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Thrombocytopenic purpura

Huang Honghui Dept. of Hematology, Renji Hospital

Definition: Thrombocytopenia is a clinical syndrome in which a decreased number of platelets in the circulating blood present as a bleeding tendency, i.e. skin, mucosa or internal organ bleeding.

It is the most common course of abnormal bleeding(30%).

Classification: idiopathic/ secondary

BPC<50000/μl----bleeding tendency

BPC<20000/μl----spontaneous hemorrhage

I

diopathic

T

hrombocytopenia

P

urpura (

ITP

)

Definition

ITP is an acquired disease of children and adults characterized by a low platelet count, an normal or increased numbers of megakaryocytes in the bone marrow, and absence of evidence for other disease.

Classification

Acute type (aITP)

Chronic type (cITP)

Etiology and Pathogenesis

Infection(bacteria or virus)

aITP--- antecedent viral infection

cITP--- state of illness worsen because of infection

anti-viral antibody or immunocomplex in plasma

Etiology and Pathogenesis

Immunologic processes

The infusion of plasma from patients with ITP into normal recipients

thrombocytopenia

The infusion of normal platelets into patients with ITP

destructed within 12-24h

platelet associated antibodies ( PAIgG, PAIgA, PAIgM )

Glucocorticoid, plasmapheresis, HD-Ig --- good response

Etiology and Pathogenesis

Role of the liver and spleen

The site of production of platelet antibodies.

The site of platelet clearance.

Splenic sequestration is the major site of platelet clearance in ITP.( 51 Cr-labeled isologous platelet )

Hepatic sequestration ---- severe thrombocytopenia and markedly shorten platelet survival.

Etiology and Pathogenesis

51 Cr labeled isologous platelet Administrate to patients with ITP External scintillation counting Rapid accumulation of radioactivity predominantly in the spleen Splenic sequestration is the major site of platelet clearance in ITP

Etiology and Pathogenesis

Etiology and Pathogenesis

Others

Impaired thrombopoiesis

In cITP, an Ig has been demonstrated on the surface of the megakaryocytes →the attachment of antibody may impair platelet production.

Etiology and Pathogenesis

Others

Role of estrogenic hormones

Suppress the platelet production.

Stimulate the clearance ability of monocyte macrophage against the antibody binding platelet.

Clinical Features

Acute ITP

Most frequently in children 2 to 6 years.

A history of viral infection preceding the onset of bleeding.

Acute onset.

Clinical Features

The symptoms and signs of bleeding:

Bruises and petechiae are the nearly universal presenting clinical symptom.

<1/3: bleeding.

<10%: bleeding.

epistaxis and gingival hematuria, gastrointestinal

<3%: profuse hemorrhages.) severe (massive purpura, epistaxis and retinal

Self-limited, spontaneous remission.

Clinical Features

Chronic ITP

More frequently in females(<40yrs), F:M=4:1.

Insidious onset.

Clinical Features

The symptoms and signs of bleeding:

Petechiae: asymptomatic, not palpable, most in dependent regions.

• • • •

Purpura Menorrhagia Epistaxis,gingival bleeding Gastrointestinal bleeding and hematuria are less common.

Intracerebral hemorrhage is uncommon,but it is the most common cause of death.

Fluctuating course,spontaneous remission is uncommon.

Clinical Features

Others

Anemia: iron deficiency type.

Splenomegaly

Laboratory Finding

Blood

Platelet count

• •

Acute type <20

×

10 9 /L Chronic type 30-80

×

10 9 /L

Morphology and function of platelet

Morphology:abnormal large, “giant” forms, bizarre shapes, deeply stained forms.

Functions:adhesion N/↓, aggregation N/↓

Others:

Hb: N/↓

WBC: normal/eosinophilia

Laboratory Finding

Bone marrow

megakaryocytes increased or normal.

disturbance of development and maturation: immature megakaryocytes↑, granule in cytoplasm ↓,size ↓.

platelet-producing megakaryocyte↓(<30%)

Megakaryoblast 0% Promegakaryocyte 0-5% Granular megakaryocyte 10-27% Platelet-producing megakaryocyte 44-60% Platelet

Acute ITP(BM)

1.Megakaryoblast

2.Promegakaryocyte

3.Granular Megakaryocyte

Chronic ITP(BM)

1.Granular megakaryocyte 6.Megakaryoblast in metaphase of mitosis 7.Giant platelets

Laboratory Finding

Platelet associated antibodies and complements

Assay of PAIgG and PAC3

PAIgG:

the first sensitive and reproducible method

increased

The magnitude of increase is greater in patients with more severe thrombocytopenia.

Laboratory Finding

Others

Platelet survival time ( 51 Cr labeled)

Normal: 7-11days

Acute type: 1-6 hour

Chronic type: 1-3 day

Laboratory Finding

Others

Tests of hemostasis and blood coagulation

Bleeding time: prolonged;

Clot retraction: absent or deficient;

PT, PTT, CT: normal

Diagnosis and Differential Diagnosis

Diagnostic criteria

– – – –

bleeding manifestation BPC count ↓ No or mild splenomagaly megakaryocytes increased or normal, having disturbance of maturation

Anyone of the followings

• • • • •

Response to glucocorticoid Response to splenetomy PAIg(+) PAC3(+) Platelet survival time ↓

Diagnosis and Differential Diagnosis

Exclude secondary thrombocytopenia

Such as: acute infectious illness, myelodysplastic syndrome, hypersplenism, disseminated intravascular coagulation, aplastic anemia, acute leukemia, systemic lupus erythematous.

Feature Peak age Acute ITP Children,2-6yr Ratio of F:M 1:1 Antecedent infection Onset of bleeding Common 1-3wk before Abrupt Platelet count duration Spontaneous remission Chronic ITP Adults,20-40yr 2-3:1 unusual insidious <20,000/

l 30,000-80,000/

l 2-6wk,rarely longer <6 mons Occur in 80% of cases Months or years >6 mons Uncommon

Treatment

• • • • • • •

Supporting measure Observation Glucocorticoids Splenectomy Immunosuppressive drugs Others Emergency treatment

Treatment:(1)Supporting measure

Supporting measure

Physical activity should be restricted to minimize the hazards of trauma, particularly head injury.

Drugs that impair platelet functions should be avoided.

Blood loss should be treated as otherwise indicated.

Treatment:(2)Observation

Observation

Platelet count > 50

×

10 9 /L and

Asymptomatic or have only minor purpura

Treatment:(3)Glucocorticoids

Mechanism of action:

significantly diminish immunoglobulin synthesis.

inhibit the binding of antibodies to platelets.

impair reticuloendothelial function and thereby to diminish platelet destruction.

Improve the permeability of capillary

Stimulate the hematopoisis and accelerate the release of platelet into peripheral blood.

Treatment:(3)Glucocorticoids

Initial means of therapy

Response rate: 60-90%

Dosage and regimen

Prednisone 1-2mg/kg.d p.o.

The initial course of glucocorticoids should be maintained for 3 to 4 weeks, followed by a gradual tapering of the dosage.

Therapy course: 6 months

Treatment:(4)Splenectomy

Mechanism of action

Removal of the major site of destruction of antibody-sensitized platelets.

Removal of a major site of antibody synthesis.

Treatment:(4)Splenectomy

Indications

failure to respond to glucocorticoid therapy, relapse after discontinuance of glucocorticoid therapy or reduction in the dosage.

the necessity of high doses of glucocorticoid for maintenance of a clinical status free of serious hemorrhage.

overriding contraindications due to the use of glucocorticoids.

Radioactivity index of spleen ↑( 51 Cr)

Treatment:(4)Splenectomy

Contraindications

in children under 2 years of age

in many cases of ITP in pregnant women.

in patients with cardiac or other complications who are at risk of serious sequelae from any major surgical procedure.

Treatment: (5)Immunosuppressive drugs

• –

Indications Failure to response to glucocorticoid therapy and splenectomy

Contraindications due to glucocorticoid therapy and splenectomy

Combined therapy with glucocorticoid in order to improve and decrease the dose of glucocorticoid

Treatment: (5)Immunosuppressive drugs

Vincristine: 0.025mg/kg i.v. Qw

×

4-6w (total dose <2mg)

Cyclophosphamide: 50-100mg/day orally

×

3-6w or 400-600 mg i.v. Q3-4w

Azathioprine: 100-200mg/d p.o.

×

3-6w → 25-50mg/d p.o.

×

8-12w

CSA: 250-500mg/d p.o.

×

3-6w → 50-100mg/d p.o.

×

6m

Treatment:(6)Others

Danazol: androgen with minimal virilizing side effects

Mechanism of action

induce reticuloendothelial dysfunction, possibly by diminishing Fc (IgG) receptors.

Anti-estrogen effect.

Dosage:0.3-0.6g/d

×

2-3m

Side effect: liver function abnormality, headache, nausea, etal.

Treatment:(6)Others

Rh Immune Globulin

Mechanism of Action

phagocytic cell blockade due to occupancy of the phagocytic cell Fc receptors by the IgG-sensitized RBCs

Dosage

• •

The probability of response increases with the dose administered.

A common regimen administers 25 µg/kg of anti-D intravenously and repeats the same dose 2 days later if no or minimal response is evident.

Treatment: (7)Emergency treatment

Indications:

platelet count <20

×

10 9 /L,

severe life-threatening bleeding

serious complications, e.g., intracranial hemorrhage

immediate preoperative treatment of patients or pregnant women with serious hemorrhage

Treatment: (7)Emergency treatment

Platelet transfusions

produce some increase in platelet numbers

diminish bleeding for a time

should be avoided in patients with chronic ITP

Treatment: (7)Emergency treatment

High-dose immunoglobulin

Mechanism of action

blockade of the Fc receptors of the reticuloendothelial cells

neutralization of antiplatelet autoantibodies by antiidiotypic antibodies in the preparations

Regimen: 400mg/kg/day for 5 days

Response rate: 60-80%

Treatment: (7)Emergency treatment

Exchange plasmapheresis

Mechanism of action

Remove antiplatelet antibody or immune complex

Adverse effect

allergic reactions to plasma proteins

a risk for transmissible viral infections

Treatment: (7)Emergency treatment

High-dose methylprednisolone

Mechanism: diminish platelet destruction by the reticuloendothelial system

Regimen: 1.0g/day for 3-5 days

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