THROMBOCYTOPENIA Curs an IV - - PowerPoint Presentation

Slide1

THROMBOCYTOPENIA

Curs an IV -

limba

engleza

2012-2013

Slide2

Background

1/3 of all Hematology Consults in a General Hospital are for

thrombocytopenia

5 to 10% of all hospital patients are thrombocytopenic in the ICU the number increases to 35

%

Thrombocytopenic patients in the hospital suffer a twofold greater mortality rate than those who are not

Slide3

Platelet Kinetics

Normal circulating platelet count

150.000

to

450.000/

mmc

in Northern Europeans

90.000

to

300.000/

mmc

in people of Mediterranean descent

1/3 of platelets are sequestered in the spleen

Half life of a platelet is 9 to 10 days

Platelet production is the function of the multinucleated

megakaryocyte

15.000

to

45.000

platelets are produced daily to maintain steady state

Slide4

Thrombopoietin (TPO)

TPO is the primary regulatory protein in the production of platelets

TPO gene is on chromosome 3

TPO is expressed in the liver,

kidneys, and smooth muscle cells

Has a plasma half life of 30 hours

The receptor for TPO is c-MPL which is present on the

megakaryocytes

and

platelets

TPO rises with platelet fall and declines as the

megakaryocyte

and platelet mass increase

Slide5

Thrombocytopenia – risk of bleeding

The primary reason for evaluating thrombocytopenia is to assess the risk of bleeding and assess the presence of underlying disorders (TTP, HIT etc.)

<

20.000/

mmc

increased risk of bleeding

20.000 – 50.000/

mmc

rarely

have increase risk of spontaneous bleeding but increase risk of bleeding from procedures

50.000 – 100.000/

mmc

no increased risk of spontaneous bleeding and can undergo most procedures

Slide6

Thrombocytopenia - mechanisms

Decreased production

Increased

destruction

Increased

consuption

Sequestration

Pseudothrombocytopenia

Slide7

Pseudothrombocytopenia

Artifactually

low platelet count due to in vitro clumping of platelets

Usually caused by antibodies that bind platelets only in presence of chelating agent (EDTA)

Seen in healthy individuals and in a variety of disease states

Diagnosis:

Marked fluctuations in platelet count without apparent cause

Thrombocytopenia

disproprotionate

to symptoms

Clumped platelets on blood smear

Platelet

count varies with different anticoagulants

Slide8

Pseudothrombocytopenia

Platelet clumping in EDTA

No clumping in heparin

Slide9

Decreased Platelet Production

Marrow failure (

pancytopenia

)

aplastic

anemia, chemotherapy, toxins

B-12,

folate

or (rarely) iron deficiency

Viral infection

Drugs that can selectively reduce platelet production

Alcohol

Estrogens

Thiazides

Chlorpropamide

Interferon

Amegakaryocytic

thrombocytopenia

myelodysplasia

(pre-leukemia)

immune? (related to

aplastic

anemia)

Cyclic thrombocytopenia (rare)

Inherited thrombocytopenia

Slide10

Increased Platelet Consumption

Intravascular

coagulation (DIC or localized)

Microangiopathy

– TTP, Hemolytic-uremic

sdr

Damage by bacterial enzymes, etc

Slide11

Thrombocytopenia and Infection

Immune complex-mediated platelet destruction

Childhood ITP

Bacterial sepsis

Hepatitis C, other viral infections

Activation of coagulation cascade

Sepsis with DIC

Vascular/endothelial cell damage

Viral hemorrhagic fevers

Rocky Mountain Spotted Fever

Damage to platelet membrane components by bacterial enzymes (

eg

,

S

pneumoniae

sialidase

)

Decreased platelet production

Viral infections (EBV, measles)

Mixed production defect/immune consumption

HIV infection

Slide12

Immune Platelet Destruction

Autoimmune (ITP)

Childhood

Adult

Drug-induced

Heparin

Quinine, others

Immune complex (infection, etc)

Alloimmune

Post-transfusion

purpura

Neonatal

purpura

Slide13

Idiopathic (Immune) Thrombocytopenic Purpura (ITP)

Thrombocytopenia in the absence of other blood cell abnormalities (normal RBC & WBC, normal peripheral smear)

No clinically apparent conditions or medications that can account for thrombocytopenia

Slide14

ITP - Epidemiology

ITP is a high prevalence disease 16 to 27 per million per year

Incidence increases with age

Female predominance under the age of 60 but not over the age of 60

It can have an abrupt onset or insidious onset. It is generally abrupt in onset with children

Slide15

Slide16

ITP – Clinical forms

Childhood form

(most < 10 yrs old)

May follow viral infection, vaccination

Peak incidence in fall & winter

~50% receive some treatment

≥75% in remission within 6 mo

Adult

form

No

prodrome

Chronic, recurrences common

Spontaneous remission rate about 5%

Slide17

ITP - Pathogenesis

Increased platelet destruction caused by

antiplatelet

antibodies

Lack of compensatory response by

megakaryocytes

due to suppressive effect of

antiplatelet

antibodies

Pathogenesis was proved by Harrington when he infused himself with plasma from a women with ITP

Slide18

ITP - Pathogenesis

ITP plasma induces thrombocytopenia in normal subjectsPlatelet-reactive autoantibodies present in most casesOften specific for a platelet membrane glycoproteinAntibody coated platelets cleared by tissue macrophagesMost destruction in spleen (extravascular)Most subjects have compensatory increase in platelet productionImpaired production in some patientsIntramedullary destruction?Enhanced TPO clearance?

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Slide19

ITP - Clinic

Abrupt onset (childhood ITP) / Gradual onset (adult ITP)Common signs, symptoms, and precipitating factors include the following:Mucocutaneous bleedingPurpura – petechiae, echymosisMenorrhagia, metrorrhagiaEpistaxis, gingival bleedingRecent live virus immunization, recent viral illness (childhood ITP)Bruising tendencyGI bleed, CNS bleed = RAREAbsence of constitutional symptoms or splenomegaly

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Slide20

ITP – Clinical manifestations

Slide21

ITP – Clinical manifestations

Slide22

ITP – Clinical manifestations

Slide23

ITP - Diagnosis

ITP is a Diagnosis of

Exclusion

No laboratory test can diagnose

ITP

Need to exclude other causes of thrombocytopenia

Slide24

ITP - Associated Disorders

SLE

Antiphospholipid

syndrome

CLL

Large granular lymphocyte syndrome

Autoimmune hemolytic anemia (Evans syndrome)

Common variable immune deficiency

Autoimmune

lymphoproliferative

disorder (ALPS)

Autoimmune thyroid disease

Sarcoidosis

Carcinomas

Lymphoma

H pylori infection

Following stem cell or organ transplantation

Following

vaccination

HIV infection

Slide25

Evaluation of Patient with Low Platelets

History

Has the patient ever had a normal platelet count?

Carefully review medications, including OTC meds.

Antibiotics, quinine, anti-seizure medications

Ask about other conditions which may be associated with low platelets

Liver Disease/hepatitis

Thyroid Disease - both hypo- and hyper-

Infections: viral,

rickettsial

Pregnancy

Ask about other conditions which may be associated with ITP

Lupus, CLL, lymphoma

Slide26

Evaluation of Patient with Low Platelets

Physical

Evaluate for

lymphadenopathy

and

splenomegaly

Look for stigmata of bleeding

Blood blisters and oral

petechiae

,

ie

“Wet

Purpura

”

best harbinger of intracranial hemorrhage

Laboratory Data

Other blood counts should be normal.

Check B12 and

folate

levels.

Look at peripheral smear to exclude

pseudothrombocytopenia

, also exclude TTP (especially if anemia also present.)

Send coagulation screens (PT/PTT) to exclude DIC

Send HIV, hepatitis

serologies

and TSH

Consider doing a bone marrow biopsy

Megakaryocytes

should be present.

Slide27

ITP - Evaluation

Features consistent with the diagnosis of ITP

Thrombocytopenia with normal or slightly large platelets

Normal RBC morphology and number (may have associated iron def or

thallasemia

etc.)

Normal white cell number and morphology

Splenomegaly

rare

Features not consistent with the diagnosis of ITP

Giant platelets

RBC abnormalities

ie

schisotocytes

Leukocytosis

or

Leukopenia

Slide28

ITP - Laboratory evaluation

Platelet

associated immunoglobulin reflect plasma concentration and alpha granule

concentration

Bone Marrow not very helpful as initial test

May be helpful in patient over 50 years and concerned about MDS

If patient has failed initial treatment and diagnosis is in

question

TSH and HIV test helpful, Peripheral Smear helpful

Slide29

ITP – Confirmatory Laboratory Testing

Serum antiplatelet antibody assay (poor sensitivity)Test for specific anti-platelet glycoprotein antibodies (more specific, negative in 10-30%)

Confirmatory testing

not necessary

in typical cases

Slide30

ITP- Principles of Management

Most patients with ITP do not have clinically significant bleeding

Risk of intracranial bleed 0.1 to 1% (This is an overestimate)

Wet

Purpura

ie

epistaxis

, gingival bleeding is a risk factor for major bleeding

In asymptomatic patients with platelets counts greater then 20 K observation is reasonable

Slide31

ITP - Pharmacologic Management

Steroids

Prednisone 1mg/kg/day with taper over 2 to 3 months

Decadron

40 mg/day x 4 days

Solumedrol

1 gram/day x 2 days

Antibodies

IVIG 1 gram/day x 2 days

Anti-D 50 mcg/kg IV x1

Slide32

ITP - Management

Splenectomy

Immunize with

Pneumovax

,

Hib

, Meningococcal

Chronic Anti-D therapy

Does not put the disease in remission

Rituximab

Immunosuppressive treatment

AMG 531,

Eltrombopag

c-MPL

agnonists

Observation

Slide33

ITP – Glucocorticoid Therapy

Mechanism of action: Slows platelet destruction, reduces autoantibody

production

Prednisone, 1-2 mg/kg/day (single daily dose

)

Begin slow taper after 2-4 weeks (if patient responds

)

Consider alternative therapy if no response within 3-4 weeks

About 2/3 of patients respond (

plts

> 50K) within 1

week

Most patients relapse when steroids withdrawn

Advantages

: high response rate, outpatient therapy

Disadvantages

: steroid toxicity (increases with time and dose), high relapse rate

Slide34

ITP - Management of Asymptomatic Adult

If platelet count is >

40.000-50.000/

mmc

,

no therapy is required.



Check

platelet counts at designated intervals.

If platelet count is <

20.000-30.000/

mmc

,

begin therapy with

corticosteroids

.

Stop all NSAIDS and ASA to improve platelet function.

Slide35

ITP - Initial Management of Adult with Symptomatic Purpura

If platelet count is >

10.000/

mmc

,

treat with

prednisone

alone - use 1 mg/kg.

If platelet count <

10.000/

mmc

,

treat with prednisone, but also add

IVIg

1g/kg/d x 2d. - may require admission

Along with prednisone, add Calcium and Vitamin D to prevent bone loss.

If patient has severe bleeding, may need

platelet transfusions

.

Slide36

ITP - Subsequent Management of Adult with Symptomatic Purpura

Follow platelet counts daily until >20, then can d/c patient with close follow-up

Once platelet count normalizes, commence a

slow steroid taper

over 6-8 weeks.

1/3 of adults will have gone into remission.

2/3 of patients will relapse during or after steroid taper.

Slide37

Management of Relapsed ITPSplenectomy

Splenectomy

is effective in 2/3 of patients, leading to normal platelet counts

.

Almost all responses occur within 7-10 days of

splenectomy

Can be performed via open method or

laparoscopically

.

Need to vaccinate against encapsulated bacteria 2 weeks before procedure.

May need steroids and/or

IVIg

before procedure to boost platelet counts preoperatively.

Operative

mortality < 1

%

Indication: Steroid failure or relapse after steroid Rx (persistent severe thrombocytopenia or significant bleeding)

Slide38

Possible mechanisms of action:Slowed platelet consumption by Fc receptor blockadeAccelerated autoantibody catabolismReduced autoantibody productionDose: 0.4 g/kg/d x 5 days (alternative: 1 g/kg/d x 2 days)About 75% response rate, usually within a few days to a weekOver 75% of responders return to pre-treatment levels within a monthAdvantages: rapid acting, low toxicityDisadvantages: high cost, short duration of benefit, high relapse rateIndications: Lifethreatening bleeding; pre-operative correction of platelet count, steroids contraindicated or ineffective

Management of Relapsed ITP

- Intravenous

immunoglobulin therapy

Slide39

Management of Refractory ITP

One third of patients will have an inadequate response to

splenectomy

.

Management of these patients involves accepting that they have a chronic, incurable condition.

Target platelet counts should be lower--aim for about

30.000/

mmc

or absence of bleeding.

Slide40

Treatment of Refractory ITP

Immunosuppressive agents

Rituximab

(anti-CD20)

Mycophenolate

mofetil

Cyclophosphamide

Vinca

alkaloids

Accessory

splenectomy

Danazol

Colchicine

Eradication of H. pylori, if

present

Adjunct

agents

Thrombopoietin

Receptor Agonists

Romiplostim

Eltrombopag

Slide41

Special aspects

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Slide42

ITP and H Pylory

Up to 50% of patients with ITP and concomitant H pylori infection improve after eradication of infection

Confirm infection via breath test, stool antigen test or endoscopy

Higher response rates in:

Patients from countries with high background rates of infection

Patients with less severe thrombocytopenia

Slide43

Thrombocytopenia and Pregnancy

Benign thrombocytopenia of pregnancy

Occurs in up to 5% of term pregnancies

Accounts for about 75% of cases of thrombocytopenia

Asymptomatic, mild, occurs late in gestation

Microangiopathy

(Preeclampsia/

eclampsia

, HELLP)

ITP (? increased incidence in pregnancy)

Slide44

ITP In Pregnancy

Mild cases indistinguishable from gestational thrombocytopenia

Rule out

eclampsia

, HIV etc

Indications for treatment

platelets <

10.000/

mmc

platelets <

30.000/

mmc

in 2nd/3rd trimester, or with bleeding

Treatment of choice is

IVIg

corticosteroids may cause gestational diabetes, fetal toxicity

Splenectomy

for severe, refractory disease

some increased risk of preterm labor; technically difficult in 3rd trimester

Potential for neonatal thrombocytopenia (approx 15% incidence)

consider fetal blood sampling in selected cases

consider

Cesarian

delivery if fetal platelets <

20.000/

mmc