Download Three cases of Thrombocytopenia

Severe
Thrombocytopenia:
Three VA cases
Sarah Walter, M.D.
Thrombocytopenia
 Thrombocytopenia
is defined as a platelet
count of < 150,000/ μL
 Due to:


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Increased destruction
Sequestration
Decreased production
Thrombocytopenia

Systematic approach to evaluating patients:

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
History (associated illness, drugs, specific symptoms)
Physical exam (anomalies, hepatosplenomegaly,
infection, tumor, lymphadenopathy, bleeding)
Careful interpretation of the complete blood count and
examination of peripheral smear
• If diagnosis not made, consider bone marrow examination
with needle aspiration and biopsy
Case 1
Case 1

49 year old female who presented to the
Dermatology clinic with a petechial rash on her
legs. She denied vaginal or mucosal bleeding.
 History of depression and PTSD treated with
ziprasidone, trazadone, vanlafaxine,
clonazepam. And she recently started
carbamazepine 2 weeks prior.
Case 1

Pre-drug lab values (2
weeks ago):
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WBC: 6.5 x 1000/μL (4.5 –
11.0)
RBC: 3.9 M/μL (4.6 – 6.2)
Plt: 272 x 1000/μL (150 –
400)
Hgb: 12.2 g/dL (14.5 –
18.1)
Hct: 35.2% (42 – 54)
MCV: 90.4 fL (80 – 100)
MCH: 31.3 pg (28 – 34)
RDW: 12.7% (11.5 – 14.5)

Laboratory data at time
of visit:
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WBC: 4.6 x 1000/μL (4.5 –
11.0)
RBC: 4.45 M/μL (4.6 – 6.2)
Plt: 3.32 x 1000/μL (150 –
400)
Hgb: 12.6 g/dL (14.5 –
18.1)
Hct: 39.5% (42 – 54)
MCV: 88.9 fL (80 – 100)
MCH: 28.4 pg (28 – 34)
RDW: 12.8% (11.5 – 14.5)
Case 1

Additional pertinent laboratory data:
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PT: 11.9 sec (10.8 – 13.7)
aPTT: 19.9 sec (21.6 – 34.2)
Occult blood: Positive
UA: Negative for blood
Fe: 93 μg/dL (35 – 145)
TIBC: 314 μg/dL (275 – 400)
Ferritin: 133 ng/mL (25 – 180)
Case 1
 Smear:
Case 1
 Differential
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diagnosis:
Drug-induced thrombocytopenia
ITP
Infectious (viral)
TTP
DIC
Case 1
 Carbamazepine
was discontinued.
 Pt. received 1 unit of platelets (posttransfusion count: 13.3
 1 week following, platelet count 383.
Case 1
Diagnosis:
 Drug-induced thrombocytopenia:


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The main differential diagnosis in a druginduced thrombocytopenia is ITP.
Drug exposure is the cause of 5-20% of
thrombocytopenias
Typically see the effect approximately 14 days
after starting the medication
Drug-Induced Thrombocytopenia
 Mechanism
of various blood dyscrasias
due to drugs:



Interference with hematopoiesis, bone
marrow suppression
Drug induced antibodies
Commonly seen with the psychotropic drugs,
quinidine, sulfonamides, and gold
• Study by Stübner et al (2004), found that clozapine
was most common psychotropic drug to cause
blood dyscrasias (0.18%) followed by
carbamazepine (0.14%).
Drug-Induced Thrombocytopenia

Mechanisms of drug-dependent antibody
formation:

Accelerated platelet destruction due to drugdependent antibody
• Reversible drug binding to one of the platelet surface
glycoproteins (GP Ib/IX, GP IIb/IIIa) causing conformational
change, resulting in the exposure of a neoepitope, expressed
by a sequence that is normally concealed within the
hydrophobic domain of the protein.
• Molecular structure of the drug becomes an integral part of
the new antigenic epitope

There are no good laboratory tests to detect these
drug-induced antibodies.
Drug-Induced Thrombocytopenia

Criteria to make diagnosis:

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
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
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1) Candidate drug preceded thrombocytopenia AND
recovery from thrombocytopenia was complete and
sustained after the drug was discontinued.
2) The candidate drug was the only drug used prior
to the onset of thrombocytopenia OR other drugs
were continued or reintroduced after discontinuation
of the candidate drug with a sustained normal platelet
count.
3) Other etiologies for thrombocytopenia were
excluded.
4) Reexposure to the candidate drug resulted in
recurrent thrombocytopenia.
Definite (Level 1): meet criteria 1, 2, 3, 4
Probable (Level 2): meet criteria 1, 2, 3
Drug-Induced Thrombocytopenia

Thrombocytopenia associated with
carbamazepine usually appears 14 to 16 days
after initiation of drug. The platelet count
completely resolved in all cases 7 days after
after the drug was discontinued.
 Gold induced thrombocytopenia doesn’t follow
this pattern, have persistently low platelets for
months because of prolonged retention of gold
salts
Case 2
Case 2
 24
year old African American female
presented with complaints of:
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Easy bruising x 1 month
Heavy menses
1-2 episodes of fever in the past month
2 days of cervical lymphadenopathy
(resolved)
Occasional night sweats
No weight loss
Case 2

Initial laboratory findings:
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WBC: 3.15 x 1000/μL (4.5 – 11.0)
RBC: 3.26 M/μL (4.6 – 6.2)
Plt: 3.16 x 1000/μL (150 – 400)
Hgb: 8.80 g/dL (14.5 – 18.1)
Hct: 26.7% (42 – 54)
MCV: 81.8 fL (80 – 100)
MCH: 27.0 pg (28 – 34)
RDW: 16.1% (11.5 – 14.5)
Abs Neutrophil: 1.63 x 1000/μL (1.8 – 7.8)
Case 2
 Smear
Case 2
 Differential
diagnosis of pancytopenia with
severe thrombocytopenia:


Marrow infiltrative process (i.e. leukemia,
lymphoma, metastatic disease)
Idiopathic Thrombocytopenic Purpura (ITP)
• Why the neutropenia and anemia?
 Next
step, bone marrow biopsy.
Case 2
Diagnosis:
 ITP
 Iron deficiency anemia, secondary to
menometrorrhagia from low platelets
 Benign neutropenia of African Americans

Low absolute neutrophil count seen in African
Americans. No increased risk of infection.
Case 2
 Patient
received steroids, IVIG x1, platelet
transfusions.

1 week following, repeat CBC with a platelet
count of 35
ITP
Epidemiology of ITP:
 Incidence of 3-5 per cases 100,000
persons
 Onset typically adults aged 20-40 years
 Female predominance
ITP

Differential diagnosis:


Diagnosis of exclusion, need to exclude drug-induced
thrombocytopenia
Familial thrombocytopenia
• Check family history of low platelets unresponsive to
treatment for ITP
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HIV-ITP
Thrombotic thrombocytopenic purpura (TTP)
Spurious thrombocytopenia resulting from platelet
clumping
• Always look at the peripheral smear of a patient with
thrombocytopenia
ITP

Mechanism:
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Patients platelets are coated with IgG antibodies the
recognize the platelet surface glycoproteins. Tissue
macrophages recognize the Fc receptor, and
phagocytose the platelet-AB complex.
May also have reduced megakaryocyte production
secondary to autoantibodies against megakaryocytes.
Most frequent target antigens include GP Ib/IX/V and
GP IIb/IIIa
ITP
Diagnosis:
 Diagnosis of exclusion
 Should exclude other causes of
thrombocytopenia
 Review the peripheral smear
 Bone marrow examination if atypical
 Detection of anti-platelet antibodies(49-66%
sensitive, 78-92% specific, interlaboratory
agreement 55-67%) (not readily used)
 Flow cytometry to detect platelet associated
autoantibodies (still being investigated but may
be promising)
ITP

Diseases and disorders associated with ITP:

HIV
• Circulating immune complexes may nonspecifically deposit
on platelet membrane, and are then cleared from system
• Direct infection of megakaryocytes by HIV infection impairs
platelet production


Hepatitis C
?? H. pylori (still being debated)
• Thought is that some strains of H. Pylori express the Lewis
(Le) antigen. The Le antigen may adsorb the the platelet
surface and serve as a target for anti-Le antibodies.

SLE
• The patient had elevated ANA titer (1:2500) (still to be
worked up)
ITP
Treatment:
 Steroids
 Anti-D

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Use in Rh+ patients. The Anti-D will coat the patient’s
RBC, so that the IgG coated RBC compete with the
IgG coated platelets for phagocytosis from the spleen,
blocking splenic destruction of platelets.
IVIG
 Splenectomy if refractory to treatment
Case 3
Case 3
 76
year old male with 80-90% stenosis of
left main coronary artery, 70% stenosis of
left anterior descending coronary artery
 Underwent Coronary Artery Bypass Graft
(CABG)
Case 3

Platelet counts:
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Pre-op: 169 x 1000/μL (150 – 400)
Day of surgery: 110
POD #1: 104
POD #2: 74.7
POD #3: 92.2
POD #4: 81.5
POD #5: 89.8
POD #6: 52.3
POD #7: 11.3
POD #8: 8.86
Case 3
 Patient
received heparin prior to and
during surgery, with no documentation of
heparin received post-operatively.
 No clinical evidence of clotting.
Case 3
 Differential
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diagnosis:
Heparin-induced thrombocytopenia (HIT)
Other drug-induced thrombocytopenia
ITP
DIC
TTP
Case 3
Diagnosis:
 Heparin-induced thrombocytopenia
 ELISA test positive
Case 3
 Patient
was switched to Argatroban, all
heparin was discontinued
 Platelet count increased to 231
 No thrombotic events
HIT
 Occurs
as a result of an antibody complex
between heparin and platelet factor 4
 IgG antibodies bind to the platelet Fc
receptor and cause platelet activation,
resulting in platelet activation as well as
clearance from circulation.
HIT
HIT
 Diagnosis:

Diagnosis rests primarily on clinical grounds
• Laboratory tests not always locally available.
• Lab tests may not be available in timely manner
• Available tests are not completely sensitive or
specific.
HIT
Clinical diagnosis (Four T’s):
 Thrombocytopenia: >50% fall in platelet count
 Timing: Days 5-10 after exposure to heparin, or
<day 1 with recent heparin exposure (past 30
days)
 Thrombosis: Proven new thrombosis; skin
necrosis; acute systemic reaction after IV
heparin
 OTher causes of platelet fall excluded
HIT
 Functional
assay: Utilize the ability of the
antibody to cause platelet activation as an
endpoint.

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Require source of normal human platelets
with variability
See platelet activation at therapeutic
concentration of heparin, but not at markedly
therapeutic levels
HIT

Functional assays:

Serotonin release assay. Most sensitive and specific
of the functional assays
• Incubate washed platelets with radiolabeled serotonin.
Metabolically active platelets tae up serotonin and store it in
their granules.
• “Hot” platelets incubated with patient’s serum in the presence
and absence of heparin at therapeutic and supratherapeutic
levels.
• Measure radioactivity in supernatant. Positive if:
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
>20% release at therapeutic heparin level
<20% release at supratherapeutic levels
• 99% specificity, high sensitivity
• Very few labs perform because of technical difficulty and use
of radioactive substances.
HIT

Functional assays:

ATP release via luminescence aggregometry
• Closely resembles SRA as alternative approach
• Able to detect ATP release of activated platelets

Platelet aggregation studies:
• Donor platelets incubated with patient’s serum and heparin.
Measure donor platelets aggregation without heparin, with
therapeutic levels of heparin, and with supratherapeutic
heparin
• Highly dependent on donor platelets

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Sensitivity 39-81%
Specificity 82%
HIT
 Immunological Assays:

ELISA to detect the Heparin-PF4 antibody
• Does not require normal platelets, technically
easier to perform
• High false positive rate, low specificity

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50-60% patients undergoing open heart surgery will have
a positive ELISA in the absence of clinical HIT
Commercially available assay detects IgG, IgA, and IgM
heparin-PF4 antibodies
• Unlikely that IgM would cause clinical disease
HIT
 Immunologic Assays:

ELISA (cont’d):
• Does have higher sensitivity than aggregation
studies

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ELISA for HIT may initially be negative at time first
clinically suspect HIT, but that a portion of those may
then develop a positive ELISA if the test is repeated
based on persisting clinical suspicion.
May have false negative because HIT is due to an
antigen other than PF4
HIT
 No
laboratory test is 100% specific or
sensitive for HIT
 Interpret results in light of the pretest
probability. Should only be performed
when there is a clinical indication of HIT
HIT
 Treatment:


Discontinue all heparin and low molecular
weight heparin
Use alternative anticoagulant (direct thrombin
inhibitor):
• Argatroban
• Lepirudin
The End