Transcript Understanding Heparin-Induced Thrombocytopenia (HIT): Historical

Heparin-Induced Thrombocytopenia
“Heparin as a Cause of Thrombosis”
and
“The HIT Syndromes”
Amjad AlMahameed, MD, MPH
Diovision of Cardiology
Beth Israel Deaconess Medical Center
Boston
Why We Should Not Talk About HIT
•
•
•
•
•
It is rare and over publicized
Not every hospitalized patient get
heparin…
No unifying clinical picture and the
serology is “poor”..
How can we justify anticoagulating
a thrombocytopenic patient using
medications that do not have
antidotes?
Most hospitalized patients with
thrombocytopenia have
multifactorial etiology..
•
Just stop haparin and it will “go
away”….
•
Or start a LMWH and don’t
worry about it any more
•
Or, start warfarin and it “will take
care of the problem”
•
This is DIC, not HIT.. You “must”
continue heparin…
•
It is a disease born in the
“industry”…
Not every hospitalized patient get heparin
Ubiquity of Heparin & Heparin-based Therapies
Increasing indications
One of the most commonly
used parenteral Rx in the
hospital setting
1000,000,000,000
Units used per year
in the US
Is heparin use
Always
Documented
In the
Chart?
12 million
patients are
exposed to
heparin
per year
Side Effects:
BOAT
“essential medication”
Fahey. J Vasc Nurs 1995;13:112-116. Kelton & Warkentin. Current Therapy in Hematology-Oncology, 1995;149-152
Is it a rare and over publicized disease
LET’S DO THE MATH
12 million
patients
exposed
annually
ｘ
Up to 5%
incidence
of HIT
＝
Up to
600,000
cases
every year
How many cases are recognized and treated properly?
18,000 !!!
Confusing Terminology
Immune HIT/HIT-T
– Also known as: HIT type II, white clot syndrome
– Heparin-dependent antibodies are usually detectable
Non-Immune HAT
– Also known as HIT type I, HAT
– Denotes absence of heparin-dependent antibodies and the
potential role for other factors in causing thrombocytopenia
Immune- vs Non Immune-Mediated HIT
Parameter
Type I HIT
Type II HIT
(non-immune mediated)
(immune –mediated)
Epidemiology
10-30% of UFH treated patients
1-5% of UFH-treated patients
Less common with LMWH
Temporal pattern
Between days 1-4 of initiating
UFH
Between days 4-16 of initiating
UFH/LMWH
Severity of
thrombocytopenia
Mild, usually platelet counts
remain > 100,000
Moderate to severe, mean platelet
count 60,000
Antibody-mediated
No
Yes
Thrombosis
common
No
yes
Management
Observe
Discontinue heparin/LMWH and start
treatment with DTI
Outcome
Self-limited
Death, arterial and venous thrombosis are potential complications
UFH: unfractionated heparin, LMWH: low-molecular weight heparin, DTI: direct thrombin inhibitor
Pathogenesis of Immune-Mediated HIT
Caiola E, Cleve Clin J Med 2000; 67:621-624
Bartholomew JR et al 2005; 72(S1):S32-S36
THROMBOSIS
THROMBOCYTOPENIA
ACTIVATION ASSAY
ANTIGEN
ASSAY
Multiple Thrombosis
Thrombosis
Endothelial cell activation by
HIT Ab, DIC w natural
Anticoagulant, Alternative
platelet-activating IgG
Concomitant factors: 0.2% – 1.0%
- ASO
- Vascular trauma (catheters)
- Post-op immobility
Thrombocytopenia
- Clinical Setting (OHS, Orthopedic pts)
- Heparin Dose
- Platelet FC receptor Number or genotype
- Definition of thrombocytopenia used
- Inflammatory response
1-3%
Antibody Formation
Frequency of HIT Ab formation depends on:
Heparin chain length and degree of sulfation
Clinical setting (OHS, orthopedic pts)
Perioperative PF4 levels
Nonimmune platelet activation
3 - 60 %
Factors Influencing the Frequency of HIT
Type of heparin
Bovine lung>porcine intestinal>LMWH
Patient population
Post- surgery>medical>obstetrical
Duration of heparin
Each day of heparin beyond day 5 and
to day 14 increases the risk
Dose of heparin
Change from prophylactic dose to
therapeutic dose can cause abrupt
platelet count fall in patient with HIT
antibodies
Sex
Female > male
Definition of thrombocytopenia
used
Proportional platelet count fall (>50%) is
more sensitive than an absolute count
(of 100,000 – 150,000)
No unifying clinical picture
DIFFERENTIATE CLASSICAL HIT FROM ATYPICAL FORMS
Variable Frequency of Reported HIT
• Technical Explanations
– Variable definition of thrombocytopenia used
– Differing baseline platelet counts permitted for inclusion
– Requirement to repeat platelet count testing to confirm
thrombocytopenia
– Variable intensity of platelet count surveillance
– Variable intensity of surveillance for thrombotic events
– Failure to exclude nonimmune heparin-associated
thrombocytopenia
Lee and Warkentin. Heparin-Induced Thrombocytopenia. New York: Marcel Dekker; 2000:81–112.
Clinically: When Should You Consider HIT?
Start with a high index of suspicion
increased awareness and vigilance are required
Heparin exposure
+
Thrombocytopenia
(absolute or relative)
HIT
Heparin exposure
+
Ongoing/New Thrombosis
Classical HIT: Thrombocytopenia Criteria
Degree of thrombocytopenia
 <150,000
 or a 50% drop in platelet
count from baseline (even
if nadir remains >
150,000)
 or >30-50% decrease with
documented thrombosis
Timing of thrombocytopenia
 Usually occurs within
5–14 days of exposure
 Within hours to days if
recent heparin exposure
(past 100days)
 After hospital discharge
(9-30 days) with
“delayed onset HIT”
“Classical” HIT Criteria: Thrombocytopenia
Tips and Clues
• Relative, rather than absolute, thrombocytopenia
• Platelet count may be normal when patient presents with
thrombosis (Delayed onset HIT)
• In skin necrosis the drop in platelets is small but it may
predict arterial thrombosis when it occurs
• Platelets recovers after heparin withdrawal (Median=4 days)
• HIT is unlikely when platelets recover despite ongoing
heparin therapy
Different Temporal Patterns of
Thrombocytopenia in HIT
Heparin (re) Exposure
Typical HIT
Early HIT
Day 1
Delayed HIT
Mean day 9
Day 4
Day 16
THROMBOCYTOPENIA (+/- THROMBOSIS)
Week + 4
Delayed-Onset HIT: Similar Pthophysiology
Very high
titers of IgG
“super”
antibodies to
Heparin
Ab
Ab
Ab
Ab
PF4
PF4
PF4
PF4
Activated
Platelet
PLATELET
PLATELET
PLATELET
PLATELET
Remember Special Cases
Early-Onset HIT
vs. Type I HIT
[Non-immune mediated HIT,
usually associated with
using large doses of Heparin,
moderate thrombocytopenia
usually > 100,000, benign
course, and platelets recover
despite ongoing heparin Rx]
HIT with “Normal”
Platelet Counts
Seen in patients with HITassociated skin necrosis
Acute Adrenal Insufficiency
(secondary to adrenal vein
thrombosis and subsequent
adrenal hemorrhagic
infarction)
Are There Other Forms of Atypical HIT?
TYPE IV
TYPE III
Reaction of antibodies
(seropositivity)
?
Reaction of antibodies
(seropositivity)
without
With
thrombocytopenia
systemic allergic reaction
Thrombocytopenia in most hospitalized patients
is multifactorial in etiology
Non Drug-Induced Thrombocytopenia
Pseudothrombocytopenia
Decreased Platelet
Production
Increased Platelet
Destruction
Dilutional
Thrombocytopenia
DIC
Viruses
Hypersplenism
Dec B12
Dec
Folate
Marrow
Replacement
Dec Fe
Autoimmune
(ITP)
Alloimmune
(PTP)
Just hold Heparin and It will Go Away!
How can we justify anticoagulating thrombocytopenic patients with medications
that do not have antidotes?
HIT is a
Thrombotic
Storm!
Thrombosis Begets Thrombosis!
HIT = Thrombin Generation
The Actions of Thrombin
Releases from
endothelium:
NO
PGI2
t-PA
von Willebrand
ADP
Activation of platelets
Prothrombin
thrombin
Factor V
Factor VIII
Va
VIIIa
Thrombin
Fibrinogen
fibrin
Fuster V, Verstraete M. In: Braunwald E, ed. Heart Disease: A Textbook of
Cardiovascular Medicine. Philadelphia: WB Saunders Company; 1997:1809–1842.
Factor XIII
XIIIa
cross-linked fibrin
Cumulative Frequency of Thrombosis in Isolated HIT
w/o effective anticoagulation
100
Cumulative frequency of
thrombosis (%)
90
80
70
52.8%
60
50
40
30
N=62
20
10
0
0 2
4
6
8 10 12 14 16 18 20 22 24 26 28 30
Days after isolated HIT recognized
Warkentin and Kelton. Am J Med. 1996;101:502-507.
Just hold Heparin and It will Go Away!
How can we justify anticoagulating thrombocytopenic patients with medications
that do not have antidotes?
•
•
A transient increase in risks of
new thrombosis is observed once
heparin is stopped w/o an
alternative AC (Greinacher Blood 2000)
Patients with the lowest platelet
counts are most likely to
experience devastating
thrombosis and are in greatest
need of alternative
anticoagulation (Rice, Arch Intern Med
2004)
•
10 of HIT pts have platelets
10,000-20,000. Bleeding is rare
even when fully anticoagulated.
(Rice, Arch Intern Med 2004)
•
6% per day incidence of new
thrombosis while awaiting
serologic confirmation w/o DTI
Rx. This was decreased to 1.3%
per day after Refludan Rx
(Greinacher et al Blood 2000)
•
Therapeutic dose Argatroban
lowered new thrombosis from
23% to 6-8% (P < 0.001) and
lowered the frequency of
composite end point of new
thrombosis, all cause mortality,
and limb amputation from 39% to
26-28% (P = 0.04) (Lewis BE.
Circulation 2001 and Arch Intern Med 2003)
Could not start DTI
due to recurrent GI
bleed
1 week later
1 week later, L foot
2 weeks later
L arm
Decision making when confronting possible HIT
DEGREE OF ACTION
Very Low
Moderate
Continue heparin
Continue Heparin
Very High
Start Direct Thrombin Inhibitor
Stop Heparin
Send heparin-Platelet Antibody test
Rice L, Arch. Intern Med Vol 164, Oct 11 2004
Decision making when confronting possible HIT
DEGREE OF ACTION
Very Low
Moderate
Very High
Continue heparin
Start Direct Thrombin Inhibitor
- Platelet fall < 30%
-> 50% platelet fall
- Platelet nadir 20-100 x 109/L
- Onset between day 5-10 of exposure
- Onset < 1 day w prior exposure- 100 d
- New thrombosis
- Skin necrosis
- Systemic reaction
- No other cause identified
- Platelet nadir < 10,000
- Platelet fall too early
w/o previous exposure
-No thrombosis
- Other cause present
Rice L, Arch. Intern Med Vol 164, Oct 11 2004, British of Haematology. 123(2):374-375, Oct 2003
Just Switch to LMWH
•
•
•
•
HIT incidence in pts receiving LMWH 0.5%
Once HIT diagnosed, all heparinoids are
contraindicated
The vast majority of HIT antibodies cross
react with PF-4/ LMWH complex
May give unusual skin necrotic lesions distal
to injection sites
Necrotic lesion in HIT patient
receiving LMWH injections
Skin Necrosis at
UFH injection
Sites
(Prophylactic
dose)
Warkentin TE. Br J Haematol. 1996;92:494–497.
Necrotic lesions in HIT patient
receiving LMWH injections
L arm
Necrotic lesion in HIT patient
receiving LMWH injections
This can’t be HIT because the platelet count
is not low, (or too low)
Number of patients with HIT
Distribution of Platelet Count in HIT
Median nadir=59  109/L
40
10% of pts
30
10% of pts
20
No thrombosis
10
With thrombosis
0
3
5
10 15 20 30
50 70 100
200 300 500
Platelet count nadir  109/L
Warkentin. Semin Hematol. 1998;35(suppl 5):9-16.
1000
Thrombotic Complications of HIT
~50% of untreated HIT patients with isolated thrombocytopenia progress to
thrombosis
~4:1 Incidence Ratio Venous to Arterial
VENOUS
• Deep vein thrombosis
• Pulmonary embolism
• Cerebral dural sinus
thrombosis
• Adrenal hemorrhagic
infarction
ARTERIAL
• Aortic occlusion
• Acute thrombotic stroke
• MI
• Intracardiac thrombosis
• Peripheral arterial
thrombosis (limbs,
mesenteric, renal
and spinal arteries)
Warkentin & Kelton. A 14-year study on HIT. Am J Med 1996; 101:502-507.
Well, what about “good ol’ Coumadin”?
Let’s get a therapeutic INR, quickly..
Serologic Tests: A Quick Overview
Laboratory Tests for HIT
Functional (activation)
Washed
Platelets
Serotonin release
 HIPA
 ATP release
 Flow cytometry

Antigen
Citrated
Plasma*
Platelet
aggregation
 Flow cytometry

Serum or
Plasma
HeparinPF4 ELISA
 Other IA

* Citrated plasma is not recommended because of low sensitivity and low specificity
Laboratory Testing for HIT
Test
Advantages
Disadvantages
SRA
Sensitivity: high
Specificity: high
(false positives rare)
Technically demanding
(radioisotopes)
Not readily available
Platelet (HIPA)
aggregation
Specificity: high
Sensitivity: low
Technique-dependent
Immunoassay
Sensitivity: high
Technically easy
Rapid turnaround time
Specificity: low (false (ELISA)
positives common for
some populations)
Fabris et al. Arch Pathol Lab Med. 2000;124:1657-1666; Kelton. Semin Hematol. 1999;36(suppl 1):17-21.
Now……
Which Serologic Markers are
Required
to Establish the Diagnosis of HIT?
HIT is a CLINICAL DIAGNOSIS
HIT is a CLINICAL DIAGNOSIS
HIT is a CLINICAL DIAGNOSIS
HIT is a CLINICAL DIAGNOSIS
HIT is a CLINICAL DIAGNOSIS
HIT is a CLINICAL DIAGNOSIS
HIT is a CLINICAL DIAGNOSIS
HIT is a CLINICAL DIAGNOSIS
HIT is a CLINICAL DIAGNOSIS
HIT is a CLINICAL DIAGNOSIS
HIT is a CLINICAL DIAGNOSIS
HIT is a CLINICAL DIAGNOSIS
HIT is a CLINICAL DIAGNOSIS
HIT is a CLINICAL DIAGNOSIS
HIT is a CLINICAL DIAGNOSIS
HIT is a CLINICAL DIAGNOSIS
Serologic Markers and the Diagnosis of HIT
• Serologic markers (SRA, HIPA, PF4) are helpful, BUT:
• They must be interpreted within the CLINICAL context,
AND:
• They are NOT required as part of the diagnostic criteria
Principles of Management of HIT
Treatment of Suspected HIT
•
Discontinue ALL heparin immediately
•
Initiate alternative anticoagulation
•
Monitor carefully for thrombosis
•
Avoid prophylactic platelet transfusions
•
Document HIT in medical records
•
Laboratory evaluation
•
Monitor platelet counts recovery
•
Medi-alert bracelets, heparin “allergy” education
Discontinue ALL Heparin Exposure
• Heparin gtt, SQ, line flushes
• LMWH SQ therapeutic and prophylactic doses
• Heparin-coated catheters
• Hemodialysis
• TPN preparations
• Other sources of potential; heparin exposure include: ECMO,
CPB, Cardiac cath/endovascular intervention procedures
Direct Thrombin Inhibitors in HIT
Argatroban
Indication
Anticoagulant for prophylaxis or
treatment of thrombosis in patients
with HIT and
in patients with or at risk of HIT
undergoing PCI
Elimination Half-life*
Major Route of Elimination
Dosing
40-50 min
Hepatic
HIT: 2 mcg/kg/min - Adjustments should be made
as clinically indicated (not to exceed 10
mcg/kg/min)
PCI: Start infusion at 25 mcg/kg/min & a bolus of
350 mcg/kg administered over 3-5 minutes, check
ACT 5-10 min after bolus dose is complete,
therapeutic ACT values are usually attained within
10-15 min after initiating the bolus
Lepirudin
Anticoagulant in patients with HIT and
associated thromboembolic disease in order to
prevent further thromboembolic complications
1.3 h
Renal
HIT:
0.4-mg/kg† bolus
Slowly, intravenously followed by 0.15 mg/kg/h
IV as a continuous infusion for 2-10 days if
clinically needed
PCI:
NOT INDICATED
(See full prescribing information)
Antidote
Formation of
antibodies
None
None
No
40% (anti-hirudin)
* In healthy subjects
† Body weight up to 110 kg;aPTT, activated partial thromboplastin time. Refludan ® [lepirudin (rDNA) for Injection] [prescribing information]
Berlex Laboratories; October 2002. Argatroban Injection [prescribing information]. GlaxoSmithKline; 2003.
Anticoagulants Not
Indicated for HIT
HIT
Indication
Type
Bivalirudin
Angiomax®
No
DTI
Enoxaparin
Lovenox®
No
LMWH
Fondaparinux
sodium
No
Activated
Factor X (Xa)
Inhibitor
Contraindicated in patients with thrombocytopenia associated
with a positive in vitro test for antiplatelet antibodies in the
presence of fondaparinux sodium; half-life 17 to 21 hours.
No
Vitamin K
antagonist
Initiation during acute HIT may lead to venous limb gangrene
due to initial reduction in protein C levels.
Drug
Name
Arixtra®
Warfarin
Coumadin®
Limitations
Requires dose adjustment for patients with renal impairment.
Limited data in HIT. Not approved for HIT.
Nearly 100% risk of cross-reactivity with HIT antibodies;
contraindicated for patients with HIT.
DTI=direct thrombin inhibitor; LMWH=low molecular weight heparin; PCI=percutaneous coronary interventions.
Angiomax® (bivalirudin) for Injection [prescribing information]. The Medicines Company; 2004. Lovenox® (enoxaparin sodium injection) [prescribing
information]. Aventis Pharmaceuticals Inc.; 2004. Arixtra® (fondaparinux sodium) injection [prescribing information]. GlaxoSmithKline; 2004. Coumadin®
(Warfarin Sodium for Injection, USP) [prescribing information]. Bristol-Myers Squibb Company; 2002.
Heparin as a Cause of Thrombosis
“Heparin-Induced Thrombocytopenia”
and
“The HIT Syndromes”
Amjad AlMahameed, M.D.
Associate Staff
Section of Vascular Medicine
Department of Cardiovascular Medicine
Cleveland Clinic Foundation
Lepirudin
63
60
65
COO–
10
Tyr
3
C 0
14
ys
6
Cys
Leu1
NH3+
50
47
L
ys
Lepirudin (recombinant herudin) is indicated for
anticoagulation in patients with HIT and associated
thromboembolic disease in order to prevent further
thromboembolic complications
2 C
1
8 ys
6C
ys Cys2
2
20
39 C
ys
40
Val
Argatroban
Argatroban is indicated as an
anticoagulant for prophylaxis
or treatment of thrombosis in
patients with heparin-induced
thrombocytopenia
Thrombin Inhibitors:
Recommended Dosing
Argatroban
– 2 µg/kg/min
– Check aPTT after 2 hrs
– adjustment should be
made as clinically indicated
(not to exceed 10
µg/kg/min)
– Do not use if aPTT > 100
sec at baseline
Lepirudin
– Bolus 0.4 mg/kg (up to 110
kg)
– Then 0.15 mg/kg gtt for as
long as clinically needed
– Check renal function
should be considered prior
to administration
–Do not use if aPTT ratio >
2.5
Clinical Studies of Argatroban
The safety and efficacy of Argatroban
as anticoagulant therapy were demonstrated
in two (ARG-911 and ARG-915) multicenter, prospective,
open-label clinical trials
in 568 patients with HIT
Clinical Trials of Lepirudin:
HAT-1 and HAT-2 Studies on HIT
• Prospective, historically controlled trials
• Primary objective: treatment of HIT with lepirudin increases platelet
counts or maintains normal baseline values while providing
effective anticoagulation (prolongation of aPTT to 1.5 to 3 times
baseline value)
• Secondary objective: Evaluate incidences of new arterial or venous
thromboembolic complications, major bleeding complications,
surgical interventions/limb amputations, and deaths
Efficacy Results for Argatroban
Composite Endpoint
80
21% reduction in death, amputation, new thrombosis
Percent of Patients
70
60
50
43%
40
83/193
30
34%*
34%*
104/304
89/264
Study 1
Study 2
20
10
0
Historical Control
* p < 0.05 vs historical controls
Efficacy Reslts for Argatroban
Individual Components of Composite
Endpoint*† (Study 1)
Percent of Patients
60
Historical Controls
50
Argatroban
40
30
23%
20
45/193
17%
16%
53/304
10
0
All-Cause Death
4%
6%
7/193
19/304
All-Cause Amputation
* Ranked by severity (death>amputation>new thrombosis)
† p = NS
31/193
11%
32/304
New Thrombosis
Independent Efficacy Outcomes
P=0.23
Control
Initial Group
30
P<0.001
Outcome (%)
25
P=0.07
20
P<0.001
15
10
5
0
Death
Death Caused
by Thrombosis
Amputation
Lewis et al. Circulation 2001
Lewis et al. Annual American Society of Hematology Meeting; Dec 2000; Abstract 216.
Argatroban injection product information. Philadelphia, PA: GlaxoSmithKline; August 2000.
New
Thrombosis
Argatroban in Patients With HIT-T
1
0.8
Argatroban, N=144
Proportion
Events-Free
0.6
0.4
Control, N=46
0.2
P=0.014,
Hazard ratio=0.57, 95% CI=0.36–0.90
0
0
Lewis et al. Circulation 2001
10
20
Study Day
30
40
Results of HAT-1 and HAT-2:
Cumulative Risk of Death, Limb Amputation,
or Thromboembolic Complications
Lepirudin*
Historical control*
80
70
60
50
40
30
20
10
0
Cumulative Risk (%)
102
55
92
38
76
28
27
20
9
12
6
11
3
6
35
42
49
P = 0.004, log-rank test
0
7
14
21
28
Days After Start of Treatment
*Number at risk
Censored observations
Lepirudin
Historical control
(n = 113, censored = 88)
(n = 75, censored = 45)
Argatroban Impact on Anticoagulation
Mean (SD) aPTT, seconds
100
80
60
40
20
10
0
0
12
24
36
48
60
Time after initiation of argatroban, hours
Initial group; N=250–536
Lewis et al. Circulation 2001: in press.
Lewis et al. Annual American Society of Hematology Meeting; Dec 2000; Abstract 216.
Argatroban injection product information. Philadelphia, PA: GlaxoSmithKline; August 2000.
72
Bleeding in HIT
20
Rate of Major
Bleeding (%)
17
13.4
15
10
6.9
5
0
HAT-2*
HAT-1 †
Lepirudin
study
Lepirudin
study
‡
ARG-911
Argatroban
study
*Greinacher. Circulation 1999;100:587. †Greinacher. Circulation 1999;99:73. ‡Lewis et al. Circulation 2001: in press.
Safety Results for Argatroban
Major Hemorrhagic Events*
Argatroban
(n=568)
Historical Control†
(n=193)
Overall Bleeding
GI
5.3%
2.3%
6.7%
1.6%
GU & hematuria
0.9%
0.5%
 Hgb & Hct
Multisystem Bleed
0.7%
0%
& DIC
0.5%
1%
Limb & BKA
0.5%
0%
0%
0.5%
ICH
Patients may have experienced more than one adverse event * Defined as overt with a hemoglobin decrease 2 g/dL, that led
Results of HAT-2:
Platelet Count Recovery Profile
Platelets x 109/L
n = 60 63
500-
62
60
57
60
Before Nadir Before 2
heparin
lepirudin
3
4
54
57
58
51
5
6
7
8
51
51
37
400300-
2001000-
Day 1 = Start of infusion of lepirudin
Day
9
10
11
Guidelines for Conversion to Oral
Anticoagulant Therapy
4 days overlap (Warfarin & Argatroban)
Use expected Warfarin dose (no loading dose)
Reduce Argatroban dose to 2 g/kg/min 4-6 hours
prior to measuring INR
Measure INR daily
INR 4.0,
continue concomitant Rx
INR >4.0,
stop argatroban infusion
Repeat INR 4–6 hours later
INR therapeutic on warfarin
alone, continue warfarin
monotherapy
INR sub therapeutic for
warfarin alone, resume
argatroban therapy
Impact of HIT Therapy:
Complication Development
14
No complications
12
Complications
10
Number of
patients
8
6
4
2
0
No Delay in
Anticoagulant
P=0.034 Fishers exact test
Gene G. Gibson, PharmD, University of Pennsylvania Medical Center
Delayed
Anticoagulant
Impact of HIT Therapy:
Overall Costs of Therapy
$25,000
Complications/Length of Stay
Drugs
$20,000
Ancillary/Lab
$15,000
$10,000
$5,000
$0
No Delay in
Anticoagulant
Delayed
Anticoagulant
Overall Mean Cost of Therapy=$9,131 (±SD $11.702)
Courtesy of Gene G. Gibson, PharmD, University of Pennsylvania Medical Center
Impact of HIT Therapy:
Total Attributed Therapy Days
11.5
12
Days
10
8
6
6.56
4
2
0
No Delay in
Delayed
Anticoagulant
Anticoagulant
P=0.0043, Wilcoxon Rank-Sum: a significant difference existed between groups with
respect to total potential therapy days.
Gene G. Gibson, PharmD, University of Pennsylvania Medical Center
Conclusions
• Heparin, although an important anticoagulant, has several
drawbacks, most notably its ability to cause HIT
• HIT can lead to severe and even life-threatening
thromboembolic disorders
• Treatment of HIT should be initiated before laboratory
confirmation
• A new generation of drugs such as the thrombin inhibitors,
including the hirudins, may provide important new options for the
treatment and possible prevention of HIT
Interpretation of Laboratory Testing for HIT in Postoperative Cardiac
and Orthopedic Surgical Patients with Late-Onset thrombocytopenia
Antigen Assay (Anti PF4-H ELISA)
Post-op
Pretest
Patient
Prob.
Population for HIT
CARDIAC
0.5 (mod)
Posttest
Prob.
If Result is:
Sensitivity Specificity Pos
0.95
0.50
0.90 (high)
ORTHOPEDIC
0.50 (mod)
0.90 (high)
Activation Assay (SRA or HIPA)
0.95
0.92
Neg
0.66
0.09
0.94
0.47
0.92
0.05
0.99
0.33
Posttest
Prob.
If Result:
Sensitivity
0.95
Specificity Pos
0.80
Neg
0.83 0.06
0.98 0.36
0.95
0.97
0.97 0.05
0.997 0.32
Greinacher et al. 1994a; Visentin et al; 1996, Bauer et al; 1997, Warkentin et al 2000, Warkentin and Greinacher 2001.