Paroxysmal Nocturnal Hemoglobinuria (PNH)


Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired hematologic condition caused by the premature, complement-mediated intravascular hemolysis of erythrocytes. As a result of the hemolysis, free hemoglobin accumulates in the blood and is excreted in the urine.1 

Hemolysis is ongoing in patients with PNH. Periods of stress, such as physical exertion, pregnancy, infection, or injury, may also exacerbate intravascular hemolysis, with the development of sudden episodes of severe hemolysis.1-4  

Concern for Surgery as a Trigger of Hemolysis

Major surgery can trigger complement activation and worsen hemolysis in patients with PNH when they undergo surgical interventions.3,4 Postoperative thrombosis presents an additional risk for these patients if they require surgery.3 

Surgery used to be considered a high-risk event for patients with PNH. After the advent of complement inhibitor therapies, patients can undergo surgery safely provided they receive adequate perioperative management.3

Read more about PNH risk factors

Perioperative Management

Soliris® (eculizumab) and Ultomiris® (ravulizumab) are humanized monoclonal antibodies developed to target terminal complement 5 (C5). These drugs prevent formation of the membrane attack complex on the surface of erythrocytes, effectively reducing intravascular hemolysis, thrombosis, and inflammation in patients with PNH.5 If surgery is required for a patient with PNH, perioperative management of the patient’s complement inhibitor therapy can prevent hemolytic complications and improve surgical outcome.6 

Read more about PNH therapies

Studies on Perioperative Management in PNH

In 2018, a panel of Belgian experts published recommendations for the diagnosis and management of patients with PNH, including guidelines for surgical management.6 The guidelines suggested that patients currently receiving Soliris should undergo elective surgery within 7 days of the last Soliris infusion. In the case of emergency surgery, patients should receive an additional infusion of Soliris if the last treatment was administered more than 7 days before the surgery.6

More recent recommendations for the treatment of PNH, based on the best available evidence and international guidelines published in 2021, suggest that Soliris be administered the day before an elective surgery.7 

A Japanese study indicated that the administration of Ultomiris 1 day before surgery effectively prevented hemolytic complications in a patient with PNH who underwent laparoscopic cholecystectomy.8

Read more about PNH clinical trials

Management of PNH During Pregnancy 

Complement inhibitor therapy is recommended for women with PNH during pregnancy to avoid breakthrough hemolysis and maternal and fetal complications during pregnancy and delivery.6,7 Women with PNH should not discontinue these therapies during pregnancy or while breastfeeding. Anticoagulation prophylaxis with warfarin can also be implemented during pregnancy.7

Breakthrough Hemolysis on Complement Inhibitor Therapy

Breakthrough hemolysis can occur during complement-amplifying conditions, such as major surgery and pregnancy, when an excess accumulation of complement 3b (C3b) on the surface of PNH erythrocytes results in a conformational change in C5. The C5 conformational change decreases the ability of Soliris or Ultomiris to bind to C5, so that breakthrough hemolysis may occur even in the absence of elevated levels of free C5.4 

For patients experiencing breakthrough hemolysis during or after a surgical procedure, an extra dose of Soliris should be considered to control the hemolysis.7

Read more about PNH complications

Thrombotic Prophylaxis After Surgery

Because thrombosis is one of the main clinical features and causes of patient mortality in PNH, postoperative thrombosis is a concern for patients with this disease. Surgery and the immobilization that follows surgery increase thrombotic risk.3,9

Perioperative prophylactic anticoagulation with low-molecular-weight heparin or coumarins to prevent hemolysis is mandatory for patients with PNH.7,10 

Read more about PNH guidelines

References

  1. Paroxysmal nocturnal hemoglobinuria. NORD (National Organization for Rare Disorders). Accessed November 25, 2022.
  2. Fassett MJ, Hernandez Lopez AL. Treatment of paroxysmal nocturnal hemoglobinuria in pregnancy with eculizumab: a case report. Case Reports in Women’s Health. 2021;30:e00294. doi:10.1016/j.crwh.2021.e00294
  3. Tsutsui M, Gotoh A, Yasuda H, Ono E, Tanaka M, Komatsu N. [Successful management of orthopedic operations requiring general anesthesia in a PNH patient after introduction of eculizumab]. [Article in Japanese]. Rinsho Ketsueki. 2015;56(4):423-427. doi:10.11406/rinketsu.56.423
  4. Brodsky RA. How I treat paroxysmal nocturnal hemoglobinuria. Blood. 2021;137(10):1304-1309. doi:10.1182/blood.2019003812
  5. Connell NT. Ravulizumab: a complementary option for PNH. Blood. 2019;133(6):503-504. doi:10.1182/blood-2018-12-891499
  6. Devos T, Meers S, Boeckx N, et al. Diagnosis and management of PNH: review and recommendations from a Belgian expert panel. Eur J Haematol. 2018;101(6):737-749. doi:10.1111/ejh.13166
  7. Cançado RD, Araújo A da S, Sandes AF, et al. Consensus statement for diagnosis and treatment of paroxysmal nocturnal haemoglobinuria. Hematol Transfus Cell Ther. 2021;43(3):341-348. doi:10.1016/j.htct.2020.06.006
  8. Kimura M, Nishiyama Y, Ueda H, et al. [Perioperative management of laparoscopic cholecystectomy in a patient with paroxysmal nocturnal haemoglobinuria undergoing ravulizumab treatment]. [Article in Japanese]. Rinsho Ketsueki. 2022;63(4):260-264. doi:10.11406/rinketsu.63.260
  9. Hill A, Kelly RJ, Hillmen P. Thrombosis in paroxysmal nocturnal hemoglobinuria. Blood. 2013;121(25):4985-4996. doi:10.1182/blood-2012-09-311381

Schubert J, Röth A. Update on paroxysmal nocturnal haemoglobinuria: on the long way to understand the principles of the disease.Eur J Haematol. 2015;94(6):464-473. doi:10.1111/ejh.12520

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

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