Case Studies on Paroxysmal Nocturnal hemoglobinuria

Case Studies on Paroxysmal Nocturnal hemoglobinuria

1. Paroxysmal Nocturnal hemoglobinuria Cases

2. Decay accelerating factor (DAF) DAF prevents formation of C3 convertases of complement system

3. CD59 CD59 inhibits formation of the membrane attack complex .

4. PNH DAF and CD59 (proteins) linked to plasma membranes by glycophosphatidylinositol (GPI) anchor. An acquired deficiency of enzyme that creates GPI anchors  deficiency of regulators  excessive complement activation. Leads to lysis of red cells = paroxysmal nocturnal hemoglobinuria (PNH) Intravascular hemolysis

5. mutation Phosphatidylinositol glycan complementation group A gene ( PIGA ) X-linked - subject to lyonization

6. Why ‘nocturnal’ slight decrease in blood pH during sleep This increases the activity of complement

7. Hemosiderinuria leads to iron deficiency This can exacerbate anemia (if untreated) Thrombosis - leading cause of death in PNH! 40% of patients - venous thrombosis

8. Why thrombosis Not clear ? Absorption of NO by free hemoglobin ? endothelial damage caused by the C5-9 membrane attack complex

9. Eculizu mab Monoclonal antibody prevents the conversion of C5 to C5a

10. case 1 A 24-year-old Caucasian woman presented for evaluation of new tea-colored urine noticed intermittently over the past five days Her last menstrual cycle was two weeks ago, regular.

11. no history of- renal stones NSAID abuse weight loss night sweats Fever Melena hemoptysis

12. Her vital signs were unremarkable CBC, urinalysis, and renal ultrasound were normal urine pregnancy test was negative

13. A few days later, she developed jaundice with abdominal pain.

14. Repeat testing showed: WBC count 3600/mm3 hemoglobin 4 g/dL platelet count 189,000/ mm3 MCV 75 fl RDW 28 reticulocyte count 10.9 percent (N.V.= 0.5-2.3%)

15. total serum bilirubin 7.5 mg/dL (N.V.= 0.10-1.2 mg/dL) indirect bilirubin 5.5 mg/dL (N.V.= 0.10-1.0 mg/dL) AST 213 U/L serum LDH 1500 U/L ( nv = 259-613) serum haptoglobin 10 mg/dL (decreased)

16. The urinalysis showed hemoglobinuria Direct Coomb test is negative Liver ultrasound shows mild hepatomegaly and no signs of stones, biliary ductal dilatation, or hepatic mass Flow cytometry of peripheral blood showed absent expression of CD 55 and CD 59 on 78 percent of red blood cells.

17. Case 2 21-year-old female jaundice x one month Fever, abdominal pain and distension x 15 days Admitted in an hospital with complaints of : left sided headache blurring of vision (right) eye x one day

18. No history of any significant illness or chronic drug intake She had a younger brother who is healthy. On examination Afebrile pulse rate 80/min blood pressure 110/70 mmHg marked pallor was present Cardiovascular and respiratory examination – normal

19. Abdomen - soft with minimal distension + diffuse tenderness + hepatomegaly + shifting dullness. CNS examination - no focal neurological deficits Fundus Examination - few superficial hemorrhages in the retina of right eye visual acuity 6/6

20. Findings anemia with thrombocytopenia MRI scan of BRAIN revealed left parietal and occipital hemorrhages

21. ANA, dS -DNA and APLA all negative. Bone marrow biopsy revealed hypercellular marrow Homocysteine level was normal.

22. USG Abdomrn USG Abdomen thrombosis involving intrahepatic segment of Inferior vena cava and hepatic confluence. There was also hepatomegaly with coarse echotexture with ascites. CECT scan of abdomen consistent with USG abdomen Budd–Chiari syndrome

23. Computed tomography scan of abdomen-Intra hepatic portion of inferior vena cava showing thrombosis as shown in circle.

24. MRI brain with venogram sub acute hemorrhage in left occipital lobe absent flow in left transverse sigmoid sinuses upper jugular vein = cerebral venous thrombosis

25. Triad of Bicytopenia ( anemia and thrombocytopenia) Hemolysis Thrombosis = PNH suspected

26. T o confirm, flow cytometry granulocytes and monocytes CD 59  47% NEG (>20% NEG in granulocytes) CD 55–56.7% NEG

27. Management LMWH enoxaparin 60 mg sc twice daily for five days oral anticoagulant, acenocoumarol 4 mg three units of packed cell transfusions definitive therapy - hemopoietic stem cell transplantationbone marrow transplantation E culizumab- C5 complement antagonist - patient could not afford folic acid 2 mg daily and ferrous fumerate 300 mg twice daily

28. Thank You