1. HEPARIN INDUCED THROMBOCYTOPENIA (HIT)
Who gets it
How and why they get it
How to recognize it
How to treat it

2. HEPARIN-INDUCED THROMBOCYTOPENIA
Causative agents
Unfractionated heparin (UFH) (beef > pork)
Continuous iv infusion
Cardiopulmonary bypass
Low dose sq
Heparin flushes
Heparin-bonded catheters
Low molecular weight heparin
More likely to cause HIT if pt previously exposed to UFH
Most cases associated with administration of UFH for treatment or prophylaxis

3. HEPARIN-INDUCED THROMBOCYTOPENIA
Clinical manifestations
Isolated thrombocytopenia (“Isolated HIT”)
Arterial or venous thrombosis (HITT)
DVT, PE, MI, stroke, peripheral arterial occlusion
DIC, microangiopathic hemolytic anemia
Skin necrosis (at injection sites or distant)
Venous limb gangrene (? Role of warfarin)
Sudden death
ARDS
Hemorrhagic adrenal infarction

4. HEPARIN-INDUCED THROMBOCYTOPENIA
Epidemiology
UFH > LMWH >> Fondaparinux
Duration of heparin treatment ≥ 6 days
Rarely occurs in patients < 40 years old
2-3 fold higher incidence in women
Surgical > medical > obstetric patients
Incidence in trauma patients proportional to severity of trauma
Related to degree of platelet activation?
Blood 2012; 119: 2209

5. HEPARIN-INDUCED THROMBOCYTOPENIA
Incidence and presenting features
Warkentin and Kelton, Am J Med 1996;101:502
Presenting with thrombosis (n=65)
Presenting with no thrombosis (n=62)
Total (n=127)
Age
67 ± 10.7
66.7 ± 12.3
67.0 ± 11.4
Male/Female
27/38
33/29
60/67
SURGICAL PTS 51 33
84 (66.1%)
Orthopedic 25 15 40
Cardiovascular 10 9 19
Oncology 7 6 13
General 2 8
Neurosurgery 3 1 4
MEDICAL PTS 14 29
43 (33.9%)
Cardiac 16
DVT or PE 11
Other 12
In retrospective studies, HIT most often recognized in surgery pts, esp ortho surgery
? Because they are at higher risk for thrombosis to start with

6. THROMBOTIC COMPLICATIONS IN HIT
Am J Med 1996;101:502
Type of thrombosis
Pts presenting with thrombosis (n=65)
Pts presenting with only thrombocytopenia (n=62)
VENOUS (n=78) 54 24
DVT (n=61) 40 21
New 35
Progression 4
Recurrence 1
PE (n=32) 26 6 25 5
ARTERIAL (n=18) 12
Limb 7 2
Myocardial infarct 3
Thrombotic stroke
Other (n=3)
Sudden death
Adrenal hemorrhage
NO THROMBOSIS (n=30) NA 30
Most thromboses venous
Pts diagnosed with “isolated HIT” have high likelihood of subsequent thombosis

7. ISOLATED HIT IS ASSOCIATED WITH A HIGH RISK OF SUBSEQUENT THROMBOSIS
Caveat: retrospective study, potential for diagnostic selection bias
But it seems clear from this and other studies that isolated HIT does create a very high risk for subsequent thrombosis
Am J Med 1996;101:502
Over 50% of patients presenting with “isolated HIT” had a subsequent thrombotic episode within 30 days
Substitution of warfarin for heparin after the onset of thrombocytopenia did not prevent thrombosis

8. UNFRACTIONATED HEPARIN IS MORE LIKELY TO CAUSE HIT THAN LMWH
Randomized trial in pts having hip surgery
Warkentin et al, NEJM 1995;332:1330
3-4% incidence of HIT in hip surgery, probably the highest risk group

9. Odds ratio for thrombosis 37 times higher in HIT pts
THE FREQUENCY OF THROMBOSIS AFTER HIP SURGERY IS MUCH HIGHER IN PATIENTS WITH HIT THAN IN THOSE WITHOUT HIT
Warkentin et al, NEJM 1995;332:1330
Odds ratio for thrombosis 37 times higher in HIT pts

10. THE HIT INCIDENCE IN MEDICAL PATIENTS TREATED WITH LOW DOSE SQ UFH IS ABOUT 2% Girolami et al, Blood 2003;101:2955
But medical pts at substantial risk as well
All cases in patients receiving UFH as prophylaxis
HIT associated with 40-fold increase in risk of thrombosis

11. LMWH IS MORE LIKELY TO CAUSE HIT IN PATIENTS WITH PRIOR UFH EXPOSURE Prandoni et al, Blood 2005;106:3049
Prospective cohort study, 1754 medical pts
0.8% overall incidence of HIT
0.3% incidence if no prior UFH exposure
1.7% incidence if prior UFH exposure
All cases in first 2 weeks
Prevalence of thromboembolism 16.6x higher in patients with HIT (29% vs 2.4%)
Incidence of HIT in pts getting LMWH after prior exposure to UFH roughly comparable to incidence with UFH

12. Lubenow, N. et al. Blood 2010;115:1797-1803
Development of HIT antibodies is more common in major surgery than minor surgery, and more common with UFH than LMWH Results of a prospective trial
Lubenow, N. et al. Blood 2010;115:

13. THROMBOSIS IN HIT MAY OCCUR WITH NORMAL PLATELET COUNT
Warkentin et al, NEJM 1995;332:1330

14. THE PLATELET COUNT DROPS PRIOR TO THROMBOSIS IN HIT
Warkentin et al, NEJM 1995;332:1330 *
Platelet count normally rises steadily for at least a week after hip surgery. Note that all pts with HIT and normal plts had at least two days of dropping plts before thrombotic event
*Thrombotic episode

15. Recent heparin exposure may cause “rapid onset” HIT
Warkentin and Kelton, NEJM 2001;344:1286
HIT virtually never happens less than 4 days after starting heparin UNLESS there has been prior exposure to heparin

16. Rapid-onset HIT is associated with
re-exposure to heparin within 90 days
Warkentin and Kelton, NEJM 2001;344:1286
And this exposure usually has been within a month, almost always within 3 months

17. Heparin-dependent antibodies usually disappear within 90 days an episode of HIT
Warkentin et al, NEJM 1995;332:1330
Because the antibodies that cause the problem disappear during this time period – functional assay being more predictive of the condition

18. DELAYED ONSET HIT
Ann Intern Med 2002;136:210
Describes 14 patients treated with heparin, discharged, and later re-hospitalized with thromboembolism and positive tests for HIT antibodies
Most patients got heparin during cardiac surgery
12/14 had mild thrombocytopenia (66-145K) at time of thrombotic episode
Median time between discharge and readmission 14 days, maximum 40 days
11 patients re-treated with heparin: all had clinical deterioration and worsening thrombocytopenia
3 patients died
We have said that HIT can occur without thrombocytopenia. It can also occur when a patient is no longer getting heparin. This is a particularly difficult form of HIT to diagnose, and the consequences of not diagnosing it can be dire

19. PATHOPHYSIOLOGY OF HIT

20. HIT IS CAUSED BY ANTIBODIES AGAINST A HEPARIN-PLATELET FACTOR 4 COMPLEX3
Antibody binds heparin-PF4 complex
Fab FC
Antibody binding to platelet FC receptor activates platelet 4
Heparin-induced thrombocytopenia: Platelet factor 4 (PF4) released by activated platelet. This binds heparin, creating a potential neoantigen. Antibody binds the complex of heparin-PF4. The antigen antibody complex then binds to the FC receptor on another platelet, causing platelet activation. This may account for the association between HIT and thrombosis in some patients. 2
Heparin
PF4 binds heparin 1
PF4
Activated platelet
secretes PF4
FC receptor
Platelet membrane

21. PATHOPHYSIOLOGY OF HIT Warkentin, Brit J Haematol 2003;121:535
Heparin-PF4 complexes stimulate antibody production
Ag-Ab complex binds to and activates platelets, monocytes
Size of immune complex is critical, varies with PF4 and heparin concentrations
Inhibited by high heparin concentrations
Activated platelets release procoagulant microparticles
Activated monocytes produce tissue factor
Antibodies may cross-react with PF4 bound to endothelial cell heparan sulfate → vessel wall injury
Some HIT antibodies can activate platelets in the absence of heparin

22. Heparin concentration affects the size and charge of heparin:PF4 complexes and their ability to activate platelets
Low heparin:PF4 ratio → small complexes
High heparin:PF4 ratio → small complexes
1:1 heparin:PF4 → large complexes
Charge of complexes
Heparin conc→
Blood 2007;110:4253

23. Smaller heparin molecules → less platelet activation by HIT antibodies
NEJM 2013;368:737

24. Clinical factors may help determine the likelihood of developing HIT
Healthy volunteers given heparin or LMWH make IgM antibodies to heparin/PF4
Pathologic HIT antibodies are usually IgG
Concomitant immune stimulus necessary to promote IgG HIT antibody formation?
Higher PF4 levels after surgery or acute illness may promote formation of larger immune complexes
Formation of DNA-PF4 complexes following tissue injury may initiate immune response, antibodies can cross-react with heparin-PF4 complexes
Blood 2007;110:4253
J Thromb Haemost 2012;10:1446
Blood 2013;122:272

25. HIT Antibodies can activate platelets in the absence of heparin
J Thromb Haemost 2005;3:2168

26. Why is HIT so different from other immune-mediated drug reactions?
Disease feature
Possible explanation
Higher incidence after surgery or trauma
More platelet activation and PF4 release→ more/larger immune complexes
Higher incidence with unfractionated heparin
Larger heparin molecules → larger immune complexes
Paradoxical thrombosis
Activation of platelets & monocytes by immune complexes
Onset may follow heparin discontinuation
Damage to endothelial cells by antibodies bound to PF4/heparan sulfate complexes?
Heparin-independent antibodies?
Lack of recurrence with heparin re-exposure
Complex pathophysiology, antibody formation necessary but not sufficient to cause clinical disease

27. DIAGNOSIS OF HIT

28. DISTINGUISHING IMMUNE FROM NON-IMMUNE HEPARIN INDUCED THROMBOCYTOPENIA
Many patients have a transient decrease in platelets within 24 hours of receiving heparin.
This is not an antibody-mediated effect and not associated with thrombosis
How can it be distinguished from HIT?
By the time course
By the clinical picture
By serology and other lab tests

29. Severe thrombocytopenia is rare in HIT
Warkentin, Brit J Haematol 2003;121:535
Median platelet nadir 55K
15% had nadir >150K (diagnosed because platelet count fell more than 50% or because of clinical events)
The severity of thrombocytopenia did not predict thrombotic events
15% are not thrombocytopenic at all.
Rarely does plt count drop below 20K
No connection between severity of thrombocytopenia and clinical course

30. Clincal features that favor a diagnosis of HIT
Thrombocytopenia usually but not always present and typically not severe
Blood 2012;119:2209

31. The 4 T score predicts a positive HIT antibody test J Thrombos Haemost 2006;4:759
A corollary – more likely to get false + test if 4T score low – so don’t order test willy-nilly
Score
% Testing positive
<4
0.8%
4-5
11%
>5
34%

32. LABORATORY DIAGNOSIS OF HIT
Immunoassay for heparin-PF4 antibodies (EIA)
Very high sensitivity, rapid turnaround
“High positive” results typical of HITT
Rapid “bedside” assay
Many false positive results, not recommended
C14 Serotonin release assay (SRA)
Measures heparin-dependent platelet activation
Best predictor of thrombotic risk
Limited availability (Blood Center of SE Wisconsin), slower turnaround
A positive EIA test in a patient with a low pre-test probability of HIT according to 4T rule is likely to be a false positive
ELISA a very good screening test and it’s all you need if the clinical picture fits
Consider SRA when clinical picture cloudy or when risk of giving alternative anticoagulant high

33. The serotonin release assay predicts thrombosis in HIT
SRA and EIA negative
EIA positive, SRA negative
SRA and EIA positive
Am J Hematol 2007;82:1037

34. The incidence of HIT antibody formation and risk of HIT varies among different patient populations
The “Iceberg” model
Cardiac patients have high incidence of serologic abnormalities but low incidence of clinical HIT
Ortho patients getting UFH have highest risk of clinical HIT
Warkentin, Brit J Haematol 2003;121:535

35. A STRONGLY POSITIVE EIA RESULT IS ASSOCIATED WITH HIGHER RISK OF SUBSEQUENT THROMBOSIS
We don’t routinely report OD here
OD values in HIT vs HITT patients
Thrombosis-free survival vs OD
J Thrombos Haemost 2004;2:2133-7

36. The dilemma of HIT testing in critically ill patients
Most critically ill patients receive heparin products
Up to 20% have at least one clinical criterion for HIT
Only about 1% actually develop HIT
Prediction rules (4T score, etc) do not function well in this patient population
A diagnosis of HIT in a critically ill patient should always be confirmed by SRA testing
Crowther et al, Blood 2011;118:198

37. TREATMENT OF HIT

38. TREATMENT OF HIT Discontinue all heparin, including flushes
LMWH may cross-react with HIT antibodies, should not be used
If thrombosis present: give alternative thrombin inhibitor
Consider treating even if thrombosis absent (high risk of thrombosis in patients with isolated HIT)
Treatment alternatives:
Direct inhibitors
Lepirudin
Bivalirudin (little data, but approved for HIT patients having PCI)
Argatroban
Dabigatran?
Indirect inhibitors
Fondaparinux
Do not give warfarin (risk of venous gangrene)

39. DIRECT THROMBIN INHIBITORS
Argatroban (Novastan®)
Synthetic arginine derivative
Clearance mainly hepatic (can use in renal failure); halflife min
Given by continuous iv infusion, monitoring aPTT
Coagulopathic patients (long baseline aPTT) difficult to monitor
No antidote
No data yet for oral thrombin and Xa inhibitors
Most of the data on the efficacy of these drugs is on lepirudin

40. Argatroban therapy in HIT
Pooled data from 2 prospective non-randomized trials
Hazard ratio with argatroban 0.3 vs historical controls
No difference in major bleeding vs controls
Chest 2006;129:1407

41. ARGATROBAN IN HIT ACCP RECOMMENDATIONS
Bolus: None
Continuous infusion:
Normal organ function: 2 mcg/kg/mon
Liver dysfunction, post cardiac surgery, anasarca: mcg/kg/mon
Adjust aPTT to x baseline
Check aPTT q 4h
Argatroban prolongs PT/INR, making transition to warfarin tricky

42. FONDAPARINUX (Arixtra®)
Synthetic polysaccharide, inhibits factor Xa preferentially
Does not typically cross-react with HIT antibodies
Long half-life (17-20 h), no antidote
SQ administration
Monitoring unnecessary
Not FDA-approved for HIT treatment
Rare reports of fondaparinux-associated HIT (NEJM 2007; 356:2653)

43. Fondaparinux appears to be effective and safe in patients with HIT
Reference N
New thrombosis
Major Bleeding
Kuo & Kovacs
Thromb Haemost 2005 5
0/5
Lobo et al
Thromb Haemost 2007 7
0/7
Grouzi et al
Clin Appl Thromb Haemost 2009 24
0/24
Pooled Data 36
0/36
Warkentin, Hematol Oncol Clin N Am 2010; 24:755

44. VENOUS GANGRENE Arch Intern Med 2004;164:66 Tissue death
Starting warfarin too soon in HIT may promote this process
Arch Intern Med 2004;164:66

45. WARFARIN MAY PROMOTE VENOUS GANGRENE IN HIT
Ann Intern Med 1997;127:804-12
Retrospective review of 158 cases of HIT
8/8 patients with venous limb gangrene treated with warfarin, vs 3/10 with arterial thrombosis (p=.004)
Median INR 5.8 in patients with venous gangrene vs 3.1 in those who did not (p<.001)
Elevated ratio of thrombin-antithrombin complex to protein C activity in patients with venous gangrene vs controls
Conclusion: warfarin treatment of DVT associated with HIT may cause venous limb gangrene, possibly because of acquired defect in protein C pathway
Do not start warfarin treatment until HIT resolves (platelet count returns to normal)
Retrospective study in which all of the HIT patients who developed VG had been treated with W
Long INR not protective
Biochemical evidence that warfarin’s effect on protein C levels may mediate this effect

46. Platelet transfusions are associated with worse outcomes in HIT & TTP
Blood 2015;125:1470

47. How long should anticoagulation continue after diagnosis of HIT?
HIT with thrombosis: 3-6 months
Isolated HIT (no thrombosis): at least until platelets normal, consider continuing for 30 days

48. Can patients with a history of HIT be given heparin again?
Heparin should not be given while tests for heparin antibodies remain positive
If cardiac surgery cannot be delayed, use alternative anticoagulant (e.g., bivalirudin)
HIT recurrence or secondary antibody response uncommon in patients with “remote HIT” and negative HIT antibody test
Heparin administration should be limited to the intraoperative period

49. SUMMARY-1
HIT typically occurs after 5+ days of exposure to unfractionated heparin
Suspect HIT if platelet count falls by > 50% during heparin administration, or if new thrombotic event occurs within 2-3 weeks of heparin exposure
Onset may be earlier if there was prior exposure to heparin within past 100 days
Onset may follow discontinuation of heparin
LMWH rarely causes HIT but may perpetuate it
Risk of thrombosis in HIT is high even if patient does not have thrombosis at time of diagnosis

50. SUMMARY-2
HIT is caused by production of antibodies to heparin-PF4 complex that activate platelets
HIT is unlikely if tests for heparin-PF4 antibodies are negative
Patients with HIT should generally be treated with a thrombin or Xa inhibitor other than heparin or LMWH
Warfarin treatment should be delayed until platelet count is normal