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The Scarlet Bedwetter

The Scarlet Bedwetter. L. Carolina I. Dumlao Internal Medicine Year Level I. Objectives. To distinguish cases of Paroxysmal Nocturnal Hemoglobinuria from other hemolytic anemias To identify clinical manifestations, especially life threatening sequelae of PNH. Case: Identifying Data. C.R.

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The Scarlet Bedwetter

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  1. The Scarlet Bedwetter L. Carolina I. Dumlao Internal Medicine Year Level I

  2. Objectives • To distinguish cases of Paroxysmal Nocturnal Hemoglobinuria from other hemolytic anemias • To identify clinical manifestations, especially life threatening sequelae of PNH

  3. Case: Identifying Data • C.R. • 39 year old • Female • Filipina • Married • Caloocan • Call center

  4. Case: Chief complaint Anemia

  5. Case: History of present illness 30 years PTA low Hgb levels Iron supplementation 10 years PTA Hgb = 4-5 Transfused with 4’u’ PRBC

  6. Case: History of present illness 6 months PTA Tea-colored urine at night or early morning 3 months PTA Shortness of breath (+) menorrhagia Hgb = 7 2’u’ PRBC

  7. Case: History of present illness Consulted hematologist Peripheral blood smear : Microcytic/hypochromic Decreased WBC Normal platelet Iron deficiency anemia

  8. Case: History of present illness Iron studies = normal Repeat PBS Normocytic/normochromic Decreased Hgb Decreased WBC

  9. Case: History of present illness Patient advised to undergo BMA ADMISSION

  10. Case: Review of Systems GENERAL No weight loss or weight gain. No focal weakness. SKIN No history of easy bruisability, no sores, no rashes nor pruritus HEENT No headaches, dizziness or vertigo. Does not wear corrective glasses, no history of eye pain, blurring of vision, excessive tearing, diplopia; gross hearing is intact, no ear pain, discharge or infection; no post- nasal drip or sinus pain; no history of frequent sore throats PULMO No cough, no hemoptysis, CVS No history of orthopnea, chest pain, or bipedal edema. No palpitations noted.

  11. Case: Review of systems GIT No anorexia. No history of dysphagia, odynophagia, or jaundice. No hematemesis, hematochezia or melena. No note of change in character ot frequency of bowel movement. URINARY No history of UTIs. No intermittency, decreased caliber or incontinence. NEURO No history of syncope, seizures or tremors. No numbness or loss of sensation. HEMA No history of prolonged bleeding. ENDOCRINE No history of polyuria, polyphagia, polydipsia. No excessive sweating

  12. Case: Past health • Non-hypertensive • Non-diabetic • No allergies • No previous operations

  13. Case: Obstetric/Gynecologic history • Menarche at 12 years of age • Monthly, 2-3 pads per day, lasting 3 days • Married for 10 years • G0P0

  14. Case: Personal/Social history • 2-3 pack smoker • Stopped 1 year ago • Occasional alcoholic beverage drinker

  15. Case: Family history • Great grandfather - leukemia

  16. Case: Physical Exam VITAL SIGNS BP=100/70mm Hg sitting HR=92bpm RR= 18breaths/min T=36.8C GENERAL Conscious, coherent, oriented to person, place and time. Weight = 45kg Height = 152.4cm BMI = 19.4 SKIN All extremities warm to touch. No discolorations, bruises or rashes. HEENT Normocephalic; slightly icteric sclerae, pink conjunctivae; no naso-aural discharge; dry oral mucosa; no tonsillopharyngeal congestion; no neck mass noted; no cervicolymphadenopathy noted.

  17. Case: Physical exam CHEST/LUNGS Equal chest expansion, no retractions; clear breath sounds, no crackles or wheezing; equal tactile and vocal fremitus CVS Adynamic precordium; normal rate, regular rhythm, distinct S1/S2, no murmurs/gallops, PMI and apex beat at the 5th intercostal space left midclavicular line; visible neck veins on supine position flattening with inspiration, full and equal pulses bilaterally (Gr. 3/5). ABDOMEN flabby abdomen; normoactive bowel sounds, soft, no guarding or direct tenderness, rebound tenderness was absent ; no splenomegaly EXTREMITIES Normal muscle bulk and tone; no cyanosis, edema or deformities; no limitation of motion; pale nail beds

  18. Case: Salient features • 39/F • Chronic anemia • Tea-colored urine • Iron studies normal • Peripheral blood smear normocytic/normochromic

  19. Anemia flowchart Anemia Volume depleted Normovolemic Reticulocytes increased Reticulocytes decreased Transfusion Green, H. Decision Making in Medicine: An algorithmic approach

  20. Anemia flowchart Reticulocytes increased Coomb’s test positive Coomb’s test negative Warm Ab Cold Ab -Autoimmune hemolytic anemia -Drug induced AHA -1/2cold agglutinin -PCH

  21. Anemia flowchart Coomb’s test: NEGATIVE Spleen palpable Normal spleen Congenital Acquired -Hypersplenism -Thalassemia -Abnormal Hemoglobin (eg. HbSC) -Drug related -Enzyme defect -Membrane defect -Abnormal HgB • Microangiopathic hemolytic anemia • Paroxysmal nocturnal hemoglobinuria

  22. Case: Initial impression • Paroxysmal nocturnal hemoglobinuria • Myelodysplastic syndrome • Leukemia

  23. Case: Course in the wards • On admission: CBC • Hgb: 9.5 • Hct: 31.8 • RBC: 2.9 • WBC: 3,550 • Eosinophils: 1.00 • Segmenters/Neutrophils: 61.00 • Lymphocytes: 31.00 • Monocytes: 7.00 • Plt Ct: 173,000

  24. Course in the wards • 1st Hospital Day: • Underwent BMA • Flow cytometry (sent to SLMC) • PNH Panel report (By Flow Cytometry: Peripheral Blood) • Discharged • Prednisone 20mg OD every other day • Folic acid 500mg OD

  25. PNH Panel Report

  26. Case: Diagnosis • Paroxysmal Nocturnal Hemoglobinuria

  27. Paroxysmal Nocturnal Hemoglobinuria (PNH) • acquired chronic non-immunologic hemolytic anemia • arises from a somatic mutation in a hematopoietic stem cell (PIG-A) • Deficient in surface protein normally attached to cell membrane by a GPI anchor • renders the red cells highly susceptible to complement mediated lysis resulting in the characteristic hemolysis.

  28. History Investigator Year Contribution Gull 1866 Described nocturnal and paroxysmal nature of “intermittent haematinuria” in a young tanner. Strubing 1882 Distinguished PNH from paroxysmal cold haemoglobinuria and march haemoglobinuria. Attributed the problem to the red cells. van den Burgh 1911 Red cells lysed in acidified serum. Suggested a role for complement. Enneking 1928 Coined the name “paroxysmal nocturnal haemoglobinuria”. Marchiafava 1928- Described perpetual hemosiderinemia in absence of and Micheli 1931 hemolysis. Their names became eponymous for PNH in Europe.

  29. History Ham 1937-1939 Identified the role of complement in lysis of PNH red cells. Developed the acidified serum test, also called the Ham test, which is still used to diagnose PNH. Demonstrated that only a portion of PNH red cells are abnormally sensitive to complement. Davitz 1986 Suggests defect in membrane protein anchoring system responsible Hall & Rosse 1996 Flow cytometry for the diagnosis of PNH

  30. Epidemiology • Rare disease • frequency unknown • thought to be on the same order as aplastic anemia (2-6 per million) • Median age at diagnosis • ~ 35 yrs • PNH reported at extremes of age

  31. Epidemiology • Female:Male ratio = 1.2:1.0 • No increased risk of PNH in patient relatives • Median Survival after diagnosis ~ 10-15 yrs

  32. Pathogenesis: The Defect • Defect - Somatic mutation of PIG-A gene (phosphatidylinositol glycan complementation group A) located on the X chromosome in a clone of a hematopoietic stem cell • >100 mutations in PIG - A gene known in PNH • The mutations (mostly deletions or insertions) generally result in stop codons - yielding truncated proteins which may be non or partially functional

  33. PNH Defect Hillmen and Richards, Br J Haematol, 2000

  34. Dual Pathogenesis Hypothesis Hillmen and Richards, Br J Haematol, 2000

  35. Molecular lesion • Frameshift mutations • Type III cells • Total absence • Missense point mutations • Small amounts of GPI anchor proteins • Partial expression/residual activity • Type II cells Richards, et. al. Cytometry 42: 223-233 (2000)

  36. Pathogenesis: Functional consequences of lack of GPI linked proteins • CD55 (decay accelerating factor) inhibits the formation or destabilizes complement C3 convertase (C4bC2a) • CD59 (membrane inhibitor of reactive lysis, protectin, homologous restriction factor) Protects the membrane from attack by the C5-C9 complex • Inherited absences of both proteins in humans have been described • Most inherited deficiencies of CD55 - no distinct clinical hemolytic syndrome • Inherited absence of CD59 - produces a clinical disease similar to PNH with hemolysis and recurrent thrombotic events

  37. CD55 inhibits assembly, regulating complement cascade at C3 step

  38. CD59 limits polymerization of C9 in membrane C5b-9 complex

  39. Missing proteins of importance Complement regulating proteins: • CD59 (aka MAC inhibitor/protectin) • Homologous restriction factor (HRF) • CD55 (aka decay accelerating factor) Thrombosis regulating proteins: • CD87 (aka urokinase-type plasminogen activator receptor)

  40. Clinical manifestations of PNH • Highly variable and dependent upon the size of the abnormal clonal population in any individual • Hemolysis • mild to very brisk • dependent upon • size of abnormal clone (1->90%) • content of complement defense proteins (PNHII/III) • presence of concomitant infection or other factor activating complement

  41. Clinical Manifestations: Hemolysis • chronic hemolysis with acute exacerbations (hallmark) • only 1/3 exhibit hemolysis at diagnosis

  42. Clinical manifestations: Hemolysis • Recurrent attacks of intravascular hemolysis are usually associated with: • Hemoglobinuria • Abdominal pain • Dysphagia • Impotence • Dependent upon: • Size of abnormal clone (1->90%) • Content of complement defense proteins (PNH II/III) • Presence of concomitant infection or other factor activating complement

  43. Clinical manifestations: Thrombosis • Hepatic vein most common • common cause of fatality • Cerebral vein thrombosis • sagittal sinus in particular • Abdominal veins • Dermal veins • Pulmonary embolism - unusual

  44. Clinical manifestations: Cytopenia • Relative/absolute bone marrow failure • present to some degree in all patients • relative granulocytopenia/thrombocytopenia • decreased capacity to form myeloid colonies

  45. Clinical Features: Dilemma in diagnosis • Variable expression of symptoms often causes considerable delay in the diagnosis

  46. Presenting features in 80 patients with PNH Dacie and Lewis, 1972

  47. Laboratory Evaluation of PNH • Acidified Serum Test (Ham Test 1939) • Acidified serum activates alternative complement pathway resulting in lysis of patient’s rbcs • May be positive in congenitial dyserythropoietic anemia • Still in use today • Sucrose Hemolysis Test (1970) • 10% sucrose provides low ionic strength which promotes complement binding resulting in lysis of patient’s rbcs • May be positive in megaloblastic anemia, autoimmune hemolytic anemia, others • Less specific than Ham test

  48. Diagnosis: HAM test • Lysis of PNH cells by activated complement • Semi-quantitative • Cannot differentiate Type III from Type II • Cannot provide information on cell lineages other than red cells

  49. Laboratory Evaluation of PNH • PNH Diagnosis by Flow Cytometry (1986) • Considered gold standard for diagnosis of PNH (1996) • Detects actual PNH clones lacking GPI anchored proteins • More sensitive and specific than Ham and sucrose hemolysis test

  50. PNH Diagnosis by Flow Cytometry • Flow Cytometry is method of choice • More studies are needed to better define whether the type (I, II, or III), cell lineage, and size of the circulating clone can provide additional prognostic information. • Theoretically - should be very valuable

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