1. Heparin induced thrombocytopenia
Hank Ng
9/26/18

2. Learning Objectives Definition Pathogenesis Risk Factors
Evaluation and Diagnosis
Management

3. HIT Prothrombotic adverse drug effect Type 1 Type 2 Nadir 100,000
Timing first 2 days
Direct effect on platelet aggregation
Not associated with thrombosis
Don’t have to discontinue heparin
Type 2
PF4/antibodies
Increased risk of thrombosis – heparin induced thrombocytopenia and thrombosis (HITT)
IgG antibodies form quickly over days

5. Ddx of thrombocytopenia
Disseminated intravascular coagulation (DIC)
Immune thrombocytopenia (ITP)
Thrombotic microangiopathy (TMA) – TTP, HUS
Drug-induced thrombocytopenia
Systemic lupus erythematosus (SLE)
Antiphospholipid Syndrome (APS)

7. PF4 on platelets binds to heparin and forms a neoantigen
Individuals with HIT Ab bind the PF4/heparin complex – platelets get activated
Thrombocytopenia – caused by removal of IgG coated platelets of reticuloendothelial system
Unlike other drug induced thromocytopenia – HIT activates platelets and aggregation causes thrombosis

8. Incidence 0.2-5% of patients treated with heparin Risk Factors
UFHvs LMWH
Meta analysis of 15 studies comparing incidence of HIT (thrombocytopenia and +HIT Ab) predominantly orthopedic patients found UFH 2.6% vs LMWH 0.2% absolute risk
Another meta analaysis 13 studies 5,275  patients for medical VTE treatment with HIT diagnosed by Hit Ab showed no difference in UFH vs LMWH
Older age (rare <40) and therapeutic doses (0.76% vs <0.1%)

9. Considering HIT Thrombocytopenia Thrombosis Average nadir 60,000
Counts rarely drop below 20,000
Thrombosis
Venous (20-50%) > arterial (3-10%)
Rarer complications
Limb gangrene - usually venous
Necrotizing skin lesions
Adrenal v. thrombosis and hemorrhage
Stroke, MI, organ infarction
Anaphylaxis, systemic reaction

11. Timing Most common 5-10 days Early onset – within 24 hrs
Patient exposed to heparin previously in the past 100 days with circulating antibodies

12. Evaluation: 4T Score

13. Intrepretation 0-3 points = low probability
4 to 5 points = Intermediate probability
6 to 8 points = High probability
Meta-analysis over 3000 patients with clinically suspected HIT
Negative predictive value with low HIT score .098
PPV for intermediate 0.14 and high 0.64

14. Diagnostic score for heparin‐induced thrombocytopenia after cardiopulmonary bypass
Example of platelet time courses from 2 distinct patients. Representation of one pattern A (biphasic pattern, solid triangles), characterized by a fall in the platelet count more than 4 days after CPB (the initial fall immediately after CPB is followed by a rise within 5 days and then by a further fall) and one pattern B (open circles), characterized by post‐CPB thrombocytopenia persisting beyond day 4. Platelet counts are reported until the index date (first day of suspected HIT, arrows).
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Diagnostic score for heparin‐induced thrombocytopenia after cardiopulmonary bypass, Volume: 2, Issue: 11, Pages: , First published: 10 November 2004, DOI: ( /j x)

15. Retrospective French study looking at 84 patients suspected HIT
Variables
Score
Platelet count time course
Pattern A 2
Pattern B 1
Time from CPB to index date
≥ 5 days
< 5 days
CPB duration
≤ 118 min
> 118 min
Total score
Classification
High probability of HIT
≥ 2
Low probability of HIT
< 2
Retrospective French study looking at 84 patients suspected HIT
NPV 97%
Identified 34/35 HIT cases

16. Diagnosis HIT antibody testing Immunoassay: ELISA
Detects presence of anti- (PF4)/heparin antibodies in patient serum
ELISA: add patient serum to plate coated with PF4/heparin – add another Ab to test
Functional: test the ability of HIT antibodies from patient serum to activate test platelets
SRA: Normal test platelets are radiolabeled with 14C-serotonin and incubated with patient serum plus heparin at therapeutic or excessive concentrations. A positive test is the release of 14C-serotonin when therapeutic heparin concentrations are used (0.1 units/mL)
Heparin-induced platelet activation (HIPA): platelets /platelet-rich plasma (PRP) from healthy donors is added to serum of patient and platelet activation is measured in the absence of heparin and in the presence of low and high heparin concentrations. A positive test shows minimal platelet activation in the absence of heparin and in the presence of high heparin concentrations (eg, 10 to 100 units/mL) and strong activation in the presence of low heparin concentrations
HIPA tests platelet aggregation

17. ELISA OD < 0.4, rules out HIT
OD > 2.0 for intermediate probability 4T score or OD > 1.5 for high probability 4T score rules in HIT

18. Management Stop heparin Reverse warfarin Argatroban (direct thrombin)
Use in renal insufficiency
maintain the aPTT at 1.5 to 3 times baseline
Bivalirudin (direct thrombin), off label
Use in renal/hepatic insufficiency
aPTT 1.5 to 2.5 times baseline
Danaparoid (heparnoid) – not available in the US
monitor anti-Xa - adjust to
Fondaparinux - synthetic pentasaccharide – inhibits Xa
Direct oral anticoagulants – observational studies
Small review 12 pts – no new thrombosis or major bleeding

19. Further Management Once HIT confirmed
Lower extremity U/S
Thrombosis – anticoagulation for 3 months (ASH and ACCP guidelines
No thrombosis – anticoagulation for 1 month
One review of 127 patients with diagnosed HIT found risk of 30 day thrombosis without anticoagualtion was 53%
Platelets should recover in 7 days

20. oral anticoagulants Warfarin DOAC
start when PLT > 150,000 and stably anticoagulated with another agent
5 day overlap recommended
DOAC
overlap with IV anticoagulants for dabigatran or edoxaban

21. Cardiac or vascular surgery
Test for PF4/heparin antibodies
If not present – can get heparin day of surgery, but avoid pre and post op heparin
If antibodies present and heparin needed during surgery – plasmapheresis or IVIG

22. Sources
Cuker A, Gimotty PA, Crowther MA, et al: Predictive value of the 4Ts scoring system for heparin-induced thrombocytopenia: a systematic review and meta-analysis. Blood 120:4160-7, 2012
Lillo-Le Louet A, Boutouyrie P, Alhenc-Gelas M, et al: Diagnostic score for heparin-induced thrombocytopenia after cardiopulmonary bypass. Journal of Thrombosis and Haemostasis 2: , 2004
Warkentin TE, Kelton JG: A 14-year study of heparin-induced thrombocytopenia. Am J Med 101:502-7, 1996