Laboratory HIT Testing in Critically Ill Patients
Authors: Crowther Mark A. , Langevin Stephan , Cooper Jamie L , Dodek Peter , Muscedere John , Albert Martin , Khwaja Kosar , Kutsiogiannis Jim , Mehta Geeta , Klinger James , Friedrich Jan , McIntyre Lauralyn , Ostermann Marlies , Guyatt Gordon , Zytaruk Nicole , Heels-Ansdell Diane , Sheppard Jo-Ann , Cook Deborah J , Warkentin Theodore E. 
Published: October 2019

Abstract
Abstract 198FN2

Introduction:
Many critically ill patients are frequently suspected of having HIT because heparin exposure is nearly universal and up to 45% of medical-surgical ICU patients have a platelet count of less than 150 × 109.

Methods:
Our objectives were: (1) To estimate the incidence of suspected and objectively confirmed HIT; and (2) To evaluate whether a published clinical prediction rule (the 4T's score) reliably rules out HIT in ‘low risk' ICU patients. PROTECT was a multinational, concealed, stratified, randomized blinded trial enrolling medical-surgical critically ill patients to evaluate thromboprophylaxis with the low molecular weight heparin (LMWH) dalteparin 5,000U daily vs unfractionated heparin (UFH) 5,000 twice daily on the primary outcome of proximal leg deep vein thrombosis (DVT). Patients were evaluated for HIT and included in this HITEC Substudy if 1) their platelet count decreased to less than 50 × 109/L, 2) if there was an otherwise unexplained platelet count decrease to less than 50% of the patient's baseline (defined as the value found on the first platelet count after ICU admission as long as the count is >100 × 109/L), or 3) if venous thrombosis occurred, and 4) if HIT was otherwise suspected. There were 2 laboratory components to HIT testing (local and central). For local real-time clinical care, HIT was evaluated and treated as per local practice. Centrally, blood samples were analyzed at the laboratory of Dr Ted Warkentin at McMaster University. The 4Ts Score was completed by Research Coordinators (RCs) and by central adjudication. We defined HIT as a clinical suspicion of HIT and a positive serotonin release assay (SRA).

Results:
The PROTECT trial enrolled 3746 patients of whom 763 patients (397 allocated to UFH and 366 to LMWH) met HITEC enrollment criteria; 151 because of an absolute platelet count of less than 50×109, 253 because of a fall in their platelet count of greater than 50% from the time of ICU admission and 534 because venous thrombosis developed and 128 because of a clinical suspicion of HIT (categories are not mutually exclusive). Of these 763 patients, 475 had a central or local laboratory HIT test performed and were adjudicated. HIT was present in 15/3746 patients enrolled in the PROTECT study (0.4%, 95% CI 0.2% to 0.7%), and 15/475 (3.2%) with local or central testing, while 432 patients with RC 4Ts scores were matched to an adjudicated outcome. Using the 4Ts score, RCs and central adjudication classified patients as low risk (4Ts score of 3 or less) in 71.1% and 86.3% of cases, respectively, moderate risk (score or 4 or 5) in 25.7% and 12.0% of cases, and high risk (score of 6 or more) in 3.2% and 1.7% of cases. There was a good correlation between a low pretest probability according to the RCs' scores and the absence HIT (prevalence of adjudication confirmed HIT 1.6% (95% CI 0.5 to 3.7%).There was a moderate correlation between a low pretest probability according to central adjudication and the absence HIT (prevalence of adjudication confirmed HIT 2.6% (1.3 to 4.7%).

Discussion:
HIT occured in less than 1% of medical-surgical critically ill patients, and in 3% of patients who had at least one criterion to suspect HIT. We failed to confirm our pre-specified criteria for successful implementation of the 4T's score (that the upper boundary the 95% confidence interval about the proportion of patients with confirmed HIT and a low 4Ts score was less than 3%) and thus we conclude that use of the 4Ts score does not rule out the presence of platelet-activating antibodies in medical surgical critically ill patients with clinically suspected HIT; SRA testing is recommended.

Funding:
Canadian Institutes for Health Research and Heart and Stroke Foundation of Canada

Disclosures:
Crowther: CSL Behring: Consultancy; Leo Pharma: Consultancy, Research Funding; BI: Research Funding; Bayer: Research Funding; Pfizer: Consultancy, Research Funding; Octapharm: Consultancy; Artisan: Consultancy. Off Label Use: Dalteparin is not indicated for prolonged DVT prophylaxis in medical intensive care unit patients. Zytaruk:Pfizer: donated study drug dalteparin for PROTECT. Cook:Pfizer: donated study drug dalteparin for PROTECT. Warkentin:GTI Diagnostics: Consultancy, Research Funding; GlaxoSmithKline: Consultancy, Research Funding; Pfizer Canada: Speakers Bureau; Sanofi-Aventis: Speakers Bureau; Informa: Patents & Royalties; Canyon Pharma: Consultancy, Speakers Bureau.