Heparin-Induced Thrombocytopenia
(HIT)
Heparin-Induced Thrombocytopenia
(HIT)
HIT
is an immune-mediated
adverse effect of heparin that
paradoxically increases risk of thrombosis
HIT is a clinico-pathological syndrome
Clinical
• Thrombocytopenia and/or
• Thrombosis
Pathological
• Heparin-dependent, platelet-activating IgG antibodies
Warkentin TE, Chong BH, Greinacher A. Thromb Haemost 1998;79:1-7.
Greinacher et al. Blood 2005;106:2921-2922.
Greinacher et al. Thromb Haemost 2005;94:132-135.
Heparin-induced thrombocytopenia (HIT)
Less frequent clinical manifestations
• Anaphylactoid reaction after i.v. heparin bolus
• Skin lesions at s.c. heparin injection sites
• Overt (decompensated) disseminated intravascular
coagulation (DIC)
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
Clinical events associated with HIT
• Venous thrombosis (30-70%)
• Deep vein thrombosis (DVT)
• Pulmonary embolism (PE)
• Adrenal necrosis (adrenal vein thrombosis)
• Cerebral venous (sinus) thrombosis
• Venous limb gangrene (VKA associated)
• Arterial thrombosis (“white clots”) (15-30%)
•
•
•
Limb artery thrombosis
Stroke
Myocardial infarction
• Skin lesions at heparin injection sites (10%)
•
•
Skin necrosis
Erythematous plaques
• Acute reactions after i.v. heparin bolus (10%)
• Disseminated intravascular coagulation (DIC) (10%)
Drugs associated with HIT
• Unfractionated heparin
•
•
•
•
Prophylactic dose
Therapeutic dose
Flushes
Heparin-coated devices
• Low-molecular-weight heparin
• Prophylactic dose
• Therapeutic dose
• Other highly sulfated polysaccharides
• Pentosan polysulfate
• Hypersulfated chondroitin sulfate
• PI-88 (anti-angiogenic drug)
HIT:
a link between
immune system
and hemostasis
Heparansulfate
FcgRIIa
Heparin
PF4
B-L
PF4 tetramer
EC
Ring of positive
charge
Tissue factor
Thrombin
Li et al, Blood 2002; 99:1230
Thrombosis
Warkentin TE, Chong BH, Greinacher A. Heparin induced thrombocytopenia: Towards consensus. Thromb Haemost 1998,79:1-7
Sequence of events
in the development of HIT
Initiation
• Current or recent exposure to heparin
• Immune response against platelet factor 4 (PF4)/heparin
complexes
• Anti-PF4/heparin IgG antibodies crosslink platelet Fc
receptors and trigger platelet activation
• Positive feedback for platelet activation (e.g., adenosine
diphosphate, thromboxane A2)
• Platelet activation results in shedding of procoagulant
platelet microparticles
Sequence of events
in the development of HIT
Development of a hypercoagulable state
• Platelet microparticles promote thrombin generation
• Endothelial cell injury and monocyte activation further
enhance thrombin generation
• PF4 release neutralizes heparin
• PF4 release leads to formation of additional PF4/heparin
complexes, exposing more antigens, and thus further
amplifying platelet activation
HIT - a vicious cycle of
platelet activation and coagulation
PF4/Heparin/HIT-IgG
Platelet Activation
Thrombosis
Endothelial Cell
Injury
PF4 /HIT-IgG
Embolism
Morbidity
&
Death
Release PF4
Coagulation
Platelet Activation
Release PF4
/HIT-IgG
Monocyte Activation
Platelet Activation
Coagulation
Factors influencing frequency of HIT
Factor
Type of heparin
Patient population
Duration of heparin
Influence
Bovine UFH > porcine UFH > LMWH
Post-surgery > medical > obstetrical
5 or more days heparin use > 1-4 days
Dose of heparin
Change from low to full dose can lead
abrupt platelet  in immunized patient
Gender
Female > male
Definition of thrombocytopenia
Proportional platelet count fall (e.g. >50%)
more sensitive than absolute platelet 
“Iceberg model” of HIT
HIT and associated thrombosis occurs in the subset of
patients with platelet-activating anti-PF4/H antibodies
Thrombosis
HIT
syndrome
Thrombocytopenia
Positive
washed
platelet
activation
assay
Positive
PF4
antigen
assay
Numbers of Patients
Adapted from Warkentin TE. Br J Haematol 2003,121:535
Platelet count nadir distribution in HIT
60
Number of Patients
50
Type of HITassociated thrombosis
Median platelet count nadir
55 x 10 9 /L
Nil (N=72)
Venous (N=132)
40
Venous & arterial (N=6)
Arterial (N=24)
Platelet fall <50%
30
20
10
0
Platelet Count Nadir (x 109 /L)
Adapted from Warkentin TE. Br J Haematol 2003,121:535
Management of HIT – diagnosis
Three different clinical presentations
Adapted from Warkentin TE. Br J Haematol 2003, 121: 535
Detection of HIT antibodies
• Platelet activation assays
• Serotonin release assay (SRA; uses “washed” platelets)
• Heparin-induced platelet activation (HIPA) assay (uses
“washed” platelets)
• Platelet aggregation test (PAT; uses citrate-anticoagulated
platelet-rich plasma)
• Platelet microparticles (flow cytometry)
• Antigen assays
•
•
•
•
PF4/heparin-enzyme immunoassay (EIA)
PF4/polyvinyl sulfonate EIA
Fluid-phase EIA
Particle gel immunoassay
Detection of HIT antibodies
Specificity (%)
Sensitivity (%)
Early platelet 
Late platelet 
Serotonin release assay
(SRA)
90-98
>95
80-97
Heparin-induced platelet
activation assay (HIPA)
90-98
>95
80-97
Platelet aggregation (PRP)
35-85
90
82
PF4/heparin EIA
>90
>95
50-93
Combination of platelet
activation assay & PF4
antigen EIA
100
>95
80-97
Diagnostic assay
Adapted from 7th. ACCP Conference 2004 Chest 126, 311S
Detection of HIT antibodies
• High negative predictive value
• Negative test usually rules out HIT *
• Moderate positive predictive value
• Stronger test result = higher chance of HIT
• Routine antibody testing is NOT recommended unless:
•
•
•
•
Thrombocytopenia or >50%  in platelet count
Thrombosis
Heparin-induced skin necrosis
Other sequelae of HIT
* Applies to solid-phase EIAs and washed platelet activation assays
7th. ACCP Conference 2004 Chest 126, 311S
Clinical signs of HIT
Erythematous plaques 1
Deep venous thrombosis 1
Skin necrosis 1
Venous gangrene 2
1 Reproduced with permission Blackwell Publishing (Warkentin TE. Br J Haematol 1996
2 Warkentin TE et al. Ann Intern Med 1997
Clinical signs of HIT
Acute reactions after intravenous heparin bolus
•
•
•
•
Fever, chills, flushing
Respiratory distress
Hypertension, tachycardia, chest pain
Transient global amnesia, headache
Venous and/or arterial thrombosis
• Deep vein thrombosis
• Pulmonary embolism
• Limb ischemia and infarction
• Thrombotic stroke and cerebral (sinus) vein thrombosis
• Myocardial infarction
• Adrenal necrosis
Differential diagnosis
•
•
•
•
•
•
•
•
•
•
•
•
•
Hemodilution post-surgery
Severe pulmonary embolism
Sepsis
DIC (multiple causes besides HIT)
Cancer-associated DIC
Antiphospholipid syndrome
Thrombolytic therapy
EDTA-induced pseudothrombocytopenia
GP IIb/IIIa inhibitor-induced thrombocytopenia
Drug-induced thrombocytopenia (other than heparin)
Post-transfusion purpura
Thrombotic thrombocytopenic purpura
Non-immune heparin-associated thrombocytopenia
Platelet count monitoring is recommended in
patients at risk of HIT > 0.1%*
Platelet count monitoring
Patient population
Yes/No
Frequency
Risk for HIT common (>1%)
Receiving therapeutic dose UFH
Yes
min. alternate day  14 d
Receiving post-op prophylactic dose UFH
Yes
min. alternate day 4 - 14 d
Starting UFH/LMWH & have received UFH in last 100 d or
exposure uncertain
Yes
baseline value-repeat in 1 d
Systemic reaction after UFH bolus
Yes
immediate – compare with
pre-bolus value
Risk for HIT infrequent (0.1-1%). Medical/Obstetric UFH;
Post-op LMWH; Post-op UFH ‘flush’; LMWH after UFH
Yes
every 2 -3 days, 4 - 14 d
Risk HIT < 0.1%. Medical/obstetric patients on LMWH
No
-
* 7th. ACCP Conference 2004 Chest, 126: 311S
Diagnosis - pretest probability: the 4 T’s
Points: Score 0, 1 or 2 for each of 4 categories:
2
A
B
1
0
Thrombocytopenia
> 50% platelet count
fall to nadir ≥ 20
30-50% platelet count
fall to nadir 10-19
<30% platelet count
fall to nadir ≤ 10
Timing of fall in platelet
Onset d 5-10 or < 1 d (if
heparin exposure
within 30 d)
> d 10, or timing
unclear, or < d 1 with
recent heparin 31-100 d
Platelet count fall < d 4
(without recent heparin
exposure)
Progressive or
recurrent thrombosis;
erythematous skin
lesions; suspected
thrombosis – not
confirmed
None
Possible other cause is
evident
Definite other cause is
present
count or other sequelae
C
sequelae
New thrombosis; skin
necrosis; post-heparin
bolus acute systemic
reaction
D
OTher cause for
thrombocytopenia
No other cause for
platelet count fall is
evident
Thrombosis or other
Adapted from Lo et al. J Thromb Haemost 2006, in press
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 in
therapeutic doses
Adapted from Lo et al. J Thromb Haemost 2006, in press
Management of HIT – treatment
When HIT is strongly-suspected:
• Stop heparin (UFH/LMWH), even in patients
without thrombosis
• Initiate alternative non-heparin anticoagulant
because of high risk of symptomatic thrombosis
• Test for HIT antibodies
• Duplex ultrasonography for lower-limb DVT
Management of HIT – treatment
When HIT is strongly-suspected:
• Do not start a vitamin K antagonist (VKA) - if started
prior to diagnosis it should be reversed by vitamin K *
• Do not use low-molecular-weight heparin (LMWH)
• Do not give platelet transfusions unless needed to
manage serious hemorrhage
* Recommendation to give vitamin K applies particularly to direct thrombin
inhibitors (DTIs), because prolongation of the aPTT by warfarin can lead to
underdosing of DTI therapy (in contrast, danaparoid is not monitored by
aPTT)
•7th. ACCP Conference 2004 Chest, 126: 311S-337S
•Warkentin TE. J Thromb Haemost 2006; in press.
Management of HIT – treatment
When the diagnosis of HIT is confirmed:
• Postpone starting overlapping coumarin until the
platelet count has recovered to at least 100 (and
preferably) 150 x 109/L
• Therapeutic doses of alternative, non-heparin
anticoagulants are usually required
• If a sensitive test for HIT is negative, heparin
therapy may be re-started with regular platelet
count monitoring
* 7th. ACCP Conference 2004 Chest, 126, 311S-337S
Management of HIT – treatment
When HIT is clinically possible but platelet count
decrease is more likely caused by other reasons:
• If the patient requires therapeutic dose
anticoagulation for non-HIT reasons, use
alternative anticoagulant in therapeutic dose.
• If patient does not require therapeutic dose
anticoagulation for non-HIT reasons, consider
prophylactic-dose alternative anticoagulation,
e.g. danaparoid 750 U b.i.d. or t.i.d. until HIT
antibody test results are available.
Selleng K and Greinacher A: Intensiv up-2-date 2005;1:329-341
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
70
60
50
40
30
20
10
0
N = 62
52.8%
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.
Odds ratios for risk of thrombosis
•
•
•
•
•
•
•
Prothrombin anomaly
Lupus anticoagulant
Factor V Leiden
Protein S deficiency
Dysfibrinogenaemia
Protein C deficiency
Antithrombin deficiency
• HIT
2.0
5.4
6.6
10.9
11.3
14.4
24.1
20-40
Warkentin TE. Can J Cardiol 1995;11(Suppl. C):29C-34C
Warkentin TE. Thromb Res; 2003; 110:73-82
Management of HIT – treatment
Suitable alternative non-heparin antithrombotic
therapies are:
• Danaparoid – Xa/IIa inhibitor (anti-Xa >> anti-IIa)
• Direct thrombin inhibitor (DTI):
•
Lepirudin
• Argatroban
•
Bivalirudin
* 7th. ACCP Conference 2004 Chest 126: 311S-337S
HIT – summary & conclusions
1.
HIT is a potentially fatal side effect of heparin
that is more common with UFH than LMWH
2.
HIT is a clinico-pathologic syndrome: its
diagnosis is based on compatible clinical
features and presence of HIT antibodies
3.
Antibodies against PF4/heparin are formed
commonly during heparin treatment; HIT occurs
in the subset of patients with strong plateletactivating IgG antibodies
HIT – summary & conclusions
4.
Binding of HIT antibodies to PF4/heparin
complexes on the platelet surface results in
platelet activation, thrombocytopenia and
increased risk of arterial thrombosis
5.
Platelet, monocyte, and endothelial cell
activation results in a hypercoagulable state, and
increased risk of venous thrombosis
6. HIT-associated thrombosis occurs in some
patients 1 – 2 days before platelet counts
decrease
HIT – summary & conclusions
7.
Platelet count monitoring is important to diagnose
isolated HIT and thus has the potential to prevent
thrombosis
8.
Recognizing a relative decrease of platelet count is
important since platelets do not always fall below
150 x 109/L
9.
Platelet count monitoring is recommended in most
patients receiving UFH and in some patients
receiving LMWH.
HIT – summary & conclusions
9.
Heparin should be stopped immediately in all
situations where HIT is strongly suspected
10. Due to the high risk of thrombosis in patients with
HIT anticoagulation with a non-heparin
anticoagulant should be started even in the
absence of overt thrombosis
11. Danaparoid provides an option for anticoagulation
in either prophylactic or therapeutic doses
Heparin-Induced Thrombocytopenia
(HIT)