1. Heparin Induced Thrombocytopenia (HIT-Type 2) by: Tom Pizzoferrato, PharmD

2. Heparin-Induced Thrombocytopenia Learning Objectives
Understand the etiology and pathogenesis of Heparin-Induced Thrombocytopenia
Be able to differentiate the two types of HIT; Type I and Type II.
Recognize the signs and symptoms of Heparin-Induced Thrombocytopenia and institute appropriate treatment
Gain the knowledge and skills necessary to assist physicians and nurses in starting Argatroban for a patient suspected for having HIT Type 2
Effectively monitor a patient on the IV Argatroban Protocol to achieve optimal outcomes
Assist providers in transitioning to warfarin

3. Many OTHER Causes of Thrombocytopenia
Pseudothrombocytopenia- plt. clumping
Decreased Platelet (plt) Production
- viral infections, HIV, congenital or acquired bone marrow aplasia or
hypoplasia
- Etoh toxicity
- B12/ Folate deficiency
* Increased Plt. Destruction
- ITP
- Drugs- heparin, quinine, quinidine, and valproic acid
- DIC, Sepsis- common in ICU patients
- TTP
- HELLP syndrome (hemolytic anemia, elevated liver function tests, and low platelet count) in pregnant women
- Mono, CMV
Dilutional –Common w Blood products, IVF’s
Spenic Sequestration

4. Types of HIT Type 1 HIT – common form of thrombocytopenia
- no clinical consequence
- slight fall in platelet count within the first two days after heparin (plt. >100,000)
- returns to normal with continued heparin administration
- nonimmune
Type 2 HIT = heparin associated thrombocytopenia
- less common
- serious consequences- thrombosis and white clot ( arterial)
- large fall in platelet count within 1-7 days after heparin (Plt < 100,000)
- platelets rise in 6-8 days after all heparin/lmwh is dc’d
- immune-mediated with Antibodies vs Plt-F4

5. HIT –Type 2 Antibody-mediated, adverse effect of heparin
•Affects 1-4% of patients receiving heparin for at least 7 days
–Higher rate for UFH
–Lower for LMWH
•Strong association with venous and arterial thrombosis
(30-75% risk in untreated patients)

6. HIT- type 2 Clinical features
Thrombocytopenia occurring after 5-7 days of heparin therapy, can occur sooner on re-exposure
Platelet count nadir is between 20,000 and 150,000/ul, median 50,000/ul
Bleeding is rare

7. Mechanisms of Type 2 HIT
Heparin-PF4 complex binds to activated platelet surface and forms heparin-PF4-AB complex on the platelet surface [32,42].
The Fc portion of this bound IgG further activates other platelets and leads to more platelet activation with further release of PF4
Activated PLT-Hep-PF4-AB complex undergoes aggregation and are removed prematurely from the circulation leading to thrombocytopenia (HIT)
Generation of procoagulant platelet-derived microparticles, frequently resulting in thrombin generation and thrombosis (HITT)
The AB complex also activates microvascular endothelial cells, resulting in release of IL-6- von Willebrand factor can injure endothelium which promotes thrombosis [

8. missing data, onset after day 10, or fall <1 day,
T Score System
2 points
1 point
0 point
Thrombo-
cytopenia
Plt Ct fall > 50% and
plt nadir > 20K
Plt Ct fall 30-50% or nadir
10-19K
Plt ct fall <
30% or nadir
<10K
Timing of Plt Ct Fall
Onset between days
5-10 or < 1 day if
prior hep exposure
w/in 30 days
Consistent w/ fall
between days 5-10, but
missing data, onset after
day 10, or fall <1 day,
hep exposure
days ago
Plt ct fall < 4
days without
recent
exposure
Thrombo-sis, of other
sequelae
New thrombosis, skin
necrosis, acute
systemic reaction,
post IV UFH bolus
Progressive or recurrent
thrombosis, non
necrotizing skin lesions,
suspected clots, not
proven
None
OTher causes for
Thrombo-cytopenia
T Score:
Probability
None apparent
6-8 pts- HIT Likely
Possible
4-5- HIT Possible
Definite
0-3- HIT Unlikely

9. Possible sequela from HIT (Heparin/LMWH Exposure)
These may be indication of Developing HIT Type 2
Erythematous Plaques
Heparin-Induced Skin Necrosis
Venous Gangrene (extremities)
Warkentin TE. Heparin Induced Thrombocytopenia, 2nd Ed. Marcel Dekker, Inc; New York 2001

10. HIT should be considered a clinico-pathologic syndrome
HIT – Diagnosis
HIT should be considered a clinico-pathologic syndrome
•Diagnosis requires both a compatible clinical history and demonstration of HIT antibody seroconversion
•Demonstration of a heparin dependent platelet antibody alone is insufficient
* Use T score to help screen
* The HIT tests should NOT be used for screening of asymptomatic patients prior to or during heparin exposure
-Warkentin, 2005

11. Heparin Antibody Assays
Platelet Aggregation- not useful
14C-Serotonin Release Assay (SRA)
For confirmation
Heparin-Induced Platelet Agglutination (HIPA)
Heparin/PF4 ELISA- Initial screen

12. Test
Advantages
Disadvantages
SRA=Serotonin Release Assay “ Gold Std.”
For confirmation
Sensitivity: high
Specificity: high
Rare false +’s
Technically demanding,
Not readily available- sent out- 4-7 days turnover
Platelet Aggregation
Plt-F 4 Ab
Sensitivity: low
Specificity: ?
Technique-dependent
Immunoassay=(ELISA)
for Initial screen w
T Score probability/clinical presentation
Technically easy
Faster turnaround time
Specificity: low (false+
common for Faster turnaround time some
PIFA®
Rapid turnaround time
Sensitivity: poor
Specificity: poor
not “quantifiable”

14. HIT
The incidence of HIT is likely to increase as an aging patient population develops diseases and undergoes more complex procedures requiring heparin anticoagulation.
Early recognition, thorough risk assessment and platelet count monitoring, and appropriate treatment of HIT are critical in reducing morbidity and mortality.
The essence of appropriate treatment is:
- Immediate discontinuation of all sources of heparin,(IV, subq, Heparin coated catheters & flushes and LMWH’s) and warfarin.
- Initiation of alternative anticoagulant (even if no clinical
thrombosis)
- Do not delay treatment pending confirmation by laboratory tests.

18. Treatment Goals Based on Pathophysiology and Clinical Studies
Interrupt the immune response
- Discontinue heparin & flushes, LMWH
Inhibit thrombin generation
- Treat active thrombosis
Prevent new thrombosis
Minimize complications of HIT
- Thromboses, limb amputation, death

19. Half-life in healthy subjects 39-51 min 1.3 hours 25 minutes
Argatroban
Lepirudin
Bivalirudin
Half-life in healthy subjects
39-51 min
1.3 hours
25 minutes
Elimination
Hepatic
Renal
80% Enzymatic
20% Renal
Monitoring needed
aPTT, ACT
aPTT
Thrombin binding
Reversible
Irreversible
Partially
reversible
Antidote
Adapted from Chen JL. Heart Dis.2001;3:
None
Warkentin, TE, GreinacherA. Heparin-Induced Thrombocytopenia. 3rd ed. Revised and Expanded. 2004;:

20. Direct Thrombin Inhibitors: FDA Indications and Usage
Argatroban - Preferred
-Indicated as an anticoagulant for prophylaxis or
treatment of thrombosis in patients with HIT Type 2
- Indicated as an anticoagulant in patients with or at risk
for HIT undergoing PCI – bivalirudin is JDH
*Lepirudin- not made, supplies to be exhausted in mid2013
- Indicated for anticoagulation in patients with HIT and
associated thromboembolic disease to prevent further
thromboembolic complications
Bivalirudin
- Indicated as an anticoagulant in patients undergoing
percutaneoustransluminalcoronary angioplasty (PTCA)

23. Argatroban Indication: Treatment of Heparin Induced thrombocytopenia
Dosing: Infusion Concentration
250 mg/ 250 mls NS= 1mg/1 ml= 1000 mcg/ml
No initial bolus dose required.
Criteria for Use:
- Patient at intermediate to high risk for HIT
Have MD’s follow existing protocol
If you receive a request to vary from protocol
1st. Discuss w provider that the Hem/Onc team has agreed to protocol and no literature demonstrates that varying the Goal PTT is of benefit. If still an issue then
2. Call Clinical Coordinator to have discussion w provider

24. IV Argatroban- High Expense ( > $1,000/day) High Alert Med)
Argatroban Initial dose: 2 mcg/kg/min for HIT Titrate to maintain aPTT x pt’s baseline or x mean of lab control range (27 sec). = Goal aPTT secs
Draw a PTT 2 hours after initiation of infusion x 2 and 2 hours after each dose change x 2 then follow the titrating chart below:
Lab result Infusion Rate Change Next aPTT
Ptt (sec) mcg/kg/min
< 30 sec increase CI rate by in 2 hr
30-40 sec increase CI rate by in 2 hr
40-70 sec same rate in 2-4 hrs,
if in range aPTT in am
71-90 sec decrease CI rate by in 2 hrs
> 90 sec decrease CI rate by in 2 hrs
Notes:
Patients usually reach goal PTT between mcg/kg/min
Max dose is 10 mcg/kg/min.
No initial dose adjustment with renal impairment, in absence of factors requiring dose reduction as listed HIT.
Hepatic elimination. Not renally cleared.

25. Warfarin Overlap with Argatroban
Argatroban will significantly elevate PT/INR values. Follow warfarin dosing guideline below when determining adjustment of warfarin dosing.
1. Initiate warfarin only when the platelet count has substantially recovered to > 100,000 cells/mm 3 or greater.
2. Obtain a baseline PT/INR prior to starting the warfarin. Do not give a loading dose of warfarin
3. Initiate warfarin dose at a low, maintenance dose ( maximum of 5 mg unless patients was stable on prior doses > 5mg.
4. Adjust warfarin dose for approximate goal of INR 4-5 during the first 5 days of concomitant argatroban and warfarin therapy.
5. After 5 days of concomitant argatroban and warfarin therapy, decrease argatroban rate to 2 mcg/kg/min (if > 2 mcg/kg/min) and check INR:
A. If INR ≥ 4, Discontinue argatroban and recheck INR in 6 hrs.
a. If INR is 2-3 , restart argatroban at 2 mcg/kg/min (or original rate if <2 mcg/kg/min) and keep patient on same
warfarin dose. Repeat process daily until INR off argatroban remains 2-3 for 2 consecutive days. Then
discontinue argatroban
b. If INR >3, restart argatroban and reduce warfarin dose. Repeat process daily until INR is within range for 2
consecutive days. Then discontinue argatroban.
c. If INR <2, increase argatroban to original therapeutic rate and increase warfarin dose and repeat above
process the next day

26. Argatroban Protocol
B. If INR < 4, Return argatroban infusion to original therapeutic rate and increase
warfarin dose. Check INR daily for 2 days.
a. If after 2 days INR has not increased, increase warfarin dose and repeat process.
b. If INR has increased but still < 4, repeat process at same warfarin dose until
INR ≥ 4, then follow as in a above
c. If new INR ≥ 4, follow as in a above
MD/LIP Responsibility: Order labs: Baseline: PT, PTT, CBC with platelet count, Stool for blood, urinalysis
Platelet count, Hematocrit q 2-3 days
Nursing Responsibility:
Requires RN/LPN verification double check on MAR.
Infusion via Guardrails on Alaris Volumetric Infusion Pump
Order f/u PTT’s and Monitor PTT
Monitor bleeding symptoms,
Pharmacist responsibilities:
- Upon initial Order validation provide Argatroban written protocol for RN, Review w them
- Assure DC of all heparin/lmwh sources
- Double calc’s, monitor supplies and dispensing to minimize waste
- Monitor daily & document in Siemans notes, PUP Com. sheet, shift report
- Warfarin dose validation
- Monitor for compliance with transition to warfarin - to references for transition to warfarin.
Adjust dose for approximate goal of INR 4-5 during the first 5 days of concomitant argatroban and
warfarin therapy.

27. ACCP Guidelines: HIT
Do not use Vitamin K antagonists (\warfarin) until after the platelet count is > 150,000/ul
And only during overlap with alternative anticoagulation
Start VKA at lower dose (5-6 mg)
Alternative anticoagulants should not be dc’d until platelet count has reached a stable plateau and with at least the last 2 days of INR within target therapeutic range

28. The End Proceed to Post Test