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PNH

PNH. What Is It And What Can We Do About It. What Does The Name Mean. P AROXYSMAL – happens now and then N OCTURNAL – at night H EMOGLOBINURIA – hemoglobin (Hgb), the red pigment of the blood, appears in the urine. PNH Is:. A disorder of blood Rare

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PNH

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  1. PNH What Is It And What Can We Do About It

  2. What Does The Name Mean • PAROXYSMAL – happens now and then • NOCTURNAL – at night • HEMOGLOBINURIA – hemoglobin (Hgb), the red pigment of the blood, appears in the urine

  3. PNH Is: • A disorder of blood • Rare • Due to a glitch (a mutation) in a gene in a single cell • Manifest in a variety of ways • Able to be treated

  4. What We Will Cover Today • What are the ways PNH affects the patient? • How does PNH get started? • What can be done to treat PNH?

  5. The Clinical Manifestations of PNH “Lazy” Bone Marrow Intravascular Hemolysis Thrombosis

  6. Definitions • Intravascular hemolysis – breakdown of red blood cells as they circulate • Thrombosis – clotting of the blood within the blood vessels • “Lazy” bone marrow – bone marrow that does not make blood cells (red, white, and platelets) in normal amounts

  7. The Fundamental Manifestations of PNH “Lazy” Bone Marrow Intravascular Hemolysis Thrombosis Fatigue Damage toTissues Free Hgb In Blood Anemia Low WBC Platelets StrokesLiver DamageBig Spleen, etc Nitric Oxide Removed Iron Loss Hgb in Urine Chest Pain, Abdominal Pain, Blood Pressure Changes Renal Failure Kidney Damage

  8. The Clinical Manifestations of PNH Intravascular Hemolysis Fatigue Free Hgb In Blood Anemia Nitric Oxide Removed Iron Loss Hgb in Urine Renal Failure Kidney Damage

  9. Action of Nitric Oxide (NO) NO NO Smooth Muscle Relaxation Smooth Muscle Contraction

  10. Free Hemoglobin Binds NO NO NO Smooth Muscle Relaxation NO Free Hemoglobin Smooth Muscle Contraction

  11. The Clinical Manifestations of PNH “Lazy” Bone Marrow Intravascular Hemolysis Thrombosis Fatigue Damage toTissues Free Hgb In Blood Anemia Low WBC Platelets StrokesLiver DamageBig Spleen, etc Nitric Oxide Removed Iron Loss Hgb in Urine Chest Pain, Abdominal Pain, Blood Pressure Changes Renal Failure Kidney Damage

  12. How PNH Arises

  13. How PNH Arises Mutation in One Gene in One Blood Stem Cell

  14. A Blood Stem Cell Can Give Rise To All The Different Cells Of The Blood T LYMPHOCYTES BLOOD STEM CELL B LYMPHOCYTES ERYTHROCYTES GRANULOCYTES MONOCYTES PLATELETS

  15. In PNH, a single mutation occurs in one blood stem cell T LYMPHOCYTES STEM CELL B LYMPHOCYTES ERYTHROCYTES GRANULOCYTES MONOCYTES ALTERED GENE PLATELETS

  16. That Altered Stem Cell Can Give Rise to an Abnormal Clone NORMAL CLONES ABNORMAL CLONE

  17. How PNH Arises Mutation in One Gene in One Blood Stem Cell Blood Cells Lack “Anchored” Proteins

  18. The Beginning of PNH • The change that occurs in PNH stops the production of an anchor that ties some protein molecules to the cell

  19. Molecules Are Attached to the Surface of Cells

  20. How Molecules Are Attached Molecule Stuck Through Membrane Molecule Attached To Anchor in Membrane Anchor Cell Membrane

  21. The Defect in PNH The Cell Cannot Make The Anchor

  22. PROTEIN Asp NORMAL C=O NH CH 2 CH 2 O O=P=O O ( 1-2) ( 1-6) ( 1-4) O O-P=O N O CH CH NH 2 2 2 O O-P-O O CH CH CH 2 2 C=O O O C=O (18:0,1) (16:0) (22:4,5) The GPI Anchor Defect in PNH PNH O O-P-O O CH CH CH 2 2 O O C=O (18:0,1) (22:4,5)

  23. What Kinds of Proteins Are Missing From the Membrane in PNH • Complement defense proteins • Enzymes • Immunological proteins • Structural proteins • Proteins of unknown function

  24. How PNH Arises Mutation in One Gene in One Blood Stem Cell Blood Cells Lack Anchored Proteins AplasticAnemia

  25. PNH and Aplastic Anemia

  26. What Does PNH Have To Do With Aplastic Anemia • Many PNH patients have aplastic anemia or a history of aplastic anemia • Many PNH patients show signs of inadequate blood cell formation • Low granulocyte (white cell) and low platelet counts are such signs

  27. What Does PNH Have To Do With Aplastic Anemia • All PNH patients have evidence of a “lazy” bone marrow • Therefore, whatever causes aplastic anemia (immune suppression?) may allow PNH to develop

  28. Aplastic Anemia and PNH PNH Cell Normal Marrow AplasticMarrow PNH Marrow

  29. How PNH Arises Mutation in One Gene in One Blood Stem Cell Blood Cells Lack Anchored Proteins AplasticAnemia The Abnormal Clone Expands

  30. 60 50 40 30 20 10 0 <1% 1-19% 20-49% 50-79% 80-100% Percentage of Abnormal Granulocytes in 518 PNH Patients

  31. How PNH Arises Mutation in One Gene in One Blood Stem Cell Blood Cells Lack Anchored Proteins AplasticAnemia The Abnormal Clone Expands “Lazy” Bone Marrow

  32. Diagnosing PNH A Digression

  33. Monoclonal Antibody in the Diagnosis of PNH Fluorescein Anti-CD59 CD59 GPI Anchor

  34. FLAER in the Diagnosis of PNH Fluorescein GPI Anchor Aerolysin

  35. M.B. Control Control C.J R.K PNH II PNH III Normal PNH II Normal Flow Cytometric Analysis of Red Blood Cells from Patients with PNH Control Counts PNH III Normal CD59

  36. FLAER and Anti CD24 on Granulocytes

  37. FLAER and Anti CD24 on Granulocytes A B

  38. A Small Population of Red Cells

  39. How PNH Arises Mutation in One Gene in One Blood Stem Cell Blood Cells Lack Anchored Proteins AplasticAnemia The Abnormal Clone Expands Blood Cells Lack The Complement Defense Proteins

  40. Complement and PNH

  41. What is Complement and What Does It Have To Do With PNH? • Complement is the name given to a group of blood proteins that act together to help the body get rid of microbiological invaders

  42. Complement Attacks a Bacterium

  43. Complement Attacks a Bacterium

  44. What is Complement? Complement circulates in an inactive form

  45. Things That Activate Complement In Vivo • ‘Tick-over’ activation • Endotoxin from gastrointestinal tract • Nocturnal periodicity • Massive hemolysis with gastrointestinal illness • Almost any infection, surgery, or trauma • External immune reactions

  46. How PNH Arises Mutation in One Gene in One Blood Stem Cell Blood Cells Lack Anchored Proteins AplasticAnemia The Abnormal Clone Expands Blood Cells Lack The Complement Defense Proteins Complement Is Activated “Lazy” Bone Marrow

  47. How PNH Arises Mutation in One Gene in One Blood Stem Cell Blood Cells Lack Anchored Proteins AplasticAnemia The Abnormal Clone Expands Blood Cells Lack The Complement Defense Proteins Complement Is Activated “Lazy” Bone Marrow Intravascular Hemolysis Thrombosis

  48. Complement Attacks a Red Cell Complement

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