This document discusses the approach and management of thrombocytopenia and immune thrombocytopenic purpura (ITP). It defines thrombocytopenia and its causes, provides diagnostic criteria for ITP, and outlines treatment approaches including corticosteroids, IVIG, anti-D, thrombopoietin receptor agonists, splenectomy, rituximab, and experimental therapies. It also addresses management of severe bleeding, pregnancy-associated thrombocytopenia, and thrombocytopenia in the settings of HIV and hepatitis C infection.

1. Approach to Thrombocytopenia and
Management of ITP
Ajay Kumar Yadav
PGY3,Medicine
IOM-TUTH, Kathmandu

2. Layout
• Mechanism of thrombocytopenia
• Causes of thrombocytopenia
• ITP
Diagnosis
Management
• Thrombocytopenia in pregnancy
• HIT

3. • Most common cause of abnormal bleeding
• Results from any of the four processes:
- Pseudothrombocytopenia,
- Deficient platelet production,
- Accelerated platelet destruction, and
- Abnormal distribution or pooling of the platelet

4. Wintrobe's Clinical Hematology 13th edition

5. Causes of thrmbocytopenia

6. Causes cont..

7. Causes cont..

8. Approach for evaluation of thrombocytopenia
Wintrobe's Clinical Hematology 13th edition

9. Pseudothrmobocytopenia
• Platelet agglutinins,
• Abnormal amounts of plasma proteins in various paraproteinemias,
• Previous contact of platelets with foreign surfaces such as dialysis
membranes,
• Large or giant platelets(bernrard soullier syndrome),
• Platelet satellitism,
• Lipemia,
• EDTA induced platelet clumping
Wintrobe's Clinical Hematology 13th edition

11. Cont..
Wintrobe's Clinical Hematology 13th edition

12. IMMUNE
THRMBOCYTOPENIC
PURPURA

13. When to suspect ITP ?
• Definition
- Platelet count < 1 lakh
- Diagnosis of exclusion
• Hallmark
 Autoimmune destruction of platelets
 Suppression of platelet production by BM megakaryocytes

14. Some terminology
• Primary ITP
• Secondary ITP
• Severe ITP
o Refers to ITP with bleeding symptoms sufficient to require
treatment
o Typically occurs when platelet counts are below
20,000/microL.

15. Terminology cont..
• Newly diagnosed – Up to three months since diagnosis
• Persistent – 3 to 12 months since diagnosis
• Chronic – More than 12 months since diagnosis

16. Pathogenesis

17. Acute ITP Vs Chronic ITP

18. Clinical manifestations
• Bleeding
- Petechiae
- Purpura : Dry(cutaneous) Vs Wet(mucosal bleed)
- Epistaxis
- Severe hemorrhage : ICH , UGI bleed, menorrhagia
• Predictors of severe bleeding
- Degree of thrombocytopenia (<20,000),
- Previous minor bleeding, and
- Chronic ITP (ie, diagnosis >12 months prior)

20. History : A stitch in time saves nine!!

21. Drug history

22. • Physical examination
- Look esp. for wet bleed : poor prognosis, catastrophe
- Lymphadenopathy
- Hepatosplenomegaly
• Laboratory testing
- PBS : r/o thrombocytopenia and atypical cells
- HIV and HCV testing
- H.pylori testing
- TFT
- ANA,RF , APLA (?)
- Vitamin B12 and folate level
- Coomb’s test : 1 % have co-existing autoimmune hemolytic anemia
( Evans syndrome )

23. What is the role of Bone marrow examination?
• Not required for typical ITP
• Atypical presentations
 Unexplained cytopenias (anemia, leukopenia), dysplasia on PBS
 Pts. whose platelet counts do not respond to ITP therapy : MDS ?
Hereditary ? Acuired ?
 Age > 60 yrs ( to r/o MDS ) : no longer an indication

24. • Antiplatelet antibody testing : Not recommended
- Low sensitivity
- Lack of inter-lab reproducibility

25. Definition of response to treatment of ITP
• Complete response(CR) :
 Platelet count > 1 lakh measured on 2 occasions > 7 days apart and
absence of bleeding
• Response(R):
 > 30,000 or more than 2 fold increase in platelet count from baseline on 2
occasions > 7 days apart and absence of bleeding
• Non response :
 < 30,000 or less than 2 fold increase in platelet count from baseline or
presence of bleeding . Platelet count must be easured on 2 occasions
more than a day apart .

26. Definitions of response cont..
• Loss of complete response :
 < 1 lakh measured on 2 occasions more than a day apart or presence of bleeding.
• Loss of response :
 < 30,00 or less than 2 fold increase in platelet count from baseline or presence of
bleeding measured on 2 occasions more than a day apart.
• Corticosteroid dependence :
 Need for ongoing or repeated administration of corticosteroid to maintain platelet
count > 30,000.
• Refractory ITP :
 Failed to respond to (or relapsed after) splenectomy and is severe

27. Who do we treat ?
• All patients who present with bleeding and those with platelet counts less
than 20,000 / cu mm .
• Immediate therapy is not required for patients with platelet counts
between 20,000 and 50,000 /cu mm in the absence of bleeding or
predisposing comorbid conditions such as uncontrolled HTN, active PUD,
anticoagulation, recent surgery, or head trauma.
• S/b individiualized
- Level of activity – sports?
-

28. Hospitalization and emergency therapy : which pt ??
• Pts. with profound muco-cutaneous or internal bleeding and
• Platelet counts of less than 20,000/cu mm and a history of
significant bleeding.

29. What is the target platelet count ?
• > 30,000 in pts without co-morbidities and drugs interfering with platelet
function
• Above 40 000 to 50 000/cu mm for patients requiring aspirin, NSAIDs,
warfarin, or other anti-thrombotics.
• Minor surgery : > 50,000/cu mm
• Major surgery ( including neurosurgery ) : > 80,000/ cu mm .

30. Just for Fun

31. Treatment of ITP
Reference : UpTo date 2018

32. Algorithm for treatment
Wintrobe’s clinical hematology 13 th edition

33. Initial therapy
• Emergency treatment :
 IV methylprednisolone (1.0 g/d for 1-3 consecutive days) combined with
IVIG.
• Non-emergent therapy :
 High-dose dexamethasone, typically administered as 40 mg orally per day
for four days with no taper for 1-3 cycles, or oral prednisone at 1 mg/kg
daily for 2-3 weeks followed by a gradual taper.

34. Prednisolone Vs Dexamethasone
• Compared with prednisone, dexamethasone was associated with:
 A better overall response (platelet count >30,000/microL) at two weeks
(59 versus 79 percent; risk ratio [RR] 1.22, 95% CI 1.00-1.49).
 A better complete response (platelet count >100,000/microL) at two
weeks (36 versus 64 percent; RR 1.67, 95% CI 1.02-2.72).
 Fewer bleeding events during the first 10 days (24 versus 12 percent of
patients).
 No difference in overall or complete response at six months (43 versus 54
percent; RR 1.16, 95% CI 0.79-1.71).
 Fewer toxicities (46 versus 24 adverse events per 100 patients).
2016 meta-analysis of nine randomized trials (1138 patients) that compared outcomes for
different glucocorticoid regimens for previously untreated ITP

35. IVIG
• Raise the platelet count within 24 to 48 hours
• The effect of IVIG usually persists for 2-6 weeks.
• 1 g/kg OD for 1-2 days.
• Most adverse reactions are mild and transient.
• Serious reactions can occur : Headache, hypertension, chills, allergic
reactions, vomiting, and hypotension .
• Other rare adverse reactions include anaphylaxis, hemolytic anemia, acute
kidney injury, and thrombosis

36. Anti-D
• Alternative to conventional IVIG for patients whose RBCs are Rh(D)
positive.
• The usual dose of anti-D is 50 to 75 mcg/kg intravenously.
• Common adverse effects of anti-D include infusion reactions similar to
IVIG.
• Anti-D should be avoided in patients with preexisting hemolysis or a high
risk of hemolysis

37. TPO Receptor agonists
• Romiplostim (Nplate) : once-weekly subcutaneous injection.
Eltrombopag (Promacta, Revolade) : once-daily pill.
• There are no data directly comparing the efficacy or toxicity of
romiplostim versus eltrombopag in ITP or other conditions
• Stimulate the production of megakaryocytes and ultimately platelets in
the bone marrow by binding to and activating the TPO receptor.
• Indication : Failed one line of therapy such as corticosteroid or IVIG and
who have not had splenectomy.

38. TPOR agonist cont..
• A TPO-RA may also be used as a temporizing measure in a patient who
requires an increase in platelet count for a period of time.
• Generally used as maintenance therapy for ITP because, except in the rare
patient, they do not induce remission.
• Risk : BM reticulin formation and thrombosis

39. Emergency surgery
• Properly timed glucocorticoids or IVIG can often be used to
raise the platelet count.

41. SPLENECTOMY
• Indication : Failed corticosteroid therapy
• Single best option to convert a patientwith ITP into a “nonpatient” .
• IVIG, IV anti-D, or pulse doses of corticosteroids are used in known responders
to boost the platelet count prior to splenectomy.
• Approximately 85% of patients attain a hemostatic response after
splenectomy and two thirds achieve a durable response (Kojouri et al and
Schwartz et al).
• Immunize with polyvalent pneumoccocal, H influenzae type b, and
quadrivalent meningococcal polysaccharide vaccines at least 2 weeks prior to
splenectomy if possible.
• Antibiotic prophylaxis : penicillin ,Erythromycin

42. Treatment of chronic ITP

43. RITUXIMAB
• Indication : Pts in whom splenectomy fails
• Anti-CD20 monoclonal antibody
• Dose : 375 mg/m2 IV every week for 4 weeks
• Responses are usually noted within 4 to 8 weeks after the first infusion but may
occur as late as 4 months.
• A complete or partial remission occurs in 25% to 50% of Patients.
• Side effects are mostly related to the first infusion (fever, chills, hypotension,
bronchospasm, etc).
• Serious infection other than reactivation of hepatitis B in chronic carriers is rare
and generally

44. Experimental Therapy
• Thrombopoietic factor
• AMG 531
– Thrombopoietin receptor agonist
– Phase 2 placebo-controlled trial

45. Hep-C with ITP
• Antiviral therapy s/b considered in the absence of contraindication.
• T/t of ITP =IVIG
• Corticosteroid increases viral load
• Platelet count s/b closely monitored ( INFs S/E – thrombocytopenia )

46. HIV with ITP
• Antiviral therapy s/b considered before any other t/t
• T/t : Corticosteroid , IVIG or anti D
• Those who fail above t/t : Splenectomy

47. Management of patient with severe bleed
• Platelet transfusion.
• IVIG : 1g/kg, repeated the following day if the platelet count remains
<50,000/microL).
• Glucocorticoids (eg, methylprednisolone, 1 g IV , repeated daily for 3
doses; or dexamethasone, 40 mg orally or intravenously, repeated daily for
four days).
• Romiplostim, 500 mcg subcutaneously

48. • Other hemostatic agents in severe bleeding that does not respond to platelet
transfusions:
 Tranexamic acid
o Antifibrinolytic agent
o Orally (1 to 1.5 g three to four times daily) or intravenously (1 g over 10 minutes,
followed by 1 g over the next eight hours).
 EACA
o Antifibrinolytic agent
o Doses in the range of 4 to 12 g/day, administered orally or intravenously for
several days up to several months
 Activated factor VII (factor VIIa)

49. Thrombocytopenia in pregnancy
• Most common hematological abnormality

50. GESTATIONAL THROMBOCYTOPENIA
• For the thrombocytopenia to be consistent with gestational
thrombocytopenia
 Women should have no past history of thrombocytopenia (except
during a previous pregnancy),
 The thrombocytopenia resolved spontaneously within 1-2 months
after delivery,
 The fetus/newborn baby should not have had thrombocytopenia
 GTP is unlikely if platelet count < 50,000.

52. Gestational thrombocytopenia Vs ITP

53. ITP in pregnancy
• ITP occurs in 1 per 1000 to 1 per 10,000 pregnancies, accounting for
approximately 3% of women who are thrombocytopenic at delivery.
• ITP should be suspected any time during pregnancy with isolated
thrombocytopenia of less than 50,000/cu mm , esp. during the first 2
trimesters.
• In the absence of symptoms or treatment : monitor platelet counts at least
monthly through the first 2 trimesters, biweekly in the third, weekly as term
approaches and more often, if indicated.
• Ideally, maternal platelet counts should be maintained above 20,000/cu mm
throughout pregnancy and above 50,000/cu mm near term to minimize the
need for platelet transfusions in the event an emergency CS.
Blood journal 2018

54. ITP in pregnancy cont..
• Use corticosteroids as initial therapy, but this can induce or exacerbate
GDM, bone loss, HTN , and perhaps abruption and prematurity = For this
reason, we tend to rely more on IVIG together with low-dose prednisone
(20 mg every day).
• Splenectomy should be avoided if possible, and deferred to the second
trimester when necessary.
• We do not use danazol, cyclophosphamide, anti-CD20, vinca alkaloids,
and other potentially teratogenic therapy.
• Mode of delivery is based entirely on obstetric indications
Blood journal 2018

56. HEPARIN INDUCED THROMBOCYTOPENIA(HIT)
• Differs from other DIT in two major ways.
 The thrombocytopenia is not usually severe, with nadir counts rarely
<20,000/μL.
 HIT is not associated with bleeding and, in fact, markedly increases the risk
of thrombosis.
• Mechanism of thrombocytopenia : Antibody formation to a complex of
the PF4 and heparin.
• A fraction of those who develop antibodies will develop HIT, and a portion
of those (up to 50%) will develop thrombosis (HITT).

57. HIT cont..
• UFH > LMWH
• 4 Ts in the diagnostic algorithm for HIT
• Thrombocytopenia ( rarely , 20,000)
• Timing of platelet drop : within 5-14 days of heparin exposure
• Thrombosis
• Other causes of Thrombocytopenia ruled out

58. HIT cont..
• Diagnosis
• Clinical diagnosis
• Anti-heparin/PF4 Abs : ELISA
- Low specificity
• Serotonin release assay
- Lower sensitivity but higher specificity than ELISA

59. Treatment of HIT
• Prompt discontinuation of heparin.
• Direct thrombin inhibitors( DTIs) : Argatroban and Lepirudin – FDA
approved
• DTI Bivalirudin and Fondaparinux : Effective but not FDA approved .
• Consider anticoagulation even in the absence of thrombosis
• If thrombosis present: warfarin for 3- months , started only with overlap of
DTI or Fondaparinux and after resolution of thrombocytopenia

60. Reference
• Harrison’s 19th edition
• Wintrobe’s 13th edition
• How I treat ITP and refractory ITP Blood journal 2018
• How I treat thrombocytopenia in pregnancy Blood Journal
• ASH guidelines on ITP 2017
• UpToDate 2018
• Robbin’s pathology

61. Thank you !!!