Paroxysmal nocturnal hemoglobinuria (PNH) is a condition that is poorly defined and difficult to diagnose. Characterized by episodic complement-mediated hemolysis, its classic presentation is the sudden, episodic, and night-time occurrence of hemoglobin in the urine. The most common symptom shared by patients with this disease is debilitating fatigue. 

According to the International Paroxysmal Nocturnal Hemoglobinuria Interest Group, there are 3 subcategories of the disease. This classification system, while not universally used, takes into account variations in presentation, clinical manifestations, and disease progression in patients. 

“Because of the rarity of PNH, the incidence and prevalence rates have been poorly reported and have likely been underestimated,” Bektas and colleagues wrote in the Journal of Managed Care + Specialty Pharmacy.

This means that epidemiological data regarding this disease is often unreliable. Nevertheless, it is estimated that 5000 to 6000 individuals in the US are affected by the disease. A long-term study in the UK estimated that it has an annual incidence of 0.13 per 100,000 population in the regions studied. 

Hemolytic Anemia Holds Great Importance

“Among the clinical symptoms of PNH, the greatest importance is attributed to chronic hemolysis in the intravascular system caused by a deficiency of the complement inhibitory proteins CD55 and CD59 on [red blood cells],” Szlendak and colleagues wrote in the Polish Archives of Internal Medicine. 

The formation of membrane attack complex on red blood cells and increased hemolysis result in free hemoglobin being released into the plasma, which is then renally excreted. Over time, kidney damage can occur, predisposing one to recurrent urinary tract infections. It is estimated that 4 in 10 untreated patients have renal dysfunction, contributing to 8% to 18% of deaths.

Read more about PNH symptoms

As free hemoglobin binds with nitric oxide, nitric oxide deficiency occurs, leading to gastrointestinal muscular dystopia. The most common manifestations of this condition are abdominal pain and flatulence. Meanwhile, vascular muscular dystopia can result in additional symptoms, such as headache, fatigue, and back pain. 

Nitric oxide deficiency also causes blood vessels to narrow, leading to hypertension (arterial and pulmonary) and pulmonary microembolism; over time, blood flow through the parenchymal organs undergoes significant changes. 

Because nitric oxide regulates smooth muscle cells, low nitric oxide levels in the body can lead to a host of complications, such as erectile dysfunction, gastrointestinal spasms, abdominal pain, dyspnea, and pain elsewhere. Nitric oxide depletion can also lead to thrombosis, causing the aggregation of platelets. 

Intravascular hemolysis remains the leading cause of hemolytic anemia in PNH. This condition may be aggravated by bone marrow failure. Common causes of worsening hemolysis in patients with PNH hemoglobinuria are stress, infection, or trauma. 

“In the case of hemolysis-associated with [bone marrow failure], abnormal erythropoiesis is found,” Szlendak et al wrote. “[Complete blood count] shows a decrease in the number of peripheral blood reticulocytes, thrombocytopenia, and leukopenia.” 

Thrombotic Complications Are Frequent

One of the key characteristics of PNH is the frequency of thrombotic symptoms noted during diagnosis. Around a third of patients are diagnosed with thromboembolic events at least once in their lifetime. 

“Clinical presentation of thrombosis may vary and be difficult to distinguish from general PNH symptomatology, which includes fatigue, abdominal pain, and chest pain,” Bektas et al wrote. “In patients with PNH, platelets appear to be more susceptible to terminal complement-induced prothrombin effects, potentially explaining the tendency toward thrombosis.” 

The introduction of eculizumab has drastically improved outcomes; before this drug was available, thrombosis was a leading cause of death, occurring in up to two-thirds of patients. Thrombosis most commonly occurs in the liver (venous thrombosis), abdomen, and brain. The risk of developing thrombosis increases with a greater proportion of PNH clones and greater severity of intravascular hemolysis. 

Vulnerability to Bone Marrow Failure 

Patients with PNH are particularly susceptible to bone marrow failure, although the exact mechanisms of this are poorly understood. Some theorize that it is caused by the activation of T and natural killer cells against normal stem cells. 

Bone marrow failure can occur preceding PIGA gene mutation, which contributes to the clonal dominance of defective hematopoietic stem cells. About 30% to 40% of patients with the classical form of PNH develop some degree of bone marrow failure.

For all 3 areas covered in this article—hemolytic anemia, thrombosis, and bone marrow failure—our understanding of the pathophysiological processes underpinning them is patchy at best. What is clear is that PNH is a deadly disease, especially if left undiagnosed. Even when the correct diagnosis is reached, patients remain at risk of fatal complications, such as thrombotic and hemorrhagic events. 

References

Szlendak U, Budziszewska B, Spychalska J, Drozd-Sokołowska J, Patkowska E, Nowak J. Paroxysmal nocturnal hemoglobinuria: advances in the understanding of pathophysiology, diagnosis, and treatmentPol Arch Intern Med. 2022;132(6):16271. doi:10.20452/pamw.16271

Bektas M, Copley-Merriman C, Khan S, Sarda SP, Shammo JM. Paroxysmal nocturnal hemoglobinuria: role of the complement system, pathogenesis, and pathophysiologyJ Manag Care Spec Pharm. 2020;26(12-b Suppl):S3-S8. doi:10.18553/jmcp.2020.26.12-b.s3