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

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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

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

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; 535-555 Davoren A, et al. Am J Hematol. 2006: 81:36-44

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; 121:535-555

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) 25 - 50 % 1 – 2% General Medical 8 - 20% 0.8 - 3% Neurology PCI for ACS Acute hemodialysis Low to Rare General Pediatrics 0 - 2.3% 0 - 0.1% Pregnant women Chronic hemodialysis LMWH 2 – 8% 1 – 0.9% unknown 0 – 1% Adapted from Arepally GM et al. N Engl J Med. 2006; 355:809-817

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; 332:1330-1335

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%

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; 106:3049-3054

Frequency of HIT in Critical Care Incidence of thrombocytopenia in ICUs is 20 - 45% 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):745-53.

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; 2:148 - 157

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; 25:287-293

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; 30:1615-1624. Klenner Af, et al. Thrombosis& Hemostasis. 2004; 91:719-724

Severity of Thrombocytopenia and Thrombotic Complications in HIT Adapted from Warkentin TE et al. Br J Hematol. 2003; 121:535-555

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;101:502-507.

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).

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

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

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

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;82:439-447.

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;83:575-582 ©2007 by The Fellowship of Postgraduate Medicine

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;124:1657-1666. 2. Messmore HL, Jeske WP, Wehrmacher WH, Walenga JM. Benefit-risk assessment of treatments for heparin-induced thrombocytopenia. Drug Safety. 2003;26:625-641. 3. Leo A, Winteroll S. Laboratory diagnosis of heparin-induced thrombocytopenia and monitoring of alternative anticoagulants. Clin Diagn Lab Immunol. 2003;10:731-740. 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;124:1657-1666. 2. Messmore HL, et al. Drug Safety. 2003;26:625-641. 3. Leo A, et al. Clin Diagn Lab Immunol. 2003;10:731-740. 4. PIFA® Heparin/Platelet Factor 4 Rapid Assay [package insert]; 2005. 23

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)

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

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

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

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

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

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

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) > 0.400. STAGO positive test = OD range = 0.41 - 0.48). 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 2007. College of American Pathologists Chicago, Ill

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; 6:1304-1312

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

PIFA® Assay Principle

Akers Biosciences PIFA® Heparin/PF4 Rapid Assay NEGATIVE POSITIVE

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.

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.

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.

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]

* * * 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.

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

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; 104.11.Abstract 1775

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

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

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.

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;103:1838-1843. Argatroban Injection [package insert]. GlaxoSmithKline; 2009.

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;163:1849-1856.

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. 2005. 3:2428-2436.

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. 2005. 3:2428-2436.

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 1.5-3.0 times baseline value† Argatroban injection [prescribing information]. GlaxoSmithKline; 2002.

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; 2002. Sheth et al. Thromb Haemost. 2001;85:435-440.

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.

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 59.8 (38.8-82.9) 3.2 (1.7-7.0) cotherapy 68.6 (44.5-104) 5.3 (2.4-16.0) 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; 11:279-287.

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

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.

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