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
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
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 .
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
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
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
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)
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.
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
55.
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
temporizing measure in a patient who requires an increase in platelet count for a period of time (eg, during an acute bleeding episode, in preparation for elective surgery, or while deciding about, planning, or awaiting splenectomy).