History and exam

Key diagnostic factors

common

hemoglobinuria

Seen in almost all patients at some point, often with infections or as paroxysms lasting 2 to 6 days.[1][10] Dark urine is a presenting symptom in about 20% of patients.

Budd-Chiari syndrome

Hepatic venous thrombosis, characterized by right upper quadrant pain, liver enlargement, and ascites with documentation of thromboses by imaging techniques, occurs in about 10% of patients with PNH.[15][18][23]

thrombosis

Seen in approximately 40% of patients of European ancestry. Usually venous and often in unusual sites.[11][15][18][23] Incidence in East Asian populations is much lower (approximately 20%).[18] Deep vein thrombosis is common, but cerebral sinuses or arteries may be involved.

Other diagnostic factors

common

history of aplastic anemia

See in about 20% of patients with PNH, often successfully treated with immunosuppression.[15][18]

fatigue

Almost all patients with PNH, regardless of the degree of anemia, have fatigue and listlessness.[1]

anemia

More than 90% of patients with PNH are anemic at presentation. Degree of anemia varies greatly and is accompanied by signs of intravascular hemolysis (increased reticulocyte count, increased serum LDH, low haptoglobin).[18] In descending order, hemolysis, iron deficiency, and concomitant bone marrow hypoplasia contribute to the anemia of PNH patients.

abdominal pain

May be caused by smooth muscle dystonia (due to lack of nitric oxide) or intra-abdominal venous thrombosis.[9] May last only hours or up to 2 to 4 days. Pain could be severe or relatively mild. May be located in any area of the abdomen.[1]

dysphagia and odynophagia

Difficult or painful swallowing due to increased esophageal contractions. Symptoms worsen during hemolytic episodes.

erectile dysfunction

Almost all men have erectile dysfunction, especially during paroxysms of hemoglobinuria.[9]

dyspnea

Many patients have dyspnea, which may be due to anemia or pulmonary hypertension.[9]

infections

Moderately common due to granulocytopenia.[15]

uncommon

bleeding diathesis

Petechiae, ecchymoses, or frank bleeding (epistaxis, mucosal bleeding, gastrointestinal bleeding, genitourinary bleeding) may occur in the setting of concomitant marrow hypoplasia or myelodysplastic syndrome with low platelet numbers.

neurologic signs and symptoms

Usually related to cerebrovascular thrombotic events. Signs of elevated intracranial pressure (headache/vomiting, papilledema, coma in severe cases) and/or frank sensorimotor deficits according to the affected site.[20]

Risk factors

strong

aplastic anemia/hypoplastic bone marrow

About 50% of patients with aplastic anemia have a clone of paroxysmal nocturnal hemoglobinuria (PNH) cells, predominantly small and asymptomatic.[7]​​ Expansion of the clone, sufficient to cause symptoms, occurs in about 15% of patients with aplastic anemia successfully treated without stem cell transplantations.[12] The reason for the expansion of the clone(s) in these patients is unknown.

The presence of a PNH clone, regardless of its size, has been associated with a favorable response to immunosuppressive therapy (IST) and stem cell transplantation (SCT) in aplastic anemia. Patients with PNH positivity showed higher success rates for IST response and hematopoietic SCT outcomes compared with those without PNH. Additionally, PNH positivity had a beneficial impact on clonal evolution.[13]

All patients with PNH have a degree of marrow hypoplasia, often detected only by marrow culture studies.[14] Patients with classic PNH may have bone marrow failure as a late event.[15]

weak

myelodysplasia

Small PNH clones have been described in patients with low-risk myelodysplasia, particularly refractory anemia with a hypoplastic marrow. Clinical PNH arises in a few of these patients.[16][17]​​ The presence of a PNH clone, regardless of its size, has been associated with a favorable response to IST and stem cell transplantation in myelodysplastic syndromes.[13]

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