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Section 5 HA. Paroxysmal Nocturnal Hemoglobinuria (PNH). Definition Etiology and pathogenesis Characteristics of PNH ( clinical and lab ) Diagnostic process. Definition.

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Paroxysmal Nocturnal Hemoglobinuria (PNH)

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Paroxysmal nocturnal hemoglobinuria pnh

Section 5 HA

Paroxysmal Nocturnal Hemoglobinuria (PNH)

Definition

Etiology and pathogenesis

Characteristics of PNH (clinical and lab)

Diagnostic process


Paroxysmal nocturnal hemoglobinuria pnh

Definition

PNH is a clonal disorder of hematopoietic stem cells caused by a somatic mutation of the pig-A gene on the short arm of the X chromosome . And the patients with it may present either with a HA( with intravascular hemolysis and episodes of nocturnal hemoglobinuria) or pancytopeniawith a dysplastic or aplastic marrow morphology.

GPI - glycosylphosphatidylinositol glycan


Paroxysmal nocturnal hemoglobinuria pnh

Etiology and pathogenesis of PNH


Paroxysmal nocturnal hemoglobinuria pnh

Marrow damage

complete or partial failure in the production of GPI anchor protein

Loss of several GPI-anchored membrane proteins

increased sensitivity to C-mediated lysis

Neutrophils

decrease

complement-driven activation of platelets, impaired fibrinolysis

Intravascular hemolysis

Platelet falls,bleeding

Hypercoagulabe state

infection

thrombosis

hemoglobinuria

pancytopenia

anemia

mutations of pig-A gene in HSC

CD59 : membrane inhibitor of reactive lysis,

CD55(decay accelerating factor

CD58

CD16

CD14


Paroxysmal nocturnal hemoglobinuria pnh

  • Severity of anemia is variable .

Severe anemia:fatigue, weakness, pallor, dyspnea

Clinical featuresof PNH

2. Dark urine : paroxysmal or on awakening or no.

(hemolysis episode after infection, transfusion, acid food or drugs, stress, fatigues or after aplastic or hypoplastic anemia.)

PNH I : GPI-negative cells(normal)

PNH II : Partial deficiency

PNH III:Complete deficiency

Complement activation


Paroxysmal nocturnal hemoglobinuria pnh

Clinical featuresof PNH

3. Splenomegaly in some patients

4. Venous thrombosis (hepatic, portal, splenic mesenteric veins) or DIC

5. Major bleeding or infection.

Some die of thrombotic diseases, some die of leukemia, some develop(or revert to AA.


Paroxysmal nocturnal hemoglobinuria pnh

  • Blood:

  • Ret serum bilirubin

  • RBC, Hb

  • usually hypochromic andnormochromic anemia

dimorphic

Lab findings of PNH

  • WBC : neutropenia, low LAP score or absence.

  • BPC: fall, abnormal platelet function


Paroxysmal nocturnal hemoglobinuria pnh

Hypochromic anemia of PNH


Paroxysmal nocturnal hemoglobinuria pnh

Lab findings of PNH

  • 2. Bone marrow

  • hyperplasia or hypoplasia (aspiration site)

  • hypochromic and normochromic erythrone

  • Iron stain is often absent.(iron deficiency)


Paroxysmal nocturnal hemoglobinuria pnh

PNH: hypercellularity


Paroxysmal nocturnal hemoglobinuria pnh

Bone marrow of PNH: erythroid hyperplasia


Paroxysmal nocturnal hemoglobinuria pnh

bone marrow of PNH


Paroxysmal nocturnal hemoglobinuria pnh

Hypochromic, polychromic, stippling


Paroxysmal nocturnal hemoglobinuria pnh

Why the patien with hypochromic anemia?

A. intermittent hemoglobinuria

hemosiderinuria

B. sideropenia (secondary to iron deficiency)

C. marrow insufficiency


Paroxysmal nocturnal hemoglobinuria pnh

Lab findings of PNH

3. Urine: sometimes hemoglobinuria,URO +

constanthemosiderinuria (Rous test +)

4. Specific tests

--- Sugar water test: screening test for PNH

--- Ham test: definitive test for PNH

5. Immunophenotype:decreased CD55, CD59


Paroxysmal nocturnal hemoglobinuria pnh

Urine of PNH patient in the morning


Paroxysmal nocturnal hemoglobinuria pnh

3. Urine: URO +


Paroxysmal nocturnal hemoglobinuria pnh

結果


Paroxysmal nocturnal hemoglobinuria pnh

room temperature 1h

no hemolysis

hemolysis

PNH(lysis>5%)

exclude PNH

MA, IHA or some leukemia

SUGAR WATER TEST

【Method】

Red cells suspension(patient)

control serum ( or same blood type)

sucrose


Paroxysmal nocturnal hemoglobinuria pnh

HAM’S TEST

【Principle】 The complement present in serum is responsible for lysis of PNH cells with sensitivity to acidifiction.

patient’s red cells suspension

acidified pH6.5 , 37℃1h

mixed with fresh complement

( same type control serum or patient’s own serum)

lysis: no lysis:

PNH normal orlack of PNH cells


Paroxysmal nocturnal hemoglobinuria pnh

Control tubes for excluding false negative

Red cells suspension

+

inactivated serum(56℃, 30’)

pH6.5 , 37℃1h

no lysis:


Paroxysmal nocturnal hemoglobinuria pnh

流式细胞仪检测PNH细胞群


Paroxysmal nocturnal hemoglobinuria pnh

Progressive Studies

1. kinetic studies with 51Cr labeled ,the red cells show a double population:

A. with a short half-life

B. with a subnormal survival

2. A cytometric assay of CD16 and CD66b on granulocytes in patients with equivocal red cell

3. GPI anchor protein and PIG-A gene.


Paroxysmal nocturnal hemoglobinuria pnh

Diagnosis for PNH:

Clinical featrues

Plus

two of the following or

one of the following

  • > twice +,

  • Hemoglobinuria +

  • evidence of intravascular hemolysis

  • Exclude HS,IHA,G-6PD deficiency and PCH

Sugar water test: (+)

Ham test: (+)

Rous test +

Plus

exclude AA.(exp. hypoplasia)


Paroxysmal nocturnal hemoglobinuria pnh

Case assay:

A 30-year-old male came to see the physician because of increasing fatigue over the previous few months.

PE : a pale but otherwise normal-appearing adult male, the liver and spleen slightly enlarged.

The patient reported noticing that his first urine of the morning was occasionally brown.


Paroxysmal nocturnal hemoglobinuria pnh

Case assay:


Paroxysmal nocturnal hemoglobinuria pnh

Case assay:

CBC:

Hb:85 g/L

Hematocrit 0.25 l/L

RBC 2.6×1012/L

WBC 4.4×109/L

Blood smear

Ret 13%


Paroxysmal nocturnal hemoglobinuria pnh

Bone marrow figure


Paroxysmal nocturnal hemoglobinuria pnh

Case assay:

Rous test


Paroxysmal nocturnal hemoglobinuria pnh

Case assay:

Questions:

1. What is the most probably diagnosis of this patient? List your evidence of the diagnosis.

2. If you want to have an exact diagnosis of this patient, which tests are supposed to be done and what are the expected results?

3. Can you explain the following results with the patient?

Serum iron: 8.1umol/L, TIBC: 66umol/L


Paroxysmal nocturnal hemoglobinuria pnh

  • Questions :

  • What is the etioloy of PNH?

  • How to diagnose PNH?

  • 3.How to differentiate PNH and AA?

  • 4. How to differentiate PNH and IDA?


Paroxysmal nocturnal hemoglobinuria pnh

AA

Typical

atypical

AA and PNH:

AA-PNH syndrome

AA crisis

PNH

Clinical features of AA

Ham test positive or Hburia,Rous test positive


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