The Scarlet Bedwetter L. Carolina I. Dumlao Internal

The Scarlet Bedwetter L. Carolina I. Dumlao Internal Medicine Year Level I Objectives 1. 2. 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. 39 year old Female Filipina Married Caloocan Call center Case: Chief complaint

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

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 2u PRBC

Case: History of present illness Consulted hematologist Peripheral blood smear : Microcytic/hypochromic Decreased WBC Normal platelet Iron deficiency anemia Case: History of present illness Iron studies = normal Repeat PBS

Normocytic/normochromic Decreased Hgb Decreased WBC Case: History of present illness Patient advised to undergo BMA ADMISSION 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 HEENTNo 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 postnasal 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. Case: GIT Review of systems

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 Case:

Past health Non-hypertensive Non-diabetic No allergies No previous operations Case: Obstetric/Gynecologic history Menarche at 12 years of age Monthly, 2-3 pads per day, lasting 3 days

Married for 10 years G0P0 Case: Personal/Social history 2-3 pack smoker Stopped 1 year ago Occasional alcoholic beverage drinker Case:

Family history Great grandfather - leukemia Case: Physical Exam VITAL SIGNS BP=100/70mm Hg sitting HR=92bpm RR= 18breaths/min T=36.8C 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. 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 Case: Salient features

39/F Chronic anemia Tea-colored urine Iron studies normal Peripheral blood smear normocytic/normochromic Anemia flowchart Anemia Volume depleted Transfusion Normovolemic Reticulocytes increased

Reticulocytes decreased Green, H. Decision Making in Medicine: An algorithmic approach Anemia flowchart Reticulocytes increased Coombs test positive Warm Ab Cold Ab -Autoimmune hemolytic anemia -1/2cold agglutinin

-Drug induced AHA -PCH Coombs test negative Anemia flowchart Coombs test: NEGATIVE Spleen palpable Normal spleen Congenital -Hypersplenism -Thalassemia

-Abnormal Hemoglobin (eg. HbSC) -Drug related -Enzyme defect -Membrane defect -Abnormal HgB Acquired -Microangiopathic hemolytic anemia -Paroxysmal nocturnal hemoglobinuria Case:

Initial impression Paroxysmal nocturnal hemoglobinuria Myelodysplastic syndrome Leukemia 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

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 PNH Panel Report Marker Lineage of cells commonly labelled % labelled Reference Range % CD 55

Broad (decay accelerating factor DAF for C3 and C5, GPI-linked; deficiency leads to paroxysmal nocturnal hemoglobinuria PNH) 1.98% 65.42-81.82% CD59 Protectin or Membrane Inhibitor of Reactive Lysis (MIRL) 6.23%

73.24-87.00% Case: Diagnosis Paroxysmal Nocturnal Hemoglobinuria 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. 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 and Micheli 19281931

Described perpetual hemosiderinemia in absence of hemolysis. Their names became eponymous for PNH in Europe. 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 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 Epidemiology

Female:Male ratio = 1.2:1.0 No increased risk of PNH in patient relatives Median Survival after diagnosis ~ 10-15 yrs 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 PNH Defect Hillmen and Richards, Br J Haematol, 2000 Dual Pathogenesis Hypothesis Hillmen and Richards, Br J Haematol, 2000

Molecular lesion 1. Frameshift mutations 2. 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) 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 CD55 inhibits assembly, regulating complement cascade at C3 step CD59 limits polymerization of C9 in membrane C5b-9 complex 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) 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 Clinical Manifestations: Hemolysis chronic hemolysis with acute exacerbations (hallmark) only 1/3 exhibit hemolysis at diagnosis 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 Clinical manifestations: Thrombosis 1. Hepatic vein most common 2. Cerebral vein thrombosis

3. 4. 5. common cause of fatality sagittal sinus in particular Abdominal veins Dermal veins Pulmonary embolism - unusual Clinical manifestations: Cytopenia Relative/absolute bone marrow failure

present to some degree in all patients relative granulocytopenia/thrombocytopenia decreased capacity to form myeloid colonies Clinical Features: Dilemma in diagnosis Variable expression of symptoms often causes considerable delay in the diagnosis Presenting features in 80 patients with PNH Signs and Symptoms

# of Px (%) Symptoms of anemia 28 (35) Hemoglobinuria 21 (26) Hemorrhagic signs and symptoms 14 (18) Aplastic anemia 10 (13)

Gastrointestinal symptoms 8 (10) Hemolytic anemia and jaundice 7 (9) Iron-deficiency anemia 5 (6) Thrombosis or embolism 5 (6) Infections

4 (5) Neurologic signs and symptoms 3 (4) Dacie and Lewis, 1972 Laboratory Evaluation of PNH Acidified Serum Test (Ham Test 1939)

Acidified serum activates alternative complement pathway resulting in lysis of patients 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 patients rbcs May be positive in megaloblastic anemia, autoimmune hemolytic anemia, others

Less specific than Ham test 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 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 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 Flow cytometry Extent of PNH clone 2 classifications of PNH: 1. Hemolytic PNH 2.

Overt episodes Venous thrombosis in 50% Hypoplastic PNH No overt hemolysis 10% die due to aplastic anemia Richards, et. al. Cytometry 42: 223-233 (2000) Flow cytometry: Red cells

CD55 and CD59 Negative or partially deficient cells must be present for both in order to establish a diagnosis of PNH Provides clearest discrimination between types May predict clinical phenotype Flow cytometry: Granulocytes

CD55/CD16 or CD59/CD16 plus an additional antibody - CD15 or CD33 Percentage of PNH granulocytes reflects most accurately size of PNH clone Size of PNH clone is a determinant of the clinical phenotype of individual patients Serial studies allow prediction of prognosis Richards, et; al; Cytometry 42: 223-233 (2000) Flow cytometry: Serial monitoring Clinical relevance is unclear. Size of PNH clones if not constant with time British Journal of Hematology. 2000. 108: 470-479

From Purdue Cytometry CD-ROM vol3 97 Natural History of PNH Long term study of 80 patients with PNH seen at one institution between 1940 and 1970 Results median age at diagnosis: 42 (16-75) median survival: 10 years 28% survived more than 25 years 39% had one or more episodes of venous thrombosis 12 experienced spontaneous clinical recovery leukemia did not develop in any of the patients Hillmen et al, NEJM, 1995

Clinical features: Sequelae Major cause of death 25% of PNH patients survive >25 years - one half of these go on to spontaneous remission Remission patients

venous thrombosis complications from progressive pancytopenia hematological values revert to normal no PHN rbcs or granulocytes detected PNH lymphocytes - still detected but no clinical consequence Higher incidence of acute leukemia (6%) preleukemic condition most likely bone marrow failure not PNH Clinical features: Sequelae Significant proportion of patients survive for

prolonged periods (25% over 25 years) 15% will experience recovery from PNH with no sequelae attributable to their disease Hillmen, et al, 1995 Sites of thrombosis in PNH Sites and Types of Thrombosis Number of patients Intraabdominal Hepatic vein

8 Inferior vena cava 3 Mesenteric vein 4 Splenic vein 1 Hillmen et al, NEJM, 1995 Sites of thrombosis in PNH Sites and Types of Thrombosis

Number of patients Other venous sites Cerebral 4 Pulmonary embolism 9 Deep vein 7 Superficial

3 Arterial Myocardial infarction 6 Cerebrovascular accident 2 Hillmen et al, NEJM, 1995 Natural history of PNH Causes of death in 60 patients with PNH # of patients

Probably related to PNH Venous thrombosis Hepatic Vein 7 Inferior vena cava 1 Cerebral vein 1 Mesenteric vein 2

Pulmonary embolism 3 Hemorrhage Gastrointestinal 6 Hillmen et al, NEJM, 1995 Natural history of PNH Causes of death in 60 patients with PNH # of patients Subarachonoid 3

Intracerebral 2 Miscellaneous Liver failure 2 Intraabdominal event 1 Probably unrelated to PNH Arterial thrombosis Myocardial infarction

2 Cerebrovascular accident 6 Hillmen et al, NEJM, 1995 Natural history of PNH Causes of death in 60 patients with PNH # of patients Bronchopnuemonia 3 COPD plus cor pulmonale

2 Cardiac tamponade 1 Constrictive pericarditis 1 Renal failure 1 Amyloidosis 1

Lymphoma 1 Bronchial carcinoma 1 Unknown 12 Hillmen et al, NEJM, 1995 Natural History of PNH Hillmen et al, NEJM, 1995 Relationship to aplastic anemia (AA)

AA described as pancytopenia with nonfunctioning bone marrow. Cytopenia in one or all cell lineages also common to PNH High percentage of patients with AA develop clinical PNH or have lab evidence of PNH abnormality at some point (52%) Have lower risk of thrombosis Fujioka & Asai, 1989; Dunn, et al, 1991 Venous thrombosis

Anticoagulation Recommended for patients with large PNH populations With no contraindications to anticoagulation British Journal of Haematology 108: 470-479 Pancytopenia 10% will die from aplastic anemia Good response to immunosuppresion

Antilymphocyte globulin Cyclosporin A Ebenbichler et al, 1996 Stoppa, et al, 1996 Paquette et al, 1997 Schubert et al. 1997 PNH and Leukemia

Incidence similar to the risk of AML in aplastic anemia (5%) AA predisposes to clonal hematopoietic disorders (AML, PNH, MDS) PNH clone does not increase the risk of AML/MDS Not preleukemic British Journal of Haematology 108_:470-179 Therapy Bone Marrow Transplantation

Only curative treatment Immunosuppressive therapy Antilymphocyte globulin &/or cyclosporine A Does not alter proportion of PNH hemopoiesis Growth Factors

Some improvement no evidence that normal clones respond better than PNH clones Treatment Supportive, prevent complement activation Prednisone Therapy for/prevention of thrombosis thrombolytics acutely anticoagulation

Stimulate hematopoiesis G-CSF Immunosuppression ATG Cyclosporine Stem Cell Transplantation in PNH Flotho et al, Br J Haematol, 2002 Stem Cell Transplantation in PNH Summary of single institution trials

Approximately 12 reported Number of patients ranges from 1-16 Survival rates typically higher (58-100%) Likely high degree of reporting bias, based on outcomes seen using registry data Results Sustained engraftment: 77% Graft failure: 17% Grade 2-4 acute GVHD: 34% Chronic GVHD: 33%

Causes of death: graft failure (7), int. pneumonitis (4), GVHD (3), infection (3), ARDS (2), hemorrhage (1) IBMTR Data Saso et al, Br J Haematol, 1999 Stem Cell Transplantation in PNH EBMT Database (unpublished)

46 transplants using HLA-ID sibs reported from 1979 to 1997 Median age at diagnosis: 29 (10-46) Median interval from diagnosis to BMT: 794 days (30-8680) Actuarial 5 yr survival: 52% Main cause of death: acute GVHD Stem Cell Transplantation in PNH Conclusions from reported series:

BMT may cure 50-60% of selected patients with HLAidentical siblings Most patients transplanted have been < 30 years of age Regimen related toxicity and GVHD remain significant hurdles Role of alternative donor transplants unclear, though initial reports are not encouraging except in pediatric population Prognosis Based on Management Luzzatto, Haematologica, 2001 PNH: Management Guidelines Luzzato, ASH, 2001

Updates Eculizimab (Soliris) 1st drug to be approved for the treatment of PNH Complement inhibitor Humanized monoclonal antibody against terminal complement protein C5 Update:

Eculizimab 600mg IV Q7 days x 4 doses, then 900mg IV, 7 days after 4th dose, then 900mg IV Q14 days Must give meningococcal vaccine 2 weeks before treatment Thank you !

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