HEPARIN INDUCED
THROMBOCYTOPENIA
(HIT)
Roy R. Danks, DO, FACOS
HEPARIN-INDUCED THROMBOCYTOPENIA
Clinical manifestations
• Isolated thrombocytopenia (“Isolated HIT”)
• Arterial or venous thrombosis (HITT)
– DVT, PE, MI, stroke, peripheral arterial occlusion
• DIC, microangiopathic hemolytic anemia
• Skin necrosis (at injection sites or distant)
•
•
•
•
Venous limb gangrene (? Role of warfarin)
Sudden death
ARDS
Hemorrhagic adrenal infarction
Three Characteristic Features of HIT vs
“thrombocytopenia” (NOS)
• Timing: Platelet count decreases beginning 5-14 days
after the start of heparin treatment
• Severity of thrombocytopenia: it’s usually mild to
moderate
• Large vessel venous or arterial thrombosis in
association with thrombocytopenia
HEPARIN-INDUCED THROMBOCYTOPENIA
Causative agents
• Unfractionated heparin (UFH) (beef > pork)
– Continuous intravenous infusion
– Cardiopulmonary bypass
– Low dose subcutaneous
– Heparin flushes
– Heparin-bonded catheters
• Low molecular weight heparin (LMWH)
– More likely to cause HIT if pt previously
exposed to UFH
HEPARIN-INDUCED THROMBOCYTOPENIA
Epidemiology
•
•
•
•
•
•
UFH > LMWH >> Fondaparinux
Duration of heparin treatment ≥ 6 days
Rarely occurs in patients < 40 years old
2-3 fold higher incidence in women
Surgical > medical > obstetric patients
Incidence in trauma patients proportional
to severity of trauma
– Related to degree of platelet activation?
Blood 2012; 119: 2209
PATHOPHYSIOLOGY OF HIT
HIT IS CAUSED BY ANTIBODIES AGAINST A
HEPARIN-PLATELET FACTOR 4 COMPLEX
4
binds
3 Antibody
heparin-PF4
complex
Fab
Antibody binding to
platelet FC receptor
activates platelet
2 PF4 binds heparin
PF4
FC
FC receptor
Platelet membrane
1 Activated
platelet
secretes PF4
PATHOPHYSIOLOGY OF HIT
Warkentin, Brit J Haematol 2003;121:535
• Heparin-PF4 complexes stimulate antibody production
• Ag-Ab complex binds to and activates platelets,
monocytes
Size of immune complex is critical, varies with PF4 and
heparin concentrations
Inhibited by high heparin concentrations
• may cross-react with PF4 bound to endothelial cell
heparan sulfate → vessel wall injury
• Some HIT antibodies can activate platelets in the
absence of heparinActivated platelets release
procoagulant microparticles
• Activated monocytes produce tissue factor Antibodies
HEPARIN-INDUCED THROMBOCYTOPENIA
Incidence and presenting features
Warkentin and Kelton, Am J Med 1996;101:502
Presenting with
thrombosis (n=65)
Presenting with no
thrombosis (n=62)
Total (n=127)
Age
67 ± 10.7
66.7 ± 12.3
67.0 ± 11.4
Male/Female
27/38
33/29
60/67
SURGICAL PTS
51
33
84 (66.1%)
Orthopedic
25
15
40
Cardiovascular
10
9
19
Oncology
7
6
13
General
6
2
8
Neurosurgery
3
1
4
14
29
43 (33.9%)
Cardiac
6
10
16
DVT or PE
4
7
11
Other
4
12
16
MEDICAL PTS
THROMBOTIC COMPLICATIONS IN HIT
Am J Med 1996;101:502
Type of thrombosis
Pts presenting with
thrombosis (n=65)
Pts presenting with only
thrombocytopenia (n=62)
VENOUS (n=78)
54
24
DVT (n=61)
40
21
New
35
21
Progression
4
0
Recurrence
1
0
PE (n=32)
26
6
New
25
5
Recurrence
1
1
ARTERIAL (n=18)
12
6
Limb
7
2
Myocardial infarct
3
1
Thrombotic stroke
2
3
1
2
Sudden death
0
1
Adrenal hemorrhage
1
1
NO THROMBOSIS (n=30)
NA
30
Other (n=3)
ISOLATED HIT IS ASSOCIATED WITH A HIGH RISK OF
SUBSEQUENT THROMBOSIS
 Over 50% of patients presenting with “isolated HIT” had a
subsequent thrombotic episode within 30 days
 Substitution of warfarin for heparin after the onset of
thrombocytopenia did not prevent thrombosis
UNFRACTIONATED HEPARIN IS MORE
LIKELY TO CAUSE HIT THAN LMWH
THE FREQUENCY OF THROMBOSIS AFTER HIP
SURGERY IS MUCH HIGHER IN PATIENTS WITH HIT
THAN IN THOSE WITHOUT HIT
LMWH IS MORE LIKELY TO CAUSE HIT IN
PATIENTS WITH PRIOR UFH EXPOSURE
Prandoni et al, Blood 2005;106:3049
• Prospective cohort study, 1754 medical pts
• 0.8% overall incidence of HIT
0.3% incidence if no prior UFH exposure
1.7% incidence if prior UFH exposure
• All cases in first 2 weeks
• Prevalence of thromboembolism 16x higher in patients
with HIT (29% vs 2.4%)
Development of HIT antibodies is more common in major surgery
than minor surgery, and more common with UFH than LMWH
THROMBOSIS IN HIT MAY OCCUR WITH NORMAL
PLATELET COUNT
Warkentin et al, NEJM 1995;332:1330
THE PLATELET COUNT DROPS PRIOR TO
THROMBOSIS IN HIT
Warkentin et al, NEJM 1995;332:1330
**
*
****
*
*Thrombotic episode
Recent heparin exposure may cause “rapid onset” HIT
Warkentin and Kelton, NEJM 2001;344:1286
Rapid-onset HIT is associated with
re-exposure to heparin within 90 days
Warkentin and Kelton, NEJM 2001;344:1286
Heparin-dependent antibodies usually disappear
within 90 days an episode of HIT
Warkentin et al, NEJM 1995;332:1330
DELAYED ONSET HIT
Ann Intern Med 2002;136:210
• Describes 14 patients treated with heparin,
discharged, and later re-hospitalized with
thromboembolism and positive tests for HIT antibodies
• Most patients got heparin during cardiac surgery
• 12/14 had mild thrombocytopenia (66-145K) at time of
thrombotic episode
• Median time between discharge and readmission 14
days, maximum 40 days
 11 patients re-treated with heparin: all had clinical
deterioration and worsening thrombocytopenia
 3 patients died
Heparin concentration affects the size and charge of
heparin:PF4 complexes and their ability to activate platelets
Charge of complexes
Low heparin:PF4 ratio → small complexes
1:1 heparin:PF4 → large complexes
Heparin conc→
High heparin:PF4 ratio → small complexes
Blood 2007;110:4253
Clinical factors may help determine the
likelihood of developing HIT
• Healthy volunteers given heparin or LMWH make IgM
antibodies to heparin/PF4
• Pathologic HIT antibodies are usually IgG
• Concomitant immune stimulus necessary to promote
IgG HIT antibody formation?
• Higher PF4 levels after surgery or acute illness may
promote formation of larger immuneBlood
complexes
2007;110:4253
J Thromb Haemost 2012;10:1446
DIAGNOSIS OF HIT
DISTINGUISHING IMMUNE FROM NON-IMMUNE
HEPARIN INDUCED THROMBOCYTOPENIA
•
Many patients have a transient decrease in
platelets within 24 hours of receiving heparin.
• This is not an antibody-mediated effect and not
associated with thrombosis
• How can it be distinguished from HIT?
1. By the time course
2. By the clinical picture
3. By serology and other lab tests
Severe thrombocytopenia is rare in HIT
Warkentin, Brit J Haematol 2003;121:535
•
Median platelet nadir 55K
•
15% had nadir >150K (diagnosed because platelet count fell
more than 50% or because of clinical events)
•
The severity of thrombocytopenia did not predict thrombotic
events
Clinical features that favor a diagnosis of HIT
Blood 2012;119:2209
The 4 T score predicts a positive HIT antibody test
J Thrombos Haemost 2006;4:759
Score
<4
% Testing
positive
0.8%
4-5
>5
11%
34%
LABORATORY DIAGNOSIS OF HIT
There are 4 Tests
1. Serotonin release assay (SRA)
2. Heparin-induced platelet aggregation assay (HIPA)
3. Solid phase imunoassay (H-PF4) (Enzyme linked
immunosorbant assay [ELISA])
4. Particle gel immunoassay
HIPA: highly specific but less sensitive than SRA
SRA: Largely restricted to centers studying HIT
C-14-SRA is the “gold standard” assay with sensitivity and
specificity of 90 and nearly 100%, respectively
A STRONGLY POSITIVE EIA RESULT IS
ASSOCIATED WITH HIGHER RISK OF
SUBSEQUENT THROMBOSIS
OD values in HIT vs HITT patients
J Thrombos Haemost 2004;2:2133-7
Thrombosis-free survival vs OD
TREATMENT OF HIT
TREATMENT OF HIT
• Discontinue all heparin, including flushes
• LMWH may cross-react with HIT antibodies, should not be
used
• If thrombosis present: give alternative thrombin inhibitor
• Consider treating even if thrombosis absent (high risk of
thrombosis in patients with isolated HIT)
• Treatment alternatives:
– Direct inhibitors
•
•
•
•
Lepirudin (Refludan)
Bivalirudin ( Angiomax)(approved for HIT patients having PCI)
Argatroban (Acova)
Dabigatran (Pradaxa: not approved for HIT, per se)
– Indirect inhibitors
• Fondaparinux ((Arixtra): poor evidence, further studies needed
• Do not give warfarin (risk of venous gangrene)
DIRECT THROMBIN INHIBITORS
• Lepirudin (Refludan®)
– Recombinant form of leech anticoagulant
– Clearance mainly renal (avoid in renal failure); halflife
normally 80 min
– Antibody formation may cause drug accumulation or
anaphylaxis (rare)
• Argatroban (Novastan®)
– Synthetic arginine derivative
– Clearance mainly hepatic (can use in renal failure);
halflife 40-50 min
• Both given by continuous iv infusion, monitoring aPTT
• Coagulopathic patients (long baseline aPTT) difficult to
monitor
• No antidote for either drug
LEPIRUDIN IN HIT
ACCP RECOMMENDATIONS
• Bolus 0.2 mg/kg only if life- or limb-threatening thrombosis
present
• Continuous infusion rate:
– Cr < 1.0: 0.1 mg/kg/hr
– Cr 1.0-1.6: 0.05 mg/kg/hr
– Cr 1.6-4.5: 0.01 mg/kg/hr
– Cr > 4.5: 0.005 mg/kg/hr
• Adjust to aPTT 1.5-2.0 times baseline
• Check aPTT q 4h
 These doses are lower than recommended in the drug
package insert
Argatroban therapy in HIT
• Pooled data from 2 prospective non-randomized trials
• Hazard ratio with argatroban 0.3 vs historical controls
• No difference in major bleeding vs controls
Chest 2006;129:1407
ARGATROBAN IN HIT
ACCP RECOMMENDATIONS
• Bolus: None
• Continuous infusion:
– Normal organ function: 2 mcg/kg/mon
– Liver dysfunction, post cardiac surgery,
anasarca: 0.5-1.2 mcg/kg/mon
• Adjust aPTT to 1.5-3.0 x baseline
• Check aPTT q 4h
• Argatroban prolongs PT/INR, making transition to
warfarin tricky
FONDAPARINUX (Arixtra®)
• Synthetic polysaccharide, inhibits factor Xa
preferentially
• Does not typically cross-react with HIT antibodies
• Long half-life (17-20 h), no antidote
• SQ administration
• Monitoring unnecessary
• Not FDA-approved for HIT treatment

Rare reports of fondaparinux-associated HIT
(NEJM 2007; 356:2653)
Fondaparinux appears to be effective and safe in
patients with HIT
Reference
N
Major Bleeding
5
New
thrombosis
0/5
Kuo & Kovacs
Thromb Haemost 2005
Lobo et al
Thromb Haemost 2007
7
0/7
0/7
Grouzi et al
Clin Appl Thromb
Haemost 2009
24
0/24
0/24
Pooled Data
36
0/36
0/36
0/5
Warkentin, Hematol Oncol Clin N Am 2010; 24:755
FONDAPARINUX DOSING
• Weight based:
< 50 kg: 5 mg sc daily
50-100 kg: 7.5 mg sc daily
> 100 kg: 10 mg sc daily
• Prophylactic dose: 2.5 mg sc daily
• With renal insufficiency:
CrCl 30-50 ml/min: use caution
CrCl < 30: do not use
VENOUS GANGRENE
Arch Intern Med 2004;164:66
WARFARIN MAY PROMOTE VENOUS
GANGRENE IN HIT
•
•
•
•
Ann Intern Med 1997;127:804-12
Retrospective review of 158 cases of HIT
8/8 patients with venous limb gangrene treated with warfarin, vs
3/10 with arterial thrombosis (p=.004)
Median INR 5.8 in patients with venous gangrene vs 3.1 in those
who did not (p<.001)
Elevated ratio of thrombin-antithrombin complex to protein C
activity in patients with venous gangrene vs controls
 Conclusion: warfarin treatment of DVT associated with HIT may
cause venous limb gangrene, possibly because of acquired
defect in protein C pathway
 Do not start warfarin treatment until HIT resolves (platelet count
returns to normal)
How long should anticoagulation continue after
diagnosis of HIT?
• HIT with thrombosis: 3-6
months
• Isolated HIT (no
thrombosis): at least until
platelets normal, consider
continuing for 30 days
Can patients with a history of HIT
be given heparin again?
• Heparin should not be given while tests for heparin
antibodies remain positive
– If cardiac surgery cannot be delayed, use
alternative anticoagulant (e.g., bivalirudin)
• HIT recurrence or secondary antibody response
uncommon in patients with “remote HIT” and negative
HIT antibody test
– Heparin administration should be limited to the
intraoperative period
SUMMARY-1
• HIT typically occurs after 5+ days of exposure to
unfractionated heparin
• Suspect HIT if platelet count falls by > 50% during
heparin administration, or if new thrombotic event
occurs within 2-3 weeks of heparin exposure
• Onset may be earlier if there was prior exposure to
heparin within past 100 days
• Onset may follow discontinuation of heparin
• LMWH rarely causes HIT but may perpetuate it
• Risk of thrombosis in HIT is high even if patient
does not have thrombosis at time of diagnosis
SUMMARY-2
• HIT is caused by production of antibodies to
heparin-PF4 complex that activate platelets
• HIT is unlikely if tests for heparin-PF4 antibodies
are negative
• Patients with HIT should generally be treated with
a thrombin or Xa inhibitor other than heparin or
LMWH
• Warfarin treatment should be delayed until platelet
count is normal