A Case of Thrombocytopenia
in the ICU:
is heparin a big HIT, or not ais heparin a big HIT, or not a
player at all?
Joan Ng...
Learning Objectives
1. To describe the pathophysiology,
presentation, and diagnosis of heparin-
induced thrombocytopenia (...
Outline
• Patient Case Introduction
• Drug Related Problems
• Heparin-Induced Thrombocytopenia
– Pathophysiology, Presenta...
My Patient
59 yo female, 150 kg, 5’4’’, no known drug allergies
Admitted to SPH ICU on Dec 27, 2013, transferred from a pe...
Brief Summary of Stay
Medical Condition History of Management and Current Status
Hypercapnic
respiratory failure
Patient i...
Review of Systems (Jan 16, 2014)
Vitals Tmax = 37.4 HR = 75 BP = 130/60 RR = 10-22
CNS/Neuro/ψ RASS = -2/0 Delirium Score ...
Medical Problems and Medications
Medical Problem Medication (regimen, dates)
Respiratory Failure None; not on any respirat...
Hematologic Profile Trend
Dec27 29 31 Jan2 9 12 13 14 15 16
WBC 11.5 7.8 8.9 8.7 7.9 8.9 9.4 8.7 9.4 9.1
HGB 129 104 102 1...
Thrombocytopenia: Cause?
Possible Cause Patient Considerations
Drug-induced? Heparin-induced thrombocytopenia (HIT)?
• the...
Thrombocytopenia:
Further Investigations
• 4T score: 5 = intermediate risk of HIT
• HIT Screen resulted January 17 = HIT p...
DRPs
1. Patient is at risk of bleeding and thrombosis
secondary to possible heparin-induced
thrombocytopenia, and would be...
HIT
12Reference: 2,3
Presentation of HIT
• Risk: higher with UFH than LMWH
• Timing: usually within 5-10 days after
initiation of heparin
• Pla...
Diagnosis
Step 1: determine likelihood of HIT: 4T Score
14
Our patient: 2 + 1 + 0 + 2 = 5, intermediate.
Reference: 5,6,7
Diagnosis
Step 2: HIT assays
1. Enzyme Immunoassays:
– HIT Screen = HemosIL®
• Antigen-based immunoassay
– ELISA = LIFECOD...
Diagnosis
HIT Screen: HemosIL®
• Rapid results (no need to batch); next day
• Detects total immunoglobulin/antibodies in p...
Diagnosis
Further Screening: IgG ELISA
• Enzyme linked immunosorbent assay (ELISA)
• Batched screening; less immediate res...
Goals of Therapy for HIT
• To minimize risk of thrombosis from HIT
• To avoid complications associated with
thrombosis
• T...
Management: CHEST Guidelines
• Hold all heparins and LMWH
– Including heparin flushes and heparin-coated
catheters
• Initi...
Comparison of Agents
Argatroban Bivalirudin Danaparoid Fondaparinux
MoA Direct thrombin
inhibitor; Synthetic
Direct thromb...
Comparison of Agents (cont’d)
Argatroban Bivalirudin Danaparoid Fondaparinux
Adverse Effects
(unique)
Hypotension,
Vtach, ...
Clinical Question
P
In a 59 year-old, morbidly obese (BMI 56.6), critically ill female
with acute kidney injury and suspec...
Literature Search
Database EMBASE, Medline, CENTRAL, Google Scholar
Search
Terms
Heparin induced thrombocytopenia, fondapa...
24Reference: 16
Skrupky et al. 2010
[Bivalirudin vs. Argatroban] Retrospective, single-centre study
P N = 138
Patients: ≥ 18 years, receiv...
Skrupky et al. 2010
Results Dosing required:
• bivalirudin (N = 92): median dose 0.06mg/kg/h
• argatroban (N = 46): median...
Skrupky et al. 2010
Limitations • small, retrospective study
• patient baseline characteristics imbalanced (ELISA results,...
28Reference: 17
Kang et al. (2012 Poster)
[Fondaparinux vs. Danaparoid or Argatroban] Retrospective study
P
N = 239 (London Health Science...
Results
No differences in outcomes
Non-significant trend towards increased bleeding for patients on argatroban
Kang et al....
31Reference: 18
Shindewolf et al. (2013 Abstract)
[Fondaparinux vs. Argatroban, Lepirudin, or Danaparoid] Retrospective
P N = 195 (Multipl...
Results
N’s not reported in the abstract
Shindewolf et al. (2013 Abstract)
Argatroban Lepirudin Danaparoid Fondaparinux
Co...
Recommendation
• Based on limited evidence, we can say there likely is
no difference in efficacy or safety among non-
hepa...
Monitoring
Parameter Change Frequency
Efficacy Thrombosis (SOB,
stroke, AKI, cold
extremities)
Absence Daily by nurse;
fol...
What Happened?
• January 21, 2014: ELISA = negative
– Suggests the HIT screen was a false positive!
• Switched back to hep...
Questions?
37
References (1)
1. Garcia DA, Baglin TP, Weitz JI, Samama MM. Parenteral anticoagulants: Antithrombotic therapy and prevent...
References (2)
11. Bakchoul T, Giptner A, Najaoui A, Bein G, Santoso S, Sachs UJH. Prospective evaluation of PF4/heparin
i...
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A Case of Thrombocytopenia in the ICU: is heparin a big HIT, or not a player at all? (Case Presentation)

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Provided to the pharmacy staff at St Paul's Hospital, Vancouver, British Columbia on January 28, 2014.

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A Case of Thrombocytopenia in the ICU: is heparin a big HIT, or not a player at all? (Case Presentation)

  1. 1. A Case of Thrombocytopenia in the ICU: is heparin a big HIT, or not ais heparin a big HIT, or not a player at all? Joan Ng, Pharmacy Resident ICU Rotation – Case Presentation January 28, 2014 1
  2. 2. Learning Objectives 1. To describe the pathophysiology, presentation, and diagnosis of heparin- induced thrombocytopenia (HIT). 2. To discuss all the feasible non-heparin2. To discuss all the feasible non-heparin anticoagulant treatment options in the management of HIT. 2
  3. 3. Outline • Patient Case Introduction • Drug Related Problems • Heparin-Induced Thrombocytopenia – Pathophysiology, Presentation, Diagnosis, Goals of Therapy, Drug TherapyTherapy, Drug Therapy • PICO & Literature Search • Review of Literature • Recommendation, Monitoring Plan • What Happened to our patient? 3
  4. 4. My Patient 59 yo female, 150 kg, 5’4’’, no known drug allergies Admitted to SPH ICU on Dec 27, 2013, transferred from a peripheral hospital CC Respiratory Failure HPI - Dec 23: initial chief complaint of pannus ulceration and infection, which grew Proteus and B-hemolytic strep - developed respiratory distress with O2 Saturation 73%, which- developed respiratory distress with O2 Saturation 73%, which required intubation. Initial CXR showed interstitial shadowing PMHx Morbid obesity (BMI 56.6), pulmonary embolism (Aug 2011), severe sepsis secondary to leg cellulitis (Aug 2012), chronic stasis dermatitis. No cardiovascular disease history, diabetes, or smoking. Fam Hx Unknown PTA Meds Nothing on Pharmanet; Atrovent MDI (usage?) 4
  5. 5. Brief Summary of Stay Medical Condition History of Management and Current Status Hypercapnic respiratory failure Patient improved, was extubated, but required reintubation January 12. CXRs (Dec 27, Jan 11) show atelectasis and pleural effusion. Unresolved; likely secondary to sepsis and ongoing due to obesity hypoventilation syndrome?, ruled out pneumonia Sepsis of unknown Clindamycin and moxifloxacin started at peripheral hospital,Sepsis of unknown source Clindamycin and moxifloxacin started at peripheral hospital, escalated to piperacillin-tazobactam and vancomycin, then switched to ceftriaxone (total ~14 days of antibiotics). Resolved; blood and urine cultures all negative, WBC normal. Pannus wounds Resolved; determined not to be infected or a source for sepsis on December 28 via ID consult. Wounds now clear. Acute Kidney Injury Unresolved; likely secondary to septic shock Baseline Cr 82, increased to 152 on Dec 29, remained around 400 since Jan 2, 2014. 5
  6. 6. Review of Systems (Jan 16, 2014) Vitals Tmax = 37.4 HR = 75 BP = 130/60 RR = 10-22 CNS/Neuro/ψ RASS = -2/0 Delirium Score = 2 Rousable to voice, low mood HEENT PERRL CVS Normal S1 S2, NSR MAP between 79-89 RESP Pressure Support Ventilation (PS = 10 cm H2O, PEEP = 16 cm H2O) pH = 7.36, PO2 = 109, PCO2 = 68, HCO3 = 35, FiO2 = 0.30, O2 Sat 98%pH = 7.36, PO2 = 109, PCO2 = 68, HCO3 = 35, FiO2 = 0.30, O2 Sat 98% Respiratory sounds symmetrical but decreased to left lung base; crackles GI/GU Bowel sounds present; rectal tube 140mL output over 24 hours Liver/Renal Consistent urine output; Creatinine 421mmol/L Fluids/Lytes/Heme Na 147; WBC 8.8 Hgb 97 Platelets 65 Endocrine CBG q6h = 6.8-7.3 MSK/Derm Feet are edematous ID Nothing to report 6 No further diagnostics done recently.
  7. 7. Medical Problems and Medications Medical Problem Medication (regimen, dates) Respiratory Failure None; not on any respiratory depressing meds Acute Kidney Injury None; not on any nephrotoxic medications Hypernatremia None; free water 30 mL/h added to replete volume Stress Ulcer Prophylaxis Ranitidine 150mg PO/NG daily (adjusted for AKI) DVT Prophylaxis Heparin 10,000units SC q8h (based on her weight)DVT Prophylaxis Heparin 10,000units SC q8h (based on her weight) Nutrition Multivitamin 1 tab NG daily (getting enteral feeds) Mood? - Prn: Pain Hydromorphone 0.2-5mg IV prn (none used) Prn: Delirium Haloperidol 2.5mg PO q6h prn (none used) New: Thrombocytopenia - 7Reference: 19
  8. 8. Hematologic Profile Trend Dec27 29 31 Jan2 9 12 13 14 15 16 WBC 11.5 7.8 8.9 8.7 7.9 8.9 9.4 8.7 9.4 9.1 HGB 129 104 102 102 96 96 99 98 98 97 MCV 77 80 78 78 79 81 78 79 80 81 Platelets 230 217 207 218 313 222 180 130 82 65 350 8 0 50 100 150 200 250 300 350 PlateletCount Date
  9. 9. Thrombocytopenia: Cause? Possible Cause Patient Considerations Drug-induced? Heparin-induced thrombocytopenia (HIT)? • therapeutic heparin started Dec 27 • prophylactic heparin 10,000units q8h started Dec 30 • no previous recent heparin use Ranitidine: rare thrombocytopenia reaction? Sepsis? No evidence of infection (afebrile, WBC normal) 9 Sepsis? No evidence of infection (afebrile, WBC normal) DIC? Presentation unlikely Intravascular devices? None Liver disease/hypersplenism? None Bone marrow suppression? Likely not SLE or other immune causes? No history of immune disorders Diabetic ketoacidosis? No history of diabetes
  10. 10. Thrombocytopenia: Further Investigations • 4T score: 5 = intermediate risk of HIT • HIT Screen resulted January 17 = HIT positive – Level = 2.3 (>1u/mL)– Level = 2.3 (>1u/mL) – Sensitivity = 95% – Specificity = 75% • Signs and symptoms of bleeding/thrombosis? • For now: hold all heparins, ELISA to confirm 10
  11. 11. DRPs 1. Patient is at risk of bleeding and thrombosis secondary to possible heparin-induced thrombocytopenia, and would benefit from reassessment of drug therapy. 2. Patient is experiencing low mood likely secondary to the long course of hospitalization, and would benefit from motivational support and psychiatry consult for reassessment of drug therapy. 11
  12. 12. HIT 12Reference: 2,3
  13. 13. Presentation of HIT • Risk: higher with UFH than LMWH • Timing: usually within 5-10 days after initiation of heparin • Platelet count:• Platelet count: – drops by ≥50% or – < 150 x 10^9/L • Complicated by other factors that may contribute to thrombocytopenia 13Reference: 3,4
  14. 14. Diagnosis Step 1: determine likelihood of HIT: 4T Score 14 Our patient: 2 + 1 + 0 + 2 = 5, intermediate. Reference: 5,6,7
  15. 15. Diagnosis Step 2: HIT assays 1. Enzyme Immunoassays: – HIT Screen = HemosIL® • Antigen-based immunoassay – ELISA = LIFECODES® PF4 IgG assay– ELISA = LIFECODES® PF4 IgG assay • Qualitative screening assay for IgG 2. Functional assays: – SRA (Serotonin-release assay) “gold standard” – HIPA (Heparin-induced platelet aggregation) 15Reference: 8
  16. 16. Diagnosis HIT Screen: HemosIL® • Rapid results (no need to batch); next day • Detects total immunoglobulin/antibodies in pt’s plasma that react with PF4-heparin complex • Test range 0-5.7 U/mL• Test range 0-5.7 U/mL • Samples ≥1.0 U/mL = positive test – Sensitivity: 95% – Specificity: • 75% at 1.0 U/mL cut-off; 95% at 4.0 U/mL 16 Our patient: 2.3 U/mL Reference: 9
  17. 17. Diagnosis Further Screening: IgG ELISA • Enzyme linked immunosorbent assay (ELISA) • Batched screening; less immediate results • Sensitivity: “very high”; Specificity: 89% 17Reference: 10,11
  18. 18. Goals of Therapy for HIT • To minimize risk of thrombosis from HIT • To avoid complications associated with thrombosis • To reduce morbidity and mortality• To reduce morbidity and mortality • To minimize duration of hospital stay • To minimize side effects 18
  19. 19. Management: CHEST Guidelines • Hold all heparins and LMWH – Including heparin flushes and heparin-coated catheters • Initiation of a nonheparin anticoagulant:• Initiation of a nonheparin anticoagulant: – Argatroban – Danaparoid – Bivalirudin – Fondaparinux (not a main recommendation) 19Reference: 12
  20. 20. Comparison of Agents Argatroban Bivalirudin Danaparoid Fondaparinux MoA Direct thrombin inhibitor; Synthetic Direct thrombin inhibitor; Hirudin analogue Factor Xa inhibitor Factor Xa inhibitor; Synthetic analog of Antithrombin-binding pentasaccharide Clearance Hepatobiliary Enzymatic and renal Renal Renal Half-Life 40-50 min 25 min 24 hr 17-20 hr Dosing 2ug/kg/min IV infusion 0.15-2mg/kg/h IV infusion Weight-based IV bolus, then IV infusion 400U/h x4h, 300U/h x4h, then 150-200U/h <50kg: 5mg SC qd 50-100kg: 7.5mg SC >100kg: 10mg SC qd - adjustments Liver disease, critical illness, or after cardiac surgery: ↓ to 0.5- 1.2ug/kg/min Obese: use TBW Liver: 0.14mg/kg/h Liver+renal: 0.03- 0.05mg/kg/h IV CRRT: 0.03- 0.04mg/kg/h IV Renal dosage adjustments CrCl 30-50mL/min: ↓50%; CrCl <30mL/min, not recommended** 20Reference: 3, 13, 14, 15
  21. 21. Comparison of Agents (cont’d) Argatroban Bivalirudin Danaparoid Fondaparinux Adverse Effects (unique) Hypotension, Vtach, fever Hypotension, back pain, insomnia Pain Fever, anemia, edema, rash, HIT? Monitoring Aim for aPTT 1.5-3 times baseline (max 10ug/kg/min) Aim for aPTT 1.5- 2.5 times baseline value Adjust to anti-Xa activity 0.5- 0.8U/mL None required Cost/d (based on 70kg) ~$540/day ~$3000/day ~$200/day $25/day 21 • But what about efficacy and safety? • Guidelines and review articles say that there are no good quality, large scale head-to-head trials… Reference: 3, 13, 14, 15
  22. 22. Clinical Question P In a 59 year-old, morbidly obese (BMI 56.6), critically ill female with acute kidney injury and suspected HIT I Non-heparin anticoagulants (argatroban, bivalirudin, danaparoid, fondaparinux) 22 C Each other O Efficacy (in preventing thrombosis relate to HIT) Safety (bleeding, adverse events)
  23. 23. Literature Search Database EMBASE, Medline, CENTRAL, Google Scholar Search Terms Heparin induced thrombocytopenia, fondaparinux, argatroban, bivalirudin, danaparoid, intensive care 3 Retrospective studies: 23 Relevant Results 3 Retrospective studies: • Bivalirudin vs. Argatroban (2010) • Argatroban, Danaparoid, or Lepirudin in CRRT with HIT (2012) • Fondaparinux vs. Lepirudin (2011) 2 unpublished retrospective studies: • Fondaparinux vs. Argatroban, Lepirudin, or Danaparoid (2013) • Fondaparinux vs. Argatroban, Danaparoid (2012)
  24. 24. 24Reference: 16
  25. 25. Skrupky et al. 2010 [Bivalirudin vs. Argatroban] Retrospective, single-centre study P N = 138 Patients: ≥ 18 years, received either argatroban or bivalirudin between January 2007 – July 2008 for at least 24 hours, with known or suspected HIT I Bivalirudin (N = 92) 25 C Argatroban (N = 46) O Primary Objective: dosing required, achievement of anticoagulant goals (percentage of aPTTs in therapeutic range, and time to therapeutic aPTT) Secondary Objective: compare clinical outcomes in assessing safety and efficacy (thromboembolic complications, significant bleeding, mortality) Reference: 16
  26. 26. Skrupky et al. 2010 Results Dosing required: • bivalirudin (N = 92): median dose 0.06mg/kg/h • argatroban (N = 46): median dose 1.0ug/kg/minute Achievement of target aPTT: within 6 hours of initiation and similar maintenance for both drugs 26 Clinical Outcomes: no difference in incidence of major bleeding or thromboembolic events Reference: 16
  27. 27. Skrupky et al. 2010 Limitations • small, retrospective study • patient baseline characteristics imbalanced (ELISA results, history of cardiovascular disease, malignancy, liver impairment) My Conclusion • bivalirudin appears equally effective and safe as argatroban in achieving target anticoagulation goalsConclusion argatroban in achieving target anticoagulation goals • no difference in major bleeding or thromboembolism • based on this study: • more inclined to use bivalirudin if patient has cardiovascular disease and/or liver disease • larger prospective studies required 27Reference: 16
  28. 28. 28Reference: 17
  29. 29. Kang et al. (2012 Poster) [Fondaparinux vs. Danaparoid or Argatroban] Retrospective study P N = 239 (London Health Sciences Centre, January 10, 2004 – June 21, 2011) • patients who received non-heparin anticoagulant for suspected or confirmed HIT 29 I Fondaparinux (N = 133) C Argatroban (N = 47) or Danaparoid (N = 59) O Efficacy: thrombosis or thrombosis-related death Safety: major bleeding Reference: 17
  30. 30. Results No differences in outcomes Non-significant trend towards increased bleeding for patients on argatroban Kang et al. (2012 Poster) Thrombotic events Bleeding events Argatroban n (%) Danaparoid n (%) Fondaparin ux n (%) p-value Argatroban n (%) Danaparoid n (%) Fondaparin ux n (%) p-value Matched cohort 5 (25%) 8 (20%) 22 (16.5%) 0.620 7 (35%) 5(12.5%) 28 (21.1%) 0.126 Matched cohort pooled 13 (21.7%) 22 (16.5%) 0.392 12 (20%) 28 (21.1%) 0.8 30 Non-significant trend towards increased bleeding for patients on argatroban Limitations • small (N = 239), retrospective • lack of full study data (no published paper available; drug doses unknown) • apparently propensity scores were constructed based on patient characteristics to match 133 patients to 60 controls – no details My Conclusion • study suggests that fondaparinux is similarly effective and safe compared with argatroban or danaparoid in patient’s with suspected HIT • reassuring and encouraging since fondaparinux is much easier to administer and more economical • interested to see the final published paper Reference: 17
  31. 31. 31Reference: 18
  32. 32. Shindewolf et al. (2013 Abstract) [Fondaparinux vs. Argatroban, Lepirudin, or Danaparoid] Retrospective P N = 195 (Multiple centres, diagnosed with HIT between January 2005 – October 2009) • inclusion: • if 4Ts score ≥4 •Treated with at least one dose of argatroban, lepirudin, danaparoid, or fondaparinux 32 fondaparinux I Fondaparinux (used “off-label”) C Argatroban, lepirudin, danaparoid O Incidence of thromboembolic complications, amputations, skin lesions, thrombocytopenia, platelet recovery, bleeding and fatal complications. Reference: 18
  33. 33. Results N’s not reported in the abstract Shindewolf et al. (2013 Abstract) Argatroban Lepirudin Danaparoid Fondaparinux Composite (thrombosis, amputations, skin necrosis) 8.8% 11.1% 12.9% 0.0% All cause in-hospital mortality 10.5% 22.2% 17.1% 0.0% Bleeding complications 8.8% 22.2% 5.7% 4.1% 33 Limitations • retrospective • currently only the abstract is available; a lot of information unknown (patient demographics, drug doses, etc) •Significance of differences in incidences? My Conclusion • again, suggests fondaparinux is effective and safe compared to other nonheparin anticoagulants • would like to see the final published paper Reference: 18
  34. 34. Recommendation • Based on limited evidence, we can say there likely is no difference in efficacy or safety among non- heparin anticoagulation choices • Considerations: ease of administration, monitoring, cost…all point towards fondaparinuxcost…all point towards fondaparinux – Not a continuous infusion, just a once-daily SC injection – no aPTT monitoring required – most economical ($25/day vs. up to $3000/day) • Start fondaparinux 10mg SC q48h while we await the ELISA results 34
  35. 35. Monitoring Parameter Change Frequency Efficacy Thrombosis (SOB, stroke, AKI, cold extremities) Absence Daily by nurse; followed by ICU team Platelet count Increase to ≥ 150 giga/L over 1-2 weeks Daily by nurse; followed by ICU team Toxicity Bleeding (overt signs of bleeding, sudden drop in hemoglobin) Presence Daily by nurse; followed by ICU team 35
  36. 36. What Happened? • January 21, 2014: ELISA = negative – Suggests the HIT screen was a false positive! • Switched back to heparin 10,000 units q8h • Discontinued ranitidine, switched to esomeprazole 40mg NG daily • Continuing to monitor platelets and clinical changes in pt’s status 36 12 13 14 15 16 17 18 19 20 21 23 24 25 28 PLTs 222 180 130 82 65 77 56 66 69 78 89 96 117 0 50 100 150 200 250 300 350 PlateletCount Date
  37. 37. Questions? 37
  38. 38. References (1) 1. Garcia DA, Baglin TP, Weitz JI, Samama MM. Parenteral anticoagulants: Antithrombotic therapy and prevention of thrombosis, 9th ed: american college of chest physicians evidence-based clinical practice guidelines. CHEST J. 2012 Feb 1;141(2_suppl):e24S–e43S. 2. Sakr Y. Heparin-induced thrombocytopenia in the ICU: an overview. Crit Care. 2011;15(2):211. 3. Kelton JG, Arnold DM, Bates SM. Nonheparin Anticoagulants for Heparin-Induced Thrombocytopenia. N Engl J Med. 2013;368(8):737–44. 4. Lubenow N, Kempf R, Eichner A, Eichler P, Carlsson LE, Greinacher A. Heparin-induced thrombocytopenia*: Temporal pattern of thrombocytopenia in relation to initial use or reexposure to heparin. CHEST J. 2002 Jul 1;122(1):37–42. 5. Lo GK, Juhl D, Warkentin TE, Sigouin CS, Eichler P, Greinacher A. Evaluation of pretest clinical score (4 T’s) for the diagnosis of heparin-induced thrombocytopenia in two clinical settings. J Thromb Haemost. 2006;4(4):759–65.diagnosis of heparin-induced thrombocytopenia in two clinical settings. J Thromb Haemost. 2006;4(4):759–65. 6. Cuker A, Gimotty PA, Crowther MA, Warkentin TE. Predictive value of the 4Ts scoring system for heparin-induced thrombocytopenia: a systematic review and meta-analysis. Blood. 2012 Nov 15;120(20):4160–7. 7. Wanat M, Fitousis K, Hall J, Rice L. PF4/heparin antibody testing and treatment of heparin-induced thrombocytopenia in the intensive care unit. Clin Appl Thromb Off J Int Acad Clin Appl Thromb. 2013 Jun;19(3):297– 302. 8. Ortel TL. Heparin-induced thrombocytopenia: when a low platelet count is a mandate for anticoagulation. ASH Educ Program Book. 2009 Jan 1;2009(1):225–32. 9. Davidson SJ, Ortel TL, Smith LJ. Performance of a new, rapid, automated immunoassay for the detection of anti- platelet factor 4/heparin complex antibodies. Blood Coagul Fibrinolysis Int J Haemost Thromb. 2011 Jun;22(4):340–4. 10. Althaus K, Hron G, Strobel U, Abbate R, Rogolino A, Davidson S, et al. Evaluation of automated immunoassays in the diagnosis of heparin induced thrombocytopenia. Thromb Res. 2013 Mar;131(3):e85–e90. 38
  39. 39. References (2) 11. Bakchoul T, Giptner A, Najaoui A, Bein G, Santoso S, Sachs UJH. Prospective evaluation of PF4/heparin immunoassays for the diagnosis of heparin-induced thrombocytopenia. J Thromb Haemost. 2009;7(8):1260–5. 12. Linkins L-A, Dans AL, Moores LK, Bona R, Davidson BL, Schulman S, et al. Treatment and prevention of heparin- induced thrombocytopenia: Antithrombotic therapy and prevention of thrombosis, 9th ed: american college of chest physicians evidence-based clinical practice guidelines. CHEST J. 2012 Feb 1;141(2_suppl):e495S–e530S. 13. Keegan SP, Gallagher EM, Ernst NE, Young EJ, Mueller EW. Effects of critical illness and organ failure on therapeutic argatroban dosage requirements in patients with suspected or confirmed heparin-induced thrombocytopenia. Ann Pharmacother. 2009 Jan;43(1):19–27. 14. Tsu LV, Dager WE. Comparison of bivalirudin dosing strategies using total, adjusted, and ideal body weights in obese patients with heparin-induced thrombocytopenia. Pharmacotherapy. 2012 Jan;32(1):20–6. 39 obese patients with heparin-induced thrombocytopenia. Pharmacotherapy. 2012 Jan;32(1):20–6. 15. Fondaparinux, aragatroban, bivalirudin, danaparoid. Lexi-Drugs Online [Internet]. Hudson (OH) : Lexi-Comp, Inc. 1978-2013 [cited 2014 Jan24]. Available from: http://online.lexi.com. 16. Skrupky LP, Smith JR, Deal EN, Arnold H, Hollands JM, Martinez EJ, et al. Comparison of Bivalirudin and Argatroban for the Management of Heparin-Induced Thrombocytopenia. Pharmacother J Hum Pharmacol Drug Ther. 2010;30(12):1229–38. 17. Paper: Fondaparinux Versus Argatroban and Danaparoid for the Treatment of Suspected or Confirmed Heparin- Induced Thrombocytopenia: A Propensity Score Analysis [Internet]. [cited 2014 Jan 24]. 18. Abstract 1289 Use of fondaparinux in suspected acute heparin-induced thrombocytopenia (HIT) - final results from the GerHIT multicentre registry study [Internet]. [cited 2014 Jan 24]. 19. Shepherd MF, Rosborough TK, Schwartz ML. Heparin Thromboprophylaxis in Gastric Bypass Surgery. Obes Surg. 2003 Apr 1;13(2):249–53.

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