1. MANAGEMENT OF PATIENTS WITH THROMBOCYTOPENIA
ELSHAMI M. ELAMIN, MD
CENTRAL CARE CANCER CENTER

2. ITP
DITP
HIT
TTP
ITP during pregnancy

3. INTROCUCTION
Hemostasis encompasses a series of interrelated and simultaneously occurring events involving:
Blood vessels
Platelets
Coagulation system
Defects affecting any of these major participants may lead to a hemostatic defect and a bleeding disorder

4. 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

5. THROMBOCYTOPENIA
IMMUNE CAUSES
NON-IMMUNE CAUSES

6. IMMUNE THROMBOCYTOPENIA1
IMMUNE THROMBOCYTOPENIA

7. ITP TERMINOLOGY NEW OLD (ABANDONED) Idiopathic Purpura Immune: Primary
Secondary

8. IMMUNE CAUSES Primary Immune Thrombocytopenia (ITP)
Secondary Immune Thrombocytopenia

9. Primary Immune Thrombocytopenia (ITP)

10. Primary Immune Thrombocytopenia (ITP)
Isolated thrombocytopenia
Plt count <100,000 (100k)
In children:
ITP is typically self-limited
Follows viral/infectious illness
In adults:
ITP is typically becomes persistent or chronic with no obvious precipitating events

11. Old Classification of ITP
Acute ITP (≤ 6 months)
Chronic ITP (> 6 months)

12. New Classification of ITP
Duration
Classification
< 3 month
Newly diagnosed
3-12 months
Persistent
> 12 months
Chronic
Source: Rodeghiero

13. PATHOPHYSIOLOGY Now: 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 production
Plasma level of endogenous thrombopoietin (eTPO) is suboptimal because of:
Accelerated clearance by accelerated removal of eTPO bound to antibody-coated plts
Binding to megakaryocytes in the BM
Absence of increased synthesis in response to thrombocytopenia

14. CLINICAL 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

15. DIAGNOSIS Exclude other causes
There is no “gold standard” diagnostic test
CBC
Peripheral blood film BM
HIV
HCV
H. pylori

16. The International Consensus Report (ICR)
DIAGNOSIS
ASH
The International Consensus Report (ICR)
Does not recommend routine measurement of antiplt, antiphospholipid, or ANA
Considers measurement of TPO of unproven or uncertain benefit
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

17. TREATMENT OF ITP

18. TREATMENT GOAL
To achieve a platelet count that will prevent major bleeding
To attain a sustained increase of the platelet count that is considered hemostatic
It is NOT the goal to normalize platelet count

19. 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.

20. 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)

21. MANAGEMENT OF CHILDERN WITH PRIMARY ITP
Splenectomy:
Persistent thrombocytopenia/bleeding
CR in ~ 75% of children
Deferred until after 5 yrs of age
Risk for overwhelming sepsis
Vaccines for Strep pneumoniae, Neisseria meningitides, and H influenzae type b
PCN prophylaxis is recommended until adulthood

22. 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?

23. WHAT IS THE PLATELET COUNT THRESHOLD?
ASH
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
Treat new cases if Plat < 30,000
However, no evidence for minimum plt count threshold

24. EMERGENCY TREATMENT

25. Emergency conditions Active hemorrhage:
CNS
GIT
GUT
Limb- or sight-threatening
High risk of significant bleeding
Need for surgical procedure

26. EMERGENCY TREATMENT GENERAL INITIAL TREATMENT
Cessation of drugs reducing plt function
Blood pressure control
Menses inhibition
Minimizing trauma
High-dose IV steroids + IVIg
Plt transfusion +/- IVIg

27. Alternative Emergency Treatment Options
ASH
ICR
Plt transfusion + continuous IVIg
Splenectomy +/- IVIg and/or corticosteroids
Recombinant factor VIIa
Risk of thrombosis
Antifibrinolytics (aminocaproic acid and tranexamic acid)
Anti-D
Vinca alkaloids
Antifibrinolytics with first- line therapy
Splenectomy

28. FIRST-LINE TREATMENT

29. FIRST-LINE ASH IRC Prednisone 1 mg/kg/d X3 wk
IVIg + Steroids when a rapid response required
When Steroids are contrain- dicated:
IVIg or anti-D (WinRho)
Steroids 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)

30. YOUR STEROIDS’ CHOICES
Prednisone:
Starting at 1 mg/kg daily
Tapering over a period of 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
Methylprednisolone:
1 g IV daily X 2–3

31. A.E. OF THERAPY Corticosteroids: IVIg: Anti-D (WinRho):
Behavioral changes
IVIg:
Headache
Anti-D (WinRho):
Hemolysis
Pts with a positive Coombs test should not receive it

32. !! WHEN FIRST-LINE FAILS !!

33. SECOND-LINE TREATMENT

34. SECOND-LINE ASH ICR TPO: 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
TPO:
Recommended:
After failing at least one line of therapy such as corticosteroids or IVIg

35. NOVEL APPROACH TO TREAT CHRONIC ITP
increase production
to outpace
destruction

36. 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

37. Serious A.E. of TPO Worsening thrombocytopenia after D/C
Bone marrow reticulin formation/Fibrosis with cytopenias
Thrombosis
Hematologic malignancy risk
Hepatotoxicity, cataracts (Promacta)

38. Nplate (Romiplostim) SC wkly 1 mcg/kg (actual body wt)
Common A.E. is headache
1 mcg/kg (actual body wt)
Lowest dose to maintain plt > 50,000
Do 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

39. SECOND-LINE ASH ICR Anti-CD20 (Rituxan): Anti-CD20 (Rituxan):
Considered for pts at risk of bleeding who have failed one line of therapy, such as corticosteroids, IVIg, or splenectomy
Anti-CD20 (Rituxan):
Considered in pts with refractory or relapsed ITP
Contraindicated in pts with active HBV

40. SECOND-LINE
ASH
ICR
Immunosuppressives and corticosteroid- sparing drugs (azathioprine):
Evidence-based recommendations on appropriate indications or timing of use are not made due to inadequate research
Immunosuppressives and corticosteroid- sparing drugs (azathioprine):
Elderly pts and when splenectomy is contra- indicated
Single agent or in combination with steroids

41. Surgical treatment (Splenectomy)

42. 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

43. SPLENECTOMY ASH ICR For pts who fail steroids Laparoscopic = open
When?
No optimal timing
Second-line
When?
Wait ≥6 months after diagnosis due to potential for spontaneous improvement or late remission

44. VACCINATION Splenectomized pts at risk of infection from:
Streptococcus pneumoniae
Neisseria meningitidis
Haemophilus influenzae
Vaccination preferably 4 wks before or 2 wks after splenectomy
Follow CDC recommendations
Revaccination is based on country-specific recommendations

45. REFRACTORY IMMUNE THROMBOCYTOPENIA

46. 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

47. TREATMENT OF REFRACTORY ITP

48. TREATMENT RECOMMENDATIONS
ASH
ICR
Recommends:
TPO-receptor agonists
suggests:
Anti-CD20 (Rituxan)
TPO-receptor agonists
Not FDA approved:
Anti-CD52 (Campath)
Combination chemo
HSCT

49. 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 % of pts with primary ITP

50. Secondary Immune Thrombocytopenia

51. Causes of secondary immune thrombocytopenia
Drugs:
DITP
HIT
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

52. Drug-Induced Thrombocytopenia (DITP)

53. Drug-Induced Thrombocytopenia (DITP)
Most common:
Seven days from exposure:
Quinine and quinidine (tonic water, bitter melon, and meds)
NSAIDs
Sulfamethoxazole
Rifampin
Vancomycin
Anticonvulsants
Sedatives
Within hours from exposure:
Platelet GPIIb-IIIa inhibitors (Aggrastat, Integrilin, Preopro)

54. DITP MECHANISM: TREATMENT: Diagnosis: Antibodies: Quinine
Gold, procainamide, sulfonamide, IFN
TREATMENT:
D/C drug
Plt transfusion
Diagnosis:
Clinical
? Anti-plt Abs

55. Heparin-Induced Thrombocytopenia (HIT)

56. Abs against complexes of PF4 + Heparin
Production of:
1- Platlets microparticles
2- Intensely prothrombotic state
UFH or LMWH
Abs against complexes of PF4 + Heparin
HIT Abs binds to plt Fc receptors
Activates:
1- Plts
2- Endothelial cells
3- Macrophages

57. H.I.T. NON-IMMUNE (TYPE-I) IMMUNE (TYPE-II) Thrombocytopenia:
>50% plt reduction
Timing:
5-10 day after heparin
Thrombosis
OTher:
(exclusion of other causes)
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 4T
Score

58. Timing of platelet count fall
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 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 reaction after intravenous unfractionated heparin bolus
Progressive or recurrent thrombosis; nonnecrotizing skin lesions; suspected thrombosis (not proven)
None
OTher causes for thrombocytopenia
None apparent
Possible
Definite

59. THROMBOSIS Occurs in 50% of pts with untreated HIT: DVT PE
Arterial (including limb artery) MI
Microvascular thrombosis resembling DIC
Adrenal infarction
Skin necrosis at the heparin inj sites
Anaphylactoid reactions after an IV heparin bolus
Due to PF4/heparin antibodies

60. DIAGNOSIS

61. 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.

62. H.I.T. Testing Subclinical Seroconversion HIT +/- Thrombosis
Commercial anti-PF4/Heparin (PF4/polyanion) EIA: *IgG *IgA *IgM
Anti-PF4/Heparin EIA:
*IgG
HIT +/- Thrombosis
Washed plt activation assay:
*SRA
*HIPA

63. SEROTONIN RELEASE ASSAY (SRA)
DIAGNOSIS
ELISA
SEROTONIN RELEASE ASSAY (SRA)
Quantitative PF4/Heparin immunoassay
Functional assay of HIT Abs
Gold standard

64. TREATMENT

65. TREATMENT Stop heparin Do not wait for HIT testing results
Start nonheparin anticoagulant:
Direct Thrombin Inhibitors:
Argatroban
Lepirudin
Bivalirudin (Angiomax)
Factor Xa Inhibitors:
Danaparoid (not available in US)
(Arixtra) Fondaparinux (not approved)
Start warfarin when plt >100k
Overlap with direct thrombin inhibitor
Continue warfarin for 30 days

66. NON-IMMUNE THROMBOCYTOPENIA2
NON-IMMUNE THROMBOCYTOPENIA

67. NONIMMUNE CAUSES OF THROMBOCYTOPENIA
Thrombotic Microangiopathies
Familial thrombocytopenia:
Wiskott- Aldrich syndrome
May-Hegglin syndrome
Thrombocytopenia with infection
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

68. Thrombotic Microangiopathies
Thrombotic Thrombocytopenic Purpura (TTP)
Hemolytic Uremic Syndrome (HUS)

69. Thrombotic Microangiopathies
TTP
HUS
Thrombocytopenia
Microangiopathic HA
ARF
Majority caused by Shiga toxin–producing enterohemorrhagic E-coli
Invasive pneumococcal infection
Thrombocytopenia
Microangiopathic H.A.
Renal Failure
Neurologic deficits
Fever

70. PATHOGENESIS TTP HUS ADAMTS13 enzyme deficiency: Familial Acquired:
Idiopathic
Drugs: Quinine, Ticlopidine, Clopidgrel, Cyclosporine, Tacrolimus, Mitomycin C, Gemzar
Others: Pregnancy, BMT, HIV, SLE, Malignancy
Release of large multimers of vWF
E-Coli/Inv pneumococci Shiga-toxin:
Directly toxic to endothelial cell
Prothrombotic state

71. DIAGNOSIS General Specific ADAMTS13 tests:
Clinical
CBC
Peripheral blood film
Hemolytic indices
Negative Direct Coombs
Normal Coagulation tests
BUN/Cr.
LFTs (T. Bili, LDH)
ADAMTS13 tests:
Quantitative (ELISA)
Functional
Complement factors test to confirm atypical HUS

73. Treatment of TTP No response to plasma exchange: 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
Immunosuppressants
Splenectomy
Rituximab:
Relapsed/Refractor y

74. Treatment of HUS HUS Atypical HUS Supportive Antibiotics
Controversial
Generally avoided
Plasma exchange not required
? 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

75. ITP DURING PREGNANCY

76. 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

77. DIAGNOSIS CBC Peripheral blood smear Retic count
HIV and HCV tests (high-risk)
Antiphospholipid antibodies
Coagulation screening
SLE serology
LFTs

78. DIFFERENTIAL DIAGNOSIS
Pregnancy-induced hypertension (Preeclampsia)
Gestational thrombocytopenia
HELLP syndrome (HemolysisElevatedLiverenzymesLowPlatelet)
DIC
Massive obstetrical hemorrhage
Acute fatty liver
Antiphospholipid antibody syndrome
Folate deficiency

79. 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:
Symptomatic
Have 20-30k plt

80. ITP DURING PREGNANCY: TREATMENT
ASH
ICR
Steroids as first-line
IVIg if steroids are:
Ineffective
Produce significant AE OR
If rapid plt increase is needed
Limited evidence may support use of anti-D in Rh+, non-splenectomized women
Steroids or IVIg as first- line therapy

81. ITP DURING PREGNANCY TREATMENT
Steroids and IVIg:
Considered to be safe to the fetus
Steroids:
May have maternal side effects including:
exacerbation of gestational diabetes
post- partum psychiatric disorders

82. Management during labor and delivery
The ASH guidelines and ICR recommendations indicate that the mode of delivery should be based on obstetric indications