen in any hemolytic anemia; (B) H&E-stained section showing overall nor mocellularity; (C) marked hypocellularity, as would be seen in aplastic anemia. In this case there is a patchy distribution to the marrow with some cellular areas with increased erythropoiesis interspersed with acellular areas. The immune escape hypothesis proposes that it is the aplastic marrow environment that favors the PIGA mutant clones.

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مواضيع ذات صلة

Secondary Forms of Pure Red Cell Aplasia

Pathophysiology of Paroxysmal Nocturnal Hemoglobinuria

Hypothyroidism: Etiology and Treatment

Introduction and History of Paroxysmal Nocturnal Hemoglobinuria

Diseases of The Central Nervous System

Diseases of The Oral Cavity

Diseases of The Upper Respiratory Tract

Hyperthyroidism: Etiology and Treatment

Clinical Features of Hyper- and Hypothyroidism

Clinical Associations of Aplastic Anemia

Typical and Atypical Presentations of Aplastic Anemia

Pathophysiologic Pathways Leading to Aplastic anemia