Paroxysmal Nocturnal Hemoglobinuria (PNH)


Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematologic condition affecting hematopoietic stem cells and their mature progeny, including erythrocytes, leukocytes, and platelets.1 

Patients with PNH clinically manifest with a heterogeneous range of phenotypes, primarily centered around 3 hallmark characteristics of the disease: intravascular hemolysis, thrombosis, and bone marrow failure. Additional clinical features include smooth muscle dystonia and renal dysfunction.1,2

Role of Genetics in PNH

Paroxysmal nocturnal hemoglobinuria is primarily caused by acquired somatic mutations, predominantly in the X-linked PIGA gene. Most patients with PNH exhibit multiple genetic mutations that seem to collaboratively sustain clonal expansion and survival of PNH-derived cells and act as risk factors for thrombosis in PNH. The wide variety of genetic mutations among patients with PNH also explains the clinical heterogeneity of the disease.3

Pathophysiology of Intravascular Hemolysis in PNH

One of the main features of classic PNH is intravascular hemolysis. Premature destruction of erythrocytes occurs due to activation of the complement system. PIGA mutations cause problems with the biosynthesis of glycosylphosphatidylinositol (GPI)-anchored proteins, resulting in a deficiency of these proteins on the membranes of PNH-affected hematopoietic stem cells and their mature progeny of blood cells, including erythrocytes.2

GPI-anchor proteins, especially CD55 and CD59, inhibit the activation of the complement system. A lack of these GPI-anchor proteins covering the membrane surface of erythrocytes results in the formation of the membrane attack complex (MAC) on the surface of PNH-affected erythrocytes. The MAC serves as a targeting signal for the immune system to destroy the affected blood cell.2

Intravascular hemolysis leads to a host of classic PNH signs and symptoms, including hemoglobinuria, hemolytic anemia, iron deficiency, and smooth muscle dystonia.2,4 

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Pathophysiology of Thrombosis in PNH

Thrombosis, especially venous thrombosis, is another clinical feature found in classic PNH, occurring in around 40% of patients. Venous thrombosis is among the leading causes of mortality among patients with PNH, often developing in cerebral, portal, hepatic, mesenteric, splenic, and renal veins.2

The Role of PNH Clones

The underlying pathophysiology of thrombosis related to PNH is not completely understood; however, studies have shown that patients with larger PNH clones are predisposed to developing thrombosis compared to patients whose PNH clones are smaller in size.2,5,6 Researchers hypothesize that there is a direct correlation between the number of circulating PNH-affected blood cells and thrombotic risk.2

The Role of the Fibrinolytic System

Studies have confirmed procoagulant and fibrinolytic activities indicative of increased fibrin production and turnover in patients with PNH.2,6 Additionally, researchers have identified specific failures of the fibrinolytic system, such as a deficiency in urokinase-type plasminogen activator receptors on PNH granulocytes and increased plasma levels of soluble urokinase-type plasminogen activator receptor.1,2,7 This receptor attaches to cell membranes via GPI-anchor proteins and plays a critical role in the conversion of plasminogen to plasmin.7,8 

The plasminogen activator system serves multiple roles, including the dissolution of clots formed by fibrin, angiogenesis, cell migration, wound healing, the inflammatory response, and apoptotic cell death. In many cancers, the plasminogen activator system contributes to tumor growth, angiogenesis, tumor cell invasion, migration, and metastasis.8

Other Possible Pathophysiologies

Although experiments have not confirmed any mechanisms of action, some researchers have postulated that the complement system itself might cause platelet activation and aggregation, contributing to clot formation.1    

Thrombophilia in patients with PNH may also be caused by the release of free hemoglobin in the blood during intravascular hemolysis. Free plasma hemoglobin scavenges nitric oxide from the plasma. Nitric oxide blocks platelet aggregation and adhesion to the vascular endothelium, so decreased levels of nitric oxide in patients with hemolytic PNH may contribute to thrombosis and smooth muscle dystonia.1,9 

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Pathophysiology of Bone Marrow Failure in PNH

Paroxysmal nocturnal hemoglobinuria may occur comorbidly with other bone marrow failure disorders, including aplastic anemia and myelodysplastic syndrome.2 Some extent of bone marrow failure is present in all patients with PNH, as the disorder affects hematopoietic stem cells located in the bone marrow.2,10 The degree of bone marrow failure varies, most likely due to genetic factors.2

Clonal expansion and propagation of PNH-affected stem cells result in GPI-anchor-deficient leukocytes and platelets in addition to erythrocytes.1 In severe cases of bone marrow failure, pancytopenia may develop, affecting all 3 blood cell counts.10 Bone marrow failure may evolve into myeloid malignancies, particularly acute myeloid leukemia, in some cases of PNH.11

Read more about PNH comorbidities

Pathophysiology of Renal Dysfunction in PNH

The 3 main causes of renal failure in patients with PNH include recurrent urinary tract infections (UTIs), renal vein thrombosis, and acute tubular necrosis due to pigment nephropathy.2 

Hemoglobinuria is correlated with recurrent UTIs, especially among female patients with PNH. Renal vein thrombosis causes reduced renal perfusion, leading to renal dysfunction. Acute tubular necrosis usually results from the sequelae of major hemolytic attacks, including hemoglobinuria, the toxicity of heme and iron that passes through the renal tubules, decreased renal perfusion, and obstruction of renal tubules with pigment casts.2 

Chronic renal failure occurs following years of recurrent episodes of hemolysis and hemoglobinuria, which cause significant glomerular necrosis, interstitial fibrosis of the kidneys, and atrophy of the renal tubules.2   

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References

  1. Risitano AM, Rotoli B. Paroxysmal nocturnal hemoglobinuria: pathophysiology, natural history and treatment options in the era of biological agents. Biologics. 2008;2(2):205-222. doi:10.2147/btt.s1420
  2. Bessler M, Hiken J. The pathophysiology of disease in patients with paroxysmal nocturnal hemoglobinuria. Hematology Am Soc Hematol Educ Program. 2008;2008(1):104-110. doi:10.1182/asheducation-2008.1.104
  3. Chen F, Hu S, Ruan J, Chen M, Han B. Mutational landscape and its clinical significance in paroxysmal nocturnal hemoglobinuria. Blood Cancer J. 2021;11(3):58. doi:10.1038/s41408-021-00451-1
  4. Peng G, Yang W, Jing L, et al. Iron deficiency in patients with paroxysmal nocturnal hemoglobinuria: a cross-sectional survey from a single institution in China. Med Sci Monit. 2018;24:7256-7263. doi:10.12659/MSM.910614
  5. Moyo VM, Mukhina GL, Garrett ES, Brodsky RA. Natural history of paroxysmal nocturnal haemoglobinuria using modern diagnostic assays. Br J Haematol. 2004;126(1):133-138. doi:10.1111/j.1365-2141.2004.04992.x
  6. Grünewald M, Siegemund A, Grünewald A, et al. Plasmatic coagulation and fibrinolytic system alterations in PNH: relation to clone size. Blood Coagul Fibrinolysis. 2003;14(7):685-695. doi:10.1097/00001721-200310000-00011
  7. Gao W, Wang Z, Bai X, Li Y, Ruan C. Diagnostic significance of measurement of the receptor for urokinase-type plasminogen activator on granulocytes and in plasma from patients with paroxysmal nocturnal hemoglobinuria. Int J Hematol. 2002;75(4):434-439. doi:10.1007/BF02982138
  8. Mahmood N, Mihalcioiu C, Rabbani SA. Multifaceted role of the urokinase-type plasminogen activator (uPA) and its receptor (uPAR): diagnostic, prognostic, and therapeutic applications. Front Oncol. 2018;8:24. doi:10.3389/fonc.2018.00024
  9. Rother RP, Bell L, Hillmen P, Gladwin MT. The clinical sequelae of intravascular hemolysis and extracellular plasma hemoglobin: a novel mechanism of human disease. JAMA. 2005;293(13):1653-1662. doi:10.1001/jama.293.13.1653
  10. Paroxysmal nocturnal hemoglobinuria. National Organization for Rare Disorders (NORD). Accessed November 30, 2022.

Awada H, Rahman S, Durrani J, et al. Leukemia evolving from paroxysmal nocturnal hemoglobinuria. Leukemia. 2020;34(1):327-330. doi:10.1038/s41375-019-0555-0

Reviewed by Harshi Dhingra, MD, on 11/30/2022.

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