A Case of Thrombocytopenia

in the ICU:

is heparin a big HIT, or not a is heparin a big HIT, or not a

player at all?

Joan Ng, Pharmacy Resident

ICU Rotation – Case Presentation

January 28, 2014

1

Learning Objectives

1. To describe the pathophysiology,

presentation, and diagnosis of heparin-

induced thrombocytopenia (HIT).

2. To discuss all the feasible non-heparin 2. To discuss all the feasible non-heparin

anticoagulant treatment options in the

management of HIT.

2

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

My Patient59 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

Brief Summary of StayMedical 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

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.

Medical Problems and MedicationsMedical 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

Hematologic Profile TrendDec27 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

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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

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

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

HIT

12Reference: 2,3

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

DiagnosisStep 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 = 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

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

Diagnosis

Further Screening: IgG ELISA

• Enzyme linked immunosorbent assay (ELISA)

• Batched screening; less immediate results

• Sensitivity: “very high”; Specificity: 89%

17Reference: 10,11

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

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

Comparison of AgentsArgatroban 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

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

Clinical Question

PIn a 59 year-old, morbidly obese (BMI 56.6), critically ill female

with acute kidney injury and suspected HIT

INon-heparin anticoagulants (argatroban, bivalirudin, danaparoid,

fondaparinux)

22

C Each other

OEfficacy (in preventing thrombosis relate to HIT)

Safety (bleeding, adverse events)

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)

24Reference: 16

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

Skrupky et al. 2010Results 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

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

28Reference: 17

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

IFondaparinux (N = 133)

C Argatroban (N = 47) or Danaparoid (N = 59)

OEfficacy: thrombosis or thrombosis-related death

Safety: major bleeding

Reference: 17

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

cohort5 (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

31Reference: 18

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

IFondaparinux (used “off-label”)

C Argatroban, lepirudin, danaparoid

OIncidence of thromboembolic complications, amputations, skin lesions,

thrombocytopenia, platelet recovery, bleeding and fatal complications.

Reference: 18

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

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

MonitoringParameter 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

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

050

100150200250300350

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Questions?

37

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