1. An Approach to a Patient
with Thrombocytopenia
Dr. Amina Nur Nova
Resident
Internal Medicine
BSMMU

2. Process of Hemostasis
 Vascular injury
Serotonin and thromboxane A2 (TxA2) for vasoconstriction
Exposure of basement membrane and collagen (negatively charged surface)
 Platelet adhesion and activation
 Platelet aggregation (1o homeostatic plug)
 Fibrin formation via coagulation cascade (2o homeostasis)
 Clot retraction
 Fibrinolysis and healing

4. Normal Physiology of Platelets
 Platelets are normally made in the bone marrow from
progenitor cells known as megakaryocytes.
 Normal platelet lifespan is 10d. Every day, 1/10 of platelet
pool is replenished.
 Normal platelet count is between 150,000 and 450,000/mm3
 Contain intracellular granules (α and ) that contain
coagulation factors and ADP
 Production stimulated by thrombopoietin from liver/kidney

6. Young versus old platelets
 The youngest platelets in the circulation are larger and
appear to be more hemostatically active.
 Thrombocytopenic patients with immune
thrombocytopenia (ITP) do not usually have serious
bleeding.
 The small numbers of young platelets in these patients
are more hemostatically active than mixed age platelets
in normal subjects.
 Patients with ITP also appear to have less bleeding
than patients with similar severities of thrombocytopenia
caused by marrow failure, such as subjects following
chemotherapy, who also have a population of platelets
of mixed age.

7. Reticulated platelets
 The youngest platelets in the circulation
contain RNA and have been called
reticulated platelets or the “immature
platelet fraction” (IPF).
Normal subjects — 1.3 percent
Thrombocytopenia with "normal or
decreased thrombopoietic activity" — 7.5
percent
Thrombocytopenia with "increased
platelet turnover" — 30 percent

8. Thrombocytopenia
 Thrombocytopenia is defined as a platelet count less than
150,000/microL (150 x 10 9 /L).
 2.5 percent of the normal population will have a platelet
count lower than this.
A recent fall in the platelet count by one-half, while still in
the normal range, may herald severe clinical problems and
requires active follow-up.

9. How low is too low?
 150,000 - 50,000: no symptoms
 50,000 - 20,000: first symptoms
 20,000-10,000: potentially life-threatening
 <10,000: risk for spontaneous intracranial
hemorrhage

10. Causes of
thrombocytopenia

11. Decreased production
Marrow hypoplasia
 After viral infection (Dengue, Rubella,
Mumps, Varicella, Parvo, HCV, EBV, HIV)
Childhood bone marrow failure syndromes,
e.g. Fanconi's anaemia
Idiopathic aplastic anaemia
Drug-induced: cytotoxics, antimetabolites

12. Decreased production
Marrow infiltration
Leukaemia ,Myeloma ,Carcinoma (rare),
Myelofibrosis
Haematinic deficiency
Vitamin B12 and/or folate deficiency
 Familial (macro-)thrombocytopathies
Myosin heavy chain abnormalities, e.g. Alport's
syndrome

13. Increased consumption of platelets
Immune mechanisms
Idiopathic thrombocytopenic purpura (ITP)*
Post-transfusion purpura
Neonatal alloimmune thrombocytopenia
Drug-associated, especially quinine and
Heparin
Coagulation activation
Disseminated intravascular coagulation
(DIC)

14. Increased consumption of platelets
Mechanical pooling
Hypersplenism
Thrombotic microangiopathies
Haemolytic uraemic syndrome (HUS)
Thrombotic thrombocytopenic purpura
Others
Gestational thrombocytopenia
Type 2B von Willebrand disease

16. Evaluation of Patient with Low
Platelets
History
Onset(new/chronic/relapsing)
 Recent medication or vaccination
 Recent transfusion (haemodillution)
 Recent organ transplant
 Autoimmune disease/Malignancy
 Pregnancy
 Travel
history(malaria,rickettsia,dengue)

17. Evaluation of Patient with Low
Platelets
Dietary Habit (Megaloblastic Anaemia)
Ingestion of alcohol/ Quinine
containing beverage
Risk factors for HIV and HCV

18. Clinical examination
Organomegaly (Leukaemia,
Myelofibrosis)
Joint or Soft tissue bleeding- DIC
Ischemic limb /skin necrosis- HIT

20. Morphologic aspects of the peripheral blood
smear of particular relevance to the diagnosis of
thrombocytopenia
Platelet size and granularity
 Consistently large platelets suggest
hereditary macrothrombocytopenia.
 Large platelets with a gray color on
Wright-
Giemsa stain define the gray platelet
syndrome, an autosomal-dominant
macrothrombocytopenia associated with
bleeding tendency due to absent or
greatly
reduced alpha granules.

21. Morphologic aspects of the peripheral blood
smear of particular relevance to the diagnosis of
thrombocytopenia
In thrombocytopenia due to peripheral
destruction, large platelets or giant platelets
are often seen in addition to platelets of
normal size.
When thrombocytopenia is due to reduced
platelet production (eg, after chemotherapy),
platelets are of normal size.
In myelodysplastic syndromes, platelets have
variable size (giant platelets may be seen)
and are frequently hypogranular.
In Wiskott-Aldrich syndrome, and X-linked
thrombocytopenia, both caused by mutations
of the WAS gene, platelets are small.

22. pseudothrombocytopenia
 In vitro clumping of platelets when EDTA is
used as an anticoagulant .
 Due to formation of autoantibody against a
normally concealed epitope on the platelet
membrane GP 2b/3a receptor.
 Reveals normal platelet count when
repeated with citrate or heparin anticoagulant

23. pseudothrombocytopenia

24. Isolated thrombocytopenia
 It is thrombocytopenia with normal
RBC, WBC and no sign or symptoms
of systemic illness.
 Limited DD:
◦ Drug induced thrombocytopenia
◦ ITP

25. Drug induced
thrombocytopenia
 Antibody against new epitopes of
platelet
glycoprotein.
 Moderate to severe thrombocytopenia.
 Drop in platelet count within 2-3 days
upto 1-3 weeks.
 Recovery in 5-10 days after drug
stoppage
 Should be suspected when patient has
recurrent episodes of thrombocytopenia
with prompt recovery.

26. Drugs commonly associated with
thrombocytopenia
 Abciximab
 Amiodarone
 Amphotericin B
 Carbamazepine
 Cimetidine
 Digoxin
 Eptifibatide
 Fluconazole
 Furosemide
 Heparin
 Interferon Alpha
 Phenytoin
 Piperacillin
 Quinidine
 Quinine
 Ranitidine
 Trimethoprim/Sulfamethoxazole
 Valproic Acid

27. Investigations
Drug dependent anti Platelet antibody by
flow cytometry,
Platelet Immunofluroscence test,
ELISA and
western blotting
Treatment:
If a patient’s platelets fall, all unnecessary
drugs need to be stopped.
give platelet transfusions , IVIg is particularly
helpful in quinine-induced ITP.

28. Heparin induced
thrombocytopenia (hit)
>50% decrease in platelet count or total
platelet< 1,00,000/cumm, while the
patient is on heparin.
Rare(1-3 %)
Median Platelet count 50,000-80000.
Rarely below 20000/cumm.
 Clinical manifestations may include
venous or arterial thrombosis, necrotic
skin lesions at heparin injection sites, or
acute systemic reactions subsequent to
IV heparin bolus administration.

29. Two types of HIT have been described.
Type 1 HIT is a modest transient
decrease in platelet counts.
 occurs within the first 2 to 3 days after
heparin initiation.
 returns to normal spontaneously,
even
with continuation of heparin. It is
generally of no clinical significance.

30. Type 2 HIT
 less common, seen in about 0.3 to
5% of patients treated with
unfractionated heparin.
 caused by antibodies against platelet
factor 4-heparin complex.
 usually occurs 4 to 14 days after
heparin initiation, but may occur
earlier in patients with prior exposure
to heparin.

31. Mechanism of HIT

32. Mechanism of HIT
The antibodies bind to the PF4-
heparin complexes on the platelet
surface
 induce platelet activation by cross-
linking FcγIIA receptors.
The activated platelets increase the
release and surface expression of
PF4, creating a positive feedback loop
in which further release of PF4
promotes further platelet activation.

33. Platelet activation results in the
release of procoagulant platelet
microparticles, platelet consumption,
and thrombocytopenia.
 Marked generation of thrombin,
activation of monocytes and other
inflammatory cells, and endothelial
injury and activation follow, producing
the characteristic venous and arterial
thromboses of HIT.

34. Treatment
Treatment consists of stopping heparin and
using alternate anticoagulants like
argatroban, lepirudin, bivalirudin.
Fondaparinux is a heparin pentasaccharide
analogue that does not bind to platelet-factor
4 and thus should not cause HIT.
Low molecular weight heparin is not an
appropriate anticoagulant in the setting of HIT
because of cross reactivity of the antibody.
 Platelet transfusions are relatively
contraindicated in the absence of severe
thrombocytopenia with life-threatening
hemorrhage

35. Thrombocytopenia in the cardiac
patient
 Several mechanisms in patients undergoing open heart
surgery:
Cardiopulmonary bypass may result in mechanical
destruction of platelets,
hemodilution in the bypass circuit,
drug-induced platelet destruction.
Sepsis,
Post-transfusion purpura.
 The nadir platelet count is typically seen on the second or
third day after surgery, with a rapid recovery thereafter.
 Severe thrombocytopenia is observed in 0.1%-2% of
patients after exposure to GPIIb/IIIa inhibitors (eg,
abciximab, tirofiban, eptifibatide) during percutaneous
coronary intervention.

36. Disseminated Intravascular
Coagulation (DIC)
DIC is a consumptive coagulopathy
complicating several diseases.
It is characterized by activation of
intravascular coagulation with microvascular
thrombi formation, thrombocytopenia,
depletion of clotting factors, variable bleeding
complications, and end-organ damage.

38. Acute DIC
 Acute DIC is commonly seen in severe sepsis
and septic shock, after trauma (especially
neurotrauma), after surgery, as an obstetric
complication (eg, abruptio placentae, amniotic
fluid embolism, and preeclampsia), after ABO-
incompatible blood transfusion, and as a
complication of acute promyelocytic leukemia.
 Consumptive coagulopathy in these cases is
severe and leads to bleeding manifestations (eg,
mucocutaneous bleeding and blood oozing from
wound sites) and frequent organ damage (eg,
renal and hepatic damage).

39. Chronic DIC
 Chronic DIC is more frequently observed in
solid tumors and in large aortic aneurysms,
usually with few obvious clinical or laboratory
indications of the presence of DIC.
 In chronic compensated DIC, such as a patient
with metastatic prostate or GI malignancy in
whom a slower rate of consumption of
coagulation factors may be balanced by
enhanced synthesis.
 Thus, patients may have only a modest
thrombocytopenia and normal PT and aPTT.
 The diagnosis is based on the presence of
microangiopathy on peripheral blood smear and
elevated fibrin degradation products (FDP) and
D-dimer levels.

40. Investigations
 PT - increased
 APTT - increased
 Fibrinogen - decreased
 FDP – increased
 BT- Increased.
 CT- Increased

41. Treatment
Focus on addressing underlying disorder
 Administration of Blood Components and
Coagulation Factors – platelet , FFP,
cryopricipitate
 Anticoagulation – heparin, protein C.
 Patients with DIC should not in general be
treated with antifibrinolytic therapy, e.g.
tranexamic acid.

42. Thrombotic Thrombocytopenic
Purpura
TTP - Diagnostic Features
 Microangiopathic Hemolytic Anemia (MAHA)
Elevated LDH, elevated bilirubin
Schistocytes on the peripheral smear
MUST BE PRESENT
 Low platelets - MUST BE PRESENT
 Fever
 Neurologic Manifestations - headache, sleepiness,
confusion, stupor, stroke, coma, seizures
 Renal Manifestations - hematuria, proteinuria,
elevated creatinine, BUN

43. TTP - etiology
An inherited or acquired deficiency (due
to autoantibodies) of von Willebrand
factor-cleaving protease known as
ADAMTS13.
 leads to accumulation of large multimers
of VWF which cause spontaneous
platelet aggregation and thrombi.
Can be induced by drugs, including
ticlopidine, quinine, cyclosporine,
tacrolimus, mitomycin C.
Increased incidence with pregnancy or HIV

44. TTP -lab
CBC normal or slightly elevated WBC.
Hb is moderately depressed at 8-9 g/dL.
Platelet count ranges from 20,000-50,000 per
microliter.
 PBF : Red blood cells are fragmented and
appear as schistocytes.
 Certain schistocytes have the appearance of
helmet cells (H).
 Spheroidal cells often are present (S).
Occasional nucleated erythroid precursors
may be present.

46. TTP - Course and Prognosis
Treatment relies on Plasma Exchange.
◦ Plasma exchange is superior to plasma infusion, but if
PLEX is delayed, give FFP.
Remove all inciting agents.
Platelet transfusions contra-indicated.
◦ Multiple case reports of stroke and/or death during or
immediately after platelet transfusion.
◦ Can consider giving if life-threatening hemorrhage is
present, but avoid routine platelet transfusions.
Secondary measures if no response to
plasma exchange include splenectomy,
vincristine

48. HUS - Hemolytic Uremic
Syndrome
Usually classified along with TTP as
“TTP/HUS”
Has fewer neurologic sequelae, more
renal manifestations.
Usually precipitated by diarrheal
illness, especially E. coli O157:H7 or
Shigella
Seen more in pediatric patients,
usually has better prognosis. May
respond less well to plasma

49. Thrombocytopenia in
pregnancy
Platelet counts < 150 X 109/L have been
reported in 6%-15% of women at the end of
pregnancy, but counts 100 X 109/L are
observed in only 1% of women.
 The most common causes of
thrombocytopenia are
gestational thrombocytopenia (GT; 70%),
preeclampsia (21%),
and ITP (3%).

50. Mechanism of GT
 Accelerated platelet activation in
placental circulation.
Accelerated consumption of platelet
due to reduced consumption during
pregnancy.

51. Diagnosis
 no past history of thrombocytopenia
(except during a previous pregnancy)
 Usually develops in 3rd trimester
 Mild thrombocytopenia (>70,000/cumm)
 Asymptomatic
 resolve spontaneously within 1-2 months
after delivery.
No foetal complication

52. Treatment
 no treatment needed, only
monitoring.
 Mode of delivery considered by
physician.

53. Pregnancy induced ITP
 IgG antibody against membrane
glycoprotein.
 Ab can cross placenta and cause
foetal thrombocytopenia.

54. Diagnosis
 Thrombocytopenia in 1st and 2nd
trimester.
 Persistant thrombocytopenia.
 Increased number of megakaryocytes
in
bone marrow.
 Disease of exclusion

55. Table. Suggestions for platelet transfusions
Platelet counts below which transfusion should
be
considered:
• 10,000/L - prophylactic transfusion
• 20,000/L - in the presence of bleeding,
fever, infection, platelet function defect, or
coagulopathy
• 50,000/L - prior to minor procedures, in
actively
anticoagulated patients or in the presence
of
active bleeding
• 75,000/L - prior to general surgery
• 100,000/L - prior to neurologic or
ophthalmologic surgery

56. THANK YOU