Thrombocytopenia

1. Thrombocytopenia
Professor Mona Aziz Gilani
FCPS(haematology)
Shaikh Zayed PGMI and
SKZ Medical College,
Lahore Pakistan

2. The granular appearance of the platelets helps to distinguish them from artifact in the
peripheral smear

3. Brief history of the platelet
• Osler, Hayam, and Bizzozero identified small particles in the
blood, these were believed to be either bacteria or red cell
fragments
• James Homer Wright “Wright Stain” identified platelets as a
distinct hematopoetic component arising from
megakaryocytes
• William Duke in 1910 described 3 patients with low platelet
counts that had hemorrhagic disease
• Duke created a venous shunt from a normal donor to a
thrombocytopenic recipient and showed that the platelet
count could rise and the bleeding would cease

5. Figure ; Platelets can be seen as individual structures forming on the periphery of this
megakaryocyte

6. Platelet Kinetics
• Normal circulating platelet count
– 150K to 400K (150,000/ul to 400,000/ul )
– 90 to 300 K in people of Mediterranean descent
• 1/3 of platelets are sequestered in the spleen
• lifespan of a platelet is 7 to 10 days
• 15 to 45 K platelets are produced daily to maintain
steady state

7. .
EDTA may produce this effect causing a spurious decrease in the platelet count

9. Thrombopoietin (TPO)
• TPO is the primary regulatory protein in the
production of platelets
• TPO gene is on chromosome 3
• TPO is expressed in the liver, kidneys, and smooth
muscle cells
• Has a plasma half life of 30 hours
• The receptor for TPO is c-MPL which is present on
the megakaryocytes and platelets
• TPO rises with platelet fall and declines as the megakaryocyte
and platelet mass increase

10. why we are worried about
Thrombocytopenia ?
• 1/3 of all Hematology Consults in a General Hospital are for
thrombocytopenia
• 5 -10% of all hospital patients are thrombocytopenic
• 35% patients in the ICU are thrombocytopenic
• Thrombocytopenic patients in the hospital suffer a two fold
greater mortality rate than those who are not

11. Practical Importance of Assessing
Thrombocytopenia..
 The primary reason for evaluating
thrombocytopenia is
• To assess the risk of bleeding
• To assess the presence of serious underlying
disorders (malignancy ,TTP, HIT )

12. Relation of bleeding risk and platelet
count
– < 20 K …..increased risk of bleeding
– 20 – 50 K ….. rarely have increase risk of spontaneous
bleeding but increase risk of bleeding from procedures
– 50 --100 K ……no increased risk of spontaneous bleeding
and can undergo most procedures

13. Clinical manifestations of thrombocytopenia
• Petechiae (not seen in haemophilia or VWD)
• Pupura
• Echymoses
• Mucosal bleeding
• Menorrhagia
• Intracranial bleeding (uncommon but the most feared)

14. Clinical manifestations of thrombocytopenia
• Some times
thrombosis
Infact low platelet is a manifestation of
thrombosis

15. Petechiae
Do not blanch with pressure
(cf. angiomas)
Not palpable
(cf. vasculitis)
(typical of platelet disorders)

17. Thrombocytopenia
sequestration
in spleen
• Production
– Marrow
Damage
• Aplasia
• Drugs
• Malignancy
– Congenital
Defects
– Ineffective
Production
• B12 def
• Folic acid def
• Destruction
– Non
Immune
• DIC
• TTP
• HELLP
– Immune
• ITP
• HIT
• SLE, AIDS
• TTP

18. Thrombocytopenia
• Production
– Marrow Damage
• Aplasia
• Drugs
• Malignancy
– Congenital
Defects
– Ineffective
Production
• B12 def
• Folic acid def

19. Thrombocytopenia
sequestration
in spleen • Destruction
– Non
Immune
• DIC
• TTP
• HELLP
– Immune
• ITP
• HIT
• SLE, AIDS
• TTP

20. Congenital Thrombocytopenia
• Reasons to Suspect
• Persistence of neonatal thrombocytopenia
• onset of bleeding symptoms in childhood
• Family history of thrombocytopenia or mucocutaneous
bleeding
• Platelet count unresponsive to typical treatments for ITP

21. Congenital Thrombocytopenia
Low MPV Normal MPV Large MPV
W A S (X linked) FPD/AML Bernard Soulier
TAR Platelet type vWD
AT/RS MYH9
CAT Grey Platelets
11q- disorder GATA1
Treatment of Bleeding
• platelets
• DDAVP
• Recombinant FVIIa

22. Figure 1. Giant platelets are larger than red cells

23. ITP
(Immune Thrombocytopenic Purpura)
• Isolated thrombocytopenia with no clinically
apparent associated conditions or other causes of
thrombocytopenia
• high prevalence disease
• 16 to 27 per million per year
• Incidence increases with age
• Female predominance at age < 60 but not over the
age of 60
• It is generally abrupt in onset with children
• It can have an insidious onset.

24. Types of ITP according to etiology
• ITP..(idiopathic)
• Neonatal Thrombocytopenia
Associated with Maternal ITP( transfer of IgG),Drug-Related
• Drug Induced
Quinidine, Quinine, Sulfa, Gold Salts, Abx (Vanco etc), Heparin
• Lymphoma associated
• Autoimmune disorders
Thyroiditis, SLE, Colitis, Sarcoidosis
• Infections
HIV, Rubella, viral Hepatitis, CMV,
• Pos-transfusion Purpura

25. Types of ITP according to clinical
presentation
• Acute ITP
• Chronic ITP
• Resistant ITP
• Refractory ITP

27. Pathogenesis of ITP
• Increased platelet destruction caused by antiplatelet
antibodies
• +
• Lack of compensatory response by megakaryocytes
due to suppressive effect of antiplatelet antibodies

28. Features of Acute ITP
• Peak age Children (2-6 yrs)
• Female:male 1:1
• Antecedent infection Common
• Onset of symptoms Abrupt
• Platelet count at presentation <20,000
• Duration 2-6 weeks
• Spontaneous remission Common

29. Features of Chronic ITP
• Peak age Adults (20-40 yrs)
• Female:male 3:1
• Antecedent infection Rare
• Onset of symptoms Abrupt-indolent
• Platelet count at presentation <50,000
• Duration Long-term
• Spontaneous remission Uncommon

30. Diagnosis of ITP
• Features consistent with the diagnosis of ITP
– Thrombocytopenia with normal or slightly large platelets
– Normal RBC morphology and number (may have
associated iron def or thallasemia etc.)
– Normal white cell number and morphology
– Splenomegaly rare
• Features not consistent with the diagnosis of ITP
– Giant platelets
– RBC abnormalities ie schisotocytes
– Leukocytosis or Leukopenia

31. Laboratory evaluation of ITP
• Not Much !!!!!!!
– Platelet associated immunoglobulin reflect
plasma concentration
– Bone Marrow not very helpful as initial test
• May be helpful in patient over 50 years and concerned
about MDS
• If patient has failed initial treatment and diagnosis is in
question
– TSH and HIV test helpful,
– Peripheral Smear helpful

32. Management of ITP
• Most patients with ITP do not have clinically
significant bleeding
– Risk of intracranial bleed 0.1 to 1% (This is an
overestimate)
– Wet Purpura ie epistaxis, gingival bleeding is a risk
factor for major bleeding
 In asymptomatic patients with platelets counts
greater then 20 K observation is reasonable

33. Management of Acute ITP
• First line therapy
1. Steroids
– Prednisone 1mg/kg/day , tapering over 2 months
– Decadron 40 mg/day x 4 days
– Solumedrol 1 gram/day x 3 days
2. Antibodies
– IVIG 1 gram/day x 2 days
– Anti-D 50 mcg/kg IV x1

34. Management of Acute ITP
• Second line therapy
1. Immunomodulation .
a. anti CD 20. 375mg/m2/week x 4 injections
b. Azathioprine 50-200 mg /d
c. Cyclosporine 50-200 mg/d
d. Danazol 200-800 mg/d
e. Vincritine 2mg /week x3 injections
2. Splenectomy
3. Eltrombopag 25-75 mg /day

35. Management of Chronic ITP
• Splenectomy
– Immunize with Pneumovax, Hib, Meningococcal
• Chronic Anti-D therapy
– Does not put the disease in remission
• Immunomodulation eg Rituximab
• Eltrombopag ,TPO analogue
• Observation

36. Management in pregnancy
• Gestational Thrombocytopenia
– Platelet count >70K, occurs late in gestation, not
associated with fetal thrombocytopenia, resolves
after pregnancy
• ITP in pregnancy
– Treat if symptoms, intermittent IVIG, Prednisone,
anti-D
– Epidural anesthesia appears safe if platelet count
> 50K
– Monitoring for neonatal thrombocytopenia

37. Thrombotic thrombocytopenic purpura
• Diagnostic pentad
1. Microangiopathic hemolytic anemia
2. Thrombocytopenia
3. Renal dysfunction
4. Fluctuating neurological deficit
5. Fever

39. Lab findings of TTP
• Severe thrombocytopenia <30 K to 75 -100 K
• Hemolytic anemia with several fragmented red cells
in high power oil (>1% total number of RBC
• Renal Abnormalities ,may be subtle ,initially
• Markedly elevated LDH
• Initially coagulation studies are normal

40. Figure 1. Peripheral smear showing microangiopathic hemolytic features with numerous RBC
fragments (helmet cells/schistocytes)

41. Figure 2. Peripheral smear showing RBC fragmentation consistent with a microangiopathic
hemolytic process

42. Differential Diagnosis of TTP
• Hemolytic-uremic syndrome
• DIC
• Evans Syndrome
• Malignant Hypertension
• Malfunctioning prosthetic cardiac valves
• Severe vasulitis
• Pregnancy
– Preeclampsia/eclampsia
– HELLP

43. Treatment of TTP
• Daily plasma exchange with either FFP or
cryopoor FFP (45 to 55 cc/kg/day) reduces
mortality from 100% to 20%
• Steroids
• Platelet tx …?
• no …..why?????

44. Heparin Induced Thrombocytopenia
• Described in 1958 by Rodger Weismann and
Richard Tobin after extracting platelet fibrin
thrombi that formed after 1 to 2 week course
of heparin
• HITT is the presence of a multimolecular
complex between platelet factor 4, and
heparin
• HITT is associated with thrombosis despite
profound thrombocytopenia

46. Clinical Features of HITT
• Timing
– Onset between days 5 and 10 after heparin
initiation
– Rapid onset if previously exposed to heparin
• Thrombocytopenia nadir between 15 to 150 K
• >50% develop a new thrombosis both venous and
arterial
• Absence of petechia

47. Diagnosis of HITT
• Clinical Suspicion (ie greater then 50% drop in
platelets in the setting of heparin use)
• Laboratory Studies
– Platelet Activation Studies (Complicated and
physiologic)
– PF4/Polyanion Studies (Less time consuming but
not necessarily physiologic)
• Even without evidence of thrombosis patient should
get lower extremity dopplers

48. Treatment of HITT
• Removal of all Heparin products
• Begin direct thrombin inhibitor (DTI) (Argatroban or
Refludan)
• Treat with DTI until platelet count normalizes then
may begin anticoaguation with warfarin
• Fondaparinux (Arixtra) is a reasonable agent to use
for DVT prophylaxis in patient with history of HIT

49. Disseminated intravascular coagulation

54. Treatment
• FFP and platelet transfusions in bleeding
• Trigger for prophylactic platelet tx is higher
than in ITP
• Why ?

55. Macrovascular thrombosis
• Macrovascular thrombosis eg DVT is also a
cause of low platelet s
• D dimer
• Doppler studies
• Anticoagulation with careful monitoring of
counts
• Rise in plt count is indicater of …..

56. Practical Aspects for the management of
thrombocytopenia
• What is an adequate platelet count for procedures?
– Routine Dentistry >10K
– Dental Extraction >30K
– Regional Dental Block >30K
– Minor Surgery >50K
– Major Surgery>80K
– Epidural is okay at platelet count 50K for patient with ITP
• The target platelet count for a bleeding patient is
generally >40K
• Prophylactic platelet transfusions trigger is < 10K

57. Treatment options for the Bleeding Patient
• Red blood cells
• Platelet transfusions
• Fresh frozen plasma
• Cryoprecipitate
• Amicar
• DDAVP
• Recombinant Human factor VIIa

58. 1.PRBC tx
• Laminar blood flow is disturbed at HCT <30%,
• so It is important to raise HCT by PRBC tx ,in
severely anemic and thrombocytopenic
patients.

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

60. 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)

61. Aminocaproic acid (Amicar)
• Mechanism
– Prevent activation plaminogen → plasmin
• Dose 50mg/kg po or IV q 4 hr
• Uses
– Primary menorrhagia
– Oral bleeding
– Bleeding in patients with thrombocytopenia
– Blood loss during cardiac surgery
• Side effects GI toxicity,Thrombi formation

62. Eltrombopag
• TPO analogue
• Dose 25 -75 mg OD
• Indications
• Chronic ITP
• Aplastic anemia
• CLD associated thrombocytopenia
• Chemotherapy or radiation induced thrombocytopenia
• MDS associated thrombocytopenia

63. message
• Treatment of thrombocytopenia is according to cause
• It is important to know spleen size of thrombocytopenic
patient
• Look at LDH
• Every thrombocytopenia is not ITP
• Every ITP does not need tm

64. thanks