PNH (Paroxysmal Nocturnal Hemoglobinuria) and Bone Marrow Transplantation

Introduction

Paroxysmal nocturnal hemoglobinuria (PNH) is an uncommonly acquired hematopoietic stem cell disorder. Hematopoietic stem cells are cells created in the bone marrow (spongy center of long bones) and eventually develop into platelets, white blood cells, and red blood cells. In those affected by PNH, some hematopoietic stem cells are defective, thus producing defective blood cells. These defective cells are susceptible to premature destruction.

Red blood cell destruction by complement leads to hemoglobinuria (hemoglobin in urine). This results in blood-colored urine, and the finding becomes more prominent in the morning due to concentrated urine. Affected individuals also show bone marrow dysfunction and a reduced blood cell count. Any age group can be affected, but commonly, the condition is diagnosed in young adulthood.

What Are the Causes?

• For the development of PNH, two factors are required: one is a somatic mutation (mutation occurs randomly after conception and is not inherited) in the PIGA gene that affects the hematopoietic stem cells, and the other is a process that leads to the multiplication of these defective cells.

• Due to autoimmune bone marrow failure, the body’s immune system attacks the healthy stem cells, sparing the defective ones. The exact reason behind the destruction of healthy cells and the survival of defective cells is unknown.

• The exact reason behind the expansion and multiplication of PNH cells has yet to be fully understood. Some suggest it is due to secondary genetic mutations or immune factors.

What Are the Signs and Symptoms?

• Symptoms greatly vary from one individual to another. Some present with mild symptoms that are stable, while others have symptoms that may lead to life-threatening complications.

• The primary clinical finding is hemolysis, which causes hemoglobinuria. Some people with hemolysis may not have visible hemoglobin in their urine. Dark or blood-colored urine is the characteristic finding.

• Hemolytic anemia occurs due to low levels of circulating red blood cells.

Mild hemolysis results in:

• Headaches.

• Breathing difficulty during exercising.

• Chest pain.

• Fatigue.

• Rapid heartbeat.

Severe hemolysis results in additional symptoms like:

• Swallowing difficulty.

• Disabling fatigue.

• Painful contractions in the esophagus and abdomen.

• Erectile dysfunction in men.

Chronic hemolysis may lead to:

• Blood clot formation.

• Renal diseases.

The blood clot formed may reach different body parts, resulting in complications. As a result of blood clot formation, blood flow to different parts may be restricted, especially the brain, stomach, and liver. The symptoms depend on the specific region of the body that is affected:

• Blood clots that affect cerebral veins may result in headaches and cognitive dysfunction.

• Blood clots that affect the lungs result in shortness of breath, heart palpitations, and breathing difficulties.

• Blood clots that affect the bowels and stomach result in a bloated feeling or abdominal pain.

• Blood clots that affect the liver result in jaundice and abdominal pain.

Those with anemia (due to reduced red blood cell count) present with the following symptoms:

• Irritability.

• Pale skin.

• Headache.

• Dizziness.

• Chest pain.

How Is the Condition Diagnosed?

• Diagnosis is suspected in those with symptoms of intravascular hemolysis without a definitive cause.

• Diagnosis is made based on clinical examination, detailed patient history, and by carrying out some specialized tests.

• Flow cytometry (a blood test identifying PNH cells) is the main diagnostic test.

What Are the Treatment Options?

The treatment option depends on the specific symptoms one presents with:

• The Food and Drug Administration (FDA) approved drug for PNH treatment is Eculizumab. The drug does not cure PNH but prevents red blood cell breakdown, thus reducing the risk of thrombosis. The drug blocks the body’s natural immunity, increasing the risk of meningococcal infection. Therefore, meningococcal vaccinations are taken before starting the first dose.

• Ravulizumab is another drug used for the treatment of PNH hemolysis.

• Pegcetacoplan is also FDA-approved for PNH treatment. It prevents intravascular and extravascular hemolysis and is effective in individuals with anemia.

• Symptomatic and supportive treatment is given based on the severity of bone marrow failure, age, general health, PNH severity, etc.

• Folate supplements are administered.

• Iron supplements are given to those with iron deficiencies.

• Anticoagulant therapy may be given in some cases to prevent blood clot formation.

• Blood transfusions are needed in cases of low blood cell counts.

• Synthetic growth factors (normal proteins in the body that stimulate the BM to produce blood cells) are given in cases of PNH.

• Immunosuppressive therapy may be given in cases of severe bone marrow failure. Though it does not eliminate PNH clones, it can restore bone marrow function.

• Androgen therapy is given in some cases.

Bone Marrow Transplantation

• The only curative therapy for those with PNH is bone marrow transplantation.

• It is a reasonable option for those who do not respond to eculizumab therapy.

• It cures bone marrow dysfunction.

• As there exists the risk of morbidity and mortality, bone marrow transplantation is done only in patients with serious complications (like severe bone marrow failure) or life-threatening blood clot formation.

• Allogenic bone marrow transplant is the specific bone marrow transplant used in PNH patients. In this form of a bone marrow transplant, the bone marrow of the affected person is destroyed by radiation, chemotherapy, or combination methods. The healthy marrow from the donor is then placed intravenously into the body.

• A sibling with an identical HLA type is considered the best match for a donor marrow transplant.

• An unrelated matched donor may be needed in certain cases. The morbidity and mortality rates are greater when using unrelated donors. A younger age and fully matched sibling donor increase the prognosis of marrow transplantation.

Conclusion

PNH is a disorder that leads to premature destruction and impaired production of blood cells. Stem cell transplantation or bone marrow transplantation is the only curative therapy for PNH. But even then, it is not recommended as initial therapy in conventional PNH cases due to the associated risk of morbidity and mortality. Allogenic bone marrow transplants are only indicated in severe cases of bone marrow failure, in cases of life-threatening blood clot formation, and in cases where Eculizumab therapy is ineffective.