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

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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. HIT
12Reference: 2,3

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. Diagnosis
Step 1: determine likelihood of HIT: 4T Score
14
Our patient: 2 + 1 + 0 + 2 = 5, intermediate.
Reference: 5,6,7

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. 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. Diagnosis
Further Screening: IgG ELISA
• Enzyme linked immunosorbent assay (ELISA)
• Batched screening; less immediate results
• Sensitivity: “very high”; Specificity: 89%
17Reference: 10,11

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. 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. 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. 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. 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. 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. 24Reference: 16

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. 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. 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. 28Reference: 17

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. 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. 31Reference: 18

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. 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. 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. 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. 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. Questions?
37

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. 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.