This document provides information on approaches to bleeding disorders and thrombocytopenia. It discusses idiopathic thrombocytopenic purpura (ITP), including that it is characterized by thrombocytopenia under 100,000/cm and shortened platelet survival due to the presence of antiplatelet antibodies. ITP most commonly affects children ages 2-10 years and presents with bruising of the skin and mucous membranes. Evaluation involves platelet counts and smears, while treatment options include corticosteroids, intravenous immunoglobulin, and anti-Rho(D) immune globulin.

1. Approach to a bleeding disorder,
Approach to thrombocytopenia,
Idiopathic thrombocytopenia (ITP)
Dr. Kalpana Malla
MD Pediatrics
Manipal Teaching Hospital
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3. HEMOSTASIS
1. VASCULAR PHASE
2. PLATELET PHASE
3. COAGULATION PHASE
4. FIBRINOLYTIC PHASE

4. VASCULAR PHASE
WHEN A BLOOD VESSEL IS
DAMAGED -
VASOCONSTRICTION

5. PLATELET PHASE
PLATELETS ADHERE TO THE
DAMAGED SURFACE AND
FORM A TEMPORARY PLUG

6. COAGULATION PHASE
THROUGH TWO SEPARATE
PATHWAYS THERE IS
CONVERSION OF FIBRINOGEN
TO FIBRIN

7. FIBRINOLYTIC PHASE
ANTICLOTTING MECHANISMS ARE
ACTIVATED TO ALLOW CLOT
DISINTEGRATION AND REPAIR OF
THE DAMAGED VESSEL

8. HEMOSTASIS
DEPENDENT UPON:
 Vessel Wall Integrity
 Adequate Numbers of Platelets
 Proper Functioning Platelets
 Adequate Levels of Clotting Factors
 Proper Function of Fibrinolytic
Pathway

9. Coagulation cascade
Intrinsic system (surface contact) Extrinsic system (tissue damage)
XII XIIa Tissue factor
XI XIa
IX IXa VIIa VII
VIII VIIIa
X Xa
V Va
II IIa (Thrombin)
Fibrinogen Fibrin
Vitamin K dependant factors

10. LABORATORY EVALUATION
• Platelet Count
• Bleeding Time (BT)
• Prothrombin Time (PT)
• Partial Thromboplastin Time (PTT)
• Thrombin Time (TT)

11. Laboratory Evaluation of the
Coagulation Pathways
Partial thromboplastin time(PTT) Prothrombin time(PT)
Intrinsic pathway Extrinsic pathway
Thrombin time Common pathway
Fibrin clot

12. Laboratory Evaluation of the
Coagulation Pathways
• PT prolonged in extrinsic and common
pathway
• APTT prolonged in intrinsic and common
pathway
• PT &APTT – prolonged in common pathway
,liver dysfunction ,DIC
• DIC – thrombin time is also prolonged
• Factor XIII deficiency – platelet ,APTT,PT,BT-
Normal

13. Diagnostic Approach
• Increased BT –
a) Platelet decreased – ITP
b) Platelet normal – anaphylactoid purpura
• Increased CT –
a) only PT prolonged – Factor VII deficiency
b) only APTT prolonged – factor – VIII,IX,XI,XII
and von willebrand’s disease

14. Diagnostic Approach
c) Both PT & APTT prolonged –vit –k deficiency,
severe liver ds, cong deficiency of factor V,
X.fibrinogen deficiency ,DIC

15. PLATELET COUNT
 NORMAL 100,000 - 400,000 CELLS/MM3
< 100,000 Thrombocytopenia
50,000 - 100,000 Mild Thrombocytopenia
< 50,000 Sev Thrombocytopenia

16. BLEEDING TIME
PROVIDES ASSESSMENT OF
PLATELET COUNT AND FUNCTION
NORMAL VALUE
2-8 MINUTES

17. PROTHROMBIN TIME
Measures Effectiveness of the Extrinsic
Pathway
Mnemonic - PET
NORMAL VALUE
10-15 SECS

18. PARTIAL THROMBOPLASTIN TIME
 Measures Effectiveness of the Intrinsic
Pathway
Mnemonic - PITT
NORMAL VALUE
25-40 SECS

19. THROMBIN TIME
 Time for Thrombin To Convert
Fibrinogen Fibrin
 A Measure of Fibrinolytic Pathway
NORMAL VALUE
9-13 SECS

20. So What Causes Bleeding
Disorders?
VESSEL DEFECTS ?
PLATELET DISORDERS
FACTOR DEFICIENCIES
OTHER DISORDERS
?

21. VESSEL DEFECTS
Vascular purpuras
• Infection – meningococcal meningitis, hge
measles, typhoid
• Drugs – aspirin ,indomethacin, phenytoin ,
quinine
• Anaphylactoid purpura – Henoch-schonlein P
• Metabolic – uremia, scurvy

22. PLATELET DISORDERS
Thrombocytopenia

23. FACTOR DEFICIENCIES
• Hereditary
• Hemophilia – factor VIII deficiency
• Christmas ds – factor IX deficiency
• Von-Willebrand’s ds
• Acquired
• Vit – k deficiency
• Oral anticoagulant therapy
• Liver ds

24. THRMBOCYTOPENIA
- CONGENITAL - TAR syndrome
- Fanconi’s anemia
- Wiskott Aldrich syndrome
- Acquired -Aplastic anemia
- BM replacement

25. DECREASED PRODUCTION:-
A) IMMUNE THROMBOCYTOPENIC PURPURA(ITP)
B) INFECTIONS - EBV
- HIV
- HBV
- RUBELLA
- PARVO-B19
- CMV
- TB,TYPHOID

26. C .Drug induced - NSAID, ATT, AED, QUININE,
SULFA,PENICILLIN, FRUSEMIDE, HEPARIN,
D . Autoimmune Disorders -SLE, hyperthyroidism
E . Malignancy - ALL, AML, Lymphoma,
Neuroblastoma

27. Others
- DIC
- Microangiopathic Hemolytic Anemia- HUS
-Liver disease
- Neonatal thrombocytopenia – toxoplasmosis, CMV, herpes
simplex, ITP

28. IDIOPATHIC / IMMUNE
THROMBOCYTOPENIC PURPURA
DEFINITION : is characterised by
-Thrmbocytopenia < 100.000/cm
- Shortened PLT. survival
-Presence of antiplatelet AB in the plasma.
-Increased Megakaryocytes in BM

29. BACKGROUND
 Most common causes of symptomatic
thrombocytopenia in children.
 Incidence - 3 and 8 cases per 100,000
children/yr
 Before a diagnosis of ITP – R/O other
common causes of thrombocytopenia
(concurrent infection , autoimmune disorders ,
malignancy , bone marrow failure .. )

30. CLASSIFICATION
1.Acute ITP (children)- PLT returns to normal
value before 6mth.
2.Chronic ITP (adults) - PLT remains low
after 6mth also
3.Secondary ITP (follow other diseases
4.RECCURRENT:-PLT count decreases after
becoming normal

31. ETIOLOGY
Usually benign transient immune-mediated
thrombocytolytic condition
Autoantibodies (usually IgG) directed against platelet
membrane antigens (especially glycoprotein complex
IIb/IIIa) are present
Thrombocytopenia results from phagocytosis of
antibody-coated platelets by the reticuloendothelial
system

32. ROLE OF SPLEEN
1.Auto-antibody production
2.Platelet destruction
3.Platelet storage

34. CLINICAL PRESENTATION
2- 10 years (peak 2 to 5 years )
Patients < 2 years or > 10 years at
presentation are atypical
No seasonal variation
History of a preceding infection (1-4 wks
back), in 50 to 85 % of pediatric cases
Post-vaccination cases also have been
reported ( MMR )

35. CLINICAL PRESENTATION
• Previously healthy child - sudden Skin and mucous
membrane bleeds - Petechiae, purpura
ecchymosed, Gingival bleeding and epistaxis ,
gastrointestinal , genitourinary
 Conjunctival and retinal hemorrhages may
occur
 Life-threatening bleeding, (ICH), - is very rare,
occurring with an incidence of 0.1 to 1.0 %

36. Petechiae
Do not blanch with
pressure

37. CLINICAL PRESENTATION
No other systemic symptoms - fever, anorexia,
weight loss, or bone or joint pain
No significant enlargement of lymph nodes,
liver, or spleen is present

38. LABORATORY STUDIES
 For the typical case of ITP :
CBC
platelet count
peripheral blood smear (often large
platelet forms are seen )
Mean Platelet Volume increased
Bleeding time prolonged
PT/ APTT normal
Platelet antibodies in 70-90 %

39. Fewer Platelets than normal.

40. LABORATORY STUDIES
 For the atypical case of ITP :
viral antibody titers (including HIV)
Coombs' test
Reticulocyte count
Studies for collagen vascular :
ANA , Anti dsDNA, ANCA etc
Studies for rheumatoid disorders:
RF

41. Platelet Auto-antibodies
Platelet Antigens

42. LABORATORY STUDIES
 BONE MARROW EXAMINATION (BME)
 In the past, BME was performed routinely in
children with suspected ITP
 BME are unnecessary in the "typical" case of
childhood ITP
 Bone marrow aspiration and biopsy is reserved
for - atypical presentation
 BME - who initially was diagnosed as ITP but
subsequent clinical course is inconsistent with
the natural history of acute ITP

43. DIFFERENTIAL DIAGNOSIS
1. Aplastic anemia
2. Leukemia ( ALL )
3. Autoimmune disease (SLE)
4. HSP
5. Infection - hepatitis, HIV
6. Drug exposure - heparin, quinidine,
sulfonamides

44. MANAGEMENT
 80 to 90 % of cases recover spontaneously within a few
 months (3-6 months) even without treatment
 Restriction of activity and avoidance of medications with
antiplatelet activity (aspirin , ibuprofen ,NSAID)
 Guidelines suggest :
Platelet counts >30,000 no symptoms – no
treatment
Platelet counts <30,000 with symptoms –
treatment

45. THERAPY
Corticosteroids
Intravenous immunoglobulin (IVIG)
Anti-Rho(D) immune globulin

46. CORTICOSTEROIDS
 Steroids reduce the risk of symptoms by -
1. Improving vascular integrity
2. Diminishing antibody affinity for the
platelet membrane
3. Reducing antibody production
4. Reducing reticuloendothelial system
phagocytosis of antibody-coated
platelets

47. Dosage regimens
Prednisone 1-4 mg/kg per day for 2 to 4
weeks
 Pulse IV methylprednisolone as high as 50
mg/kg per day for 3 to 7 days
Occasionally, a second course of
treatment may be necessary if significant
hemorrhagic symptoms again develop

48. CORTICOSTEROIDS
 Chronic administration of steroids -
Avoided
 Alternative therapies - IVIG or Anti-D
should be considered who need
prolonged or repeated corticosteroid
therapy

49. IVIG
 MoA: interferes with macrophage Fc receptor
clearance
 Rapid improvement in platelet numbers - 95%
patients within 48 hrs
 Dose - 400 mg/kg per day for five days
- 1 gm/kg for one to two days
 The higher, shorter dosage schedules appear to
be preferable

50. IVIG
 The side effects include :
1. Nausea and vomiting (63 %)
2. Headache (56 %)
3. Fever (19 %)
4. Neutropenia (absolute neutrophil count
<1500/microL) 30 %
 Cost must be considered in the selection of
therapy for ITP

51. ANTI-D IMMUNE GLOBULIN (Anti-Rho(D)
MoA: anti-D results in blockade of Fc receptors by
antibody coated RBCs in place of antibody coated
platelets
Dose - single dose of 50 µg/kg
80-85 % patients show rise in platelets within 48 hrs
Given to children with a Hb > 10 g/dl
One to two weeks after administration, a fall in the Hb
level of 1 to 1.5 grams - as a result of mild hemolysis of
the patient's Rho(D)-positive red cells

52. OUTCOME
80 % -90% - recovers spontaneously within three
months of presentation, with or without therapy
10 % recovers in the next few months
15 to 20 % - have moderate or major hemorrhage
 0.1 to 1 % - Life-threatening bleeding(ICH) is rare
 <5 % with acute ITP have recurrent acute
thrombocytopenia

53. CHRONIC ITP
 Definition - persistence of thrombocytopenia
beyond six months from the time of diagnosis
 10 % of patients with typical ITP will have
chronic ITP
 Patients who have atypical features at
presentation are more likely to have chronic
disease

54. CHRONIC ITP ( Management )
Aim of treatment - should focus on minimizing
the risk for bleeding
Many patients will require no treatment
 Even after years, a significant proportion of
such patients will improve

55. CHRONIC ITP ( Management )
Corticosteroids :
 Periodic short courses or pulses of corticosteroids
 For steroid dependent patients - alternate day dosing
may be effective in preventing bleeding while
reducing side effects

56. CHRONIC ITP ( Management )
Immunoglobulin therapy :
 IVIG or anti-Rho(D)- effective in chronic ITP who
are resistant to steroids
 All of these strategies offer temporary relief of
symptoms and improvement in platelet numbers
 Very costly

57. CHRONIC ITP ( Management )
Splenectomy :
 Effective in 60 to 90 % of children with chronic ITP
 Overwhelming post-splenectomy infection
 Presplenectomy immunizations and subsequent
penicillin prophylaxis are necessary for all age groups

58. CHRONIC ITP ( Management )
Splenectomy :
 No universally accepted standards for the timing
of splenectomy in chronic ITP
 Guidelines recommend waiting until at least 12
months after diagnosis
 8)Immunosupressive agents - Cyclophoshamide

59. Acute ITP Chronic ITP
Mostly children Mostly adults
Male/Female = Male/Female = -
Acute onset Usually gradual onset
Plt. Count mostly Plt. Count 20 – 50000/mm
< , /mm
Spontaneous Spontaneous remission rare
remission frequent
Chronic recurrent course
Mortality : -
Duration - mo -yrs
Duration – 2-6 wks

60. Neonatal thrombocytopenia
Systemic illness
1.Cong infections – rubella, CMV, toxoplasmosis,
syphillis
2.Gram –ve sepsis

61. Neonatal thrombocytopenia
Due to transfer of maternal antibodies directed
against fetal platelets
1. Neonatal alloimmune TP-(NATP) –
development of maternal antibody against
antigens present on fetal platelets
- develops symptoms in first few days of life
- No maternal thrombocytopenia

62. Neonatal thrombocytopenia
2. Baby of ITP mother-
• Symptoms in perinatal period
• Resolves within 2-4 months
• IVIG & steroids

63. TTP
• Thrombotic Thrombocytopenic purpura
• Pentad – fever, microangiopathic hemolytic
anemia, thrombocytopenia,impaired renal
function ,CNS changes
• Usually adolescents & adults
• Treatment – plasmapheresis – 80-95%
effective
• Steroids & splenectomy

64. Platelet transfusions
• Source
– Platelet concentrate (Random donor)
Each donor unit should increase platelet count
~10,000 /µl
– Pheresis platelets (Single donor)
• Storage
– Up to 5 days at room temperature
• “Platelet trigger”
– Bone marrow suppressed patient (>10-20,000/µl)
– Bleeding/surgical patient (>50,000/µl)

65. Danzol 400 mg/m2/d for 3 mth.
9)PLASMAPHERESIS
10) T/T Of life threatening ITP:-
PLT. TRANSFUSION
SOLUMEDROL 500 Mg/m2/day IV TID.
IVIG 2g/kg
emergency Splenectomy.
Vincristine 2 mg/kg IV.
PROGNOSIS;-
EXCELENT 70-80 % recover ithin 6mth.
spontaneous remission in 1 yr- 5yrs.

66. Approach to the thrombocytopenic
patient
• History
– Is the patient bleeding?
– Are there symptoms of a secondary illness? (neoplasm,
infection, autoimmune disease)
– Is there a history of medications, alcohol use, or recent
transfusion?
– Are there risk factors for HIV infection?
– Is there a family history of thrombocytopenia?
– Do the sites of bleeding suggest a platelet defect?
• Assess the number and function of platelets
– CBC with peripheral smear
– Platelet function study

67. Platelet transfusions
• Source
– Platelet concentrate (Random donor)
– Pheresis platelets (Single donor)
• Target level
– Bone marrow suppressed patient (>10-20,000/µl)
– Bleeding/surgical patient (>50,000/µl)

68. Platelet transfusions - complications
• Transfusion reactions
– Higher incidence than in RBC transfusions
– Related to length of storage/leukocytes/RBC mismatch
– Bacterial contamination
• Platelet transfusion refractoriness
– Alloimmune destruction of platelets (HLA antigens)
– Non-immune refractoriness
• Microangiopathic hemolytic anemia
• Coagulopathy
• Splenic sequestration
• Fever and infection
• Medications (Amphotericin, vancomycin, ATG, Interferons)

69. Approach to the WERLHOF’S DISEASE
• History
– Is the patient bleeding?
– Are there symptoms of a secondary illness? (neoplasm,
infection, autoimmune disease)
– Is there a history of medications, alcohol use, or recent
transfusion?
– Are there risk factors for HIV infection?
– Is there a family history of thrombocytopenia?
– Do the sites of bleeding suggest a platelet defect?
• Assess the number and function of platelets
– CBC with peripheral smear
– Bleeding time or platelet aggregation study
– TORNIQUET / RUMPEL-LEEDE TEST:-

70. THROMBOTIC THROMBOCYTOPENIC PURPURA(TTP)
MOSCHOWITZ’S SYNDROME
DEF:- It is rare acquired multisystem disease.
CLASSIFICATION :-
1) PRIMARY = ACUTE ,CHRONIC, RELAPSING & CONGENITAL.
2)SECONDARY = CTD, SBE, MALIGNANCY, INFECTION & DRUGS.
CLINICAL FEATURES :- Consumptive thrombocytopenia
Microangiopathic H. anaemia.
Fever, Jaundice,
Neurologic & Renal manifestations

71. DIAGNOSIS :-
TPC ,Hb % , Haptoglobin , hemoglobinuria
Decreased plasma factor - VIII & vWF.
GINGIVAL BIOPSY = Presense of segmantal hyaline microthrombi in
the microvasculature.
TREATMENT : -
PLASMAPHERESIS
FFP
STEROIDS
ANTIPLATELETS AGENTS.
SPLENECTOMY.

72. NONTHROMBOCYTOPENIC PURPURA
1)ANAPHYLACTOID PURPURA
2)INFECTIONS (Meningococcus, measles, rubella, SBE)
3)DRUGS(SULFA)
4)PURPURA FACTITIA:-It is a self inflictted lesions in a linear fashion commonly over accessible
parts of body due to Psychopathic disorder.

73. THROMBOCYTOPATHY
PLT. function disorders :-
1)BERNARD SOULIER SYNDROME
2)GLANZMAN’S THROMBASTHENIA
3)ALPORT SYNDROME(PF-3 deficiency)
4)CTD =
EHLERS DANLOS SYNDROME
PSEUDOXANTHOMA ELASTICUM
MARFAN’S SYNDROME
OSTEOGENESIS IMPERFECTA.

74. ESSENTIAL THROMBOCYTHEMIA
Diagnosed by :-TPC > 6000.000/cmm, Hb% <13gm%
RCM < 36ML/KG.
NORMAL IRON IN BM.
ABNORMAL PLT FUNCTION TEST.
NO KNOWN CAUSE OF THROMBOCTYTOSIS
- ve philadelphia chromosome.
-ve BM fibrosis.
Thrombotic & haemorrhagic features common.
TREATMENT:- Anti-platelet agents = ASA, Dipyridamole(3-6 mg/kg/d
PLT lowering drugs = Hydroxyurea - 20-30mg/kg od
Alpha 2- interferon.

75. Thank you
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