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Wellcome in our new group ..... Dr.SAMIR EL ANSARY
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HEPARIN-INDUCED THROMBOCYTOPENIA
• 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
Clinical manifestations
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
• 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
Causative agents
HEPARIN-INDUCED THROMBOCYTOPENIA
• 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?
Epidemiology
PATHOPHYSIOLOGY
OF HIT
HIT IS CAUSED BYANTIBODIES AGAINST
A HEPARIN-PLATELET FACTOR 4 COMPLEX
Platelet membrane
FC receptor
Fab
FC
Antibody binding to platelet FC receptor activates platelet
4
1
PF4
Activated plateletsecretes PF4
2 PF4 binds heparin
3 Antibody binds heparin-PF4 complex
Heparin-induced thrombocytopenia: Platelet factor 4 (PF4) released by activated
platelet. This binds heparin, creating a potential
neoantigen. Antibody binds the complex of heparin-PF4. The
antigen antibody complex then binds to the FC
receptor on another platelet, causing platelet
activation.
This may account for the association between HIT
and thrombosis in some patients.
PATHOPHYSIOLOGY OF HIT
• 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
PATHOPHYSIOLOGY OF HIT
• Some HIT antibodies can activate
platelets in the absence of heparin
• Activated platelets release
procoagulant microparticles
• Activated monocytes produce
tissue factor Antibodies
HEPARIN-INDUCED THROMBOCYTOPENIA
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
MEDICAL PTS 14 29 43 (33.9%)
Cardiac 6 10 16
DVT or PE 4 7 11
Other 4 12 16
Incidence and
presenting features
THROMBOTIC COMPLICATIONS IN HITType 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
Other (n=3) 1 2
Sudden death 0 1
Adrenal hemorrhage 1 1
NO THROMBOSIS (n=30) NA 30
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
Development of HIT antibodies is more common in major surgery than minor surgery, and more
common with UFH than LMWH
***
* ****
THE PLATELET COUNT DROPS PRIOR TO
THROMBOSIS IN HIT
*Thrombotic episode
Platelet count normally rises steadily for at least a week after hip surgery.
Note that all pts with HIT and normal plts had at least two days of
dropping plts before thrombotic event
Recent heparin exposure may cause
“rapid onset” HIT
HIT virtually never happens less
than 4 days after starting heparin
UNLESS there has been prior
exposure to heparin
Rapid-onset HIT is associated with
re-exposure to heparin within 90 days
Heparin-dependent antibodies
usually disappear within 90 days
an episode of HIT
We have said that HIT can occur without
thrombocytopenia.
It can also occur when a patient is no longer
getting heparin.
This is a particularly difficult form of HIT to
diagnose, and the consequences of not
diagnosing it can be dire
DELAYED ONSET HIT
• Some studies describes patients treated with heparin, discharged, and later re-hospitalized with thromboembolism and positive tests for HIT antibodies
• Most patients got heparin during cardiac surgery
• Some had mild thrombocytopenia (66-145K) at time of thrombotic episode
• Median time between discharge and readmission 14 days, maximum 40 days
Some patients re-treated with heparin: all had clinical deterioration and worsening thrombocytopenia
Heparin concentration affects the size and charge of heparin:PF4 complexes
and their ability to activate platelets
Low heparin:PF4 ratio → small complexes
High heparin:PF4 ratio → small complexes
1:1 heparin:PF4 → large complexes
Ch
arge
of
com
ple
xes
Heparin conc→
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 immune complexes
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
• 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
Severe thrombocytopenia
is rare in HIT
15% are not thrombocytopenic at all. Rarely does plt count drop below 20K
No connection between severity of thrombocytopenia and clinical course
Clinical features that favor a diagnosis of HIT
The 4 T score predicts a positive HIT antibody test
Score % Testing
positive
<4 0.8%
4-5 11%
>5 34%
LABORATORY DIAGNOSIS OF HITThere 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 SRASRA: Largely restricted to centers studying HITC-14-SRA is the “gold standard” assay with sensitivity
and specificity of 90 and nearly 100%, respectively
LABORATORY DIAGNOSIS OF HITThere are 4 Tests
ELISA a very good screening test and
it’s all you need if the clinical picture fits
Consider SRA when clinical picture
cloudy or when risk of giving alternative
anticoagulant high
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 OF 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 giveWarfarin
(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)
DIRECT THROMBIN INHIBITORS
• 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 HITACCP 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 IN HITACCP RECOMMENDATIONS
• Bolus: None
• Continuous infusion:– Normal organ function: 2 mcg/kg/mIn
– Liver dysfunction, post cardiac surgery, anasarca: 0.5-1.2 mcg/kg/mIn
• 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
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
Tissue death
Starting warfarin too soon in HIT
may promote this process
WARFARIN MAY PROMOTEVENOUS GANGRENE IN HIT
Retrospective study in which all of the HIT patients who developed VG VENOUS
GANGRENE had been treated with
WARFARIN
Long INR not protective
Biochemical evidence that warfarin’s effect
on protein C levels may mediate this effect
WARFARIN MAY PROMOTE VENOUS GANGRENE IN HIT
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)
Can patients with a history of HIT be given heparin again?
• HIT recurrence or secondary antibody response uncommon in patients with “remote HIT” and negative HIT antibody test
Heparin administration should be limited to the intraoperativeperiod
• CONCLUSION
• 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
• CONCLUSION
• 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
• CONCLUSION
• 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
https://www.facebook.com/groups/1451610115129555/#!/groups/1451610115129555/
Wellcome in our new group ..... Dr.SAMIR EL ANSARY
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