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Aortic Valve Replacement in the
Setting of Heparin Induced
Thrombocytopenia (HIT) with End
Stage Renal Disease
SCOTT M. NOESGES L.P., C.C.P.
BAYLOR UNIVERSITY MEDICAL CENTER
DALLAS, TEXAS

Criteria for Diagnosing HIT

Pathogenesis of HIT
• In select patient populations (e.g.,
cardiac surgery) exposed to heparin,
up to 50% can develop heparindependent
antibodies.[24] Up to 5% of
all patients exposed to heparin
develop HIT.[21] Thromboembolic
complications have been reported to
occur in half to two thirds of patients
with HIT, including those with and
without thrombosis at
diagnosis.[3,21,25] The thrombotic
complications of heparin-induced
induced
thrombocytopenia (HIT) can be
catastrophic (see Table 2).[7,10,18,21]
Clinical data have shown that
approximately 20% of patients with
thrombotic complications lose a
limb, and about 30% die without
appropriate alternative nonheparin
therapy.[10,18]

Platelet activation and
aggregation
Chun, R. et al. Anesth Analg 2002;95:879-888

Complications of HIT
• Deep vein thrombosis
• Pulmonary embolism
• Myocardial infarction
• Occlusion of limb arteries (possibly resulting in
amputation)
• Cerebrovascular accidents (stroke, TIA)
• Skin necrosis
• Ischemic organ damage (e.g., adrenal, bowel, spleen,
gallbladder or hepatic infarction; renal failure)
• Death

Baxter Heparin Issues Could Boost
Sales of fAlternative ti Blood dThinners

• Synthetic
• 526.66 daltons
• Thrombin-specific anti-thromboticthrombotic
• Direct Thrombin Inhibitor
• No risk for heparin-induced thrombocytopenia
• No risk for heparin induced thrombocytopenia
• Does not require AT III
• Does not activate platelets
• Intended for use with platelet inhibitors
• Aspirin, Integrilin, etc.

Warning
Cardiac Therapy
The safety and effectiveness of Argatroban
for cardiac indications outside of
percutaneous coronary intervention ti (PCI)
in patients with HIT have not been
established.

Case Report
May 23, 2008

Patient History
• 55 year old African-American female
• Aortic Stenosis
• EF 75%
• End stage renal disease
• Hypertension
• Atrial Fibrillation
• Diabetes Type II
• Stroke
• Morbid Obesity
• Tested positive for (PF4) platelet factor 4 / heparin
antibodies
• Presented to Baylor for kidney transplant

Patient Information
• BSA 2.00 • Drug Allergies
• 62 inches (157.5 centimeters)
• 201 pounds (91.8 Kilograms)
• Lab Values
• HCT 31.5 %
• WBC 8.4 K/cc
• K 3.8 mmol/L
• Total Bilirubin 0.4 mg/dl
• Platelet 497 k/cc
• Creatinine 8.3
• BUN 49
• Porcine Heparin

Pump Circuit
• Terumo System 1
• Terumo Capiox SX 18 with hard-shell venous
reservoir
• Terumo X-Coated tubing (Do not use Medtronic
circuit due to heparin bonding)
• Hemofilter
• 3/8 inch arterial line with A-V Bypass Loop
• Open once every 5 minutes
• Terumo arterial line filter 38 u
• ½ inch venous line

• 3/16 inch line for CO 2 infusion into the
thoracic cavity
• Terumo CDI 500
• H/S Cuvette
• 510 H arterial sensor not used
• Quest MPS
• Cobe Brat 2
• Anit-coagulant used Sodium citrate
• Drip rate 1 cc / sec
• 90 % removal

Sodium Citrate
• In 1914, the Belgian
doctor Albert Hustin
and the Argentine
physician and
researcher Luis Agote
successfully used
sodium citrate as an
anticoagulant in blood
transfusions.
• Haemonetics 4% Sodium Citrate -
-Anticoagulant--Cleared for Sale
In US; Company's First FDA...
• Publication: Business Wire
Date: Monday, March 13 2000

Perfusion Circuit

A-V Bypass Loop

Prime
• 2PRBC’s
• 0.8 Liters of crystalloid
• 400 cc Lactated t Ringers
• 400 cc Normosol-R
• 12.5 g 50 cc Albumin
• 1 Amp NaHCO 3
• 12.5 g 50 cc Mannitol
• 16 mg Argatroban

Sieving Coefficient
• Defines or describes the movement of a drug or
solute across a membrane
• Dose / Volume of Distribution / Protein Binding
are major influences
• Most valuable measurement defining ability to
remove a drug or solute via hemofiltration
• Pore size is 65,000 daltons

Calculating Sieving Coefficient
Calculation:
( 2 x Drug Concentration in Ultrafiltrate )
S = __________________________
( Filter Inlet Concentration + Filter Outlet concentration )
or
( Drug Concentration in Ultrafiltrate )
S = ___________________
( Drug Concentration at Filter Inlet )

Argatroban Dosing and
• Anticoagulation
Monitoring
i
• Loading dose 175 mcg/kg (over 3 – 5 min)
• Total of 16mg
• I. V. 3 mcg/kg/min
• Manufactures Recommendations
• Loading dose 350 mcg/kg (over 3 – 5 min)
• I.V. 2 mcg/kg/min
• Anticoagulation testing
• I-Stat with Kaolin
• Rapid Thromboelastograph (RapidTEG)
• Tests would be run every 15 min
• ACT 400-500 sec

Dosing Considerations
• Drug is metabolized in the liver
• Hydroxylation and aromatization
• Half-life 39 – 51 min
• Patients with moderate liver impairment
• Loading dose should be reduced to 0.5 mcg/Kg/min
• Consider alternative drug Angiomax
• Patients with renal impairment
• No adjustment needed

Special Considerations
• Continuous blood flow throughout the entire
circuit
• Blood should not remain static for more than 5 minutes
• Low circulating blood volume in the venous
reservoir (300 cc)
• Increased volumes lead to static areas leading to
thrombogenic events
• Hemofiltration will sieve off the drug

Monitoring: TEG Symbols
• R – Initial fibrin strands
• K – time for clot to develop
• Angle – fibrin i build-up (fibrin i function)
• MA – maximum clot strength (platelet
function)
• G – Clot strength
• ((% inhibition (G)) – G) = Net Clot Strength

Baseline TEG

On CPB
• Loading Dose given @ 1406h
• I-Stat ACT 796 sec
• Baylor Protocol
• Flow Cardiac Index 2.4 - 1.8
• Temperature range Drift 30.0-37.0
• ABGs, Blood Chemistries and Hemostasis
• CDI 500 ABG
• I-Stat Kaolin ACT
• Laboratory analysis

30 min Post Loading Dose
• I-Stat ACT
796 sec
• RTEG ACT
394 sec
• I.V. 1.5
mcg/Kg/min

• I.V. adjustment to 3.0 mcg/Kg/min ACTs
were analyzed 1455h
• I-Stat 486 / 542 sec
• Values are within CPB target range
• Patient was placed on CPB @ 1458h
• ACT analyzed 1510h
• I-Stat values 317/ 303 sec (15 min)

Venous Reservoir Thrombosis
1525h (12 min)

Argatroban Procedure

Platelet-Fibrin Clot

Revaluation
• Net Clot Strength is 16.9 (41.1% inhibition)
• Very high
• High end of normal MA 78.9
• (platelet function)
• Low end of normal Angle 61.6
• (fibrin function)
• What strategy do we employ to prevent more or
increased thrombogenic activity in the Pump?

Therapeutic Drugs
• Redose 11mg of Argatroban bolus @ 1515h
• 115mcg/Kg
• Maintenance Dose
• Increased to 6 mcg/kg/min
• Increased to 30mcg/kg/min
• Decreased to 15 mcg/kg/min
• Idea of GPIIb/IIIa inhibitor to suppress platelet function
• short-acting like Integrilin
• 0.25 mcg/Kg/min
• 1/8 normal dose
• 3 – 4 hours for full therapeutic dose to cleared
• 50% is renal cleared

30 min Post Argatroban Bolus
• I-Stat ACT >1000 sec

30 min Prior Termination CPB
• I-Stat ACT >1000 sec

CPB
• Total Bypass 98 minutes
• Total Cross Clamp 89 minutes
• No Urine Output
• Hemoconcentration 0 on pump
• Total Blood 2 PRBC’s

RTEG and I-Stat Analysis
1200
1000
800
600
I-Stat
RTEG
400
200
0
1435 1455 1515 1536 1548 1600 1617 1624 1630 1650

Time ACT ACT2 RTEG Angle MA G Hct ULF
1435 796 ------ 394 61.6 78.9 18.6 32 ------
1455 542 486 ------ ----- ----- ------ ------- ------
1515 313 356 ------ ----- ------ ------ 26.1 ------
1536 746 >1000 ------ ----- ------ ------ 26.0 ------
1548 >1000 >1000 885 39.2 79.1 14.3 26.3 ------
1608 >1000 >1000 425 60.3 80.9 21.22 26.3 ------
1631 486 >1000 ------- ----- ------ ------ 26.0 ------
Post 500
1759 633 767 ------- 51.8 82.8 24.1 ------ ------
1914 >1000 767 316 68.5 78.5 18.2 ------ ------

Quest MPS Post CPB

• I-Stat ACT 633 / 767
ICU TEG

ICU TEG RESULTS
• Prolonged R Time due to circulating
i
Argatroban
• TEG reveals platelet hyperactivity
y
• AA Inhibition 41.7 %
• ADP Inhibition 36.33 %
• G value (Net Clot Strength) 15.4 Kd/sc

• I-Stat TEG >1000 / 767
ICU TEG

Transfusion Requirements
• OR
• Autologous 750cc
• 2PRBC’s
• ICU
• 8 PRBC’s
• 4 FFP
• 10 Cryo

Concluding Thoughts
• I-Stat ACT with Argatroban did not follow
clinical activity
• RTEG ACT was more indicative of clinical
case
• In retrospect Argatroban bolus should not
have been administered
• GP IIb/IIIa antagonist should have been
administered
• Integrilin

Contact Information:
Scott Noesges L.P., C.C.P.
(214) 824 – 2510
Email: Denied