Paroxysmal Nocturnal Hemoglobinuria (PNH)


Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, potentially life-threatening hematologic condition characterized by premature complement-mediated destruction of erythrocytes, leading to the excretion of hemoglobin in the urine. Leukocytes and platelets may also be affected, depending on the extent of bone marrow involvement.1 

Paroxysmal nocturnal hemoglobinuria manifests through many signs and symptoms, indicative of hemolytic anemia, bone marrow failure, and thrombosis. Patients with PNH often present with these clinical features in varying stages and combinations.2 

Signs of Hemoglobinuria

Paroxysmal nocturnal hemoglobinuria derives its name from its most noticeable sign, which is dark-colored urine indicative of hemoglobinuria. Hemoglobinuria points to the hemolysis of erythrocytes.3 

In most cases of PNH, this dark urine is most noticeable during the night or first thing in the morning after initial elimination. Excess hemoglobin collects in the bladder overnight, allowing for higher concentrations and resulting in more visible discoloration of the urine.1,3 Hemoglobinuria may occur suddenly and worsen during periods of stress, physical exertion, or infection.4

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Signs and Symptoms of Smooth Muscle Dystonia

Intravascular hemolysis produces an excess of free hemoglobin circulating in the blood. This circulating free hemoglobin leads to the depletion of nitric oxide, which ‌results in smooth muscle dystonia and kidney dysfunction.2 Symptoms of smooth muscle dystonia include2,3:

  • Dysphagia
  • Esophageal spasms
  • Erectile dysfunction
  • Abdominal or chest pain
  • Pulmonary hypertension

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Signs and Symptoms of Hemolytic Anemia 

Due to complement-mediated, chronic intravascular hemolysis, patients with PNH may demonstrate symptoms of hemolytic anemia, which can affect daily functioning and exercise or activity tolerance. These symptoms include1,3-5:

  • Severe fatigue or tiredness 
  • Dyspnea, especially on exertion
  • Weakness
  • Extremely pale skin (pallor)
  • Jaundice 
  • Tachycardia
  • Dizziness or lightheadedness
  • Headaches
  • Chest pain

The breakdown of erythrocytes causes a lack of circulating oxygen, which is usually carried by hemoglobin in erythrocytes through the blood to the rest of the body. All cells need oxygen to produce energy for cellular functions. The lack of oxygen caused by hemolytic anemia results in these symptoms of PNH.6

Intravascular hemolysis also causes the formation of excess bilirubin, which leads to jaundice. ​​Chronic hemolysis can lead to blood clots affecting the liver, leading to conditions such as Budd-Chiari syndrome, jaundice, and abdominal pain. The exact reason for blood clots is unknown; however, they may be due to defective platelets produced by defective hematopoietic stem cells.5 

Tachycardia results from the body’s attempt to compensate for oxygen deficiency by rapidly pumping available oxygen throughout the body, which may cause left ventricular hypertrophy and cardiovascular complications in the long term.7 

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Signs and Symptoms of Bone Marrow Failure

PNH may co-occur with aplastic anemia or myelodysplastic syndrome (MDS), both of which are bone marrow failure disorders.3 Immune-mediated aplastic anemia is the greatest risk factor for developing PNH. Around 2% to 6% of patients with PNH also develop secondary MDS or acute myeloid leukemia.8 

The most common symptom of bone marrow failure is pancytopenia, a decreased count in all 3 blood cell lines (erythrocytes, leukocytes, and platelets).9 In addition to anemia symptoms, other symptoms of bone marrow failure include9,10:

  • Frequent or prolonged infections and fever due to leukopenia
  • Easy bruising or bleeding, especially mucosal bleeding, due to thrombocytopenia

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Signs and Symptoms of Thrombosis

Thrombosis, especially deep vein thrombosis, occurs in around 30% of patients with PNH, and between 29% and 44% of patients with PNH experience at least 1 thromboembolic event.5,11 Thrombosis in patients with PNH often develops in unusual veins, such as abdominal (hepatic, mesenteric, portal, splenic, inferior vena cava), dermal, and cerebral veins.11,12

Symptoms of thrombosis may include10,11:

  • Hepatomegaly due to Budd-Chiari syndrome
  • Ascites due to Budd-Chiari syndrome
  • Splenomegaly due to splenic vein thrombosis
  • Absent bowel sounds due to bowel necrosis
  • Abdominal pain
  • Papilledema, severe headache, vomiting, seizures, altered consciousness, and cranial nerve (VI and VII) palsies due to cerebral vein thrombosis, particularly in the superior sagittal sinus
  • Red, painful skin lesions due to dermal vein thrombosis.

Thromboembolic events may result in symptoms indicative of pulmonary embolism, cerebrovascular attacks, and myocardial infarction in patients in PNH, and they may even cause death.13

Clinical recognition of these signs and symptoms is necessary for the accurate and rapid diagnosis of PNH.

Read more about PNH diagnosis

References

  1. Paroxysmal nocturnal hemoglobinuria. MedlinePlus. Updated February 24, 2022. Accessed November 24, 2022.
  2. Scott BL, Dingli D, Shrit MA. Clinical consequences of paroxysmal nocturnal hemoglobinuria and aplastic anemia: a multidisciplinary discussion. Clin Adv Hematol Oncol. 2018;16(4):Supplement 11.
  3. Paroxysmal nocturnal hemoglobinuria. Cleveland Clinic. Accessed November 24, 2022.
  4. Paroxysmal nocturnal hemoglobinuria. Genetic and Rare Diseases Information Center (GARD). Updated November 8, 2021. Accessed November 24, 2022.
  5. Paroxysmal nocturnal hemoglobinuria. National Organization for Rare Disorders (NORD). Accessed November 24, 2022.
  6. What is anemia? National Institutes of Health (NIH): National Heart, Lung, and Blood Institute. Updated March 24, 2022. Accessed November 24, 2022.
  7. Mozos I. Mechanisms linking red blood cell disorders and cardiovascular diseases. Biomed Res Int. 2015;2015:682054. doi:10.1155/2015/682054
  8. Sun L, Babushok DV. Secondary myelodysplastic syndrome and leukemia in acquired aplastic anemia and paroxysmal nocturnal hemoglobinuria. Blood. 2020;136(1):36-49. doi:10.1182/blood.2019000940
  9. Nagalla S. Bone marrow failure: etiology. Medscape. Updated December 6, 2021. Accessed November 24, 2022.
  10. Besa EC. Paroxysmal nocturnal hemoglobinuria clinical presentation: physical. Medscape. Updated May 20, 2021. Accessed November 24, 2022.
  11. Hill A, Kelly RJ, Hillmen P. Thrombosis in paroxysmal nocturnal hemoglobinuria. Blood. 2013;121(25):4985-4996. doi:10.1182/blood-2012-09-311381
  12. Besa EC. Paroxysmal nocturnal hemoglobinuria clinical presentation: history. Medscape. Updated May 20, 2021. Accessed November 24, 2022.
  13. Gris JC, Chéa M, Guillotin F, et al. Thrombosis and paroxysmal nocturnal haemoglobinuria. Thrombosis Update. 2021;5:100074. doi:10.1016/j.tru.2021.100074

Reviewed by Debjyoti Talukdar, MD, on 11/30/2022.

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