MANAGEMENT OF PATIENTS WITH

THROMBOCYTOPENIA

ELSHAMI M. ELAMIN, MD

CENTRAL CARE CANCER CENTER

ITP

DITP

HIT

TTP

ITP during pregnancy

INTROCUCTION

Hemostasis encompasses a series of interrelated and simultaneously occurring events involving:

1. Blood vessels

2. Platelets

3. Coagulation system

Defects affecting any of these major participants may lead to a hemostatic defect and a bleeding disorder

INTRODUCTION

The number of circulating platelets is tightly regulated by the hormone thrombopoietin (TPO)

TPO is produced by the liver

Free TPO removed from circulation by plts

THROMBOCYTOPENIA

1. IMMUNE CAUSES

2. NON-IMMUNE CAUSES

IMMUNE THROMBOCYTOP

ENIA

1

ITP TERMINOLOGYOLD

(ABANDONED)

Idiopathic

Purpura

NEWImmune:

PrimarySecondary

IMMUNE CAUSES

1. Primary Immune Thrombocytopenia (ITP)

2. Secondary Immune Thrombocytopenia

Primary Immune Thrombocytopenia

(ITP)

Primary Immune Thrombocytopenia (ITP)

Isolated thrombocytopeniaPlt count <100,000 (100k)

In children: ITP is typically self-limitedFollows viral/infectious illness

In adults: ITP is typically becomes persistent or chronic

with no obvious precipitating events

Old Classification of ITP

Acute ITP (≤ 6 months)

Chronic ITP (> 6 months)

New Classification of ITP

Duration Classification

< 3 month Newly diagnosed

3-12 months Persistent

> 12 months Chronic

Source: Rodeghiero 2009.1

PATHOPHYSIOLOGY

Historically: ITP was thought to be due to increased plt destruction

caused by autoantibodies (anti– GPIIb-IIIa and anti–GPIb-IX)

Now: • It is recognized that ITP is also a result of

suboptimal platelet productionPlasma level of endogenous thrombopoietin (eTPO) is suboptimal because of:

1. Accelerated clearance by accelerated removal of eTPO bound to antibody-coated plts

2. Binding to megakaryocytes in the BM3. Absence of increased synthesis in response to

thrombocytopenia

CLINICAL PRESENTATION

Presentation: No symptoms Minimal bruising Serious bleeding

Mucocutaneous bleeding is the hallmark of severe primary ITP and manifests as:

Petechiae, purpura, ecchymosis, epistaxis, menorrhagia, oral mucosal bleeding, GI bleeding, or rarely, intracranial hemorrhage

Bleeding is not expected with plt >30,000

DIAGNOSIS

Exclude other causes

There is no “gold standard” diagnostic test CBCPeripheral blood film BM HIVHCV H. pylori

DIAGNOSIS

ASHDoes not recommend

routine measurement of antiplt, antiphospholipid, or ANA

Considers measurement of TPO of unproven or uncertain benefit

The International Consensus Report

(ICR)

Did not find sufficient evidence to recommend or suggest the routine use of anti-plt, antiphospholipid, ANA, and TPO levels in evaluation of pts with suspected ITP

BM test only to exclude other causes of thrombocytopenia

TREATMENT OF ITP

TREATMENT GOAL

1. To achieve a platelet count that will prevent major bleeding

2. To attain a sustained increase of the platelet count that is considered hemostatic

3. It is NOT the goal to normalize platelet count

MANAGEMENT OF CHILDERN WITH PRIMARY ITP

During the first month of diagnosis: Severe hemorrhage occurs in approximately 1 in 200 Intracerebral hemorrhage occurs in approximately 1 in

800

Recovery of the platelet count ultimately occurs in 80% of children.

The remaining 20% have persistent thrombocytopenia

Major bleeding is uncommon.

MANAGEMENT OF CHILDERN WITH PRIMARY ITP

Family counseling

Supportive care rather than specific drug therapy

Because spontaneous recovery is expected in most children

Drug therapy (Steroids, IVIG, Anti-D)

MANAGEMENT OF CHILDERN WITH PRIMARY ITP

Splenectomy:Persistent thrombocytopenia/bleedingCR in ~ 75% of childrenDeferred until after 5 yrs of age

Risk for overwhelming sepsisVaccines for Strep pneumoniae, Neisseria

meningitides, and H influenzae type bPCN prophylaxis is recommended until

adulthood

TREATMENT OF ADULTS WITH PRIMARY ITP

ITP in adults: Recurs and persists

Asymptomatic pts with mild-moderate thrombocytopenia require no specific treatment

Who should be treated?

WHAT IS THE PLATELET COUNT THRESHOLD?

ASH

Treat new cases if Plat < 30,000

However, no evidence for minimum plt count threshold

ICR

Plat >50,000 rarely need treatment in the absence of: Bleeding due to plt

dysfunction or another hemostatic defect

Comorbidity for bleeding Trauma Surgery Anticoagulation Lifestyle/profession

predisposing the patient to trauma

EMERGENCY TREATMENT

Emergency conditions

1. Active hemorrhage: CNS GIT GUT Limb- or sight-threatening

2. High risk of significant bleeding

3. Need for surgical procedure

EMERGENCY TREATMENT

GENERAL

1. Cessation of drugs reducing plt function

2. Blood pressure control

3. Menses inhibition

4. Minimizing trauma

INITIAL TREATMENT

High-dose IV steroids + IVIg

Plt transfusion +/- IVIg

Alternative Emergency Treatment Options

ASHPlt transfusion +

continuous IVIg

Splenectomy +/- IVIg and/or corticosteroids

Recombinant factor VIIa Risk of thrombosis

Antifibrinolytics (aminocaproic acid and tranexamic acid)

ICRAnti-D

Vinca alkaloids

Antifibrinolytics with first-line therapy

Splenectomy

FIRST-LINE TREATMENT

FIRST-LINE

ASHPrednisone 1 mg/kg/d

X3 wk

IVIg + Steroids when a rapid response required

When Steroids are contrain- dicated:

IVIg or anti-D (WinRho)

IRCSteroids X 4 wk or

longer

Pts with bleeding, high risk of bleeding, or contraindications to steroids: IVIg (0.4 g/kg/dX5 or IVIg 1 g/kg/d X1-2

days or Anti-D (50-75 μg/kg

single dose)

YOUR STEROIDS’ CHOICES

Prednisone: Starting at 1 mg/kg daily Tapering over a period of 4 - 8 weeks)

OR High-dose dexamethasone in cycles:

40 mg daily for 4 days Repeated monthly for up to 6 cycles or every other week for 4 cycles

OR Methylprednisolone:

1 g IV daily X 2–3

A.E. OF THERAPY

1. Corticosteroids:Behavioral changes

2. IVIg:Headache

3. Anti-D (WinRho): Hemolysis

Pts with a positive Coombs test should not receive it

!! WHEN FIRST-LINE FAILS !!

SECOND-LINE TREATMENT

SECOND-LINE

ASHTPO:

Recommended: After splenectomy If contraindications

to splenectomy and failed at least one other therapy

Considered: If failed one line of

therapy such as corticosteroids or IVIg

ICRTPO:

Recommended: After failing at least

one line of therapy such as corticosteroids or IVIg

NOVEL APPROACH TO TREAT CHRONIC ITP

increase production

to outpace

destruction

Thrombopoietin (TPO) receptor agonists

Romiplostim (Nplate):SC

Eltrombopag (Promacta):PO

Bind and activate the TPO receptor increase plt production

They have no structural similarity to endogenous TPO They do not stimulate cross-reactive TPO antibodies

They are effective in up to 70% of pts with ITP before and after splenectomy Responses appear to be more pronounced before splenectomy

Plt count responses are generally maintained as long as the drug is administered

Serious A.E. of TPO

1. Worsening thrombocytopenia after D/C

2. Bone marrow reticulin formation/Fibrosis with cytopenias

3. Thrombosis

4. Hematologic malignancy risk

5. Hepatotoxicity, cataracts (Promacta)

Nplate (Romiplostim)

SC wkly Common A.E. is headache

1 mcg/kg (actual body wt)Lowest dose to maintain plt > 50,000Do not attempt to normalize plt counts

Wkly CBC and smear until counts are stable > 50k, then monthly

D/C Nplate if no clinical benefit after 4 wks of max dose

SECOND-LINE

ASH

Anti-CD20 (Rituxan): Considered for pts at

risk of bleeding who have failed one line of therapy, such as corticosteroids, IVIg, or splenectomy

ICR

Anti-CD20 (Rituxan):

Considered in pts with refractory or relapsed ITP

Contraindicated in pts with active HBV

SECOND-LINE

ASH Immunosuppressives

and corticosteroid- sparing drugs (azathioprine):

Evidence-based recommendations on appropriate indications or timing of use are not made due to inadequate research

ICR Immunosuppressives

and corticosteroid- sparing drugs (azathioprine):

Elderly pts and when splenectomy is contra- indicated

Single agent or in combination with steroids

Surgical treatment

(Splenectomy)

Splenectomy is recognized by both the ASH 2011 guideline and the ICR recommendations as the only treatment to provide sustained off-

treatment remissions lasting ≥1 year in approximately two-thirds of patients

SPLENECTOMY

ASH

For pts who fail steroids

Laparoscopic = open

When? No optimal timing

ICR

Second-line

When? Wait ≥6 months

after diagnosis due to potential for spontaneous improvement or late remission

VACCINATION

Vaccination preferably 4 wks before or 2 wks after splenectomy

Follow CDC recommendations

Revaccination is based on country-specific recommendations

Splenectomized pts at risk of infection from:

1. Streptococcus pneumoniae

2. Neisseria meningitidis

3. Haemophilus influenzae

REFRACTORY IMMUNE THROMBOCYTOPENIA

REFRACTORY ITP

Pts are considered to have refractory ITP if they do not attain hemostatic platelet count either:

After splenectomy OR After first- and second-line medical treatment OR After initially responding to splenectomy and

relapsing thereafter

AND Either exhibit severe ITP or have a risk of

bleeding that requires therapy based on the clinical judgment

TREATMENT OF REFRACTORY ITP

TREATMENT RECOMMENDATIONS

ASH

Recommends: TPO-receptor

agonists

suggests: Anti-CD20 (Rituxan)

ICR

TPO-receptor agonists

Not FDA approved: Anti-CD52

(Campath) Combination

chemo HSCT

SUMMARY

Workup of patients with suspected ITP requires: Thorough search for nonimmune causes (secondary ITP)

Primary ITP in children often resolves spontaneously or with minimal treatment

Adult-onset primary ITP tends to relapse and often requires ongoing therapy

Splenectomy is associated with a durable response in 2/3 of pts with primary ITP Relapses occur 15% of adults.

TPO receptor agonists: Increase plt production Effective in 60 - 70% of pts with primary ITP

Secondary Immune

Thrombocytopenia

Causes of secondary immune thrombocytopenia

Drugs:DITPHIT

Antiphospholipid syndrome

SLE

Common variable immune deficiency

Post-BMT

Post-vaccination

Lymphoproliferative disorders

Evans Syndrome

Thyroiditis

MGUS

Infections CMV H. pylori HCV HIV Varicella zoster

Drug-Induced Thrombocytopenia

(DITP)

Drug-Induced Thrombocytopenia (DITP)

Most common: Seven days from exposure:

1. Quinine and quinidine (tonic water, bitter melon, and meds)

2. NSAIDs

3. Sulfamethoxazole

4. Rifampin

5. Vancomycin

6. Anticonvulsants

7. Sedatives

Within hours from exposure: Platelet GPIIb-IIIa inhibitors (Aggrastat, Integrilin, Preopro)

http://www.ouhsc.edu/platelets

DITP

MECHANISM: Antibodies:

Quinine Gold, procainamide,

sulfonamide, IFN

Diagnosis: Clinical ? Anti-plt Abs

TREATMENT: D/C drug Plt transfusion

Heparin-Induced Thrombocytopenia

(HIT)

UFH or LMWH Abs

against complexes of PF4 + Heparin

HIT Abs binds to plt Fc receptors

Activates: 1- Plts 2- Endothelial cells3- Macrophages

Production of: 1- Platlets microparticles2- Intensely prothrombotic state

H.I.T.NON-IMMUNE

(TYPE-I)

First 2 days after heparin

Caused by plt agglutination because of heparin’s strong negative charge

Spontaneous recovery or with heparin interruption

No clinical significance

IMMUNE (TYPE-II)

Thrombocytopenia: >50% plt reduction

Timing: 5-10 day after heparin

Thrombosis

OTher: (exclusion of other

causes)

4TScore

4T Score (low 0–3; intermed 4–5; high 6–8) To determine the pretest probability of HIT

4Ts

2 ponits 1 point 0 point

Thrombocytopenia

Plt decrease of >50% and platelet nadir > 20k

Plt decrease of 30%–50% or platelet nadir of 10–19k

Plt decrease of 30% or platelet nadir <10k

Timing of platelet count fall

Clear onset of thrombocytopenia 5–10 days after heparin administration; or platelet decrease within 1 day, with prior heparin exposure within 30 days

Consistent with day 5–10 decrease but not clear (eg, missing platelet counts) or onset after day 10; or decrease within 1 day, with prior heparin exposure 30-100 days ago

Platelet count decrease<4 days without recent exposure

Thrombosis or other sequelae

New thrombosis (confirmed); skin necrosis (lesions at heparin injection site); acute systemic reactionafter intravenous unfractionated heparin bolus

Progressive or recurrent thrombosis; nonnecrotizing skin lesions; suspected thrombosis (not proven)

None

OTher causes for thrombocytopenia

None apparent Possible Definite

THROMBOSIS

Occurs in 50% of pts with untreated HIT:DVTPEArterial (including limb artery)MIMicrovascular thrombosis resembling DICAdrenal infarctionSkin necrosis at the heparin inj sitesAnaphylactoid reactions after an IV heparin

bolusDue to PF4/heparin antibodies

DIAGNOSIS

HIT is caused by anti-PF4/heparin Ig-G that activates plts

Although many susceptible patients form IgG, IgM, and IgA Abs to PF4/heparin complexes after exposure to heparin, only a few will have platelet-activating IgG Abs that cause HIT.

H.I.T. Testing

Subclinical Seroconversion

Commercial anti-PF4/Heparin (PF4/polyanion) EIA:*IgG*IgA*IgM

Subclinical Seroconversion

Anti-PF4/Heparin EIA:*IgG

HIT +/- ThrombosisWashed plt activation assay:*SRA*HIPA

DIAGNOSIS

ELISA

Quantitative PF4/Heparin immunoassay

SEROTONIN RELEASE

ASSAY (SRA)

Functional assay of HIT Abs

Gold standard

TREATMENT

TREATMENT1. Stop heparin

2. Do not wait for HIT testing results

3. Start nonheparin anticoagulant: Direct Thrombin Inhibitors:

Argatroban Lepirudin Bivalirudin (Angiomax)

Factor Xa Inhibitors: Danaparoid (not available in US) (Arixtra) Fondaparinux (not approved)

4. Start warfarin when plt >100k Overlap with direct thrombin inhibitor Continue warfarin for 30 days

NON-IMMUNE THROMBOCYTOPE

NIA

2

NONIMMUNE CAUSES OF THROMBOCYTOPENIA

1. Thrombotic Microangiopathies

2. Familial thrombocytopenia: Wiskott- Aldrich

syndrome May-Hegglin

syndrome

3. Thrombocytopenia with infection

4. Hemophagocytic syndrome (EBV)

5. Hypersplenism

6. Myelodysplasia/Leukemia

7. BM suppression (valproic acid, alcohol, chemo)

8. von Willebrand disease type 2B

9. Thrombocytopenia in the critically ill

Thrombotic Microangiopathies

1. Thrombotic Thrombocytopenic Purpura (TTP)

2. Hemolytic Uremic Syndrome (HUS)

Thrombotic Microangiopathies

TTP

1. Thrombocytopenia

2. Microangiopathic H.A.

3. Renal Failure

4. Neurologic deficits

5. Fever

HUS

1. Thrombocytopenia

2. Microangiopathic HA

3. ARF

Majority caused by Shiga toxin–producing enterohemorrhagic E-coli

Invasive pneumococcal infection

PATHOGENESIS

TTP

Release of large multimers of vWF

HUS

Prothrombotic state

• ADAMTS13 enzyme deficiency:• Familial• Acquired:

• Idiopathic• Drugs: Quinine, Ticlopidine,

Clopidgrel, Cyclosporine, Tacrolimus, Mitomycin C, Gemzar

• Others: Pregnancy, BMT, HIV, SLE, Malignancy

•

• E-Coli/Inv pneumococci Shiga-toxin:• Directly toxic to

endothelial cell

DIAGNOSIS

General Clinical

CBC

Peripheral blood film

Hemolytic indices

Negative Direct Coombs

Normal Coagulation tests

BUN/Cr.

LFTs (T. Bili, LDH)

Specific

ADAMTS13 tests: Quantitative

(ELISA) Functional

Complement factors test to confirm atypical HUS

Treatment of TTP

Plasma exchange: 85% mortality 85%

Survival 1 – 1.5 plasma volume

Until: Plt >150k Normal LDH Symptoms resolved

FFP and cryosupernant plasma (depleted of vWF)

? ASA/Anti-Plt

No response to plasma exchange:

Steroids ImmunosuppressantsSplenectomyRituximab:

Relapsed/Refractory

Treatment of HUS

HUSSupportive

Antibiotics Controversial Generally avoided

Plasma exchange not required

Atypical HUS ? Plasma exchange

Eculizumab (SOLIRIS): Inhibits complement-mediated

thrombotic microangiopathy Be aware of:

Life-threatening and fatal meningococcal infections Meningococcal vaccine at

least 2 wks before 1st dose Vaccinate children against

Strep and H influ

ITP DURING PREGNANCY

ITP DURING PREGNANCY

INCIDENCE: 1 in 1000 to 1 in 10,000

Pregnant women may have lower plt counts than normal (Gestational Thrombocytopenia)

May be due to a combination of hemodilution and increased platelet activation and clearance

DIAGNOSIS

CBC

Peripheral blood smear

Retic count

HIV and HCV tests (high-risk)

Antiphospholipid antibodies

Coagulation screening

SLE serology

LFTs

DIFFERENTIAL DIAGNOSIS

Pregnancy-induced hypertension (Preeclampsia)

Gestational thrombocytopenia

HELLP syndrome (HemolysisElevatedLiverenzymesLowPlatelet)

DIC

Massive obstetrical hemorrhage

Acute fatty liver

Antiphospholipid antibody syndrome

Folate deficiency

ITP DURING PREGNANCY TREATMENT

Same as non-pregnant pts who have chronic ITP

ASH: No platelet count threshold for treatment

ICR: Treat pregnant women in the first two

trimesters who are:

1. Symptomatic

2. Have 20-30k plt

ITP DURING PREGNANCY: TREATMENT

ASH

Steroids or IVIg as first-line therapy

ICR

Steroids as first-line

IVIg if steroids are:1. Ineffective

2. Produce significant AE OR

3. If rapid plt increase is needed

Limited evidence may support use of anti-D in Rh+, non-splenectomized women

ITP DURING PREGNANCYTREATMENT

Steroids and IVIg:Considered to be safe to the fetusSteroids:

May have maternal side effects including: exacerbation of gestational diabetes post- partum psychiatric disorders

Management during labor and delivery

The ASH guidelines and ICR recommendations indicate that the mode of delivery should be based on obstetric

indications