Heparin-induced Thrombocytopenia:
Pathogenesis, Diagnosis, and
Management
Andreas Greinacher
Institut für Immunologie und Transfusionsmedizin
Ernst-Moritz-Arndt-Universität Greifswald
Brædstrup, April 2006
Heparin-Platelet Interactions
• (Non immune heparin-associated thrombocytopenia (HIT type I))
• Immune-mediated heparin-induced
thrombocytopenia (HIT type II)
= HIT
clinico-pathological syndrome
(clinical symptoms + antibodies)
Platelet count decrease > 50% and/or
new thrombotic complications between
day 5-14 of heparin
Heparin-induced
thrombocytopenia
a link between
immune system
and hemostasis
Heparansulfate
FcgRIIa
Heparin
PF4
B-L
Lys + Arg
Warkentin TE & Greinacher A. Heparin induced thrombocytopenia, 3rd ed, Marcel Dekker, New York 2004
Heparin-induced
thrombocytopenia
a link between
immune system
and hemostasis
Heparansulfate
FcgRIIa
Heparin
PF4
B-L
Lys + Arg
Warkentin TE & Greinacher A. Heparin induced thrombocytopenia, 3rd ed, Marcel Dekker, New York 2004
Heparin-induced
thrombocytopenia
a link between
immune system
and hemostasis
Heparansulfate
FcgRIIa
Heparin
PF4
B-L
EC
Lys + Arg
Tissue factor
Thrombin
Thrombosis
Warkentin TE & Greinacher A. Heparin induced thrombocytopenia, 3rd ed, Marcel Dekker, New York 2004
Greinacher et al. Blood. 2000;96:846-51.
art. central N=47
20,9
art.periph N=62
27,6
art.other N=3
1,3
ven.prox. N=82
36,4
29,3
ven. distal N=66
43,6
Pulm. emb. N=98
4,9
ven.0thers N=11
N=320
0
10
20
30
40
Greinacher Thromb Haemost 2004
%
50
HIT: Platelet Counts in LaboratoryConfirmed HIT May Be Normal
40
~15% of patients with HIT
have normal platelet counts
No HIT-associated
thrombosis
HIT-associated
thrombosis
HIT-associated thrombosis
occurred in patients with platelet
counts >150,000/mm3
30
No. of
Patients
With HIT
20
10
0
5
10
20
30
50
70
100 150 200 300
500
1000
Platelet Count Nadir
(1000/mm3)
Adapted with permission from Warkentin TE. Semin Hematol. 1998;35(suppl 5):9-16.
HIT: Temporal Aspects
Typical-onset HIT
(within 4 to 14 days)
Rapid-onset HIT
(previous heparin exposure typically within 4 – 6 weeks)
Delayed-onset HIT
(average of 9 days after heparin is stopped)
0
1
2
3
4
5
6
7
8
9 10 11 12 13 14 15 21
Days
40
Heparin exposure
1. Warkentin TE, Greinacher A, eds. Heparin-Induced Thrombocytopenia. 2. Warkentin TE,
Kelton JG. N Engl J Med. 3. Warkentin TE, Kelton JG. Ann Intern Med. 4. Rice L et al. Ann Int Med.
5. Lubenow et al. Chest.
Differential Diagnosis of HIT
Pseudothrombocytopenia
Drug dependent TP/PTP
HIT is unlikely if:
Platelet counts decrease between day 1 and 5 of heparin
Patient shows overt bleeding
Patient receives GPIIb/IIIa inibitors
GPIIb/IIIa Inhibitor induced TP
Patient is septic
Clinical Features of HIT: 4 T’s
• Thrombocytopenia
• Timing (of onset of platelet fall or
thrombosis)
• Thrombosis
• oTher (diagnoses not seen)
Diagnosis - pretest probability: the 4 T’s
2
A
B
Thrombocytopenia
Timing of fall in platelet
count or other
sequelae
C
Thrombosis or other
sequelae
D
OTher cause for
thrombocytopenia
1
0
> 50% platelet count
fall to nadir ≥ 20
30-50% platelet count
fall to nadir 10-19
<30% platelet count
fall to nadir ≤ 10
Onset d 5-10 or < 1 d
(if heparin exposure
within 30 d)
> d 10, or timing
unclear, or < d 1 with
recent heparin 31100 d
Platelet count fall < d
4 (without recent
heparin exposure)
New thrombosis;
skin necrosis; postheparin bolus acute
systemic reaction
Progressive or
recurrent
thrombosis;
erythematous skin
lesions; suspected
thrombosis – not
confirmed
None
No other cause for
platelet count fall is
evident
Possible other cause
is evident
Definite other cause
is present
Lo et al. J Thromb Haemost 2006
Diagnosis - pretest probability
Interpretation of 4 T’s score
• Score 0 - 3:
very unlikely to be HIT (<5%)
• Score 4 - 5:
a minority have HIT (10-30%)
• Score 6 – 8 :
20 to >80% have HIT, depending on the
clinical setting and scorer´s experience:
these patients usually require an
alternative, non-heparin
anticoagulant
Lo et al. J Thromb Haemost 2006
Thrombocytopenia > 50% decrease : 2
Onset day 2
:0
Thrombosis, no
:0
Other reason, definite
:0
350
300
•
•
•
HIT•
•
•
250
200
150
74 year old male patient
heart failure
sepsis
multiorgan failure
ICU, renal replacement CVVH
UFH
Heparin i..v
Heparin s.c.
CVVH
Orgaran s.c.
Orgaran i.v.
Hämodialyse
100
50
UFH
0
36
33
30
27
24
21
18
15
12
9
6
3
1 2 3 4
0
Platelets [x109/L]
Übernahme aus
admittance
in ICU
anderem Krankenhaus
Tage
Days
Thrombocytopenia > 50% decrease : 2
Onset day 9
:2
Thrombosis, no
:0
Other reason, probably
:1
300
Übernahme
aus
Transfer
from
anderem
anotherKrankenhaus
hospital
250
HIPA and
HIT
ELISA
IgG pos
200
Heparin i..v
Heparin s.c.
CVVH
Orgaran s.c.
Orgaran i.v.
Hämodialyse
150
100
50
UFH
36
33
30
27
18
15
12
9
6
3
0
24
non heparin anticoagulant
21
UFH
0
Platelets [x109/L]
350
Tage
Days
Heparansulfat
FcgRIIa
Heparin
Antigen test
PF4/heparin ELISA
Microcolumn
IgG/A/M
PF4
B-L
Functional test
HIPA-test
14C-SRA
IgG/ other antigens
TAT
D-Dimer
EC
Tissue factor
Thrombin
Thrombosis
Frequency of “HIT”: Platelet Fall >30%
and/or Thrombosis (Pos HIPA test)
UFH
HIT-T
HIT
HIPA
*
6/231 (2.6%)
0/271 (0.0%) P<0.0092
12/231 (5.2%)
0/271 (0.0%) P=0.00008
25/202 (12.4%)
EIA
LMWH*
46/196 (23.5%)
Enoxaparin
13/238 (5.5%)
19/228 (8.3%)
P=0.0101
P=0.00002
HIT-T
HIT
HIPA
EIA
Greinacher et al. Blood 2005;106:2921-2
Association of Risk for New
Thrombosis and Positive HIT Test
Schenk S et al. J Thorc Vasc Surg 2006 in press.
Occurrence of symptomatic thrombosis after stopping
heparin in patients confirmed to have isolated HIT
14-year retrospective study
Cumulative thrombotic event-rate (%)
100
90
80
N = 62
70
52.8%
60
50
40
30
20
10
0
0
2
4
6
8
10
12 14
16
18
20
22
24
26 28
30
Days After Isolated HIT Recognized
Adapted from Warkentin TE, Kelton JG. Am J Med. 1996;101:502–507.
HIT = White Clot Syndrome
Recurrent arterial white clots
LMWH
UFH
danaparoid
LMWH
LMWH
Risk of Thrombosis in Acute HIT
Average event rate per day
Start treatment at high clinical suspicion of HIT
Lab-test confirms the diagnosis retrospectively
0.06
0.051
0.04
0.02
0.004
0.002
0.00
before
(n=381)
(d=1.3)
during
(n=381)
(d=15.0)
after
(n=345)
(d=12.0)
Period relative to onset of lepirudin
Lubenow et al. JTH 2005;3:2428-36
When HIT is strongly-suspected
• Stop heparin (UFH/LMWH)
• Duplex ultrasonography for lowerlimb DVT
• Order test for HIT antibodies
• Initiate alternative non-heparin
anticoagulant in therapeutic dose
even in patients without thrombosis
ACCP: Treatment of HIT
“For patients with strongly suspected (or
confirmed) HIT whether or not complicated by
thrombosis we recommend use of an alternative,
non-heparin anticoagulant in therapeutic doses
such as”
– Danaparoid (Grade 1B)
– Lepirudin
(Grade 1C+)*
– Argatroban (Grade 1C)*
– Bivalirudin (Grade 2C)
*Differences in level of recommendations based primarily on availability of prospective,
randomized, controlled trial data in HIT and non-HIT patients.
Warkentin TE, Greinacher A. Chest. 2004;126:311S-337S.
heparin
anticoagulatory
factors
procoagulatory
factors
1. steady state of haemostasis
heparin
HIT-related clotting
activation
3. HIT-patient (still on heparin)
lepirudin/danaparoid/
argatroban
HIT-related
clotting
activation
5. acute HIT-patient
(heparin stopped,
on compatible anticoagulant)
2. heparinized patient
HIT-related
clotting
activation
4. HIT-patient (heparin stopped)
lepirudin/danaparoid/
argatroban
HIT-related
clotting
activation
6. subacute HIT-patient
(heparin stopped,
on compatible anticoagulant)
approval/availability?
experience?
renal impairment?
liver impairment?
isolated thrombocytopenia?
uncomplicated DVT?
monitoring tools?
costs?
Which treatment is optimal?
Danaparoid?
Lepirudin?
Argatroban?
P. Eichler
N. Lubenow
K. Selleng
D. Juhl
C. Blumentritt
U. Strobel
B. Fürll
T. Lietz
T.E. Warkentin
B. Pötzsch
University Hospital Greifswald
Decrease of plt count > 50%
and/or
New thrombosis
HIT possible
stop heparin
Perform antigen test
for HIT
Therapeutic dose AC
necessary due to
primary disease?
HIT test positive?
Onset > 5 days of heparin?
No
Yes
Previous heparin
within the last 30 days?
No
Yes
Other cause likely?
Yes
No
No
HIT very unlikely
maintain heparin
Yes
High bleeding risk?
No
Yes
HIT unlikely
restart heparin
HIT possible
Perform antigen test
to rule out HIT
Yes
Functional
test for HIT
positive?
No
Yes
plt – platelet
AC – anticoagulation
t.i.d. – three times daily
Use prophylactic dose AC
e.g. danaparoid 750 t.i.d.
(option in European Union, Australia, Canada)
Use therapeutic dose
alternative AC
HIT
No
HIT unlikely
Patient Population affected by HIT
is changing
1994 - 1997
2003 - 2004
Medical
143/408 (35.0%)
101/207 (48.8%)
General surgery
53/408 (13.0%)
17/207 (8.2%)
Cardio-vascular surgery
31/408 (7.6%)
24/207 (11.6%)
Orthopedic/trauma
125/408 (30.6%)
2/207 (0.9%)
Urology
Gynecology
2/207 (0.9%)
48/408 (11.8%)
3/207 (1.4%)
Surgical intensive care
31/207 (14.9%)
No information
17/207 (8.2%)
Greinacher et al. 2005 and unpublished data
Which drug for which patient?
Renal
impairment
Liver
impairment
Multi organ
dysfunction
Prophylactic
dose
history of HIT
1.Argatroban# 1.Danaparoid* 1.Danaparoid* 1.Danaparoid
2.Danaparoid* 2.Lepirudin#
2.Bivalirudin#
3.Bivalirudin
3.Bivalirudin
3.(Argatroban) 2.Fondaparinux
4.(Lepirudin)
4.(Argatroban) 4.(Lepirudin)
(history)
*preferable use in stable patients not expecting surgery;
# preferable use in patients requiring invasive procedures with major bleeding risk;
() use drug with great caution to avoid overdose
Danaparoid in HIT
• Danaparoid is used to anticoagulate HIT patients
>20 years
• One small prospective randomized trial:
danaparoid+dextran superior to
warfarin+dextran
• Large international compassionate use program
~1000 patients
• Danaparoid is effective, dosage schedules are
defined, bleeding complications do occur but
therapeutic range is wide
Review: B.H.Chong in Heparin-induced thrombocytopenia 3rd ed 2004; Warkentin&Greinacher eds
Cross-reactivity and
platelet count recovery
Frequency of platelet count
recovery (≥ 150 x 109/L)
1.0
0.9
0.8
0.7
0.6
0.5
No cross-reactivity (N=16)
Cross-reactivity (N=13)
0.4
0.3
0.2
0.1
0
0
2
4
6
8
10
12
14
16
18
30
Days to platelet count recovery during danaparoid treatment
Unpublished data by Warkentin TE - used with permission
Cross-reactivity and
platelet count recovery
300
lepirudin
0.15 mg/kg b.w./h
danaparoid
heparin
7,500IU bid 200 aFXaU/h
x 100 platelets/µL
250
200
phenprocoumon
pulmonary embolism
and DVT
150
OP
100
HIT antibody testing
50
0
0
2
9
11
13
15
17
19
days
21
23
25
27
29
31
Lepirudin
COO-
Thrombin
+H N
3
1
Warkentin. Best Pract Res Clin Haematol 2004; 17: 105-125.
Endpoints of lepirudin in HIT (HAT-1,-2,-3)
Cumulative incidences of major bleeding
Cumulative incidences of new TEC
0.4
0.4
p=0.0148
p=0.0008
0.2
0.2
0.0
0.0
0
7
14
21
28
35
days after start of selected treatment
Hist. control n=120
0
7
14
21
28
35
days after start of selected treatment
Lepirudin n=339
Lubenow et al. JTH 2005;3:2428-36
% patients with major bleeding
Lepirudin Renal Function and
Bleeding Risk (HAT-1,-2,-3)
35
30
25
20
15
10
5
0
- 50
(1 of 26)
51 - 90
(28 of 243)
> 90
(32 of 97)
Creatinine value (µmol/l)
Lubenow et al. JTH 2005;3:2428-36
Anaphylactic reactions due to Refludan
(lepirudin?)
64 m
condition
cardiac
bolus
<5min
outcome
recovered
preexposure
severe
?
62 f
cardiac
bolus
<5min
recovered
moderate
?
57 f
HIT/cardiac
bolus
<5min
recovered
severe
?
63 m
hist.
HIT/cardiac
bolus
<5min
fatal
2 months
62 m
hist HIT
vasc-surg
?
?
fatal
3 months
5 anaphylactic reactions
67 f
cardiac
bolus
<5min
recovered
severe
?
reported in ~ 32,500 treatments (0.015%)
72 m
acute
infusion <5min
recovered moderate
yes
4 anaphylactic
reactions
during
reexposure;
HIT/cardiac
reexposure
81 m
hist.
bolus rate
<5min~7.5%
fatal(0.16%)
8days
HIT/cardiac
Start
treatment in a setting with access to
67 f
hist.
bolus
<5min
fatal
1month
treatment
of
anaphylaxis
HIT/cardiac
Greinacher et al. Circulation; 2003:108: 2060-5
Argatroban
1
argatroban
DTIs differ in their effects on
the INR
Bivalirudin
Melagatran
8
Argatroban
7
7
6
5
4
Lepirudin
3
INR (Innovin)
INR (Simplastin)
8
6
5
3
2
1
1
60
70
80
90
100
110
120
130
140
Bivalirudin
4
2
50
Argatroban
Melagatran
Lepirudin
50
60
70
80
90
100
110
120
130
140
APTT, sec
Warkentin TE, Greinacher A, et al.Thromb Haemost 2005, 94:958-64
Comparison of Danaparoid and Lepirudin in HIT with Thrombosis
25%
lepirudin with TEC at baseline n = 124
20%
cumulative incidence
danaparoid with TEC at baseline n = 86
15%
10%
P=0.91
5%
0%
0
7
14
21
28
35
42
days afte r start of the rapy
Farner B et al. Thromb Haemost 2001;85:950-957.
Major bleedings > 2RBCs
cumulative incidence
20%
lepirudin
15%
10%
P=0.0123
danaparoid
5%
0%
0
7
14
21
28
35
42
49
56
18
14
13
8
11
3
days after start of treatment
danaparoid1 122
lepirudin1
173
107
159
87
152
58
118
41
47
28
25
Farner B et al. Thromb Haemost 2001;85:950-957.
Duration of Anticoagulation after HIT
• HIT with thrombosis: 3 – 6 months
• Isolated HIT: ???
• At least until platelet counts normalized to
a stable plateau
cumulative
Average
rate per day
eventincidence
60%
50%
0.06
0.051
40%
0.04
30%
0.02
20%
0.004
0.002
10%
0.00
0%
before
(n=381)
0 (d=1.3)
7
during
(n=381)
14
(d=15.0)
21
28
after
(n=345)
35
(d=12.0)
42
days after start of therapy
Period relative to onset of lepirudin
Lubenow et al. JTH 2005
Farner et al Thromb Haemost 2001
T.E. Warkentin, J.Kelton Am J Hematol 1996; 101:
Cumarine immer überlappend
mit parenteralem
Antikoagulans beginnen. Max.
6 mg/Tag
Protein C
• In 2006 HIT is a widely recognized syndrome
• Catastrophic patients are rare in the clinic but
HIT is increasing in out-patients
• Lab-assays rule out HIT, but antigen assays
have the risk to overdiagnose HIT by 100%
• Effective drugs for management of HIT are
available: balance risk of thrombosis/bleeding
Basic research
Clinical studies
New drugs
HIT
Continous medical
education
Lepirudin
Life threatening thrombosis?
No
Yes
Omit bolus dose
Give bolus dose
0.4mg/kg b.w.
Renal impairment?
Yes or unclear
No
Reduce maintenance dose
Creatinine unknown or 100-200 µmol/L: 0.05mg/kg/h
Severe renal impairment:
0.001mg/kg/h
Maintenance dose
0.1mg/kg/h
b.w. – body weight
* e.g. liver impairment, DIC; previous treatment with
vitamin K antagonists
** depending on laboratory dose response curve
Monitor every 4h until
steady state is reached
No
Low prothrombin?*
Monitor by aPTT
Yes
1.5-2.5x baseline,
but not >80s**
Monitor by prothrombin
independent assay,
e.g. ECA test
Yes
No
0.5-1.0 µg/mL
No change
Adjust dose, decrease or
increase dose by 20%
Argatroban
liver impairment (Child-Pugh score >6)
Yes
No/
unclear
Low cardiac output/ cardiac shock
Risk of reduced liver perfusion
Yes
No
Start with 0.5µg/kg/min
Start with 1.0µg/kg/min
Monitor after 2h
Low prothrombin*
*e.g. liver impairment,
DIC;
pretreatment with
vitamin K antagonists
Yes
No
Use
ECA test
use aPTT
1.5-3x baseline,
but not >100s
Yes
No
No change
Adjust dose,
0.2-0.5µg/kg/min
1. Heparin weitergeben, da es andere Erklärungen für die Thrombozytopenie gibt?
2. Heparin absetzen und therapeutische Dosierung alternatives Antikoagulanz beginnen?
3. Weitere Information einholen und HIT Test anfordern, Heparin weitergeben?
300
Übernahme aus
anderem Krankenhaus
•
•
250
HIT•
200
•
•
150
74jähriger Patient, männlich
dekompensierte globale
Herzinsuffizienz
kardiogener Schock mit
Multiorganversagen
Intensivtherapie, CVVH
unfraktioniertes Heparin zur
Antikoagulation
Heparin i..v
Heparin s.c.
CVVH
Orgaran s.c.
Orgaran i.v.
Hämodialyse
100
50
0
36
33
30
27
24
21
18
15
12
9
6
3
1 2 3 4
0
Thrombozyten [x109/L]
350
Tage
1. Heparin weitergeben, da es andere Erklärungen für die Thrombozytopenie gibt?
2. Heparin absetzen und therapeutische Dosierung alternatives Antikoagulanz beginnen?
3. Heparin absetzen und sehen was klinisch passiert?
300
Übernahme aus
anderem Krankenhaus
250
HIPA und
HIT
ELISA
IgG pos
200
Heparin i..v
Heparin s.c.
CVVH
Orgaran s.c.
Orgaran i.v.
Hämodialyse
150
100
50
36
33
30
27
24
21
18
15
12
9
6
3
0
0
Thrombozyten [x109/L]
350
Tage
Thrombozyten [x109/L]
350
Übernahme aus
anderem Krankenhaus
300
250
Heparin i..v
HIT
200
Heparin s.c.
CVVH
Orgaran s.c.
150
Orgaran i.v.
Hämodialyse
100
50
0
0
3
6
9
12
15
18
21
24
27
30
33
36
Tage
70year old female (No.77)
700
SIRS,
ARDS
Tracheotomie
600
discharge
to another
hospital
HIPA+
Elisa+
Plateletsx1000/µl
500
Was machen Sie:
1. Heparin weiter?
2. Alternative Antikoagulation?
3. HIT Test durchführen?
400
300
200
100
Score:5
Enoxaparin
Heparin
Heparin
Enoxa
parin
Danaparoid
14.10
15.10
16.10
17.10
18.10
19.10
20.10
21.10
22.10
23.10
24.10
25.10
26.10
27.10
28.10
29.10
30.10
31.10
1.11
2.11
3.11
4.11
5.11
6.11
7.11
8.11
9.11
10.11
11.11
12.11
13.11
14.11
15.11
16.11
17.11
18.11
19.11
20.11
21.11
22.11
23.11
24.11
0
•Primary disease:
• acute pancreatitis
• low grade malignant NHL (known for 2 years)
70year old female (No.77)
700
SIRS,
ARDS
Tracheotomie
600
discharge
to another
hospital
HIPA+
Elisa+
Plateletsx1000/µl
500
400
Was machen Sie:
1. NMH weiter?
2. HIT Test anfordern?
3. Alternative AK beginnen,
dann HIT Test anfordern?
14 days
300
8 days
200
100
Score:5
Enoxaparin
Heparin
Heparin
Enoxa
parin
Danaparoid
14.10
15.10
16.10
17.10
18.10
19.10
20.10
21.10
22.10
23.10
24.10
25.10
26.10
27.10
28.10
29.10
30.10
31.10
1.11
2.11
3.11
4.11
5.11
6.11
7.11
8.11
9.11
10.11
11.11
12.11
13.11
14.11
15.11
16.11
17.11
18.11
19.11
20.11
21.11
22.11
23.11
24.11
0
•Primary disease:
• acute pancreatitis
• low grade malignant NHL (known for 2 years)
Score:
Thrombozytenabfall > 50%:
Beginn zwischen Tag 5 und 10 (UFH):
andere Erklärung für TP: 01.11. ja; 06.11. nein:
70year old female (No.77)
700
SIRS,
ARDS
Tracheotomie
600
discharge
to another
hospital
HIPA+
Elisa+
Plateletsx1000/µl
500
400
14 days
300
8 days
200
100
Score:5
Enoxaparin
Heparin
Heparin
Enoxa
parin
Danaparoid
14.10
15.10
16.10
17.10
18.10
19.10
20.10
21.10
22.10
23.10
24.10
25.10
26.10
27.10
28.10
29.10
30.10
31.10
1.11
2.11
3.11
4.11
5.11
6.11
7.11
8.11
9.11
10.11
11.11
12.11
13.11
14.11
15.11
16.11
17.11
18.11
19.11
20.11
21.11
22.11
23.11
24.11
0
•Primary disease:
• acute pancreatitis
• low grade malignant NHL (known for 2 years)
2
2
2
N. Lubenow
K. Selleng
D. Juhl
P. Eichler
C. Blumentritt
U. Strobel
B. Fürll
T. Lietz
T.E. Warkentin
G. Lo
S. Schenk
B. Pötzsch
University Hospital Greifswald
Approach to diagnose HIT
Yes
HIT
Thrombocytopenia (> 50% decrease)
+
Possible
Timing 5-14 days after starting heparin
+
Thrombosis
+
Unusual thromboembolism;
skín lesions; anaphylaxis
OTher cause not apparent
+
+
Strongly Suspected
Test for HIT antibodies positive
(usually strongly positive)
+
Confirmed when positive
in context of strong
clinical suspicion
Studies comparing UFH and LMWH in medical patients,
plus a large review of LMWH treatment during pregnancy
Type of
study
Patient
population
HIT
HIT Antibodies
LMWH
UFH
P
LMWH
UFH
P
Prospective
cohorts 1;2
General
medical
14/1754
(0.80%)
5/598
(0.84%)
1.00
NR
NR
---
RCT 3
DVT
treatment
1/720*
(0.1%)**
8/356
(2.2%)**
0.00087
45/720*
(6.2%)***
75/356
(21.1%)***
<0.0001
Prospective
cohort 4
Neurology
0/111
(0.0%)
5/200
(2.5%)
0.17
2/111
(1.8%)
41/200
(20.5%)
<0.0001
Review 5
Pregnancy
0/2,777
(0.0%)
---
---
---
---
---
* combines short- and long-treated LMWH groups
** endpoint shown is symptomatic thrombosis associated with antibody formation (as per Table II in reference 4); for true HIT endpoint
(defined as thrombocytopenia plus positive antibody), values are LMWH = 0/762 vs UFH = 1/375 (0.3%); p = 0.33
*** as per Table II in reference 4.
1 Girolmi et al Blood 2003;
2 Prandoni et al Blood 2005;
3 Lindhoff-Last et al Brit J Haematol 2002;
4 Pohl et al. Neurology 2005;
5 Greer et al. Blood 2005
Warkentin TE and Greinacher A, Blood 2005;106: 2931 – 2932