Paroxysmal Nocturnal Hemoglobinuria (PNH)

What causes PNH

PNH begins with a mutation in the PIGA gene in a single blood stem cell. It is acquired, not inherited. The mutation stops cells from making an anchor (GPI) that holds protective proteins, CD55 and CD59, on the cell surface. Without them, the complement system, which normally attacks bacteria, punches holes in red blood cells (hemolysis). The PNH stem cell can expand, especially when the rest of the marrow is damaged, which is why PNH is closely linked to aplastic anemia.

Symptoms

• Hemolysis: fatigue, shortness of breath, pale skin, jaundice, and dark urine from hemoglobin, classically worse in the morning, though only a minority notice this
• Smooth muscle symptoms: free hemoglobin depletes nitric oxide, causing abdominal pain, difficulty or pain swallowing, back pain, and erectile dysfunction
• Blood clots (thrombosis): the leading cause of death in untreated PNH. Clots often occur in unusual places: - abdominal veins: liver veins (Budd-Chiari syndrome), intestinal veins - brain veins (cerebral venous thrombosis) - deep veins of the legs and lungs
• Bone marrow failure: low white cells (infections) and low platelets (bruising and bleeding)
• Kidney damage from chronic hemoglobin in urine
• Pulmonary hypertension

Symptoms may come in flares triggered by infection, surgery, stress or pregnancy.

Diagnosis

• Flow cytometry of blood is the standard test. It detects red cells and white cells missing GPI-anchored proteins and measures the PNH clone size.
• Signs of hemolysis: high LDH, low haptoglobin, raised reticulocytes and bilirubin, negative direct antiglobulin (Coombs) test.
• Blood count, iron studies and urine tests (hemosiderin).
• Bone marrow biopsy to look for aplastic anemia or MDS.
• Imaging for clots when symptoms suggest them.

Who should be tested: people with unexplained hemolysis (Coombs-negative), unusual clots, aplastic anemia or MDS, or unexplained cytopenias.

Treatment

Complement inhibitors

These have transformed PNH care by blocking red cell destruction and greatly reducing clots.

• C5 inhibitors: eculizumab (IV every 2 weeks), ravulizumab (IV every 8 weeks), and crovalimab (subcutaneous)
• Proximal inhibitors: pegcetacoplan (C3 inhibitor, subcutaneous injection), iptacopan (oral factor B inhibitor), and danicopan (oral factor D inhibitor, added to a C5 inhibitor), which help with hemolysis that continues outside blood vessels

Because complement fights certain bacteria, people on these drugs must be vaccinated against meningococcus (and often pneumococcus and Haemophilus), may take preventive antibiotics, and must seek urgent care for fever.

Other treatment

• Anticoagulation for people with clots
• Blood transfusions, folic acid and iron as needed
• Stem cell transplant: the only cure, mainly for people with severe aplastic anemia or uncontrolled disease
• Immunosuppression when PNH accompanies aplastic anemia

Pregnancy

Pregnancy in PNH carries high risks of clots and needs specialist care, often with complement inhibitors and anticoagulation.

Outlook

Before complement inhibitors, about a third of patients died within 5 years, mainly from clots. With modern treatment, survival is close to that of the general population for many patients. Some people have a spontaneous remission.

Frequently asked questions

What is PNH?

PNH is a rare acquired blood disease in which red blood cells lack proteins that protect them from the immune complement system. They are destroyed, causing anemia, dark urine, fatigue and a high risk of blood clots.

What are the symptoms of PNH?

Symptoms include fatigue, breathlessness, dark or cola-colored urine, jaundice, abdominal pain, difficulty swallowing, erectile dysfunction and blood clots in unusual places such as abdominal or brain veins. Low blood counts can cause infections and bleeding.

How is PNH diagnosed?

PNH is diagnosed by flow cytometry, a blood test that detects cells missing the protective GPI-anchored proteins. Blood tests also show signs of hemolysis, such as high LDH and low haptoglobin.

Is PNH curable?

Stem cell transplant can cure PNH but carries significant risks, so it is reserved for selected patients. Complement inhibitor medicines control the disease effectively and allow most people to live near-normal lives.

Why do PNH medicines require meningitis vaccines?

Complement inhibitors block part of the immune system that kills Neisseria meningitidis bacteria. This raises the risk of meningococcal infection, so vaccination is required before treatment, and any fever should be treated as an emergency.