Thrombocytopenia due to Paroxysmal Nocturnal Hemoglobinuria
• Paroxysmal nocturnal hemoglobinuria (Marchiafava- Micheli syndrome) is a rare, acquired, potentially life- threatening disease of the blood characterized by complement-induced intravascular hemolytic anemia (anemia due to destruction of red blood cells in the bloodstream), red urine (due to the appearance of hemoglobin in the urine) and thrombosis.• It is the only hemolytic anemia caused by an intrinsic defect in the cell. It may develop on its own ("primary PNH") or in the context of other bone marrow disorders such as aplastic anemia ("secondary PNH").
• Thrombocytopenia (or thrombopenia) is a relative decrease of platelets in blood.• A normal human platelet count ranges from 150,000 to 450,000 platelets per microlitre of blood.• One common definition of thrombocytopenia is a platelet count below 50,000 per microlitre.
EPIDEMIOLOGY• PNH is rare, with an annual rate of 1-2 cases per million. Many cases develop in people who have previously been diagnosed with aplastic anemia or myelodysplastic syndrome. The fact that PNH develops in MDS also explains why there appears to be a higher rate of leukemia in PNH, as MDS can sometimes transform into leukemia.• 25% of female cases of PNH are discovered during pregnancy. This group has a high rate of thrombosis, and the risk of death of both mother and child are significantly increased (20% and 8% respectively).
• Forty percent of patients develop thrombocytopenia. This is the main cause of severe complications and death in PNH. These may develop in common sites (deep vein thrombosis of the leg veins and resultant pulmonary embolism when these clots break off and enter the lungs), but, in PNH, blood clots may also form in more unusual sites: the hepatic vein(causing Budd-Chiari syndrome), the portal vein of the liver (causing portal vein thrombosis), the superior or inferior mesenteric vein (causing mesenteric ischemia), and veins of the skin. Cerebral venous thrombosis, an uncommon form of stroke, is more common in PNH.
Etiology• PNH is an acquired genetic mutation resulting in a membrane defect in stem cells and their progeny, including RBCs, WBCs, and platelets. It results in unusual sensitivity to normal C3 in the plasma, leading to ongoing intravascular hemolysis of RBCs and diminished marrow production of WBCs and platelets.
• Persons with this disease have blood cells that are missing a gene called PIG-A. This gene allows a substance called glycosyl-phosphatidylinositol (GPI) to help certain proteins stick to cells.• Without PIG-A, important proteins cannot connect to the cell surface and protect the cell from substances in the blood called complement. As a result, red blood cells break down too early. The red cells leak hemoglobin into the blood, which can pass into the urine. This can happen at any time, but is more likely to occur during the night or early morning.
Thrombocytopenia is often caused by:• Low production of platelets in the bone marrow• Increased breakdown of platelets in the bloodstream (called intravascular)• Increased breakdown of platelets in the spleen or liver (called extravascular)
Disorders that involve low production in the bone marrow include:• Aplastic anemia• Cancer in the bone marrow• Cirrhosis (chronic liver disease)• Folate deficiency• Infections in the bone marrow (very rare)• Myelodysplasia• Vitamin B12 deficiency
Signs and symptomsA person with PNH :• Abdominal pain• Back pain• Blood clots -- may form in some people• Dark urine -- comes and goes• Easy bruising or bleeding• Headache• Shortness of breath
A person with thrombocytopenia:• Bruising• Nosebleeds or bleeding in the mouth and gums• Rash
TESTS• Flow cytometry for CD55 and CD59 on both WBCs and RBCs• DAT(direct antiglobulin test)• Sucrose lysis test• Complete blood count (CBC)• Coombs test• Flow cytometry to measure certain proteins• Hams (acid hemolysin) test• Serum hemoglobin and haptoglobin• Sucrose hemolysis test• Urinalysis• Urine hemosiderin
TREATMENT• Supportive measures• Possibly monoclonal antibody• Allogeneic bone marrow transplantation is the only curative therapy• Steroids or other drugs that suppress the immune system may help slow the break down of red blood cells.• Blood transfusions• Soliris (eculizumab) is a drug used to treat PNH. It blocks the breakdown of red blood cells.• Bone marrow transplantation can cure this disease.• All patients with PNH should receive vaccinations against certain types of bacteria to prevent infection.