Paroxysmal Nocturnal Hemoglobinuria (PNH)


Paroxysmal nocturnal hemoglobinuria (PNH) is a rare disorder in which somatic mutations in the phosphatidylinositol glycan class A (PIGA) gene result in impaired production of glycosylphosphatidylinositol (GPI) anchor proteins on hematopoietic stem cells. GPI anchors, which are glycolipid moieties by which numerous proteins attach to the surface of cells, include the complement-inhibitory proteins CD55 and CD59. 

The deficiency of GPI-anchored complement-regulatory proteins renders the red blood cells susceptible to complement-driven intravascular hemolysis, which can lead to hemolytic anemia, venous and arterial thrombosis, smooth-muscle dystonia, and bone marrow failure. Various signs and symptoms of PNH include fatigue, shortness of breath on exertion, inability to engage in physical activity, abdominal pain, esophageal spasm, bloating, back pain, headache, male erectile dysfunction, and dysphagia.1

In some cases, serious symptoms of PNH progress to life-threatening complications such as thrombosis, in which blood flow to vital organs is cut off. Common complications of PNH include venous or arterial thrombosis, acute or chronic kidney dysfunction, arterial and pulmonary hypertension, recurrent infectious diseases, and bone marrow failure.1

Since the approval of the complement inhibitors Soliris® (eculizumab) in 2007 and Ultomiris® (ravulizumab) in 2018, the symptoms related to intravascular hemolysis have been mostly eliminated, the risk for thrombosis has been significantly reduced, and median survival, formerly 15 to 20 years, has increased to match that of age-matched controls.2

Although C5 inhibitors have improved the clinical outcomes of patients with PNH, reducing morbidity and mortality, they are unable to prevent breakthrough hemolysis and extravascular hemolysis due to the deposition of C3 on red blood cells. Thus, patients continue to experience hemolysis, persistent chronic anemia, fatigue, and impaired quality of life.3

Pulmonary Hypertension

Pulmonary hypertension (PH) in patients with PNH is rare and often associated with pulmonary emboli, but it can also be caused by nitric oxide depletion in the pulmonary circulation. The significant increase in free hemoglobin in the circulation caused by complement-mediated hemolysis results in reduced levels of nitric oxide. Nitric oxide depletion inhibits smooth-muscle relaxation and induces an increase in systemic and pulmonary vascular resistance, which may lead to PH. PH stresses the heart, which must work harder to pump blood through the body. Symptoms of PH include tiredness, dizziness, shortness of breath, chest pain or pressure, and swelling in the ankles or legs.4

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Renal Failure 

Renal failure is a complication of PNH caused by repeated severe acute episodes of hemolysis, chronic intravascular hemolysis, microvascular thrombosis, and urinary infection. The kidneys may be affected by acute or chronic intravascular hemolysis as a consequence of the release of free heme into the plasma and subsequent nitric oxide depletion. This results in renal arterial constriction and iron deposition (renal hemosiderosis), with alterations in renal blood flow, hemosiderin deposition in the proximal renal tubules, tubulo-interstitial inflammation, intraluminal cylinder formation, cortical infarcts, and impaired proximal tubule function.5,6

With the availability of complement inhibitors, the renal function of patients with PNH has improved as a consequence of decreased intravascular hemolysis, normalized nitric oxide levels, and improved vascular tone.7

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Thrombosis

Although the incidence of thrombosis has decreased significantly since the introduction of complement inhibitor therapies, thrombosis is still the most frequent and feared complication of PNH. Thrombosis is a natural mechanism that helps to stop bleeding in a healthy individual. However, the risk for thrombosis is increased in patients with PNH. Thrombosis may block the flow of blood to vital organs, such as the heart and brain, and cause life-threatening complications. Symptoms of thrombosis include swelling, pain, change of skin color, headache, and numbness or weakness on one side of the body.8

Although thrombosis in PNH can occur at any site, it develops more frequently in veins (80%-85%) and rarely in arteries (15%-20%). The common venous sites of occurrence include the cerebral veins, intraabdominal veins (eg, portal, mesenteric, and splenic veins), and hepatic veins. The hepatic veins are reported to be the most common site of thrombosis (hepatic vein thrombosis, or Budd-Chiari syndrome), which may lead to hepatic failure. Cerebral venous thrombosis may occur in the sagittal sinus, lateral sinus, cavernous sinus, and sigmoid sinus, causing neurological symptoms such as vomiting, severe headache, altered level of consciousness, and seizures. 

Painful, discolored skin lesions may be the consequence of dermal vein thrombosis. In small, peripheral mesenteric veins, thrombosis may induce transient ischemia and cause symptoms such as abdominal pain, fever, obstruction, and rectal bleeding. Thrombosis in duodenal veins may cause papillary endothelial hyperplasia, ulceration, and a circumferential mass in the third portion of the duodenum. Thrombosis in the renal vein or renal artery is rare but may lead to renal impairment. Thrombosis in the deep veins of the lower limbs and blood vessels of the lungs may also occur in patients with PNH.2,8,9

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Aplastic Anemia

Aplastic anemia (AA) is an autoimmune disorder caused by the T-cell-mediated destruction of hematopoietic stem and progenitor cells (HSPCs) and is closely associated with PNH. PNH is found concurrently in approximately 20% of patients with AA at diagnosis. It is possible that this close association may arise from overlapping etiologies. In most patients who have PNH with AA, the PNH clone is very small (<10%). In such patients, underlying bone marrow failure and hemolysis are associated with 2 or 3 cytopenias, such as hemoglobin level below 10 g/dL, neutrophil count below 1000/µL, and platelet count below 80,000/µL. It is important to screen for PNH clones in patients with AA because the response to immunosuppressive therapy is better when PNH cells are present.6,10

Bone Marrow Failure (Hematologic Malignancies)

In approximately 2.3% to 6.4% of patients with PNH, secondary hematologic malignancies — myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) — develop after 7 to 10 years of follow-up. However, the development of leukemic or MDS clones from the PNH clone remains debatable. In one study, the rate of mutations in ASXL1, RUNX1, and SETBP1 was higher in patients who had PNH with secondary MDS than in those who had PNH without secondary MDS. Common symptoms of AML and MDS include weakness, tiredness, occasional shortness of breath, frequent infections, and easy bruising or bleeding.6,11,12

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References

  1. Shah N, Bhatt H. Paroxysmal nocturnal hemoglobinuria. StatPearls [Internet]. Updated August 1, 2022. Accessed December 3, 2022.
  2. Brodsky RA. How I treat paroxysmal nocturnal hemoglobinuria. Blood. 2021;137(10):1304-1309. doi:10.1182/blood.2019003812
  3. Bektas M, Copley-Merriman C, Khan S, Sarda SP, Shammo JM. Paroxysmal nocturnal hemoglobinuria: current treatments and unmet needs. J Manag Care Spec Pharm. 2020;26(12-b Suppl):S14-S20. doi:10.18553/jmcp.2020.26.12-b.s14
  4. Hill A, Sapsford RJ, Scally A, et al. Under-recognized complications in patients with paroxysmal nocturnal haemoglobinuria: raised pulmonary pressure and reduced right ventricular function. Br J Haematol. 2012;158(3):409-414. doi:10.1111/j.1365-2141.2012.09166.x
  5. Hillmen P, Elebute M, Kelly R, et al. Long-term effect of the complement inhibitor eculizumab on kidney function in patients with paroxysmal nocturnal hemoglobinuria [published correction appears in Am J Hematol. 2010;85(11):911]. Am J Hematol. 2010;85(8):553-559. doi:10.1002/ajh.21757
  6. Devalet B, Mullier F, Chatelain B, Dogné JM, Chatelain C. Pathophysiology, diagnosis, and treatment of paroxysmal nocturnal hemoglobinuria: a review. Eur J Haematol. 2015;95(3):190-198. doi:10.1111/ejh.12543
  7. Villegas A, Núñez R, Gaya A, et al. Presence of acute and chronic renal failure in patients with paroxysmal nocturnal hemoglobinuria: results of a retrospective analysis from the Spanish PNH Registry. Ann Hematol. 2017;96(10):1727-1733. doi:10.1007/s00277-017-3059-x
  8. Hill A, Kelly RJ, Hillmen P. Thrombosis in paroxysmal nocturnal hemoglobinuria. Blood. 2013;121(25):4985-4996. doi:10.1182/blood-2012-09-311381
  9. Griffin M, Munir T. Management of thrombosis in paroxysmal nocturnal hemoglobinuria: a clinician’s guide. Ther Adv Hematol. 2017;8(3):119-126. doi:10.1177/2040620716681748
  10. Fattizzo B, Ireland R, Dunlop A, et al. Clinical and prognostic significance of small paroxysmal nocturnal hemoglobinuria clones in myelodysplastic syndrome and aplastic anemia. Leukemia. 2021;35(11):3223-3231. doi:10.1038/s41375-021-01190-9
  11. 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
  12. Negoro E, Nagata Y, Clemente MJ, et al. Origins of myelodysplastic syndromes after aplastic anemia. Blood. 2017;130(17):1953-1957. doi:10.1182/blood-2017-02-767731

Reviewed by Hasan Avcu, MD, on 12/6/2022.

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