Paroxysmal Nocturnal Hemoglobinuria (PNH)


Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, chronic, hematologic condition in which erythrocytes undergo complement-mediated hemolysis. This in turn increases the volume of hemoglobin in the blood, which is eventually excreted through the urine.1 

In addition to the presence of hemoglobin in the urine, patients with PNH also demonstrate an increased likelihood of thrombosis, especially in medium and large vessels in the hepatic, abdominal, cerebral, and dermal veins.2

Clinicians should test for PNH if any patient presents with: hemoglobinuria; unexplained hemolysis accompanied by elevated lactate dehydrogenase (LDH) levels and absent serological haptoglobin; a history of large- or medium-vessel thrombosis; and/or thrombocytopenia, macrocytosis, or other signs of hemolysis.3 However, it is important to rule out conditions that may present with similar signs and symptoms. During the workup for PNH, many differential diagnoses need to be considered, including3: hemolytic anemia, paroxysmal cold hemoglobinuria (PCH), mesenteric artery ischemia, and thrombosis, such as mesenteric artery thrombosis, portal vein obstruction, and renal vein thrombosis.3

Hemolytic Anemia

Other causes of anemia, particularly autoimmune hemolytic anemia (AIHA), must be ruled out to accurately diagnose PNH.2

AIHA occurs when the body produces autoantibodies against its own erythrocytes, leading to their premature destruction.4 Hereditary spherocytosis (HS) is an inherited condition in which affected individuals experience a shortage of functional erythrocytes due to the abnormal spherical shape of the red blood cells.5,6 

One study published in 2018 compared hemolytic characteristics of patients diagnosed with PNH (n=108), AIHA (n=127), and HS (n=172). Patients with PNH (43.5%) were less likely to have splenomegaly than those with AIHA (98.6%) or HS (100%). The mean reticulocyte percentage was significantly lower (6.70%) and mean LDH levels were significantly higher (1500 U/L) in patients with PNH than in patients with AIHA (14% and 487 U/L, respectively) or HS (11.83% and 252 U/L, respectively).7 

In contrast, patients with HS had a higher prevalence of cholelithiasis (43.1%) and higher total bilirubin levels (mean: 79.3 μmol/L) than patients with PNH (2.9% and 26.2 μmol/L, respectively) or AIHA (10.5% and 57.6 μmol/L, respectively).7

Additionally, patients with AIHAs, such as cold agglutinin disease and warm autoimmune hemolytic anemia, test positive on the Coombs test, which is indicative of the presence of antibodies on the surface of erythrocytes. Patients with PNH test negative on the Coombs test.8,9

Read more about PNH testing

Paroxysmal Cold Hemoglobinuria

Paroxysmal cold hemoglobinuria is a rare hematologic condition in which the body’s immune system produces autoantibodies that prematurely destroy erythrocytes when the affected person is exposed to cold temperatures.10 

Similar to AIHA, individuals with PCH test positive on the Coombs test, whereas patients with PNH test negative.9

Read more about PNH clinical features

Mesenteric Artery Ischemia

Mesenteric artery ischemia is caused by a blockage or stenosis in 1 or more of the 3 major arteries supplying the small and large intestines with blood. This can result from atherosclerosis or thromboembolisms.11 

Around one-third of patients with PNH present with abdominal pain at the time of diagnosis. One study using perfusion and flow magnetic resonance imaging (MRI) scans showed that the impairment of small bowel blood supply was significantly correlated with symptoms of abdominal pain in patients with PNH. Mean blood flow MRI data for the superior mesenteric artery and vein showed decreased flow among patients with PNH experiencing abdominal pain compared with those of patients without abdominal pain.12 

Determining the underlying cause of ischemia helps to ascertain if it occurs in relation to PNH or if it is caused by other conditions.

Read more about PNH complications

Thrombosis

Mesenteric artery thrombosis, portal vein obstruction, and renal vein thrombosis all are differential diagnoses that must be considered, given the increased likelihood of thromboembolic events in patients with PNH.3 Thromboembolisms are a major cause of death in patients with PNH.12

Studies indicate that over 30% of patients with PNH experience thromboembolic complications related to the disease. Around 18.5% of thromboembolic events in patients with PNH originate from deep vein thrombosis in the mesenteric or splenic veins and 16.9% originate in the portal vein.12 The occurrence of renal vein or artery thrombosis is uncommon among patients with PNH.13 

Portal vein obstruction may also occur secondary to nearby malignancies and is a complication of several different metabolic and autoimmune diseases.14

Clinicians must rule out PNH as a contributing factor for any thrombosis that occurs, especially for thrombotic events in medium and large hepatic, abdominal, cerebral, and dermal blood vessels.

Read more about PNH diagnosis

Given the known association between PNH and bone marrow failure, any patients diagnosed with aplastic anemia or myelodysplastic syndrome (MDS) should repeatedly be tested for PNH at least every 6 months to 1 year.3 

Bone marrow failure due to aplastic anemia or MDS may cause anemia and other cytopenias either in the absence or in the presence of PNH clones. Patients with aplastic anemia or MDS should be tested for these PNH clones to confirm comorbidity with PNH. A clinical study published in 2021 conducted by Fattizzo and colleagues reported comorbid PNH and MDS in one-fifth of the patients and comorbid PNH and aplastic anemia in two-thirds of the patients.15

Read more about PNH comorbidities

References

  1. Paroxysmal nocturnal hemoglobinuria. MedlinePlus. Updated February 24, 2022. Accessed November 21, 2022.
  2. Paroxysmal nocturnal hemoglobinuria. Orphanet. Accessed November 21, 2022.
  3. Besa EC. Paroxysmal nocturnal hemoglobinuria differential diagnoses: diagnostic considerations. Medscape. Updated May 20, 2021. Accessed November 21, 2022.
  4. Immune hemolytic anemia. MedlinePlus. Accessed November 21, 2022. 
  5. Hereditary spherocytosis. MedlinePlus. Updated September 1, 2013. Accessed November 21, 2022.
  6. Hereditary spherocytosis. Nemours KidsHealth. Accessed November 21, 2022.
  7. Li WW, Shi J, Huang ZD, et al. [Comparison of hemolytic characteristics among paroxysmal nocturnal hemoglobinuria, autoimmune hemolytic anemia and hereditary spherocytosis]. Zhonghua Xue Ye Xue Za Zhi. 2018;39(4):299-304. Chinese. doi:10.3760/cma.j.issn.0253-2727.2018.04.008
  8. Theis SR, Hashmi MF. Coombs test. In: StatPearls [Internet]. Treasure Island, FL: StatPearls Publishing; 2022. Updated September 12, 2022. Accessed November 21, 2022.
  9. Zumberg M. Hemolytic anemia: autoimmune hemolytic anemia and PNH. Powerpoint presented at: University of Florida; May 2010. Accessed November 21, 2022.
  10. Paroxysmal cold hemoglobinuria (PCH). MedlinePlus. Accessed November 21, 2022.
  11. Mesenteric artery ischemia. Mount Sinai. Accessed November 21, 2022.
  12. De Cobelli F, Pezzetti G, Margari S, et al. New insights in abdominal pain in paroxysmal nocturnal hemoglobinuria (PNH): a MRI study. PLoS One. 2015;10(4):e0122832. doi:10.1371/journal.pone.0122832
  13. Hill A, Kelly RJ, Hillmen P. Thrombosis in paroxysmal nocturnal hemoglobinuria. Blood. 2013;121(25):4985-4996. doi:10.1182/blood-2012-09-311381
  14. Malik A, Sharma S, Young M, Giwa AO. Portal vein obstruction. In: StatPearls [Internet]. Treasure Island, FL: StatPearls Publishing; 2022. Updated May 5, 2022. Accessed November 21, 2022.
  15. 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

Reviewed by Harshi Dhingra, MD, on 11/23/2022.

READ MORE ON PNH