Transcript What’s with HIT?

What’s with HIT?
Heparin Induced Thrombocytopenia
A Perfusion Perspective
M. Savelberg
June 2010
Overview
What is HIT?
Diagnosis/Testing
Management
Recent Literature
Perfusion Considerations
Summary
Characteristics of HIT
HIT 1
HIT 2
Etiology
Non-immune mediated
Occurs in 10-20% of patients2.
Immune mediated, aka HAT, HIT/T
and White Clot Syndrome
Occurs in 1-4% of patients.
Onset Time
1-4 days
5-10 days
Prognosis
Resolves when heparin stopped, not
associated with significant clinical
findings.
May have serious consequences
Platelet Count
Mild thombocytopenia
(usually >100 x 109/L)
30-50% reduction in baseline
(usually <<100 x 109/L but not
exclusive to)
Complications
May be associated with
thromboembolic complications
(TEC) which has high association
with mortality (25-30%).
Thromboembolism (20-40%),
myocardial ischemia,
pulmonary emobolus, limb
amputation, stroke, death.
Diagnosis
Exclusion of other causes
Detection of antibodies
Length of Treatment
6-14 days
Minimum of 6 months
(1) Cheng, D.., (2006) Perioperative Care in Cardiac Anesthesia and Surgery. Chp 19: HIT and Alternatives to Heparin Table taken from pg.174,
(2) (Gurbuz, A.T., et al., 2005) European Journal of Cardio-thoracic Surgery 27:138-149
HIT 2
Caused by heparin-dependent
immunoglobin G (IgG) antibodies (HITIgG) binding to a conformationally
modified epitope on platelet factor 4
(PF4) antibodies present in 18% of
patients exposed to UFH (Gurbuz,
2004)
The binding of heparin and other
glycosaminoglycans to PF4 = heparinPF4 complex, alters its shape rendering
it immunogenic. Against which IgG
antibodies are formed.
(Antigenicity of the heparin-PF4 complex
depends on the molecular weight and
degree of sulfation of the heparin
molecule.)
HIT 2
The IgG- PF4-heparin immune complex bind to
platelets through the platelet Fc receptor, resulting
in platelet activation, degranulation and (releases
intracellular protein kinases) causing aggregation.
Generation of platelet derived microparticles
(procoagulants) = trigger thrombotic complications
Activated platelets trigger a host of other systems
including inflammatory cells, coagulation pathways
and endothelial cells.
Thomboxane A2 is synthesized and released into
circulation.
This leads to generation of thrombin and
intravascular coagulation.
Image taken from: Gurbuz, A.T., et al.,(2005) European Journal
of Cardio-thoracic Surgery 27:138-149
HIT : The Big Picture
Frequency of HIT
Highly variable and influenced by many
factors:
Patients receiving UFH > 1week ( with
incidence ranging from 0.1%-1.0%)
Heparin from bovine lung is more likely to
produce HIT than the heparin from porcine
intestine.
(Warkentin, 2000; 2005)
Unfractionated heparin (UFH) is more
likely to cause HIT-2 than LMWH because
heparin chains bind to PF4 in relation to
chain length.
Females more likely to have HIT than
males
(Warkentin, 2006)
Warkintin, T.E., et al. (2006) Gender imbalance and the risk factor interactions in heparin-induced thrombocytopenia. Blood; 108;2937-2941
Suspected HIT?
Standard management
protocol used in cases of
suspected HIT following
exposure to UFH resulting in
thrombocytopenia.
Less
Expensive
More
Expensive
Test
Gurbuz, et al. (2005) Heparin Induced Thrombocytopenia in the Cardiovascular Patient: Diagnostic and Treatment Guidelines, Eur. J of Card-Thor Surg. 27:138
Thromboembolic Complications
Electron micrograph of thrombus
Diagnosis
1. Thrombocytopenia during heparin therapy.
Note: Thrombocytopenia during first 4 postoperative days of cardiac surgery due to
hemodilution and platelet consumption is rarely
HIT related.
2. Exclusion of other causes of thrombocytopenia
i.e. septicemia, MOF (multi-organ failure),posttransfusion purpura.
3. Diagnosis confirmed by:
a) Detection of HIT-IgG antibodies by ELISA, for
heparin-PF4 complexes using goat antihuman antibody (antigen assay)
b) Or by a heparin-induced platelet aggregation
study (HIPAA)
4. Resolution of thrombocytopenia after cessation
of heparin.
ELISA Plate
General HIT Management

Suspicion of HIT includes:
 Thrombocytopenia (PLT count falls by > 50%) *
 Resistance to heparin anticoagulation*
 Thrombosis during heparin therapy*

Stop all forms of heparin
 Including LMWH, flush solutions, catheters

To avoid a hypercoagulable state
 Warfarin should be started once platelet count is > 100 x 109/L, and continued for up to 3 months
since the risk of thrombosis remains high up to 6 weeks after discontinuing heparin in HIT patients.
(Gurbuz, 2005)
 The American College of Chest Physicians suggests (Grade 2C) that vitamin K should be given to
minimize the risk of warfarin induced limb gangrene or skin necrosis.
 Overlap alternative anticoagulant agents with Warfarin at least 5 days due to protein C deficiency
(otherwise could lead to microvascular thrombi and limb gangrene)

Start a rapidly acting, non-heparin anticoagulant
 i.e. danaparoid [Grade 1B], lepirudin [Grade 1C], argatroban [Grade 1C], fondaparinux [Grade
2C], bilvalrudin [Grade 2C] are recommended over the further use of UFH or LMWH

Prophylactic platelet transfusions may contribute thrombotic risk, and are NOT recommended.
(Levy; 2007, Warkentin; 2008)
Gurbuz, et al. (2005) Heparin Induced Thrombocytopenia in the Cardiovascular Patient: Diagnostic and Treatment Guidelines, Eur. J of Card-Thor Surg. 27:138-149
Levy, et al., (2007) Reducing Thombotic Complications in the Perioperative Setting: An Update on Heparin Induced Thrombocytopenia. Anes. Analg. 105(3):570582
Warkintin, T.E., et al. (2008) Treatment and Prevention of Heparin-induced Thrombocytopenia. Chest; 133;340S-380S
Management of HIT
Site-Dependent Considerations
for the Management of HIT




Availability of drug
Laboratory monitoring
Previous physician experience
Patient dependent factors (renal or hepatic insufficiency).
- Alcoholism, diabetic nephropathy?
Management of HIT: The Evidence

June 2008, American College of Chest Physicians published Evidence-based
Guidelines for the Treatment and Prevention of HIT. Chest;133;340S-380S

Treatment Guidelines look at the two categories of heparin alternatives.
Non-thrombin inhibitors: low molecular weight heparin (LMWH), danaproid and ancrod.
Direct thrombin inhibitors: hirudin and its recombinant derivative lepirudin as well as the
synthetic direct thrombin inhibitors
Alternative Anticoagulant
Protocols for CPB in HIT Patients
Warkentin, T.E., et al. (2008) Treatment and Prevention of Heparin-induced Thrombocytopenia. Chest; 133;340S-380S
Management of HIT for Pts
Undergoing Cardiac Surgery

Management depends on if patient undergoing surgery is a
previous HIT patient or Acute/Subacute HIT patient :
Previous HIT:

If patient is HIT antibody negative and require cardiac surgery it is recommended that
UFH is used over a non-heparin alternative [Grade 1B]
(Pre and Post-operative anticoagulation should be using non-heparin anticoagulant)

If patient is HIT antibody positive by PF4
dependent enzyme immunoassay (EIA)
but antibody negative by washed platelet
activation assay (PAA) the use of UFH over
non-heparin alternative is again
recommended [Grade 2C]
Warkentin, T.E., et al. (2008) Treatment and Prevention of Heparin-induced Thrombocytopenia. Chest; 133;340S-380S
Management of HIT for Pts
Undergoing Cardiac Surgery
Management depends on if patient undergoing surgery is a previous
HIT patient or Acute/Subacute HIT patient :
Acute HIT:

Acute HIT (thrombocytopenic & HIT antibody positive)
i.
Delay surgery if possible until HIT has resolved and antibodies are negative
(or weakly positive) (mean time 50-80 days). [Grade 1B]
The time in days (is shown to the right)
to a negative test by both the activation
and antigen assay. (Warkentin, 2001)
The antigen test tended to become
negative more slowly.
At 100 days, heparin-associated antibodies
disappeared, with less than 20% tested positive.
Warkentin, T.E., et al. (2008) Treatment and Prevention of Heparin-induced Thrombocytopenia. Chest; 133;340S-380S
Warkentin, T.E., et al. (2001) Heparin-induced thrombocytopenia. Marcel Dekker Inc. NY. Second Edition. pg. 51
Management of HIT for Pts
Undergoing Cardiac Surgery
Management depends on if patient undergoing surgery is a previous
HIT patient or Acute/Subacute HIT patient :
Acute HIT:

Acute HIT (thrombocytopenic & HIT antibody positive)
ii.
iii.
iv.
Use bivalirudin for intraoperative coagulation during CPB or OPCAB (adapting
surgical and anesthesia techniques according to bivalrudin pharmacology)
[Grade 1B]
Using lepirudin for intraoperative anticoagulation (if ECT available, and patient
has normal renal function with little risk for post-op renal failure). [Grade 2C]
Using UFH + antiplatelet agent epoprostenol (Flolan®) (if ECT not available or
renal function precludes lepirudin use) [Grade 2C]
Warkentin, T.E., et al. (2008) Treatment and Prevention of Heparin-induced Thrombocytopenia. Chest; 133;340S-380S
Bivalirudin – Angiomax®

Direct thrombin inhibitor (DTI)

Synthetic peptide (20 amino acids) with lower MW
that hirudin.

T1/2 = 25 mins via proteolytic cleavage (80%) present
in blood when exposed to foreign/wound surfaces.

Minor renal excretion (20%) – can be used in patients
with both renal or hepatic impairment (Cheng, D.,
2006)

Minimal immunological activity, <1% after 5 day
infusion.

ECT (Ecarin clotting time) preferred monitor on CPB
Levy, et al., (2007) Reducing Thombotic Complications in the Perioperative Setting: An Update on Heparin Induced Thrombocytopenia. Anes. Analg.105(3):570-582
Bivalirudin – Angiomax®
CPB Dosage:
Initial dose IV bolus = 1.5mg/Kg followed by continuous infusion at the rate of 2.5 mg.Kg/hr
during CPB. (Cheng, 2006) In agreement with Toronto General Hospital protocol (2006),
Initial IV bolus dose of 1.0mg/Kg used by London Health Sciences Center.
 A bolus of 50 mg should be added to the priming solution (by perfusionist)
 ECT should be maintained between 400-500 sec or >370 seconds ACT (must not go
on before!).
 Clots noted in areas of stagnant blood is normal – to be taken back by cell saver.
 Infusion can be terminated 15 minutes prior to decannulation. (TGH/LHSC Protocol)
 Maintain a core temperature of >34 37 degrees after CPB
 A bolus of 25-50mg should be added to pump after CPB.
 Followed by a continuous infusion at 50mg/hr into pump after CPB, taken from
anesthesia.
(Levy; 2007, Cheng; 2006; and TGH protocol 2006)

If there is need to go back on bypass, the full loading dose should be re-administered to
patient, and into extracorporeal circuit.
IV Line Incompatibilities with Angiomax®
Alteplase
Amiodarone HCl
Amphotericin B
Cloropromazine HCl
Diazepam
Dobutamine HCl (at 12.5 mg/mL)
Prochlorperazine edisylate
Reteplase
Streptokinase
Vancomycin HCl
Bilvalirudin – Angiomax®
Perfusion Specific Considerations:

Circuit Stagnation:
Cardioplegia: must be continually re-circulated during periods without administration.

A plan must be developed regarding cardioplegia delivery; either continuous blood,
crystalloid, intermittent blood every 10 minutes or any other method that will prevent stasis

The cardioplegia line from the pump to the table may be flushed with normal saline, if
blood cardioplegia is to be used, following administration in order to prevent clot formation
in line. The line flush should be placed in a sterile bowl at the table, and sent back to the
cell saver.

The line from double spike (where crysalloid cardiplegia is hung to cardioplegia device
(Myotherm®) must be re-flushed with high potassium cardioplegia and then cardiplegia
delivery line reflushed to table between each administration.
Purges: All purges must be flushed every 10 minutes (min) on bypass.

These include: arterial filter bypass line, mannifold (if off for any period of time),
recirculation line, one-way de-airing line from oxygenator (if you plan to use again).
Bilvalirudin – Angiomax®
Perfusion Specific Considerations:

Circuit Stagnation:
Suckers: Intracardiac blood can be sent back to the pump, however any and
all pericardial blood should be sent to the cell saver.
Venting: Technique would need to be procedure and patient dependent:




In the case of a CABG procedure, where much venting is not expected, this
blood may be sent back to the cell saver.
In the case of a valve or with a CABG where mod-severe AI may be present,
increased venting may require the vent line to be flushed during periods of no
venting to prevent fibrin/clot formation in vent line.
The vent can be wye’d and flush diverted to sequestration bag if required.
Cell Salvage:


Shed pericardial blood should not be re-infused, and cell salvage should be
used. (Levy; 2007)
Cell salvage must be done with sodium citrate. Contact pharmacy in advance.
Bilvalirudin – Angiomax®
Perfusion Specific Considerations:

Elimination Considerations:
 Drugs:
 Lasix with increase the elimination of the drug and therefore should be
avoided during CPB. Also should be avoided prior to CPB, so as not to alter
anticipated pharmokinetics.
 Mannitol: Although an oxygen free radical scavenger, as an osmotic
diuretic you may wish to avoid additional doses on bypass unless anuric to
prevent excessive elimination.
 Hemoconcentration/Dialysis: Will decrease the concentration of Bilvalirudin
within circulation rapidly, and therefore should be avoided. If necessary, should
monitor ACTs/ECTs consecutively and increase rate of Bilvalirudin infusion
during CPB.
 MUF: MUF post bypass to decrease Bivalirudin for severe hemorrhage

Emergency:
 Emergency pump set-up: Should have an emergency pump set-up and
available in the event that massive clot is detectable.
 Oxygenator in room: Have an extra oxygenator in the room in the case of poor
gas exchange due to clot/fibrin formation on the membrane.
Bilvalirudin – Angiomax®
Other considerations for Cardiac Surgical Management with Bilvalirudin:

Heparin-free Equipment: including ECC coating free of heparin, as well as PA
catheter, Cortis®, heparin coated syringes (see ABG section below).

ABGs:
 Should use in-line blood gas monitor if available for early detection of poor gas
exchange with may indicate oxygenator failure (due to fibrin/clot formation)
 Do ABGs regularly at least every 15 minutes if in-line monitor not available.
Sampling Technique:
Option #1: Sample with a non-heparinized syringe and transfer to a heparinized
syringe for ABG analysis.
Option #2: After sampling with heparin coating syringe, pull back another 1-3cc,
to flush stopcock and prevent possible contamination of line with heparin.

Blanket warmers should be used so as not to prolong ACT at cooler temperatures
yielding more inaccurate ACT interpretation.
 Cooler temperatures also decrease drug metabolism worsening problems with
eliminating Bilvalirudin post-operatively, and increasing post-operative bleeding
and transfusion requirements.
Bilvalirudin – Angiomax®
Other considerations for Cardiac Surgical Management with Bilvalirudin:

Reservoir Levels:


Cold Cardioplegia:


Flush arterial cannula with prime following cannulation
RAP:


Is acceptable, as long as systemic temperature >34ºC, in theory should decrease
enzymatic activity and therefore decrease Bilvalirudin metabolism in cardioplegia delivery
line and within grafts.
Cannulation:


If possible maintain levels in the reservoir <1000mL in order to prevent stasis.
May be best to avoid RAP prior to CPB in the event that you may have to wait prior to
initiating CPB and stagnation occurs.
Decannulation:

Following termination of CPB a ½” x 3/8” connector should be used to reconnect the
arterial and venous lines, as soon as all transfusion forward is complete, so that the circuit
can be kept patent.
Bivalirudin – Angiomax®

Has been systematically investigated in a number of studies.

3 RCTs have examined Bivalrudin vs. UFH (with protamine reversal)
1) Utilizing fixed dose Bivalirudin protocols using routine intraoperative coagulation studies (ACT)
to ensure a minimal threshold level of anticoagulation is feasible.
Case Report:
Pappalardo, et al., 2007 reported use of Bivalrudin for anticoagulation during CPB
- Initial dose 75 mg (1mg/Kg) prior to aortic cannulation
- Put 50 mg bilvalrudin in the priming solution (1500 LR, 100mL (18%) mannitol)
- The bolus was followed by an infusion of 2.5 mg/Kg per hour during bypass
which was discontinued during cross-clamp removal or graft completion.
- ACTs were maintained perio-operatively (422-557 seconds)
- Post-operative blood loss = 390mL.
- ACTs are satisfactory method of monitoring anticoagulation with bilvalirudin (however this
statement is based on a single case report)
(Zucker et al., 2005)
2) Special surgical, anesthesiology and perfusion techniques must be used due to the unique
pharmacology of bivalirudin, in particular its progressive, nonenzymatic degradation in areas of
stagnant blood flow. (Guidelines available). If not followed, intraoperative clot formation in the
bypass grafts and stagnant areas have been found.
3) Compared in both on-pump and off-pump cases, the efficacy and safety results of bivalirudin in
comparison to UFH/protamine are comparable in both transfusion requirements and postoperative bleeding.
Pappalardo, F., Franco, A., Crescenzi, G., Zangrillo, A., Zoster, A., (2007) Successful use of bilvalirudin for cardiopulmonary bypass in a patient with heparin
allergy. Perfusion: 2267-69
Bivalirudin – Angiomax®

Surgical Considerations:

Stasis Management:


Graft Patency:



Flush coronary grafts with crystalloid solution to keep them patent
Considerations for flushing IMA
Sucker Blood Management:


Ensure there is no stasis in the surgical field.
Send intra-cardiac blood back to the pump, and pericardial blood to the cell saver.
Plan for Cardioplegia Delivery:


A plan must be developed regarding cardioplegia delivery; either continuous blood,
crystalloid or intermittent blood cardioplegia every 10 minutes.
Any method that will prevent stasis.
Bivalirudin – Angiomax®
Current Research

CABG HIT/TS On- and Off-pump Safety and
Efficacy: on pump (CHOOSE-ON) was a Phase III
multicenter, open-label trial designed to assess the
safety and efficacy of bivalirudin in 50 patients
compared to a historical control group of 50 patients
with or at risk of HIT/HITTS undergoing on-pump
cardiac surgery.
Procedural Success Rate
94%
94%
92%
90%
88%

49 patients treated with Bivalirudin: 43 had acute
HIT and thrombosis syndrome with antibodies at the
time of surgery.
86%
86%
84%
82%
82%


Mean intra-operative blood loss = 575 ± 524 mL
24 hr post-operative blood loss = 998 ± 595 mL
Blood Product Usage
5.6 ± 3.8 units RBCs
8.6 ± 7.2 units platelets
6.0 ± 4.7 units FFP
80%
78%
76%
Day 7
Day 30
Day 84
Time
Koster et al., (2007) Bivalirudin During Cardiopulmonary Bypass in Patients With Previous or Acute Heparin-Induced Thrombocytopenia and Heparin Antibodies:
Results of CHOOSE-ON Trial The Societ y of Thoracic Surgeons 83:572-577
The EValuation of patients during coronary Artery Bypass Graft Operation:
Linking UTilization of Bilvalirudin to Improved Outcomes
and New Anticoagulation Strategies.

Randomized, open-label, multicenter trial.Published March 2006 in the Journal of Thoracic and Cardiovascular Surgery.

21 institutions enrolled 150 patients in the United States and Germany.
 101 were randomized to Bivalirudin arm

49 to Heparin-Protamine reversal arm.

Clinical Outcomes:
 Procedural success rates at 7 days/discharge were:
94.9% (Bivalirudin grp) vs. 96.2% (Heparin grp).

Major bleeding events at day 7/discharge occurred in:
6.1% (Bivalirudin grp) vs. 1.9% (Heparin grp).

Transfusion rate was:
58.2% (Bivalirudin grp) vs. 59.6% (Heparin grp).
Dyke, et al., (2006) A comparison of bivalirudin to heparin with protamine reversal in patients undergoing cardiac surgery with cardiopulmonary bypass:
The EVOLUTION-ON study. The Journal of Thoracic and Cardiovascular Surgery. 131:533-9

Dosing for Bivalirudin with an intial bolus dose of 1.0
mg/Kg followed by 2.5 mg/Kg/hr during
cardiopulmonary bypass, and 50 mg added to the
pump by the perfusionist.

Additional doses of 0.1-0.5 mg/Kg to maintain ACT >
2.5x baseline (routine institutional values.

No incident of thrombosis in oxygenator, arterial
line, or cardioplegia line.

In 6 cases clot was observed in the cell salvage
device (separate from CPB circuit)

Atrial fibrillation was reported in 9.6% of patients
receiving heparin and 9.2% of patients receiving
Bivalirudin.

Acute renal failure occurred in 2 patients in the
heparin and bivalirudin groups, respectively (3.8% vs
2.0%)
Post-op chest tube output was higher for the
Bivalirudin treatment group at 2 hrs (p=0.009)
However was NOT statistically significant
between groups at 24 hrs (p =0.13)
Bilvalirudin – ECT or ACT?

How the Ecarin Clotting Time Test works:
The TIM- ECT test uses a flat test card containing dried
agents and thrombolytic assessment system (TAS) (Bayer
Diagnostics, Rapid Point)
Test card is inserted into instrument, a drop of blood is
placed on the reaction chamber on the card.Reagents
are rehydrated (including ecarin, and paramagnetic iron
oxide particles).

Iron particles are subjected to oscillating magnetic field
under the card.

Formation of fibrin clot restricts the movement of these
particles (detected by the analyzer’s infared optical system)
allowing calculation of clotting time.

Ecarin activates prothrombin producing meizothrombin :
with excessive hemodilution resulting in prolonged ECT
times, due to diluted prothrombin levels.

Fabrizio, and colleagues in 2001, successfully used ECT
and lepirudin during CPB for a patient undergoing coronary
artery bypass grafting.
Bilvalirudin – ECT or ACT?

ECT (Ecarin clotting time) vs. ACT (Activated clotting
time) significant correlation differences with
bilvalirudin concentration (Casserly, 2004)

Thrombin inhibitor management (TIM) has been
suggested to be more accurate with ECT rather
than ACT anticoagulation management.

Multi-center study, 170 patients undergoing PCI, blood
samples were taken at 6 different time points measuring
ECT, and ACT (using Hemochron Jr.)

For each sample, ECT, ACT and bilvalirudin concentration
were determined.

Correlations were 0.96 for ECT citrated, 0.93 for ECT non
citrated, 0.90 with ACT

At therapeutic levels of bilvalirudin, correlation coefficients
were 0.75, 0.59, and 0.37 respectively.

Therefore ECT would be a much better indicator of
bilvalirudin concentration during CPB.
Lepirudin- Refludan®

Direct thrombin inhibitor (DTI)

Is a recombinant form of hirudin aka. r-hirudin (which comes
from the cloning and expression of yeast cells) is a 65 amino
acid peptide.

Elimination half life = 0.8-2.0 hours in patients with normal
renal function (exclusively renal elimination) in patients
with renal impairment you have prolonged lepirudin
concentrations in the plasma which result in prolonged
leeding post-operatively.
 Dependent on creatinine clearance.
 Has stable pharmacokinetics.

Requires ECT monitoring = ecarin clotting time is required
which is not a point of care testing coagulation assay
available in the cardiac operating room (In Canada can be
requested on humanitarian grounds for acute HIT for CPB–
Bayer® Diagnostics)
 Shows linear correlation with plasma r-hirudin levels.

No antidote

Anaphylaxis with repeat administration

Antibodies to r-hibrudin are reported in 56-74% after 10
days, but do not appear to cause an allergic reaction
Lepirudin- Refludan®

CPB Dosage:
 Initial bolus of 0.25 mg/Kg given 10 mins prior to CPB

A bolus of 0.20 mg/Kg should be added to the pump prime.

A continuous infusion of 0.5 mg/min should be maintained until 15-30
mins before CPB is terminated.

Supplemental dosages (5-20 mg) to maintain plasma levels >
3.5ug/mL (as determined by ECT)

After CPB 5mg of lepirudin is added to the pump circuit volume to
prevent clotting.
(Cheng, D. et al., 2006)

Literature:
1) Largest study involving the use of Lepirudin in patients with
previous acute or HIT reported surgery without thrombosis in
95% of patients.
2) Reports of excessive bleeding post-operatively.
3
UFH + Prostacyclin Analogue
or Tirofiban

Prostacyclin Analogue: Epoprostenol (Arixtra®) or Iloprost
- Two reports using UFH + epoprostenol, one including 9 patients, had
favorable outcome in 100% of patients.

Tirofiban (Aggrastat®): Antiplatelet Agent
- platelet glycoprotein IIb/IIIa antagonist
- In a report using Tirofiban there was successful outcome in 44 of 47 patients.
However the manufacturer does not recommend use in cardiac surgical
patients as there have been reports of fatal bleeding in two patients with
anuria.
- 10ug/Kg bolus and then continuous infusion (0.15ug/Kg) + full dose UFH has
provided effective anticoagulation during CPB without any TEC
(Koster, 2001)
- hemofiltration decreases Tirofiban concentration during CPB
Koster, et al., (2001) One-year experience with the platelet glycoprotein IIb/IIIa antagonist tirofiban and heparin during cardiopulmonary bypass in patients
with heparin induced thrombocytopenia type II. J Thorac Cardiovascular Surgery 122:1254-1255
Danaparoid Sodium – Orgaran®

Low molecular weight heparinoid (6,000 Da) derived from porcine
intestine mucosa

Is a mixture of polysulfated glycosaminoglycans (84% heparan
sulfate, 12% dermatan sulfate, and 4% chondroitin sulfate)
derived from porcine intestinal mucosa.

Mechanism: accelerates the activity of ATIII against factor Xa and
factor IIa, which is similar to that of heparin but which greater
effect on anti-Xa. It is a potent thrombin inhibitor that binds to PF4
and in high doses inhibits platelet activation by the HIT-IgG.

Cross-reactivity of HIT-IgG for Danaparoid leading to
exacerbation of HIT has occurred in up to 10-20% (Gurbuz,
2004), therefore screening test should be done prior to use.

Long t1/2 = 25 hrs (anti-Xa activity) with no effect on PTT and INR.

Half life = 7-8 hrs for the inhibition of thrombin formation.

Major route of excretion is through the kidney, and it is not
metabolized by the liver.

No specific antidote.

No longer available in USA (2002), but still available in Canada
and Europe.

ACTs are unsuitable for monitoring.
Danaparoid Sodium – Orgaran®

CPB dosage:





IV bolus = 125U/Kg after sternotomy
Priming dose = 3 U/L
Maintain continuous infusion of 7U/Kg which should be stopped 30 mins
prior to the end of CPB.
IF clots are seen an additional bolus of 1,250 U should be given.
Literature:





Largest clinical trial = 666 HIT patients with high clinical response rate.
Has been used in CPB
Associated with 33% of patients having intraoperative clots, and postoperative severe bleeding when used in cardiac surgery.
Reinfusion of pump blood post-operatively with cell saver is discouraged.
Should be “…used only when other anti-thrombin agents are not
available” (Gurbuz, 2004)
Agatroban – Novastan®

Relatively new direct thrombin inhibitor: Binds
competitively and reversibly inhibiting thrombin
INDEPENDENT of ATIII

Small synthetic peptide (MW 527 Da) derived from Larginine.

Primarily hepatic metabolism (may be used in patients
with renal dysfunction). However in patients with hepatic
dysfunction dosage should be decreased (0.5ug/kg per
min) (Gurbuz, et al., 2005)

No cross-reaction with heparin antibodies

T1/2 = 40-50 mins
Agatroban – Novastan®

Monitored by aPTT to 1.5-3.0x baseline

ACT = 300-400 seconds OPCAB (repeat every 15 mins) has
been recommended, and 400-600 with CPB.

In pediatric patients ACT>999 sec was associated with major
bleeding.
(Hursting, 2006)

ACT as a monitoring tool – does not appear to be reliable.
 Reports of ACT >600 sec result in excessive bleeding post
op (Martin; 2007), however in other
reports ACT > 800 sec have shown to have
thrombosis in CPB circuit (Nielsen, 2006).

CPB Dosage:
 Initial dose of 0.1mg/Kg should be administered prior to
CPB
(Cheng, D. et al., 2006)
 No requirement for additional drug in prime.
 Continuous infusion of 5-10ug/Kg/min during CPB (or
adjusted) to maintain ACT of 400-600 secs.
(Cheng, D. et al., 2006)
 40mcg/kg/min in healthy subjects produces anticoagulant
effect
Cheng, et al., (2006)
Hursting, et al., (2006) Argatroban anticoagulationin pediatric patients: a literature analysis. J Pediatric Hematol. Oncol.28:4-10
Martin, et al., (2007) Argatroban for anticoagulation in cardiovascular surgery. Eur J. Hematol, 76;161-166
Neilsen, et al., (2006) Agatroban, bilvalirudin, and lepirudin to not decrease clot propagation and strength as effectively as heparin activated antithrombin in vitro. J. Heart Lung
Transplant. 25;653-663
Ancrod – Arvin®

Direct thrombin inhibitor
Mechanism: Reduced fibrinogen levels and blood
viscosity.
Hepatic metabolism (may be used in patients with
renal dysfunction). However in patients with hepatic
dysfunction dosage should be decreased.
T1/2 = 40-50 mins
Monitored by aPTT to 1.5-3.0x baseline, as well as
fibrinogen levels.
ACT = 300-400 seconds
40mcg/kg/min in healthy subjects produces
anticoagulant effect
No cross reactivity with heparin induced antibodies

Literature:







Management of HIT for Pts
Undergoing Cardiac Surgery
Management depends on if patient undergoing surgery is a previous HIT
patient or Acute/Subacute HIT patient :
Acute HIT:

Thrombocytopenic + HIT antibody positive
v.
Using UFH + antiplatelet agent tirofiban (Aggrastat®) [Grade 2C]
vi.
Use danaproid for off-pump CAB vs UFH with on-pump CABG with postive PF4-heparin
antibodies in pts with acute or sub-acute HIT.
Subacute HIT:
•
Platelet count recovery + continuing HIT antibody positive:
i. Recommendation is to delay surgery if possible until HIT antibodies
then use heparin rather than a non-heparin anticoagulant. [Grade 1C]
are negative,
ii. If surgery cannot be delayed until that point, then it is suggested that a non-heparin
alternative be used over an UFH. [Grade 2C]
Warkentin, T.E., et al. (2008) Treatment and Prevention of Heparin-induced Thrombocytopenia. Chest; 133;340S-380S
Summary of Alternative
Anticoagulants for Cardiac Surgery
Table 4, taken from: Gurbuz, et al. (2005) Heparin Induced Thrombocytopenia in the Cardiovascular Patient: Diagnostic and Treatment Guidelines, Eur. J of Card-Thor Surg.
27:138-149
Misnomers Re: HIT & Heparin

One is usually reluctant to expose a patient with known, or strongly suggested,
hypersensitivity to the drug in question.

There are several reasons why this should not be the case with regards to
heparin re-administration in patients with HIT.
a)
b)
c)
d)
e)
f)
There is no trend to earlier onset of HIT with secondary exposure to heparin in patients
with a history of heparin exposure previously.
Among patients with rapid onset HIT – pre-existing HIT antibodies can be tested for in
advance of subsequent exposure to heparin.
There is a stronger association to HIT with recent (<100 days) rather than remote (>100
days) prior heparin exposure.
HIT antibodies are transient with a median time to disappearance being 50-80 days.
Re-administering heparin in patients with previous HIT antibodies which no longer were
present, reoccurrence of HIT antibodies did not occur.
In instances where HIT antibodies were regenerated, they did not occur sooner nor at
higher levels than the previous HIT event.
Heparin Re-challenge?

Repeat heparin exposure is an option for patients with previous acute or subacute
HIT, especially if >100 days prior.

At this point HIT antibodies are usually undetectable or weak, and are not
regenerated by the brief exposure required during cardiac surgery.

Ideally clinicians should ensure that HIT antibodies are no longer detectable
serologically prior to heparin re-exposure.

Patients with recent HIT whose platelet count has recovered, but who still have
detectable HIT antibodies (“subacute HIT”), are at risk of developing rapidonset HIT on heparin reexposure, unless a washed platelet activation assay (eg,
SRA, HIPA test) is negative and the antigen assay is only weakly positive or
strongly positive because of nonplatelet-activating (IgM, IgA) antibodies.