1. Heparin-Induced
Thrombocytopenia
Paul Basciano, MD
January 31, 2013

2. Overview
 Clinical Presentations
 Timing and degree of thrombocytopenia
 Presence of thrombosis and implications for management
 Rarer presentations
 Laboratory Diagnosis
 Heparin/PF-4 antibodies
 Serotonin release assay, HIPA
 Therapeutic Management
 DTIs, fondaparinux
 Vitamin K antagonism
 With or without thrombosis
 Cardiovascular surgery
 Heparin re-challenge
 ACP Guidelines 8th Edition, 2008
 Warkentin recent reviews
 ASH Educational Session
 Paradigms and Paradoxes, J Thromb Haemost 2011; 9 (Suppl 1):105-117

3. HIT: Features
 An atypical, drug-induced immune response
with platelet-activating IgG antibodies against a
novel epitope of PF4 induced by precise
stoichiometric amounts of heparin
 A hypercoaguable state with a high risk of
thrombosis, amputation, and death due to
activation of platelets, endothelium, and WBC
 A disease requiring a clinicopathologic diagnosis

4. HIT Immunology
 PF4 and chondroitin sulfate released from activated platelets
 PF4 forms dimers and tetramers—tetramers bind to surface of
platelets and to endothelial cells via GAGs
 The presence of long chains of heparin allow for ultra-large
aggregates of PF4 tetramers to form
 These ultra-large PF4 tetramers allows for the binding of IgG abs
which in turn bind to FcRγIIA receptors on platelets and
endothelium, leading to activation

5. The Immunology of HIT
2days
2days
Unpredictable
•By the time the platelet count has started to fall, IgG abs are above the cut-off for OK
•Therefore re-testing is unnecessary, although this doesn’t rule out human error
Warkentin et al. Blood 2009

6. Immunology of HIT
•PF4/Hep abs increase quickly like a
secondary immune response
•Unlike a true secondary immune
response, the antibodies are
relatively short-lived
•There is also no anamnestic
response

7. Immunoglobulin Subtypes
•IgG elevation occurred later in the non-HIT group
•No significant differences in IgA or IgM levels between HIT and non-HIT patients
Warkentin et al. Blood 2009

8. The Immunology of HIT: Summary
 Difference in levels of antibody formation between HIT and non-HIT
was due to IgG levels
 OD values are approximately 80% of maximal at the start of platelet
fall (before clinical susupicion), and higher at the time of 50%
reduction
 Very rapid antibody response: median 4 days from heparin
administration
 No typical Ig class switch response (e.g. IgM ->IgG)
 No association between previous heparin exposure and timing of
antibody development
 No anamnestic response in HIT; rapid reactions are from circulating antibody
 Relatively rapid loss of antibody titers.
Warkentin et al. Blood 2009

9. HIT:
CLINICAL DIAGNOSIS

11. The Four T’s
LOW: 0-3 points
INTERMEDIATE: 4-5 points
HIGH: 6-8 points
Lo et al., JThrombHaemost 2006

13. The First T: Thrombocytopenia
 Initial studies used an absolute platelet count
cut-off
 Improved sensitivity with preserved specificity for
using a relative 50% drop (some suggest even
30%--the Brittish)
 Platelet count may be normal even when
dropping; consider especially thrombocytosis
 The relative drop is based on the platelet count
at initiation of heparin; especially important in
the post-surgical patient (the double dip)
 The thrombocytopenia of HIT also tends to be
more mild than that seen with other drug
reactions

14. The Second T: Timing
 For most patients, the drop will begin 5-10d after
the initiation of heparin (nadir 10-14d)
 Upwards of 20% of patients will have drops after
heparin is stopped (delayed-onset HIT)
 Some will have thrombosis prior to platelet drop
 Early drops occur in patients with recent
exposure to heparin
 Generally within 30-100days prior
 Due to remaining PF4/heparin abs, NOT an
anamnestic response

15. The oTher T’s: Thrombosis and
oTher causes
 More on these later

16. The 4 T’s: Clinical Score
Experts
Everyone Else
Experts
Lo et al., JThrombHaemost 2006

17. The 4 T’s: Correlation with Labs
Experts Everyone Else
Lo et al., JThrombHaemost 2006

18. 4Ts in other studies

19. 4Ts in Real Life

20. 4 T’s: Summary
 A low clinical score reliably rules out HIT
 No need for lab testing
 No need to stop heparin
 A high score has a poor positive
predictive value (in the wrong hands…)
 May depend on the population
 Doesn’t reflect two main clinical parameters:
patient population and type of heparin
 Needs to be strictly applied

21. Rarer presentations of HIT
 Anaphylactic reactions to
heparin infusion
 N.b. anaphylactoid reactions
to OSCS in 2008
 Necrotizing skin lesions at
injection sites
 Platelets in the normal range
 Especially, pts with ET and
other MPDs
 Continued thrombosis despite
heparin

22. Warkentin speaks:
 Within the past 10-20 years, recognition of HIT
has evolved from gross underdiagnosis to wild
overdiagnosis
 In essence, the widespread detection of anti-
PF4/heparin antidoies by commerically-available
PF-4 dependent immunoassays has prompted
an over-diagnosis of HIT

23. HIT:
LABORATORY
DIAGNOSIS

24. ACCP Guidelines, Chest 2008

25. Laboratory Methods:
Ig Detection Assays
•Confirm assay can also be performed with addition of excess heparin
Excess heparin should inhibit antibody binding and reduce OD

26. Laboratory Methods:
Activation Assays

27. Utility of the SRA
oratory of John K elton at
preserve precious HIT sera The power of the SRA became evident when it was applied
fÔwashed plateletsÕ from a to a clinical trial of unfractionated heparin (UFH) vs.
tard [2], and the platelet
orn [13]. Thecharacteristic
–0.3 U mL ) 1 heparin and <50% serotonin release ≥50% serotonin release
mL ) 1 ) presaged the discov- (90%) (10%)
stoichiometrically precise 360
arin: at very high heparin Serotonin release
350
<50% ≥50%
Number of patients
50
40
50% serotonin-
Conventional
30 release cut-off
cut-off
<20% serotonin
20 release
10
0
0 10 20 30 40 50 60 70 80 90 100
Serotonin release (%)
Fig. 2. Dichotomization of results of serotonin-release assay (SRA) test-
ing for HIT antibodies (n = 405 patients tested). The data are shown as
deciles of mean percent serotonin-release (at 0.1 and 0.3 IU mL ) 1 un-
fractionated heparin). The conventional cut-off defining a positive SRA
test result is 20%; however, the Author generally uses 50% as the cut-off
(assuming all controls react as expected, including weak-positive control
serum), as this better discriminates between HIT and non-HIT throm-
bocytopenia. Only approximately 10% of patients investigated for HIT

28. •Clinically irrelevant antibodies detected by EIAs (IgGAM>>>IgG)
•Note even SRA% is greater than clinical HIT positivity
•This is why HIT is a clinicopathologic diagnosis, and not a pathologic diagnosis alone
•>50% of CT surgery patients will have ab positivity even though 1% will have HIT

29. EIA and SRA

30. HIT: TREATMENT

31. How to Treat HIT
 Heparin: Stop it.
 Alternative Anticoagulation: Start it.
 Warfarin: Reverse it, delay it, and overlap it.

32. (Isolated)HIT and HITT
 The difference is based on the presence of overt
thrombosis
 With i-HIT, LE dopplers should be performed on all
patients (50% silent VTE found)
 Isolated HIT requires at least cessation of heparin
plus alternative anticoagulation until platelet
recovery; warfarin use and duration is uncertain

33. Risk of Thrombosis in Isolated HIT
•High risk of thrombosis mandates treatment with non-heparin
anticoagulant, likely beyond prophylactic dosing
AACP Guidelines, Chest 2008

34. Argatroban
 2mcg/kg/min
 For Bilirubin >1.5, 0.5mcg/kg/min
 Likely for all severe illness
 PTT based assay—will be confounded by
elevations associated with DIC seen in HIT as well
as by re-warfarinization
 No studies outside of HIT

35. Lepirudin
 Renally cleared
 High incidence of antibodies after treatment; re-
treatment is not recommended
 Maybe more effective than argatroban?
 Limb loss: 5% with lepirudin, 13% with argatroban
 Likely not more bleeding than argatroban
 Dosing is a major issue, and should be based on
manufacturer and not trials:
 Infusion rate of 0.1mg/kg/h
 No bolus unless life or limb-threat: 0.2mg/kg
 Same PTT goals

36. Bivalrudin
 Only approved for use with PCI and cardiac
surgery
 Lower antigenicity and less dependence on
renal clearnece than lepirudin
 less effects on INR than argatroban
 Only reports about use outside of PCI and CT
surgery in HIT; other studies outside of HIT

37. Fondaparinux
 Some concern about cross-reactivity, but rare
 Renally cleared
 Long half life
 No monitoring required, but anti-Xa can be used
and will not be confounded like PTT
 Warkentin loves it

39. Cardiac Surgery and PCI
 Cardiac surgery options:
 Re-challenge with heparin (esp >100d since HIT,
negative SRA); use only during procedure
 Use Bivalrudin
 Use Heparin + Tirofiban or Epoprostenol
 Use Lepirudin
 Use Argatroban
 PCI options:
 Argatroban
 Bivalrudin
 Lepirudin
 (Note: no heparin re-challenge; may need later for
surgery)

40. Warfarin
 Not to be restarted until platelets >150 or
‘significantly improved’
 Argatroban and Lepirudin will affect INR
 Fondaparinux and Bivalrudin will not
 May be possible to use DTI and then change to
fondaparinux when platelets have recovered in
preparation for warfarin

41. Platelet Transfusions
 Not absolutely contraindicated
 Some concern regarding safety and
precipitation of thrombosis
 May be more of an association than causal
 Have a higher threshold to transfuse patients
with confirmed HIT, but give as needed for
significant bleeding and/or risk of bleeding
 Usually platelets >30 with HIT and no bleeding
attributable to HIT
 Co-existing conditions (DIC etc) may lower
platelet count more

42. HIT:
Decision-Making
Guidelines

43. Low Clinical Likelihood of HIT,
No Active Thrombosis
 Do not send EIA or SRA and continue heparin
 OR
 If EIA/SRA sent-> switch to prophylactic dosing of
alternative (esp fondaparinux) and wait for
results (CYA)

44. Int/High Possibility of HIT,
Active Thrombosis
 Send appropriate tests (EIA, SRA)
 Reverse any warfarin with IV or PO vitamin K
 Change to alternative anticoagulation based
on clinical setting
 Wait for platelet recovery and then begin
warfarin with overlap if HIT confirmed

45. Low Likelihood of HIT with Thrombosis or
Int/High without Thrombosis
 More difficult clinical situations
 Trust the 4Ts– if truly low likelihood, continue
heparin
 If Int/High and no renal failure or bleeding, single
dose of treatment dose fondaparinux until EIA
results may be good intermediate

46. Isolated HIT
 Perform LE dopplers to assess for silent thrombosis
 Begin alternative anticoagulation based on
clinical setting
 ?Begin warfarin when platelets recover and
continue for…

47. A History of HIT
 First, confirm the history is true
 Check ELISA
 If negative can rechallenge
 If positive, check SRA
 Can re-use heparin in situations such as
cariopulmonary bypass for brief periods
 Use alternative anticoagulation in all other
settings, including pre- and post-operative