Paroxysmal nocturnal hemoglobinuria
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PNH is a rare , acquired , clonal disorder of marrow stem cells in which there is deficient synthesis of the glycosylphosphatidylinositol (GPI)

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Paroxysmal nocturnal hemoglobinuria l.jpg
PAROXYSMAL NOCTURNAL HEMOGLOBINURIA

BY

DR. IKPONMWEN O.D

DEPARTMENT OF HEMATOLOGY AND BLOOD

TRANSFUSION


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OUTLINE

  • INTRODUCTION

  • DEFINITION

  • HISTORY

  • EPIDEMIOLOGY

  • PATHOPHYSIOLOGY

  • CLINICAL FEATURES

  • LABORATORY FEATURES

  • DIFFERENTIAL DIAGNOSIS

  • TREATMENT

  • COURSE

  • SUMMARY

  • REFERENCES


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INTRODUCTION

  • PNH is a descriptive term for the clinical manifestation of red blood cell breakdown with release of hemoglobin into the urine that is manifested most prominently by dark- color urine in the morning.

  • Characterized by a triad; hemolytic anaemia, pancytopenia and thrombosis.


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DEFINITION

  • is an Acquired chronic hemolytic anemia which arises from a somatic mutation in a hematopoietic stem cell. Most hematopoitic cell lines may be affected by the intrinsic membrane defect. This defect renders the red cells highly susceptible to complement mediated lysis resulting in the characteristic hemolysis


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DEFINITION

  • Acquired hematopoietic stem cell disorder of

    clonal origin characterized by a defect in the

    glycosylphosphotidylinositol (GPI) anchor due

    to an acquired abnormality in the

    phosphatidylinositolglycan class A (PIG-A)

    gene.


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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.

  • Ham 1937- Identified the role of complement in lysis of PNH red 1939 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


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EPIDEMIOLOGY

  • PNH is rare and there are no accurate incidence data.

  • Crude prevalence might be between 1 per million and 1 per 100, 000 population.

  • Less diagnosed than aplasticanaemia. Approximately 5-10xs less than aplasticanaemia.

  • Male = Female

  • No familial tendencies exist

  • Occurs at any age but frequently found among adults


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EPIDEMIOLOGY CONTD

  • In france, the prevalence rate is estimated to be 1.5 cases per million population per year and about twice that figure occurs in Thailand

  • Every socio-economics class is affected.


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PATHOPHYSIOLOGY

  • Hallmark of PNH blood cells is that they are deficient in all surface proteins that use a GPI –anchor molecule.

  • Today, at least 27 different GPI-linked proteins are known to be expressed on blood cells


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GPI-anchor proteins

  • Distributed among cell surface proteins in eukaryotic organism.

  • In all species, the GPI-anchor shares a common core region of ethanolamine phosphate, 3- mannose residues, glucosamine and inositol.


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  • GPI-linked proteins on hematopoietic stem cells carry out multitude of functions.

  • Ecto-enzymes

  • Accessory molecules for growth receptor

  • Complement inhibitor

  • Adhesion molecules


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.

  • Surface Proteins Missing on PNH Blood Cells

  • Antigen Expression Pattern

  • Enzymes

  • Acetylcholinesterase (AchE) Red blood cells

  • Ecto-5'-nucleotidase (CD73) Some B- and T-lymphocytes

  • Neutrophil alkaline phosphatase(NAP) Neutrophils

  • ADP-rybosyltransferase Some T-lymphs, Neutrophils

  • Adhesion molecules

  • Blast-I/CD48 Lymphocytes

  • Lymphocyte function-

  • associated antigen-3(LFA-3 or CD58) All blood cells

  • CD66b Neutrophils

  • Complement regulating surface proteins

  • Decay accelerating factor (DAF or CD55) All blood cells

  • Homologous restriction factor,

  • Membrance inhibitor of reactive lysis All blood cells

  • (MIRL or CD59)


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  • Antigen Expression Pattern

  • Other surface proteins

  • of unknown functions

  • CAMPATH-1 antigen (CDw52)Lymphocytes, monocytes

  • CD24 B lymphocytes, Neutrophils,

  • eosinophils

  • p5O-80 Neutrophils

  • GP500 Platelets

  • GPI75 Platelets


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  • PNH , all blood cell lineages and progenitors are affected.

  • Although lymphoid lineages usually are affected to lesser extent.

  • Deficiency of at least 2 of these GPI-linked molecules on circulating blood cell is sufficient for the diagnosis of PNH


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PATHOGENESIS (CONTD)

  • GENETICS OF PNH.

  • Acquired disease, no inherited form has been described.

  • PNH patients have somatic mutations in the x- linked PIG-A gene (phosphatidylinositolglycan complementation class A)

  • PIG-A encodes for a protein subunit essential for the activity of N-acetyl –glucosaminyltransferase.

  • Enzymes required for the synthesis of GPI –anchor molecules


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  • PIG-A maps to the short arm of the X-chromosome is approximately 17 kb long and 6 exons.

  • X-chromosome and due to inactivation in female somatic cell only one mutation is required in either in man and women.



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  • Complement sensitivity; classic abnormality of PNH erythrocytes is their increased sensitivity to complement –mediated lysis whether the complement is activated by the classic or the alternative pathway.

  • Activation of complement may be achieved by a variety of means;

  • Lowering of pH as in the acid hemolysis test

  • Cobra venom

  • Reducing ionic strength as in sucrose hemolysis test.

  • Increasing magnesium concentration.


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  • Free hemoglobin are released into the circulation.

  • They bind to haptoglobin. Then to nitric oxide when haptoglobin has been depleted.

  • Scavenge the nitric oxide in the circulation leading to vasoconstriction,smooth muscles contractions. This leads to numbers of symptoms in PNH


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3 CATEGORIES OF PNH

  • Based on interaction with complement.

  • PNH-1; erythrocytes react normally with complement and are thought to represent residual normal cells because they are similar to normal erythrocyte in all respects

  • PNH-11 ; Erythrocytes have moderate sensitivity to complement component c3 and are 3-5xs more sensitive to lysis by complement than are normal erythrocytes

  • PNH 11 erythrocytes appear to be deficient in complement regulatory protein DAF only.


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  • PNH 111; Erytrocytes are the cells most sensitive to complement , being 15-25xs more sensitive to complement component c3 than normal erythrocytes

  • They also have increased sensitivity to the terminal component c5-59,

  • PNH 111 are deficient in both DAF and HRF membrane proteins.

  • PHN patients usually have variable combinations of 3 different types.

  • 80%---------PNH1 and PNH 11

  • 20%----------PHN1,PNH11 and PNH 111


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    CLINICAL FEATURES

    • 3 main clinical presentations based on working classifications; variations in presentation, clinical manifesatations and natural history among PNH patients.

    • Classic PNH

    • PNH in setting of another specified bone marrow disorder e.g PNH/ aplasticanaemia or PNH/ refractory anaemia-myelodysplasticanaemia(MDS/PNH)

    • Subclinical PNH (PNH-sc) in aplasticanaemia


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    .


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    • Presents in any of the 3- syndromes or sets of symptoms.

    • HEMOLYTIC ANAEMIA; usually intravascular.

    • Hemoglobinuria

    • Jaundice , weakness ,dyspnea and palor are common

    • Splenomegaly

    • Recurrent dysphagia , erectile dysfunctions.

    • Iron deficiency

    • Bleeding


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    THROMBOSIS

    • ACTIVATION OF PLATELET BY COMPLEMENT.

    • PROCOAGULANT ACTIVITY OF RED CELL MEMBRANE

    • INTRAVASCULAR RELEASE OF ADP FROM RED CELLS LEADING TO PLATELET AGGREGATION .


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    .

    • VENOUS THROMBOSIS; Budd-chari syndrome, pain in the abdomen ,low back pain ; colicky in nature tender on palpation.

    • Frank intestinal infarction or bleeding into the intestinal wall .

    • Esophageal spasm

    • Pulmonary hypertension

    • Arterial/ venous thrombosis


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    .

    • Hyposthenuria , decline creatinine function, abnormal tubular function. Acute and chronic renal failure.

    • Severe headache or pains in the eye.


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    LABORATORY FEATURES

    • BLOOD.

    • ANAEMIA; may be severe with hemoglobin concentration level of 5g/dl but in some case hemoglobin is normal.

    • Mild to moderate reticulocytosis. Reticulocyte count tends to be lower than in other patients with chronic hemolysis.

    • Macrocytosis commensurate with the increase reticulocyte count usually present.


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    .

    • Microcytic and hypochromic in patients that have been iron deficient. Plasma iron and ferritin levels are usually low .

    • Iron binding capacity is elevated.

    • Leukocyte count is low .

    • NAP score may be diminished and surface urokinase receptor is absent.

    • Platelet count is low but may be 150,000/μl

    • Platelet survival is usually normal.


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    .


    Marrow l.jpg
    marrow

    • Erythroid hyperplasia is usually present but the overall marrow cellularity is generally not greatly increased.

    • Bone marrow biopsy usually confirms erythroid

      hyperplasia. Bone marrow may be aplastic

    • Stainable iron is often absent.


    Urine l.jpg
    URINE

    • Hemoglobin is sometimes but by no means always present in the urine.

    • Hemoglobin cast may be present.

    • Hemosiderinuria is one of the most constant features (often of considerable diagnostic importance)


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    Biochemical

    • Bilirubin level is usually only moderately increased.

    • LDH is often in the thousand

    • .

    • Haptoglobin is markedly decreased


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    DIAGNOSTIC TEST

    • FLOW CYTOMETRY

    • COMPLEMENT LYSIS SENSITIVITY TEST

    • FLUORESCENT AEROLYSIN

    • IMMUNOTYPING

    • SUGAR WATER TEST (SUCROSE HEMOLYSIS TEST)

    • HAM’S TEST (ACIDIFIED SERUM LYSIS TEST)


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    DIFFERENTIAL DIAGNOSIS

    • Diagnosis should be entertained in any patient with pancytopenia of unknown origin particularly when accompanied by reticulocytosis.

    • Isolated defects in a single lineage such as thrombocytopenia may also be the presenting finding.


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    .

    • PAROXYSMAL COLD HEMOGLOBINURIA

    • .

    • HEMOLYTIC ANAEMIA

    • MESENTERIC ARTERY THROMBOSIS

    • MESENTERIC ARTERY ISCHAEMIA

    • RENAL VEIN OBSTRUCTION

    • RENAL VEIN THROMBOSIS


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    TREATMENT

    • SUPPORTIVE AND DEFINITIVE.

    • SUPPORTIVE.; TRANSFUSION of red cells .

    • Iron therapy

    • Stereiod ; androgen and glucorticoids.FLUOXYMESTRONE 20-30mg/day

    • Anticoagulants

    • Splenectomy

    • Immunosuppressant

    • Eculizumab


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    .


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    Definitive

    • Stem cell transplant; Allogenic bone marrow transplant when HLA identical sibling is available


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    COURSE

    • Succumb to the disease in few months

    • Chronic course

    • Cure

    • 5-15% develop acute leukemia

    • MDS


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    .


    Summary l.jpg
    SUMMARY

    • ACQUIRED hematopoietic stem cell disease characterized by chronic hemolytic anaemia , thrombotic episodes and often pancytopenia.

    • Clonal disorder caused by a somatic mutation of the x-linked gene phosphatidylinositolglycan class A which is required for formation of the phosphatidylinositol anchor.

    • This leads to many membrane proteins like inhibitors of complement cascade are missing from the cell surface and erythrocytes are sensitive to hemolysis.


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    .

    • Diagnosed with sucrose hemolysis test and flow cytometry.

    • Treament is with glucocorticoids ,androgenic steriod,eculizumab and stem cell transplant

    • Median survival is approximately 10 years.


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    REFERENCES

    • Hoffbrand A, CatovskyD,Tuddenham E (2004) paroxysmal nocturnal hemoglobinuria. Postgraduate hematology 11: 169-175.

    • Lichtman M, Beutler E, Kipps T, Seligsohn U, Kaushansky K, Prchal J,(2006). Paroxysmal nocturnal hemoglobinuria.Williams hematology 38: 469-475.

    • Internet uptodate

    • Internet emedicine


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    THANK YOU


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