management of patients with thrombocytopenia
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MANAGEMENT OF PATIENTS WITH
THROMBOCYTOPENIAELSHAMI M. ELAMIN, MD
CENTRAL CARE CANCER CENTER
ITPDITPHITTTPITP during pregnancy
INTROCUCTIONHemostasis encompasses a series of
interrelated and simultaneously occurring events involving:
1. Blood vessels2. Platelets3. 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 liverFree TPO removed from circulation by
plts
THROMBOCYTOPENIA
1. IMMUNE CAUSES
2. NON-IMMUNE CAUSES
IMMUNE THROMBOCYTOP
ENIA
1
ITP TERMINOLOGYOLD
(ABANDONED)IdiopathicPurpura
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
PATHOPHYSIOLOGYHistorically:
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 PRESENTATIONPresentation:
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
DIAGNOSISExclude other causesThere is no “gold standard”
diagnostic test CBCPeripheral blood film BM HIVHCV H. pylori
DIAGNOSISASH
Does 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 counselingSupportive 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 conditions1. Active hemorrhage:
CNS GIT GUT Limb- or sight-threatening
2. High risk of significant bleeding
3. Need for surgical procedure
EMERGENCY TREATMENTGENERAL
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-DVinca alkaloidsAntifibrinolytics with
first-line therapySplenectomy
FIRST-LINE TREATMENT
FIRST-LINE ASH
Prednisone 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 THERAPY1. 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-LINEASH
TPO: 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 productionThey 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-LINEASH
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-LINEASH
Immunosuppressives and corticosteroid- sparing drugs (azathioprine):
Evidence-based recommendations on appropriate indications or timing of use are not made due to inadequate research
ICRImmunosuppressives
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
SPLENECTOMYASH
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 thereafterAND
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
SLECommon variable
immune deficiencyPost-BMTPost-vaccination
Lymphoproliferative disorders
Evans SyndromeThyroiditisMGUS 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. NSAIDs3. Sulfamethoxazole4. Rifampin5. Vancomycin6. Anticonvulsants7. Sedatives
Within hours from exposure: Platelet GPIIb-IIIa inhibitors (Aggrastat, Integrilin, Preopro)
http://www.ouhsc.edu/platelets
DITPMECHANISM:
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
THROMBOSISOccurs 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 SeroconversionCommercial anti-PF4/Heparin (PF4/polyanion) EIA:*IgG*IgA*IgM
Subclinical Seroconversion Anti-PF4/Heparin EIA:*IgG
HIT +/- ThrombosisWashed plt activation assay:*SRA*HIPA
DIAGNOSISELISA
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. Thrombocytopenia2. Microangiopathic
HA3. ARF
Majority caused by Shiga toxin–producing enterohemorrhagic E-coli
Invasive pneumococcal infection
PATHOGENESISTTP
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
DIAGNOSISGeneral
Clinical
CBC
Peripheral blood film
Hemolytic indices
Negative Direct Coombs
Normal Coagulation tests
BUN/Cr.
LFTs (T. Bili, LDH)
SpecificADAMTS13 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 HUSHUS
Supportive
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
DIAGNOSISCBCPeripheral blood smearRetic countHIV and HCV tests (high-risk)Antiphospholipid antibodiesCoagulation screeningSLE serologyLFTs
DIFFERENTIAL DIAGNOSISPregnancy-induced hypertension (Preeclampsia)Gestational thrombocytopeniaHELLP syndrome
(HemolysisElevatedLiverenzymesLowPlatelet)DICMassive obstetrical hemorrhageAcute fatty liverAntiphospholipid antibody syndromeFolate 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. Symptomatic2. 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. Ineffective2. Produce significant AE
OR3. 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
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