The document outlines the pathophysiology, clinical presentation, and management of paroxysmal nocturnal hemoglobinuria (PNH), a condition characterized by acquired deficiencies of complement regulatory proteins causing excessive complement activation and hemolysis. It discusses two case studies of patients demonstrating typical symptoms and laboratory findings associated with PNH, such as hemoglobinuria and thrombosis. Recommendations for management include anticoagulation and potential stem cell transplantation, with eculizumab as a treatment option for complement inhibition.

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. ECULIZUMAB
• 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

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

24. 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

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

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

27. TRIAD OF
• Bicytopenia(anemia and thrombocytopenia)
• Hemolysis
• Thrombosis
• =PNH suspected

28. • To confirm, flow cytometry
• granulocytes and monocytes
• CD 5947% NEG (>20% NEG in granulocytes)
• CD 55–56.7% NEG

29. 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
• Eculizumab- C5 complement antagonist- patient could not afford
• folic acid 2 mg daily and ferrous fumerate 300 mg twice daily

30. •Thank You