2. Thrombocytopenia
Normal platelet count : 150,000 to 450,000/microL.
Thrombocytopenia is defined as a platelet count less than
150,000/microL .
Not usually clinically detected until the platelet count falls to levels below
100,000/microL .
1/3 of platelets are sequestered in the spleen.
Half life of a platelet is 8 to 10 days.
15000 to 45000 platelets are produced daily to maintain steady state
3. Clinical Features
Most conditions are associated with bleeding ( ITP,
Drug induced TP, Most other TPs)
Some conditions associated with thrombosis
Thrombotic Thrombocytopenia Purpura (TTP)
Disseminated Intravascular Coagulation (DIC)
Heparin Induced Thrombocytopenia ( HIT)
4. Sites of bleeding in thrombocytopenia :
Skin and mucous membranes : Petechiae, Ecchymosis,
Hemorrhagic vesicles, Gingival bleeding and epistaxis.
Menorrhagia
Gastrointestinal bleeding
Intracranial bleeding (rarest – but most dreadful
complication)
Bleeding in to joints and soft tissues are manifestation of
coagulation factor deficiencies rather than
thrombocytopenia.
5. Stratifying levels of thrombocytopenia
Why should we evaluate thrombocytopenia…???
1. To assess the risk of bleeding and
2. To assess the presence of underlying disorders (TTP,
HIT etc.)
To assess the risk of bleeding
< 20000 - increased risk of spontaneous bleeding
20000 to 50000 - increased risk of bleeding from procedures
50000 to 1 lakh - no increased risk of spontaneous bleeding
- no risk of procedural bleeding
6. Approach to Thrombocytopenia
History
Is the patient bleeding?
Do the sites of bleeding suggest a platelet defect?
Duration - Is thrombocytopenia – acute or chronic?
Is there a history of medications, alcohol use, or recent transfusion (
post-transfusion purpura)?
Are there symptoms of a secondary illness? (neoplasm, infection,
autoimmune disease)
Is there a family history of thrombocytopenia?
Heparin exposure – recent or with in past three months (HIT)?
Are there risk factors for HIV infection?
History of liver disease?
7. Assess the number of platelets
CBC with peripheral smear :-
RBC
NEUTROPHILS
PLATELETES
Any clumps? Schistocytes? Nucleated RBCs? Any features of nutrional
deficiencies (hypersegmented neutrophils), MDS (hyposegmented
neutrophils), Myelofibrosis ( tear drop cells) ?
Isolated thrombocytopenia or any other cell line affected?
8. Typical Platelet Counts in Various
Disease States
Moderate thrombocytopenia (50–100,000 per μL)
Thrombotic thrombocytopenic purpura
Heparin-induced thrombocytopenia
Disseminated intravascular coagulation
Hemophagocytic syndrome
Severe thrombocytopenia (< 20,000 per μL)
Drug-induced thrombocytopenia
Posttransfusion purpura
Immune thrombocytopenia
11. Classification
Can be broadly classified in to five categories based on the
mechanism behind reduced platelet count:
1. Pseudo or Spurious Thrombocytopenia
2. Dilutional Thrombocytopenia
3. Decreased Platelet Production
4. Increased Platelet Destruction
5. Altered Distribution of Platelets ( Increased
Sequestration)
Most common mechanisms are decreased platelet
production and increased destruction
12. Pseudo-thrombocytopenia
An artifactual clumping of plateletsin vitro without
clinical significance
The first step in evaluating any thrombocytopenia is to
confirm if it is “true” – diagnosis by peripheral smear.
Peripheral smear for platelet clumps which can lead to
pseudo-thrombocytopenia.
Various Scenarios :
• Inadequate anticoagulation of the blood sample
• EDTA dependant platelet auto-antibodies
• Abciximab Related Pseudo-Thrombocytopenia.
13. EDTA Dependant Aggluttinins
Present in 0.1% of normal population.
Unlike true thrombocytopenias, EDTA-PTCP is associated with a
NORMAL MEAN PLATELET VOLUME
These patients have naturally occurring platelet antibodies directed
towards a normally hidden epitope on platelet membrane GP IIb/IIIa
complex The glycoprotein IIb/IIIa complex must dissociate to
expose this epitope (called the cryptantigen or neoantigen) for
antibody binding to occur.
EDTA, Drugs such as Abciximab and Mexiletene , pH and temperature
can induce dissociation of GP IIb/IIIa and may expose this
cryptantigen causing the antibody to bind and resulting in
aggluttination ( clumps).
14. EDTA Dependant Aggluttinins
EDTA – PTCP is diagnosed by examination of peripheral smear for
platelet clumping.
If platelet clumping seen, repeat the count in non-EDTA anticoagulant
( heparin or sodium citrate).
If citrate is used, remember to correct the platelet count for dilution
caused by amount of citrate solution used. No such correction
required for heparin.
Although pseudothrombocytopenia has no pathologic significance
failure to recognize it may potentially place a patient in jeopardy for
inappropriate discontinuation of the needed drug (eg: abciximab),
delay of therapies involving invasive procedures, or initiation of
unnecessary therapies, such as platelet transfusion or use of steroids.1
15. Abciximab- Pseudothrombocytopenia
Thrombocytopenia is a well-recognized adverse effect of abciximab therapy.
Two mechanisms :
1. Immune mediated thrombocytopenia ( onset with in minutes
to hours of administration rather than days to weeks seen with
other drug induced thrombocytopenias).
2. Pseudothrombocytopenia ( 1/3rd of thrombocytopenia found in
patients receiving abciximab is due to
pseudothrombocytopenia)
Abciximab-PTCP is due to the presence of EDTAas an anticoagulant in the
blood-drawing tube. EDTA exposes the cryptantigen in GPIIb/IIIa complex to
aggluttination with naturally occuring antibodies. The mechanism of
abciximab-associated, EDTA-induced plateletclumping is not clear.
Differentiation of Abciximab-PTCP from True Abciximab-TP and from HIT is
extremely crucial. Diagnosis of PTCP will avoid discontinuation of the
abciximab infusion and initiationof unnecessary therapies, such as platelet
transfusions or anticoagulants (as in HIT).
When thrombocytopeniaoccurs after abciximab treatment, first review
peripheral blood film for clumping or obtain platelet count in citrated blood.
16. Dilutional Thrombocytopenia
Large quantities of Packed-RBC transfusion to treat massive haemorrhage can
lead to Dilutional TCP.
Due to absence of viable platelets in packed RBCs.
Usual platelet counts in patients receiving 15 to 20 units of PRBCs in 24 hours
is 50k to 100k/µl.
Can be prevented by giving platelet concentrates to patients receiving more
than 20 units PRBCs in a 24 hour period.
17. Distributional Thrombocytopenia
Also, referred to as Apparent Thrombocytopenia since total platelet
mass is normal.
About 1/3rd of circulating platelets are normally sequestrated in
spleen.
Splenic sequestration of platelets may increase to 90% in
splenomegaly ( hypersplenism) secondary to portal hypertension or
other causes.
Circulating platelet count decreases but total platelet mass and
overall platelet survival remain normal.
Hence, these patients can have significant “apparent”
thrombocytopenia but rarely have clinical bleeding ( since total
available platelet mass is normal)
18. Decreased Platelet Production
Associated with decreased or ineffective megakaryopoiesis and
thrombopoiesis
Marrow Damage:
• Aplastic Anemia
• Fanconi’s anemia ( defect in DNA repair genes)
• Malignancy
Congenital defects ( Congenital thrombocytopenias)
Paroxysmal Nocturnal Hemoglobinuria
Viral infections: Rubella, CMV, EBV, HIV, Hep-C
Ineffective production :
• Nutritional Deficiencies: B12, Folate, Severe iron deficiency
Drugs: thiazides, estrogen, chemotherapy , linezolid
Toxins: alcohol, cocaine
19. Increased Destruction
Most common cause of thrombocytopenia.
Leads to stimulation of thrombopoiesis and thus an increase in
the number, size and rate of maturation of the precursor
megakaryocytes.
Increased consumption with intravascular thrombi or damaged
endothelial surfaces
22. Classification Mechanism Specific Drugs
Autoantibody Drug induces antibody that reacts
with autologous platelets in the
absence of the drug
Gold, procainamide
Drug specific antibody Antibody recognizes murine
component of chimeric Fab
fragment specific for platelet
membrane glycoprotein IIIa
Abciximab
Fiban-type drug Drug reacts with glycoprotein
IIb/IIIa to induce a conformational
change recognized by antibody
Eptifibatide, tirofiban
Hapten-dependant Hapten links covalently to
membrane protein and induces
drug-specific immune response
Cephalosporins, piperacillin
Immune complex Drug binds to platelet factor 4 to
produce an antigenic complex
against which antibodies react;
resulting immune complexes bind
to platelet Fc receptors resulting in
platelet activation
Heparin and low molecular weight
heparin
Quinine-type Drug induces antibody that binds
to membrane protein in presence
of soluble drug
Quinine, quinidine, NSAIDs,
sulfonamides
25. Frequency of HIT
Perspectives
Unfractionated heparin – 3 - 5% incidence
Heart surgery 2.5% incidence
LMWHeparin, Catheter-flushes -- ~0.5%
Frequency of thromboemboli : 30%–50% of patients with
untreated HIT will have a thrombotic complication within 30 days
Based on increased morbidity and mortality, heparin cessation
alone is inadequate in HIT management
27. HIT
Two types – HIT type I and Type II. In general, the term HIT is
used widely to refer HIT Type II, the immune form.
Presence of any of the following :
• Otherwise unexplained thrombocytopenia
• Venous or arterial thromboses associated with
thrombocytopenia
• A fall in platelet count of 50% or more from a prior value, even
if absolute Thrombocytopenia is not present.
• Necrotic skin lesions at heparin injection site
• Acute systemic ( anaphylactoid) reactions occuring after IV
heparin bolus.
28. Diagnosis of HIT
Normal platelet count before commencement of heparin
therapy
Onset of thrombocytopenia typically 5–14 days after initiation of
heparin therapy but can occur earlier
Exclusion of other causes of thrombocytopenia (eg, sepsis)
Occurrence of thromboembolic complications during heparin
therapy
30. HIT Temporal Variants
Day 1 Day 4 Day 14
Day 30
Delayed-onset
HIT
(9–40 days)
Rapid-onset
HIT
(hours–days)
Typical HIT
Mean Day 9
(5–14 days)
Heparin (re) Exposure
THROMBOCYTOPENIA (± THROMBOSIS)
31. ClinicalSuspicionforHIT
The4T’s(Warkentin,2003)Thrombocytopenia
Platelet count fall > 50% and nadir greater than 20k : 2 points
Platelet count fall 30 to 50% or nadir 10 to 19k : 1 point
Platelet count fall < 30% or nadir < 10k : 0 points
Timing of platelet count fall
Clear onset b/w days 5 to 10 or platelet count fall at ≤1 day if prior heparin exposure
within the last 30 days: 2 points
Consistent with fall at 5 to 10 days but not clear (eg, missing platelet counts) or onset
after day 10 or fall ≤1 day with prior heparin exposure within the last 30 to 100 days: 1
point
Platelet count fall at <4 days without recent exposure: 0 points
Thrombosis or other sequelae
Confirmed new thrombosis, skin necrosis, or acute systemic reaction after intravenous
unfractionated heparin bolus: 2 points
Progressive or recurrent thrombosis, non-necrotizing (erythematous) skin lesions, or
suspected thrombosis which has not been proven: 1 point
None: zero points
Other causes for thrombocytopenia present —
None apparent: 2 points
Possible: 1 point , Definite: zero points The 5th T : The TEST
32. Interpretation
A score is determined for each of the four above categories,
resulting in a total score from zero to 8.
Pretest probabilities for HIT are, as follows:
0 to 3: Low probability
4 to 5: Intermediate probability
6 to 8: High probability
33. Laboratory Testing for HIT
Test Advantages Disadvantages
SRA Sensitivity >95%, Technically demanding
Specific > 95% Low predictive value
HIPA Rapid, available Variable sensitivity (30% – 80%);
Technique-dependent
ELISA High sensitivity High cost, less specificity,
> 95% 10% false-negative tests
34. HIT - Managment
Stop all Heparin, including heparin flushes. If dialysis, must be Heparin free.
Platelet transfusions are relatively contraindicated. ( except in those with
overt bleeding).
If Intermediate or High pre-test (clinical) probability + Positive ELISA (Anti-
PF4 antibody) Start alternative anticoagulant.
For low clinical probability, positive ELISA consider false positive ELISA.
Obtain Serotonin Release Assay which is more specific.
If clinical probability increases over time from a prior value but if initial HIT
was negative Repeat HIT antibody (ELISA) (may turn positive. ) Start
alternative anticoagulant
35. Alternative Anticoagulants
Drug Indications
Argatroban FDA-approved for HIT
(also for PCI)
Lepirudin FDA-approved for HIT
Bivalirudin PCI (including HIT patients)
Fondaparinux FDA approved for DVT
Prophylaxis in patients with Hip#,
Hip or knee replacements. Also
used in Rx of VTE. Not yet
approved for HIT (Off-label use)
Danaparoid Approved for HIT in Canada,
Europe, Aust.
36. Indication Transfusion threshold
Most invasive surgery (including post-
cardiopulmonary bypass)
50000
Neurosurgery or posterior eye surgery 1 lakh
Prevention of bleeding associated with
invasive procedures
• Lumbar puncture – 50000
• Central-line insertion – 50000
• Liver, renal or transbronchial biopsy – 50000
• Gastrointestinal endoscopy with biopsy -
50000
Spinal anaesthesia 50000
Epidural anaesthesia 80000
Transfusion threshold for Plateletes in various procedures
37. ManagementofDisseminatedIntravascular Coagulation
(DIC):Transfusion
The five basic tests of hemostasisa
Hematocrit
Platelet count
Prothrombin time (PT)
Activated partial thromboplastin time (aPTT)
Fibrinogen level
Guidelines for transfusion in patients at high risk of bleeding
Platelets < 50,000 per μL: give platelet concentrates or 1 unit of single-donor
platelets.
Fibrinogen < 80–100 mg/dL: give 10 units of cryoprecipitate
Hematocrit below 30%: give red cells
INR > twofold the upper limit of normal and aPTT abnormal: give 2–4 units of
FFP
38. HELLP TTP/HUS AFLP
Hypertension Always present Sometimes present Sometimes present
Proteinuria Always present Sometimes present Sometimes present
Thrombocytopenia Always Always Always
LDH elevation Present Marked Present
Fibrinogen Normal to low Normal Normal to very low
Schistocytes Present Present Absent
Liver tests Elevated Normal Elevated
Ammonia Normal Normal Elevated
Glucose Normal Normal Low
39. Indications and contraindications
to platelet transfusion
Prophylaxis Procedures Grade >2 bleeding
TTP CONTRAINDICATION IF THERE IS AN INCREASED
RISK, PREFERABLY AFTER
STARTING PLASMA
EXCHANGE
CONSIDER
HUS NO INDICATION CONSIDER INDICATION
HELLP NO INDICATION CHILD BIRTH >20000-50000 INDICATION
DIC NO INDICATION CONSIDER INDICATION
ITP NO INDICATION CONSIDER
+ IVIG OR PREDNISOLONE
INDICATION
+ IVIG
HIT NO INDICATION CONSIDER PROVIDED
ALTERNATIVE
ANTICOAGULANTS
PROVIDED
ALTERNATIVE
ANTICOAGULANTS
40. Contraindications to platelet
transfusion
Thrombotic thrombocytopenic purpura
Hemolytic uraemic syndrome
Heparin induced thrombocytopenia unless there is life or limb
threatening haemorrhage.
Congenital IgA defeciency
41. Plasma exchange
Removes large molecular weight substance such as harmful
antibodies from plasma.
1 cycle of plasma exchange removes about 66% of intravascular
constituent and 2 cycles removes about 85%.
42. Plasma exchange - indications
Category I indications (According to ASFA)
TTP
ATYPICAL HUS
HYPERVISCOSITY SYNDROMES
SEVERE/SYMPTOMATIC CRYOGLOBULINEMIA
43. HEMOLYTIC URAEMIC
SYNDROME
Triad of renal failure, microangiopathic anemia, and
thrombocytopenia.
Typical and Atypical
Typical mainly seen in childrens
Atypical mainly in adults and without preceding gastroenteritis
or E. Coli infn.
Plasma exchange in Atypical HUS
45. Treatment of TTP
Urgent plasmapheresis ( plasma exchange)
Plasma Infusion : Infusion of FFP 30 cc/kg/day until ready for
plasma exchange ( serves as emergency initial measure in those
who do not have immediate access to Plasma exchange)
Daily plasma exchange with either FFP or cryopoor FFP (45 to 55
cc/kg/day)
Steroids (Prednisone 1 mg/kg/day) ( may help by suppressing anti-
ADAMTS13 antibodies).
Red Blood Cell transfusions if needed
Platelet transfusion may worsen the disease and are avoided. Used
only if absolutely necessary ( in very rare cases, where severe
bleeding is encountered)
Refractory TTP : In patients with worsening disease despite daily
plasma exchange + Steroids Increase plasmpheresis to twice daily
exchange.
Poorly responsive or Recurrent TTP Add Immunosuppressive
therapy -Add Rituximab or Cyclosporine
46. ImmuneMediatedThrombocytopeniaPurpura
(ITP)
Idiopathic ITP vs. Secondary ITP
Idiopathic or Primary ITP : Defined as isolated thrombocytopenia with
Platelet count < 100 x 109/L
No other cause of thrombocytopenia
No clinically evident secondary form of thrombocytopenia.
Incidence increases with age
Female predominance under the age of 60 but not over the age of 60
May have onset or insidious onset generally abrupt in onset with
children and insidious in adults.
47. Secondary ITP
Post-Infectious : HIV, HEP-C, H.PYLORI
Vasculitis : SLE
Lymphoproliferative Disorders : CLL, NHL, HD
Drug Dependant ITP (DDITP) : Drug induced TP can be
sometimes mediated by antibodies eg: quinidine, sulfa
containing drugs
48. Evaluation of ITP
Features consistent with the diagnosis of ITP
Thrombocytopenia with normal or slightly large platelets
( Increased MPV)
Normal RBC morphology and number (may have associated
iron def or thallasemia etc.)
Normal white cell number and morphology
Splenomegaly is extremely rare
Features not consistent with the diagnosis of ITP
Giant platelets ( ? Congenital)
RBC abnormalities ie schisotocytes ( ? TTP/HUS, DIC)
Leukocytosis or Leukopenia (? MPD/MDS, Sepsis )
49. Acute Pharmacologic Management of ITP
Steroids
Prednisone 1mg/kg/day with taper over 2 to 3 months
Solumedrol 30mg/kg/d x 7 days
Antibodies
IVIG 1 gram/kg/day x 2 days
Anti-D 50 mcg/kg IV x1 dose in Rh+ve patients