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Normal platelet count : 150,000 to 450,000/microL.
Thrombocytopenia is defined as a platelet count less than
Not usually clinically detected until the platelet count falls to levels below
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
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)
Sites of bleeding in thrombocytopenia :
Skin and mucous membranes : Petechiae, Ecchymosis,
Hemorrhagic vesicles, Gingival bleeding and epistaxis.
Intracranial bleeding (rarest – but most dreadful
Bleeding in to joints and soft tissues are manifestation of
coagulation factor deficiencies rather than
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,
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
Approach to Thrombocytopenia
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 (
Are there symptoms of a secondary illness? (neoplasm, infection,
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?
Assess the number of platelets
CBC with peripheral smear :-
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?
Typical Platelet Counts in Various
Moderate thrombocytopenia (50–100,000 per μL)
Thrombotic thrombocytopenic purpura
Disseminated intravascular coagulation
Severe thrombocytopenia (< 20,000 per μL)
Activated partial thromboplastin time
LDH – markedly elevated in TTP and Hantavirus infn.
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
Most common mechanisms are decreased platelet
production and increased destruction
An artifactual clumping of plateletsin vitro without
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
Various Scenarios :
• Inadequate anticoagulation of the blood sample
• EDTA dependant platelet auto-antibodies
• Abciximab Related Pseudo-Thrombocytopenia.
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).
EDTA Dependant Aggluttinins
EDTA – PTCP is diagnosed by examination of peripheral smear for
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
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
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.
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.
Also, referred to as Apparent Thrombocytopenia since total platelet
mass is normal.
About 1/3rd of circulating platelets are normally sequestrated in
Splenic sequestration of platelets may increase to 90% in
splenomegaly ( hypersplenism) secondary to portal hypertension or
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)
Decreased Platelet Production
Associated with decreased or ineffective megakaryopoiesis and
• Aplastic Anemia
• Fanconi’s anemia ( defect in DNA repair genes)
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
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
Increased consumption with intravascular thrombi or damaged
Classified as :
Immune mediated destruction
Pro-hemorrhagic : all other drugs
Pro-Thrombotic : Heparin
Classification Mechanism Specific Drugs
Autoantibody Drug induces antibody that reacts
with autologous platelets in the
absence of the drug
Drug specific antibody Antibody recognizes murine
component of chimeric Fab
fragment specific for platelet
membrane glycoprotein IIIa
Fiban-type drug Drug reacts with glycoprotein
IIb/IIIa to induce a conformational
change recognized by antibody
Hapten-dependant Hapten links covalently to
membrane protein and induces
drug-specific immune response
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
Heparin and low molecular weight
Quinine-type Drug induces antibody that binds
to membrane protein in presence
of soluble drug
Quinine, quinidine, NSAIDs,
Frequency of HIT
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
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
• 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
Diagnosis of HIT
Normal platelet count before commencement of heparin
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
Amputation 20% (arterial thrombosis)
Death 22% to 28%
Venous thrombosis >> Arterial thrombosis
Clinical Sequelae in HIT
HIT Temporal Variants
Day 1 Day 4 Day 14
Mean Day 9
Heparin (re) Exposure
THROMBOCYTOPENIA (± THROMBOSIS)
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
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
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
Laboratory Testing for HIT
Test Advantages Disadvantages
SRA Sensitivity >95%, Technically demanding
Specific > 95% Low predictive value
HIPA Rapid, available Variable sensitivity (30% – 80%);
ELISA High sensitivity High cost, less specificity,
> 95% 10% false-negative tests
HIT - Managment
Stop all Heparin, including heparin flushes. If dialysis, must be Heparin free.
Platelet transfusions are relatively contraindicated. ( except in those with
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
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,
Indication Transfusion threshold
Most invasive surgery (including post-
Neurosurgery or posterior eye surgery 1 lakh
Prevention of bleeding associated with
• Lumbar puncture – 50000
• Central-line insertion – 50000
• Liver, renal or transbronchial biopsy – 50000
• Gastrointestinal endoscopy with biopsy -
Spinal anaesthesia 50000
Epidural anaesthesia 80000
Transfusion threshold for Plateletes in various procedures
The five basic tests of hemostasisa
Prothrombin time (PT)
Activated partial thromboplastin time (aPTT)
Guidelines for transfusion in patients at high risk of bleeding
Platelets < 50,000 per μL: give platelet concentrates or 1 unit of single-donor
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
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
Indications and contraindications
to platelet transfusion
Prophylaxis Procedures Grade >2 bleeding
TTP CONTRAINDICATION IF THERE IS AN INCREASED
RISK, PREFERABLY AFTER
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
HIT NO INDICATION CONSIDER PROVIDED
Contraindications to platelet
Thrombotic thrombocytopenic purpura
Hemolytic uraemic syndrome
Heparin induced thrombocytopenia unless there is life or limb
Congenital IgA defeciency
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%.
Plasma exchange - indications
Category I indications (According to ASFA)
Triad of renal failure, microangiopathic anemia, and
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
Thrombocytopenia, microangiopathic hemolytic anemia, renal
insufficiency, neurologic phenomena and fever
LDH is prognostic factor in TTP
Plasma exchange is treatment of choice
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
Steroids (Prednisone 1 mg/kg/day) ( may help by suppressing anti-
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
Poorly responsive or Recurrent TTP Add Immunosuppressive
therapy -Add Rituximab or Cyclosporine
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.
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
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 )
Acute Pharmacologic Management of ITP
Prednisone 1mg/kg/day with taper over 2 to 3 months
Solumedrol 30mg/kg/d x 7 days
IVIG 1 gram/kg/day x 2 days
Anti-D 50 mcg/kg IV x1 dose in Rh+ve patients