management of patients with thrombocytopenia elshami m. elamin, md central care cancer center
TRANSCRIPT
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MANAGEMENT OF PATIENTS WITH
THROMBOCYTOPENIA
ELSHAMI M. ELAMIN, MD
CENTRAL CARE CANCER CENTER
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ITP
DITP
HIT
TTP
ITP during pregnancy
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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
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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
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THROMBOCYTOPENIA
1. IMMUNE CAUSES
2. NON-IMMUNE CAUSES
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IMMUNE THROMBOCYTOP
ENIA
1
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ITP TERMINOLOGYOLD
(ABANDONED)
Idiopathic
Purpura
NEWImmune:
PrimarySecondary
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IMMUNE CAUSES
1. Primary Immune Thrombocytopenia (ITP)
2. Secondary Immune Thrombocytopenia
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Primary Immune Thrombocytopenia
(ITP)
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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
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Old Classification of ITP
Acute ITP (≤ 6 months)
Chronic ITP (> 6 months)
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New Classification of ITP
Duration Classification
< 3 month Newly diagnosed
3-12 months Persistent
> 12 months Chronic
Source: Rodeghiero 2009.1
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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
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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
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DIAGNOSIS
Exclude other causes
There is no “gold standard” diagnostic test CBCPeripheral blood film BM HIVHCV H. pylori
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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
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TREATMENT OF ITP
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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
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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.
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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)
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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
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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?
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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
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EMERGENCY TREATMENT
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Emergency conditions
1. Active hemorrhage: CNS GIT GUT Limb- or sight-threatening
2. High risk of significant bleeding
3. Need for surgical procedure
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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
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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
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FIRST-LINE TREATMENT
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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)
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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
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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
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!! WHEN FIRST-LINE FAILS !!
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SECOND-LINE TREATMENT
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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
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NOVEL APPROACH TO TREAT CHRONIC ITP
increase production
to outpace
destruction
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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
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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)
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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
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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
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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
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Surgical treatment
(Splenectomy)
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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
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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
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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
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REFRACTORY IMMUNE THROMBOCYTOPENIA
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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
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TREATMENT OF REFRACTORY ITP
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TREATMENT RECOMMENDATIONS
ASH
Recommends: TPO-receptor
agonists
suggests: Anti-CD20 (Rituxan)
ICR
TPO-receptor agonists
Not FDA approved: Anti-CD52
(Campath) Combination
chemo HSCT
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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
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Secondary Immune
Thrombocytopenia
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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
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Drug-Induced Thrombocytopenia
(DITP)
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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
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DITP
MECHANISM: Antibodies:
Quinine Gold, procainamide,
sulfonamide, IFN
Diagnosis: Clinical ? Anti-plt Abs
TREATMENT: D/C drug Plt transfusion
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Heparin-Induced Thrombocytopenia
(HIT)
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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
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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
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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
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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
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DIAGNOSIS
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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.
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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
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DIAGNOSIS
ELISA
Quantitative PF4/Heparin immunoassay
SEROTONIN RELEASE
ASSAY (SRA)
Functional assay of HIT Abs
Gold standard
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TREATMENT
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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
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NON-IMMUNE THROMBOCYTOPE
NIA
2
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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
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Thrombotic Microangiopathies
1. Thrombotic Thrombocytopenic Purpura (TTP)
2. Hemolytic Uremic Syndrome (HUS)
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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
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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
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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
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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
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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
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ITP DURING PREGNANCY
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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
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DIAGNOSIS
CBC
Peripheral blood smear
Retic count
HIV and HCV tests (high-risk)
Antiphospholipid antibodies
Coagulation screening
SLE serology
LFTs
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DIFFERENTIAL DIAGNOSIS
Pregnancy-induced hypertension (Preeclampsia)
Gestational thrombocytopenia
HELLP syndrome (HemolysisElevatedLiverenzymesLowPlatelet)
DIC
Massive obstetrical hemorrhage
Acute fatty liver
Antiphospholipid antibody syndrome
Folate deficiency
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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
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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
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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
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Management during labor and delivery
The ASH guidelines and ICR recommendations indicate that the mode of delivery should be based on obstetric
indications