Paroxysmal Nocturnal Hemoglobinuria

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired, life-threatening disease of the blood characterised by destruction of red blood cells by the complement system, a part of the body's innate immune system. This destructive process occurs due to deficiency of the red blood cell surface protein DAF, which normally inhibits such immune reactions.

The red blood cell destruction (hemolysis) is considered an intravascular hemolytic anaemia. Research suggests that PNH thrombosis (a blood clot) is caused by both the absence of GPI-anchored complement regulatory proteins (CD55 and CD59) on PNH platelets and the excessive consumption of nitric oxide (NO).

PNH is the only hemolytic anaemia caused by an acquired intrinsic defect in the cell membrane (deficiency of glycophosphatidylinositol or GPI) leading to the absence of protective exterior surface proteins. It may develop on its own ("primary PNH") or in the context of other bone marrow disorders such as aplastic anaemia ("secondary PNH"). Allogeneic bone marrow transplantation is the only cure, but has significant risks. The monoclonal antibody eculizumab reduces the need for blood transfusions and improves quality of life, though it is extremely expensive.

Signs and Symptoms

The classic sign of PNH is red discolouration of the urine due to the presence of haemoglobin and hemosiderin from the breakdown of red blood cells, most pronounced in the morning. The majority of affected individuals mainly experience symptoms of anaemia, such as fatigue, shortness of breath, and palpitations. A small proportion of patients report abdominal pain, difficulty swallowing, and erectile dysfunction, attributable to spasm of smooth muscle due to depletion of nitric oxide.

Forty percent of people with PNH develop thrombosis at some point, which is the main cause of severe complications and death. These clots may form in unusual sites such as the hepatic vein, portal vein of the liver, superior or inferior mesenteric vein, and veins of the skin.

Pathophysiology

PNH occurs due to a defect in assembling glycolipid-protein structures on the surface of blood cells. The most common defective enzyme is phosphatidylinositol glycan A (PIGA), located on the X chromosome. Mutations in the PIGA gene lead to the absence of GPI anchors on the cell membrane, particularly affecting red blood cells. The main proteins that protect blood cells from destruction by the complement system are decay-accelerating factor (DAF/CD55) and protectin (CD59). The deficiency of these proteins makes red blood cells more vulnerable to lysis.

Symptoms like esophageal spasm, erectile dysfunction, and abdominal pain are attributed to the binding of haemoglobin released during hemolysis with circulating nitric oxide, which is needed to relax smooth muscle.

Diagnosis

Blood tests in PNH show changes consistent with intravascular hemolytic anaemia, such as low haemoglobin, raised lactate dehydrogenase, and raised bilirubin. The direct antiglobulin test (DAT) is negative. Historically, the Ham's acid hemolysis test was used for confirmation, but today flow cytometry for CD55 and CD59 on white and red blood cells is the gold standard. The fluorescein-labelled proaerolysin (FLAER) test is also frequently used.

Treatment

Acute Attacks

There is debate over the effectiveness of steroids in reducing the severity of hemolytic crises. Transfusion therapy may be necessary to correct significant anaemia and suppress the production of PNH cells. Iron deficiency, common over time, may require treatment, although iron therapy can exacerbate hemolysis.

Long-term

PNH is a chronic condition. Monitoring the flow cytometry every six months is recommended for those with a small clone. Preventive treatment with warfarin decreases the risk of thrombosis in those with a large clone. Episodes of thrombosis are treated conventionally, but long-term anticoagulation is often necessary.

Medications

Crovalimab

Crovalimab is a monoclonal antibody used for PNH, functioning as a complement component 5 (C5) inhibitor. It was approved for use in 2024 in several countries.

Danicopan

Danicopan is a complement inhibitor that binds to factor D. It was approved for medical use in 2024.

Eculizumab

Eculizumab is a recombinant humanised monoclonal antibody used to treat PNH by inhibiting the complement system. It reduces red blood cell destruction and the need for blood transfusions.

Iptacopan

Iptacopan is a complement factor B inhibitor that was approved for PNH treatment in 2023.

Pegcetacoplan

Pegcetacoplan, a medication that inhibits complement protein C3, was approved for PNH in 2021.

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Self-assessment MCQs (single best answer)

What is the primary cause of red blood cell destruction in Paroxysmal Nocturnal Hemoglobinuria (PNH)?

Which protein deficiency is most associated with PNH and its characteristic hemolysis?

What symptom is classically seen in PNH, especially noticeable in the morning?

What is the gold standard diagnostic test for PNH?

What is the main cause of severe complications and death in PNH patients?

Which monoclonal antibody is used to treat PNH by inhibiting the complement system?

Which enzyme's defect leads to the absence of GPI anchors in PNH?

What symptom is attributed to the depletion of nitric oxide in PNH patients?

Which of the following is a complement factor B inhibitor approved for PNH treatment in 2023?

What long-term preventive treatment is recommended for PNH patients with a large clone to decrease the risk of thrombosis?