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
11. The Four T’s
LOW: 0-3 points
INTERMEDIATE: 4-5 points
HIGH: 6-8 points
Lo et al., JThrombHaemost 2006
12.
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
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
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
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
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
38.
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
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
Notas do Editor
-Not so easy to apply accurately: the criteria are stringent
Evaluated in two clinical settings: Experts—authors at a single tertiary care center Everyone Else: Anyone ordering an ELISA, mandatory part of test ordering Note: Distribution of patients is different Results of the scores are different