1. Heparin Induced Thrombocytopenia
Daniel H. Kett, M.D.
Professor of Clinical Medicine
University of Miami School of Medicine
Department of Veterans Affairs Medical Center

2. What is this?

3. Case Study
57-year-old female admitted with pneumonia and respiratory failure
Admission platelet count was 230,000
Prophylactic UFH 5000 BID
On the 7th ICU day, the patient arrested
Platelet count 110,000
Pulmonary angiogram
Thrombolytic therapy initiated
ELISA-PF4 assay positive
Patient expired

4. Heparin-Induced Thrombocytopenia (HIT)
Immune-mediated allergic reaction to heparin/platelet factor 4 complex
Thrombocytopenia
Platelet count <100,000 or a 50% drop from baseline
Others have used a platelet count that has decreased by at least 30% from baseline or is less than 150,000/uL.
Onset generally 5-to-14 days after heparin
With or without thrombotic complications
Diagnosis is clinical-pathological
Any type of heparin or route of administration can lead to HIT
Thrombosis
Thrombocytopenia
HIT (PF4) antibody positive
Warkentin TE. Chest. 2004; 126:311S-337S

5. Molecular weight (daltons)
PF4 Tetramer
At a neutral pH, a ring of positive charges is displayed on the PF4 tetramer
Negative charges on the linear heparin polysaccharide enable it to interact with the PF4
Heparin of sufficient polysaccharide size, spans the circumference of the PF4 molecule
Molecular weight (daltons)
5,400
Warkentin TE. Br J Hemat. 2003;
Davoren A, et al. Am J Hematol. 2006: 81:36-44

6. Factors Influencing the Frequency of HIT
Influence
Type of heparin
Bovine UFH > Porcine UFH > LMWH Intravenous > subcutaneous Therapeutic-dose > prophylactic-dose
Patient population
Post surgery > medical > obstetrical
Duration of heparin
Each day of heparin use beyond day 5 increase risk of HIT
Sex
Female > male
Adapted from Warkentin TE. British Journal Hematology. 2003; 121:

7. Incidence of Heparin Induced Thrombocytopenia: According to Population
Therapy
Risk
Clinical Population
PF4-HIT Ab
HIT
UFH
High
Orthopedic surgery
14%
3 - 5%
Intermediate
Cardiac Surgery (adult/children) %
1 – 2%
General Medical
8 - 20% %
Neurology
PCI for ACS
Acute hemodialysis
Low to Rare
General Pediatrics % %
Pregnant women
Chronic hemodialysis
LMWH
2 – 8%
1 – 0.9%
unknown
0 – 1%
Adapted from Arepally GM et al. N Engl J Med. 2006; 355:

8. Heparin Induced Thrombocytopenia: LMWH vs UFH
665 patients requiring hip surgery:
UFH vs LMWH DVT prophylaxis study
387 patients tested for heparin-dependent IgG
Heparin-dependent IgG antibodies:
7.8% UFH 2.2% LMWH
Heparin-induced thrombocytopenia
2.7% UFH 0% LMWH
89% (8/9) of patients with HIT developed thrombotic events compared to 18% of patients without HIT
Warkentin TE, et al. NEJM. 1995; 332:

9. Heparin-antibody post CABG
Study
Frequency
Visentin et al (1996)
39%
Trossaert et al (1998)
27%
Pouplard et al (1999)
25%
Warkentin et al (1999)
50%
Francis et al (2002)
42%

10. Incidence of HIT in Medical Patients Treated with LMWH
1754 consecutive patients:
17 medical centers
LMWH for VTE prophylaxis or treatment
HIT diagnosis in 14 patients (0.8%):
Platelet count drop of 50% and anti-PF4 antibody
More frequent in patients who had previously received LMWH or UFH
Thrombotic complications
29% (4/14) in HIT group versus 2.4% (41/1740)
Prandoni P, et al. Blood. 2005; 106:

11. Frequency of HIT in Critical Care
Incidence of thrombocytopenia in ICUs is %
15% (n=40) of 748 consecutive patients in combined ICU/CCU met clinical criteria for HIT :
≥ 2 consecutive platelet counts below 150,000 or a ≥ 33% decrease in platelet counts 5 or more days after heparin exposure
Samples for diagnostic testing available for 32 of these 40 patients
Among these 32 patients meeting clinical criteria, and ELISA (+) anti-PF4 AB (frequency of HIT diagnosis = 3.1%)
One patient tested positive by SRA, (frequency of 0.4%)
Verma AK, et al. Pharmacotherapy. 2003;23(6):

12. Estimating the Pretest Probability of HIT
Points 2 1
Thrombocytopenia
> 50% fall or platelet nadir 20,000 to 100,000
30-50% fall or platelet nadir 10,000 to 19,000
Fall < 30% or platelet nadir < 10,000
Timing of platelet count or other sequelae
Onset between 5 and 10 days or < 1 day if heparin exposure within 100 days
Onset of thrombo-cytopenia after day 10
Platelet fall < 5 days without prior heparin exposure
Thrombosis or other sequelae
New thrombosis, skin necrosis, post heparin acute systemic reaction
Progressive or recurrent thrombosis, erythematous skin lesions, suspected thrombosis
None
oTher causes of thrombocytopenia
No other causes
Possible other causes
Definite other causes
Pretest probability score: 6-8 = high 4-5 = intermediate 0-3 = low
Adapted from Warkentin TE et al. Current Hematology Reports. 2003; 2:

13. The 4Ts for HIT in ICU Patients
Combined results of 3 prospective studies enrolling critically ill patients who were investigated for HIT if platelets fell to less than 50 × 109/L or if platelet counts decreased to less than 50% of the value upon intensive care unit admission.
Of 528 patients: 50 (9.5%) were investigated for HIT
39 (78%) of 50 of these patients were scored as “low probability” by 4Ts score and none had a positive SRA.
Of 49 patients who underwent SRA testing because of thrombocytopenia, only 2 (4.1%) had a positive SRA
1 with a moderate 4Ts score and 1 with a high 4Ts score.
Therefore, the overall incidence of HIT confirmed by SRA was 2 (0.4%) of 528 patients.
Crowther MA, et al. Journal of Critical Care. 2010; 25:

14. Frequency of HIT in Pediatrics
Greater than 70 cases reported in the literature
Newborns and infants
Generally in pedi-ICU
After undergoing cardiac surgery
Typical onset pattern occurred, but rapid onset noted
Median platelet nadir 54,000
Arterial and venous thrombosis
Mortality 15%
Limb amputation 6%
Residual hemiplegia 2%
Teenagers receiving heparin for thrombosis
Similar to adults
Risch L, et al. Intensive Care Medicine. 2004; 30:
Klenner Af, et al. Thrombosis& Hemostasis. 2004; 91:

15. Severity of Thrombocytopenia and Thrombotic Complications in HIT
Adapted from Warkentin TE et al. Br J Hematol. 2003; 121:

16. Cumulative Frequency of Thrombosis
100 90 80
52.8% 70 60
Cumulative frequency of thrombosis (%) 50 40
N = 62 30 20 10 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30
Days after isolated HIT recognized
Patients with thrombocytopenia have approximately a 50% risk
of developing a thrombotic event within the first 30 days following diagnosis
Warkentin TE, et al. Am J Med. 1996;101:

17. Rapid Onset HIT Rapid onset HIT
Platelets fall within 24 hours of starting heparin
Patients had recent exposure to heparin
Persistent circulation HIT antibodies
Within past 100 days
Especially within the last 30 days
Warkentin TE. N Engl J Med. 2001;344(17).

18. Warkentin TE. N Engl J Med. 2001;344(17).

19. Warkentin TE. N Engl J Med. 2001;344(17).

20. HITTS: Heparin-Induced Thrombocytopenia with Thrombosis syndrome
30%-70% of all HIT patients develop thrombotic complications (HITTS)
Amputation: ~20%
Death: ~20% to 50%

21. Additional Clinical Issues Associated With HIT
Deep venous thrombosis (50%)
Pulmonary embolism (25%)
Skin lesions at injection site (10%-20%)
Acute limb ischemia (5%-10%)
Warfarin-associated venous limb gangrene (5%-10%)
Acute thrombotic stroke or myocardial infarction (3%-5%)
Surgery
Venous thrombosis: more common in orthopedic surgery
Arterial thrombosis: more common in cardiac procedures
Warkentin. Thromb Haemost. 1999;82:

22. Pathophysiology of anti-PF4 antibodies in HIT
PF4 25% protein conteny in the platelet alpha granule. Highly positively charged….part of it’s physiological role (in addition to Chemokine roles) in neutralizing heparan sulfate proteoglycans on the endothelial surface at sites of endothelial injury. PF4 was developed as a drug to neutralize heparin….bad idea.
Ahmed I et al. Postgrad Med J 2007;83:
©2007 by The Fellowship of Postgraduate Medicine

23. Laboratory Assays to Confirm HIT Following Initiation of Therapy
Component measured
Advantages
Disadvantages
Serotonin-release assay (SRA)1-3
14C-serotonin released from platelets
Highly sensitive and specific
Costly, time-consuming, and technically demanding (involves radioisotopes)
Heparin-induced platelet aggregation assay (HIPA)1-3
Platelet aggregation
Highly specific, easy
Low sensitivity and technique-dependent
Enzyme-linked immunosorbent assay (ELISA)1-3
Presence of heparin-dependent antibodies
Highly sensitive, easy, rapid turnaround time
Low specificity (false positives)
PIFA® Heparin/PF4 Rapid Assay4
Presence of PF4 antibodies
Highly sensitive and specific, easy and rapid turnaround time
Fairly new with limited clinical history, positive and negative controls not provided
Currently, there are several laboratory assays available to confirm a clinical diagnosis of HIT. Because of the high thrombotic risk associated with early HIT, initiation of therapy for suspected HIT should not wait for laboratory confirmation, as the results may not be known immediately.1-3
The serotonin-release assay, or SRA, and the heparin-induced platelet aggregation assay, or HIPA, are functional tests that measure the ability of heparin to activate platelets. While the SRA is highly sensitive and specific, it is technically demanding and time-consuming. Due to its simplicity, the HIPA is used more often than the SRA; however, it is limited by low sensitivity.1-3
The enzyme-linked immunosorbent assay, or ELISA, measures antibodies that react with the PF4-heparin complex. Although the ELISA provides rapid results, is easy to use, and highly sensitive, it can give false positive results.1-3 The particle immunofiltration assay, or PIFA, is a fairly new antigenic assay that detects PF4 antibodies. The PIFA is highly sensitive and specific, and provides rapid results; however, it does not provide positive or negative controls.4
References
1. Fabris F, Ahmad S, Cella G, Jeske WP, Walenga JM, Fareed J. Pathophysiology of heparin-induced thrombocytopenia. Clinical and diagnostic implications–a review. Arch Pathol Lab Med. 2000;124:
2. Messmore HL, Jeske WP, Wehrmacher WH, Walenga JM. Benefit-risk assessment of treatments for heparin-induced thrombocytopenia. Drug Safety. 2003;26:
3. Leo A, Winteroll S. Laboratory diagnosis of heparin-induced thrombocytopenia and monitoring of alternative anticoagulants. Clin Diagn Lab Immunol. 2003;10:
4. PIFA® Heparin/Platelet Factor 4 Rapid Assay [package insert]. Thorofare, NJ: Akers Biosciences, Inc.; 2005.
1. Fabris, et al. Arch Pathol Lab Med. 2000;124: Messmore HL, et al. Drug Safety. 2003;26: Leo A, et al. Clin Diagn Lab Immunol. 2003;10: PIFA® Heparin/Platelet Factor 4 Rapid Assay [package insert]; 2005. 23

24. Classes of Clinical Diagnostic tests Two broad categories
FUNCTIONAL TESTS* (no FDA-cleared tests):
Serotonin Release Assay (SRA)
Heparin Induced Platelet Aggregation assays (HIPA)
Flow cytometry
*measure platelet activating properties of anti-PF4 Ab
ANTIGEN TESTS (FDA-cleared tests):
PF4 bound to substrates aimed at detecting Ab (IgG/M/A)
PF4/heparin ELISA (Stago)
PF4/polyvinyl sulfonate ELISA (GTI)
PF4/heparin ELISA (Aniara)
PF4 /microparticles PIFA® fluid phase (Akers Biosciences)

25. Functional Tests Serotonin Release Assay (the “Gold Standard” test)
Dependent on fresh donor platelets - very difficult to standardize
Non-routine reagents and expertise required (e.g. C14 serotonin)
Slow (several days) turnaround time
Results correlate best with clinically significant anti-PF4 antibodies
Platelet Aggregation tests
Dependent on fresh donor platelets making it very difficult to standardize
Time consuming and not applicable to large numbers of patients
Lower sensitivity compared to other tests although good specificity
Flow Cytometry tests
Least utilized functional test; not practical for most laboratories

26. Serotonin Release Assay (SRA) Not so “Golden” gold standard
Will never be widely available because of practical considerations previously described (TAT, donor platelets, radioactivity, etc.).
Method for performing SRA is not standardized.
Variability from lab to lab in protocols, such as reagents, interpretation of results, use and interpretation of controls, etc.
Antibodies other than anti-PF4 specific Ab can cause platelets to aggregate.
BUT, when available, can be a useful laboratory result in difficult clinical scenarios

27. Serotonin Release Assay (SRA) Not so “Golden” gold standard
Positive SRA results have been reported in critically ill patients without prior or current heparin exposure
Suggesting either naturally occurring antibodies or false positive results in these patients
There may exist a relationship between bacterial sepsis and anti- PF4/heparin antibodies
Non-platelet-activating PF4/heparin antibodies have been found to occur in:
The general population of blood donors without heparin exposure
In patients with periodontal disease

28. Antigen - based tests Antigen-based tests:
Reagents can be standardized and shared between laboratories
Not dependent on platelet donors
But:
Native antigenicity of PF4 is varied because antigen preparations differ between manufacturers
ELISA: proteins are dehydrated onto plastic surfaces
PIFA: antigen in fluid phase
Discuss later the significance of antigen preparation

29. Diagnostica Stago anti-PF4 test
Antigen: PF4/heparin
Qualitative Test (POS/NEG), but OD often reported

30. GTI anti-PF4 test Antigen: PF4/Polyvinylsulfonate
Qualitative Test (POS/NEG), but OD often reported

31. Comparison between Two Widely Used Anti-PF4/Heparin ELISA Tests
142 archived patient sera were tested in the same freeze - thaw cycle with GTI and STAGO platforms.
Manufacturer recommended positive breakpoints differ between platforms.
GTI positive test = optical density (OD) >
STAGO positive test = OD range = ).
Overall method agreement between GTI and STAGO was 77% (110/142).
Optical Density (OD) n
Concordance
<0.4 66
95%
0.4 – < 1.1 35
31%
>1.1 41
89%
Montague N, et al. (abstract). Sept College of American Pathologists Chicago, Ill

32. Relationship between positive SRA and ELISA optical density (OD)
The relationship between a positive SRA result for five categories of OD reactivity for two commercially available ELISAs.
405 total patients
OD ranges studied (Units)
<0.40
0.40–<1.00
1.00–<1.40
1.40–<2.00
≥2.00 OD
A weak to moderate-positive result (0.40–<1.00 OD units) by ELISA indicated a low probability (≤5%) of a strong positive SRA (>50% release)
Less than 2% of patients had SRA of 20 – 50%
The probability of PF4-ELISA antibodies being strongly positive by SRA reached ≥50% only when the OD level was ≥1.40 units.
Warkentin TE et al. J Thrombo Haemostasi. 2008; 6:

33. Akers Biosciences PIFA® test
Antigen: PF4 directly coupled to fluid-phase microparticles
Qualitative Test (POS/NEG)

34. PIFA® Assay Principle

35. Akers Biosciences PIFA® Heparin/PF4 Rapid Assay
NEGATIVE
POSITIVE

36. Evaluation of the Particle Immunofiltration Anti-Platelet Factor 4 (PIFA) Rapid Assay
Patients in the MICU were screened daily for thrombocytopenia
Platelet count that has decreased by at least 30% from baseline or is less than 150,000/uL
143 consecutive patients had anti-PF4 laboratory testing
100/143 patients had exposure to heparin
A clinical probability score for HIT known as the “the 4Ts” score was determined
Clinical data was collected for: age, sex, presence or absence of any DVT or PE, length of ICU stay, total hospital stay, vital status at hospital discharge
Andrews D et al. Critical Care 2013; 17:R143.

37. Demographics, Baseline Characteristics and Outcomes
PIFA*
GTI ELISA
Negative
(n=65)
Positive
(n=33)
(n=87)
(n=11)
Age, mean (SD)
56±14
50±12
54±14
51±12
Platelet count
103±50
86±45
100±49
73±45
4Ts score, mean (SD)
3.9±1.1
3.2±1.0
3.7±1.1
Any VTE (n, %)
8 (12%)
2 (6%)
9 (10%)
1 (9%)
LOS ICU (days)*
13±17
12±13
13±16
11±7
LOS Hospital (days)*
22±25
24±25
24±26
Hospital Mortality
16 (25%)
5 (15%)
19 (21%)
2 (18%)
* 2 patients had an inconclusive PIFA test
Andrews D et al. Critical Care 2013; 17:R143.

38. PIFA – GTI correlations
GTI ELISA
Positive
(n=87)
Negative
(n=11)
PIFA Positive (n=33) 7 26
PIFA Negative (n=65) 4 61
Of the 65 patients with negative PIFA results, 61 were negative by GTI ELISA. This represents a 93.8% concordance.
Of the 4 discordant PIFA negative samples (PIFA negative and GTI ELISA positive) the average GTI ELISA optical density was 0.62±0.21
Overall concordance was 78.6% (77/ 98) with most discordant results associated with PIFA positive/GTI negative samples.
Andrews D et al. Critical Care 2013; 17:R143.

39. PIFA – SRA correlations*
PIFA and GTI-ELISA available samples by SRA (Quest Diagnostics).
62 PIFA negative samples had serum for SRA analysis
61 (98.4%) were SRA negative
1 was SRA positive (23% release)
Of the 4 ELISA (+)/PIFA (-) results, all were SRA (-)
Of the 26 ELISA (-)/PIFA (+) results, 3 were SRA (+)
Conclusion: A negative result by PIFA correlates well (94%) with a negative SRA.
Andrews D et al. Critical Care 2013; 17:R143. [Epub ahead of print]

40. * * *
Positive D-Dimer or positive Anti-PF4 are not “Rule In” results and do not confirm the clinically suspected diagnosis - further clinical and/or diagnostic testing may be needed.

41. Management of Suspected Isolated HIT
HIT considered less likely
Pretest probability score < 4
Examples: medical or obstetrical patients, LMWH use, outside normal time frame
Send appropriate PF4 antibodies
Prophylactic dose alternative anticoagulant
Danaparoid 750 U bid or TID subcutaneously
Fondaparinux 2.5 mg QD subcutaneously
Recombinant Hirudin (Lepirudin) 15 mg BID subcutaneously
HIT considered likely
Pretest probability score 4 to 8
Examples: Surgical patients, UFH use, correct time frame
Full dose alternative anticoagulant
Full dose direct thrombin inhibitor
Adapted from Warkentin TE et al. Chest. 2008; 133:340S-380S

42. Fondaparinux in the Treatment of HIT
Fondaparinux is a synthetic pentasacharide with selective anti-Factor Xa inhibition
Inhibiting 1 factor Xa unit may inhibit generation of 50 thrombin units
20 patients with clinical and laboratory criteria for HIT
10 patients received Fondaparinux after DTI
10 patients received Fondaparinux as initial treatment
Dose of Fondaparinux 2.5 mg in 18/20 patients
Average duration of Fondaparinux therapy was 17 days
Average time to platelets recovery 3.7 days
No observed thrombotic complications
Bradner J, et al. Blood. 2004; Abstract 1775

43. Management of Strongly Suspected or Confirmed HIT
Recommend use of an alternative, non-heparin anticoagulant
Danaparoid (Grade 1B)
Lepirudin (Grade 1C)
Argatroban (Grade 1C)
Fondaparinux (Grade 2C)
Bivalirudin (Grade 2C)
Over the further use of UFH or LMWH therapy or initiation/continuation of a VKA (Grade 1B).
Adapted from Warkentin TE et al. Chest. 2008; 133:340S-380S

44. Management of Isolated HIT (Without Thrombosis)
Isolated HIT and HIT with thrombosis have the same pathophysiology
The course of thrombosis in HIT is a continuum, equal numbers of patients develop thrombosis
Initial period of falling platelets
Crossing the threshold of thrombocytopenia
Discontinuation of heparin due to thrombocytopenia
Historically, patients managed with just discontinuation of heparin
25 to 50% symptomatic thrombosis
5% fatal thrombosis
Adapted from Warkentin TE et al. Chest. 2008; 133:340S-380S

45. Direct Thrombin Inhibitors: Pharmacologic and Clinical Parameters
Argatroban
Lepirudin
Bivalirudin
Composition
Synthetic L-arginine derivative
Recombinant hirudin
Synthetic hirulog
Half-life in healthy subjects
40-50 min
1.3 hrs
25 min
Elimination
Hepatic
Renal
Monitoring needed
aPTT, ACT
aPTT
Thrombin-binding*
Reversible
Irreversible
Clot-bound thrombin*
+++ Inhibition
+ Inhibition
++ Inhibition
aPTT=activated partial thromboplastin time; ACT=activated clotting time; ECT=ecarin clotting time.
*In preclinical studies. Schwarz RP et al. Clin Appl Thrombosis/Hemostasts. 1997;3:1-15; Refludan Prescribing Information; Angiomax Prescribing Information.

46. Study 1: Secondary Efficacy Endpoints (not by severity)
Argatroban Significantly Reduced Any New Thrombosis and Death Due to Thrombosis in HIT Patients With or Without Thrombosis
Study 1: Secondary Efficacy Endpoints (not by severity)
Control n = 147
Control n = 46
Argatroban n = 160
Argatroban n = 144
Patients (%) * * * *
Any new thrombosis
Death due to thrombosis
Any new thrombosis
Death due to thrombosis
HIT arm
HITTS arm
When individual components of the composite endpoint were compared by severity in patients treated with Argatroban vs. historical controls
All-cause mortality was not significantly different in either HIT or HITTS patients
Amputation was similar in HIT patients and higher in HITTS patients
New thrombosis was significantly reduced in HIT and HITTS patients
*P <0.05 vs. historical control.
Lewis BE, et al. Circulation. 2001;103: Argatroban Injection [package insert]. GlaxoSmithKline; 2009.

47. Study 2 Plus Extension: Secondary Efficacy Endpoints (not by severity)
Argatroban Significantly Reduced Any New Thrombosis and Death Due to Thrombosis in HIT Patients With or Without Thrombosis
Study 2 Plus Extension: Secondary Efficacy Endpoints (not by severity)
Control n = 139
Control n = 46 *
Argatroban n = 189
Argatroban n = 229 *
Patients (%) * *
New thrombosis
Death due to thrombosis
New thrombosis
Death due to thrombosis
HIT arm
HITTS arm
In each study arm, patients were treated with Argatroban and compared to historical controls
All-cause mortality was not significantly different
Amputation was similar in HIT patients and higher in HITTS patients
*P <0.05 vs. historical control.
Lewis BE, et al. Arch Intern Med. 2003;163:

48. Lepirudin the Treatment of HIT/HITTS
Combined results of three clinical trials using lepirudin in patients with HIT and HITTS (403 patients)
Dose adjusted to aPTT
Compared to historical controls (120 patients)
Lubenow E, et al, J Thromb Haemost :

49. Concerns with use of DTI
Lepirudin
Increased bleeding with renal insufficiency
Antibody to Lepirudin occur in 30% of patients after initial exposure and 70 percent of patients after repeat exposure.
Fatal anaphylaxis has been reported, so patients should be treated with lepirudin only once
Argatroban
Significant dose adjustment in patients with hepatic impairment
Lubenow E, et al, J Thromb Haemost :

50. Argatroban Dosing for Prophylaxis and Treatment of HIT/HITTS
Patient Condition
Initial Dose
Dose Adjustment
HIT/HITTS
HIT/HITTS with renal impairment
HIT/HITTS with hepatic impairment
2 mcg/kg/min
0.5 mcg/kg/min*
Titrate until
steady-state
aPTT is
times
baseline
value†
Argatroban injection [prescribing information]. GlaxoSmithKline; 2002.

51. Conversion to Oral Anticoagulant Therapy
All DTIs increase prothrombin time (PT) and INR
Important to remember when converting to warfarin therapy
Co-administration of Argatroban and warfarin produces a combined effect on the laboratory measurement of the INR
INR=International normalized ratio.
Argatroban injection [prescribing information]. GlaxoSmithKline; Sheth et al. Thromb Haemost. 2001;85:

52. Conversion to Oral Anticoagulant Therapy
Initiate warfarin therapy using the expected daily dose of warfarin while maintaining infusion of Argatroban.* Do not use a loading dose of warfarin
Measure INR daily†
If INR is ≤4.0, continue concomitant therapy
If INR is >4.0, stop infusion of Argatroban and repeat INR 4-6 hours later
INR within therapeutic range on warfarin alone: continue warfarin monotherapy
INR below therapeutic range on warfarin alone: resume therapy with Argatroban
*For infusion of Argatroban at ≤2 mcg/kg/min, the INR on monotherapy may be estimated from the INR on cotherapy (see Prescribing Information).
†If the dose of Argatroban >2 mcg/kg/min, temporarily reduce to a dose of 2 mcg/kg/min 4-6 hours prior to measuring the INR.
Argatroban Injection [package insert]. GlaxoSmithKline; 2009.

53. Transition from Argatroban to Warfarin
Retrospective analysis of 165 HIT patients who received concomitant Argatroban and warfarin therapy during conversion to oral anticoagulation
Median aPTTs and INRs respectively
aPTT INR
monotherapy ( ) 3.2 ( )
cotherapy ( ) ( )
Major Bleeding
Occurred in 1 patient prior to transition postoperatively
No patients during or after cotherapy
In this clinical trial, INRs >5 commonly occurred in HIT patients during Argatroban monotherapy and cotherapy with warfarin, but these were not associated with an increase in major bleeding
Hursting et al. Clinical & Applied Thrombosis/Hemostasis. 2005; 11:

54. Flow Chart: Suspected HIT in the ICU
Heparin exposure and
Thombocytopenia
Clinical suspicion of HIT
Send antigen-based Anti-PF4 test: (such as PIFA, ELISA)
Evaluate clinical risk, such as 4T’s
“Rule Out” step
PIFA Positive:
Need for further clinical and/or laboratory evaluation. A positive PIFA, ELISA result is not a “rule in” result for HIT.
PIFA Negative:
HIT unlikely, especially with a low or intermediate clinical suspicion (4Ts ≤5)
Unless a high clinical suspicion
Need for further clinical and/or laboratory evaluation
PIFA negative:
4Ts≥6

55. Conclusions HIT is a clinical and laboratory diagnosis
Patients with HIT are at risk for life and limb threatening thrombotic disease
Treatment with alternative anticoagulants are expensive and potentially lead to increased complications
In critically ill patients, a negative antigen test (PIFA / ELISA) can exclude the presence anti-PF4 antibodies
PIFA test can be used as an effective rapid screening test for MICU patients at risk for HIT
With a low pretest probability for HIT, a negative PIFA / ELISA may serve as a “rule out” test for HIT
The clinical significance of a positive PIFA and ELISA tests must be evaluated in conjunction with clinical judgment and, as appropriate, additional laboratory testing.

56. The Direction We are Headed?