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LAB UPDATE
Feb. 15, 2006
Dr. Beverly Dickson
Heparin
Induced
Thrombocytopenia
An antibody mediated adverse effect of heparin that is important
because of its strong association with venous and arterial
thrombosis.
Heparin exposure may be any preparation (LMWH) by any route
(flushes), and with any dose.
HEPARIN INDUCED THROMBOCYTOPENIA
Clinicopathological Syndrome
Clinical:
Thrombocytopenia with or without thrombosis
Serologic:
High titer platelet activating HIT antibodies by
sensitive antigen and/or activation assays
Clinical Features of HIT
Timing of thrombocytopenia
Typical onset: between days 5 and 10 after starting heparin
Rapid onset: < 1 day following resumption of heparin (usually in a patient recently
exposed to heparin, who therefore has residual circulating HIT antibodies)
Severity of thrombocytopenia
Platelet count nadir: < 20,000/µL in 10% of patients; < 150,000/µL in 85% of
patients
Thrombosis is common
> 50% develop new thrombosis
Venous thrombosis: deep venous thrombosis > pulmonary embolism > warfarininduced venous limb gangrene > adrenal hemorrhagic necrosis* > cerebral sinus
thrombosis
Arterial thrombosis: limb artery thrombosis > stroke syndrome > myocardial
infarction > mesenteric artery thrombosis
Absence of petechiae (even with platelets < 20,000/µL)
Skin lesions at heparin injection sites
Severity ranges from erythematous plaques to skin necrosis
Acute systemic reactions following intravenous bolus heparin
Acute inflammatory or cardiorespiratory signs and symptoms associated with
abrupt platelet count fall
Consultative Hemostasis and Thrombosis, 2002, pg358.
Consultative Hemostasis and Thrombosis 2002, pg 359
DRUG INDUCED
THROMBOCYTOPENIA MECHANISMS
Heparin-induced
Thrombocytopenia
Quinine- or Sulfainduced
Thrombocytopenia
Frequency
Approx. 1/100
Approx. 1/10,000
Onset after
beginning
treatment
5-14 days
≥ 7 days
Platelet count
20 - 150x109/L*
< 20x109/L
Sequelae
Thrombosis
Bleeding
Laboratory testing
using patient
serum
Heparin-dependent platelet
activation; Immunoassay
(heparin/PF4 antigen)
Drug-dependent increase in
platelet-associated IgG
*Some patients have a fall in platelet count but platelet count remains > 150x109/L
Simposio Internacional CLAHT PERU 2004
HIT ASSAYS
Two Major Classes
Functional activation assays (Serotonin Release Assay):
Infer presence of HIT antibodies based on heparin-dependent,
platelet activating properties (washed platelets)
Antigen Assays (Heparin-PF4 ELISA):
Detect HIT antibodies based upon their reactivity with platelet
factor 4 (PF4) complexed to heparin or other polyanions (ELISA)
Specificity, %
HIT Diagnostic Assay
Sensitivity, %
Early Platelet Fall
Late Platelet Fall
Platelet SRA
90-98 *
>95
80-97 ‡
Heparin-induced platelet aggregation
assay
90-98 *
>95 ‡
80-97 ‡
Platelet aggregation test using citrated
platelet-rich plasma
35-85
90◊
82◊
PF4/heparin EIA
>90 *
>95
50-93
Combination of sensitive platelet
activation and PF4-dependent antigen
assay
100 *
>95 
80-97 
 ”Early” refers to a fall in the platelet count that begins within the first 4 d of starting heparin; “late” refers to a fall that begins on day 5 or later. The specificity
varies because late thrombocytopenia due to a reason other than HIT may nevertheless show a false-positive HIT antibody result because of subclinical HIT
antibody seroconversion.
*Sensitivity defined in relation to those patients in prospective studies who had a positive test result when the platelet count fell by ≥50% after ≥5 days of
heparin therapy, and in whom the available clinical information (particularly, evidence for alternative explanations for thrombocytopenia and the effect of
stopping or continuing heparin) supported the diagnosis of HIT. However, about 30-40% of samples (app. 2% overall) give a repeated “indeterminate” result,
and the activation assay is nondiagnostic.
‡ Assumes that the heparin-induced platelet aggregation assay test and SRA have similar sensitivity and specificity profiles; other platelet activation end points
that may also give acceptable results using washed platelets include detection of platelet-derived micro particles by flow cytometry.
◊ Assumes that a 90% specificity in early thrombocytopenia attributable to non-HIT disorders (eg, nonspecific platelet activation related to acute inflammatory
proteins) declines to an 82% specificity in late thrombocytopenia that may be attributable to subclinical HIT antibody seroconversion.
 Clinicopathologic definition assumes that at least one sensitive test result must be positive for diagnosis of HIT; specificity of the activation assay is indicated.
Localization of thromboembolic
complications associated with HIT
Thromb Haemost 2005:94:132-5.
Type of TEC
Number of TECs (%)
Arterial
126 (29.2%)
Limb artery
71 (16.4%)
Thrombotic stroke
26 (6.0%)
Aortic Thrombosis
16 (3.7%)
Myocardial infarction
10 (2.3%)
Other
3 (0.7%)
Venous
306 (70.8%)
Proximal DVT
114 (26.4%)
Pulmonary embolism
103 (23.8%)
Distal DVT
78 (18.1%)
Cerebral vein (sinus) thrombosis
7 (1.6%)
Other
4 (0.9%)
Simposio Internacional CLAHT PERU 2004
Clinical Assessment:
Inclusion Criteria
History of heparin exposure
Thrombocytopenia during and after heparin
exposure (<150,000)
Drop in platelet count (<50%) rather than absolute
thrombocytopenia
Smaller drop in platelets (especially skin necrosis)
Early-onset of thrombocytopenia with heparin re-exposure
caused by circulating antibodies
Platelet count may rarely be normal when patient presents
with thrombosis (delayed-onset HIT)
Thrombocytopenia recovers after heparin withdrawal
Median time to platelet count recovery after heparin withdrawal
is 4 days
Platelet Monitoring for HIT
ACCP Consensus Conference, 2004
HIT risk >0.1% - platelet count monitoring
Patients recently treated with heparin starting
UFH
Platelet count baseline within 24 hours
Acute systemic reaction post UFH bolus
Immediate platelet count
Patients receiving therapeutic dose UFH
Every other day platelet count until day 14 or UFH
stopped, whichever is first
Postoperative patients, UFH prophylaxis
(HIT risk >1%)
Every other day platelet count until 14 days or UFH
stopped.
HIT Patient Risk Groups
1-5% risk (highest)
Post-op vascular, ortho, cardiac patients
receiving UFH for 1-2 weeks
0.1-1% risk (rare to infrequent HIT)
Medical and obstetric patients receiving
prophylactic doses of UFH
Post-op patients receiving LMWH
Post-op/critical care patients with UFH flushes
Medical patients receiving LMWH after one or
several preceding doses of UFH
HIT
A negative laboratory
test for HIT antibodies
should never be used
as the sole criterion
for restarting heparin
therapy.
HIT CONCLUSIONS
Routine platelet monitoring rather than HIT
Antibody studies is most useful to identify
patients who are at risk for thrombosis
Although functional and antigen assays are
sensitive in detecting HIT antibodies,
neither is completely specific for HIT
syndrome
The diagnostic interpretation of these
laboratory tests must be made in the
context of clinical pretest probability of HIT
Clindamycin Disk Inductive Test for
Staphylococcus spp.
“D Test”
• Routinely performed on Staphylococcus
that test resistant to erythromycin but are
susceptible to clindamycin
• Many MRSA that cause community
acquired infections have msrA gene
D Test
Resistance to macrolides (e.g. erythromycin) can occur by two different
mechanisms with the resulting phenotypes noted below:
Mechanism
Efflux
Ribosome
alteration
Determinant
(gene)
Erythromycin
Clindamycin
msrA
R
S
erm
R
S*
erm
R
R
(constitutive)
msrA=macrolide streptogramin (type B) resistance
Erm=erythromycin ribosome methylase; encodes enzymes that confer inducible (MLSBi) or constitutive
(MLSBc) resistance to MLS agents via methylation of the 23S rRNA
*requires induction to demonstrate resistance
MLS=macrolide lincosamide (e.g. clindamycin) streptogramin (type B)
Inducible
Clindamycin
Resistance
(erm-mediated)
Helicobacter pylori
Tests at PHD
CLO-Test
Rapid urease
Invasive
HpSA
Stool antigen test
Non-invasive
FDA
Detects active
approved test
infection
for cure
Sensitivity
Specificity
CLO
80-98%
93-100%
Yes
Yes
HpSA
92-97%
90-95%
Yes
Yes
Serology
80-95%
80-95%
No
No
Helicobacter pylori
AGG/AGA Graded Recommendations 2005
For patients ≤ 55 years without alarm
features, the clinician may use either “test
and treat” for H. pylori or acid suppression
therapy. (A)
Point of Care
PT
Blood Gas (TIS)
6+
I-STAT
ACT
creatinine
i calcium
Additional POC instruments: Hemocue, Accu-Chek, Clinitek, DCA 2000 (A1c)
Point of Care
Limitations
Method dependent
Technique dependent
Interferences: known and unknown
Drugs
Metabolic
Other
Chemical Pathology
Are your hands clean enough for point-of-care electrolyte analysis?
Hugh S. Lam*, Michael H.M. Chan, Pak C. Ng*, William Wong*, Robert
C.K.Cheung, Alan K.W. So*, Tai F. Fok* and Christopher W.K. Lam
Departments of *Paediatrics and Chemical Pathology, The Chinese University of Hong
Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong
______________________________________________________________________
Pathology (August 2005) 37(4) pp.299-304
Case #1 POC/INR
The patient is a 75 year old female with history of frequent
TIA, recently placed on coumadin
Upon ambulatory clinic visit her I-STAT INR was > 8.0 but
Core Lab INR was 4.1
What might cause this discrepancy?
→ technique
→ interference
→ reagents
→ instrument malfunction
POC/INR
Interferences
Lupus anticoagulant/anticardiolipin Ab
LMWH
Direct thrombin inhibitors
Daptomycin
Case #2 ED/I-STAT +6
I-STAT Core Lab
A middle aged male
presented to the ED
post grand mal
seizure. Patient had
a history of
hyponatremic
episodes secondary
to anti-convulsant
drug therapy.
Na
132
140
K
3.7
4.0
Cl
103
100
BUN
13
10
AG
N/A
31
Glu
159
158
Hgb
17
14
Accu-Chek Inform Meter
Accu-Chek Comfort Curve Strip
A whole blood glucose test strip that
delivers plasma-like test results.
Case #3
ICU/Accu-Chek Inform Meter
The patient is a 75 year old
male who was transferred
from Lake Pointe in septic
shock s/p hernia repair.
The patient developed
renal failure, liver failure
with coagulopathy and
respiratory failure. Multiple
POC glucoses performed,
multiple results discrepant
with laboratory.
Date
Time*
Core
Lab
AccuChek
Jan 9
0754
109
140
Jan 9
0550
88
129
Jan 8
1415
63
99
Jan 8
1055
59
100
Jan 8
0630
36
75
Jan 8
0350
38
74
* Results charted within minutes of each other
Case #3
Metabolic Status
Alk Phos
374 U/L
ALT
407 U/L
AST
2697 U/L
Total Bili
5.4 mg/dL
Lipase
2347 U/L
CK
863 U/L
Creatinine
4.7 mg/dL
TnI
0.5 ng/mL
Calcium
5.5 mg/dL
i Calcium
0.71 mmol/L
Anion gap
24
PT
32.8 sec
INR
3.0
Lactic Acid
10.7 mmol/L
Accu-Chek Comfort Curve
Strip
Known Interferences
Galactose
Maltose
Xylose
Bilirubin (> 20 mg/dL)
Lipemia (> 5000 mg/dL)
Acetaminophen
(> 8 mg/dL)
Uric acid
Low Hct (< 20%)
High Hct
> 65% @ ≤ 200 mg/dL
> 55% @ > 200 mg/dL
Mannitol
Icodextrin
60 mg/dL glucose
concentration
500 mg/dL glucose
concentration
Clinica Chimica Acta 356 (2005) 178-183.
CAPILLARY BLOOD GLUCOMETER VS REFERENCE STANDARD
Crit Care Med 2005 Vol 33, no.12.
ARTERIAL BLOOD GLUCOMETER AND REFERENCE STANDARD
Crit Care Med 2005 Vol 33, No 12
POC Glucose
meters originally designed to test glucose in
diabetics with normal hematocrit
ICU patients may suffer from multiple
metabolic +/or hematologic derangements
ICU patients may be treated with multiple
drugs
Results which do not seem realistic in
view of the clinical assessment should
be repeated in the Core Laboratory.
Urine Drug Screen
Immunoassay
Does it detect oxycodone?
Basic urine drug immunoassay testing for
opiates tests primarily for morphine (heroin
and codeine metabolized to morphine).
These tests do not generally detect low to
moderate oxycodone use.
STAT Quantitative Serum Toxicology
Assays Required to Support the ED
acetaminophen
lithium
salicylate
theophylline
valproic acid
co-oximetry
digoxin
phenobarbital
iron
transferrin
ETOH
MEOH
ethylene glycol
Oxycodone
To detect compliance, abuse or toxicity
best detected by specific assay
detection levels < 100ug/L necessary
Urine Drug Screen
Immunoassay
Drug
X-reaction
PCP
Dextromethorphan,
diphenhydramine, sertraline
Opiates
Quinolone antibiotics
Amphetamines
Detects all types of
sympathomimetic amines
(including those in OTC diet
suppressants and cold
medications)