Optimizing the Diagnosis of Heparin Induced Thrombocytopenia (HIT)

Optimizing the Diagnosis of Heparin Induced Thrombocytopenia Using Quantified Anti-Platelet Factor 4 Immunological Testing: A Pilot Multicentre Cohort Study

Multicentre (Ottawa and Halifax) prospective cohort study using a diagnostic approach in patients clinically suspected to have HIT that combines pretest probability assessment with quantitative interpretation of anti-PF4 assay.

Study Overview

• Status: Unknown
• Conditions: Heparin-induced Thrombocytopenia (HIT)
• Intervention / Treatment: Diagnostic test: Diagnostic algorithm

Detailed Description

The proposed is a prospective cohort study exploring a novel diagnostic approach to Heparin Induced Thrombocytopenia (HIT) using a combination of pretest probability assessment and quantitative interpretation of the anti-platelet factor 4 Immunological assay (anti-PF4). Patient with a clinical suspicion of HIT will follow the study diagnostic algorithm (Figure 1). The study algorithm will be considered a safe approach to move forward into a larger RCT if the upper limit of the 95% confidence interval for 'false negative management failures' is ≤ 4% based on a Serotonin Release Assay (SRA) gold standard. The main objective of the pilot study is to inform feasibility and recruitment barriers for a larger randomized control trial.

• Study Type: Interventional
• Enrollment (Anticipated): 180
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Ottawa, Ontario, Canada, KIH 8L6
      • Recruiting
      • The Ottawa Hospital
      • Contact: Chantal Rockwell, BA; Phone Number: 73958 613-737-8899; Email: crockwell@ohri.ca
      • Contact: Lisa Duffett, MSc., MD; Phone Number: 71069 613-737-8899; Email: lduffett@toh.ca

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patient with clinical suspicion of HIT by treating physician

Exclusion Criteria:

1. Less than 18 years of age;
2. Prior diagnosis of HIT ever;
3. Patient enrolled within preceding 100 days;
4. Functional/ confirmatory platelet activation results available at the time of enrollment;
5. Requiring cardio-pulmonary bypass or percutaneous cardiac angioplasty or any other cardiac or vascular surgery/procedure requiring intra-operative/procedural heparin administration planned within 30 days;
6. Unable to complete study follow up;
7. Unable to obtain consent (or proxy consent from substitute decision maker where applicable);
8. Life expectancy less than 30 days;
9. Greater than 72 hours from clinical suspicion of HIT and/or request for HIT anti-PF4 ELISA testing.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: DIAGNOSTIC
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: diagnostic algorithm; Optimizing the interpretation of the more readily available anti-PF4 assay would reduce the reliance on functional testing/ confirmatory testing (Serotonin Release Assay, SRA) and the number of patients exposed to unnecessary changes in anticoagulation therapy while awaiting the timely functional test results	Diagnostic test: Diagnostic algorithm; The treating physician will complete an enrollment assessment including the 4T score pretest probability assessment14. All patients will have laboratory testing for HIT anti-PF4 as well as SRA testing. Results of the anti-PF4 assay (OD value) will be available to the treating physician who will be instructed to follow the study diagnostic algorithm

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Recruitment	The pilot will be considered feasible if recruitment of at least 7.5 patients per month (total between the two sites) is achieved.	2 years
False negative management failures	The rate of false negative 'management failures' where the study protocol concludes HIT unlikely but SRA (reference standard laboratory test) is positive for HIT (≥50% Serotonin release).	2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Major arterial and venous thromboembolism events	Events will be ascertained from the date of study consent. However, venous or arterial thrombotic events detected on investigations ordered within 24 hours of study entry will be captured as baseline events and will be counted separately from thrombotic events which occur after the initial 24 hours of study enrolment.	24 hours of baseline and 24 of study enrolment
Proximal deep vein thrombosis	Testing performed because of symptoms in a patient with (new) non-compressibility of the common femoral vein, popliteal vein or calf trifurcation vein of the leg on ultrasound; or new non-compressibility or visualization of thrombus in the jugular vein, subclavian vein or axillary vein on ultrasound; or an intraluminal defect seen in one more than one view in proximal leg or arm veins on venography will be diagnostic for deep vein thrombosis.	2 years
Pulmonary embolism	Testing performed because of symptoms in a patient with a high probability lung scan (i.e. at least one segmental perfusion mismatch) or CT pulmonary angiography (i.e. intraluminal filling defect in the main, lobar or segmental pulmonary arteries) will be diagnostic for pulmonary embolism.	2 years
Stroke	New infarction or hemorrhagic event confirmed on CT or MRI.	2 years
Myocardial infarction	Detection of rise and/or fall of cardiac biomarkers (preferably troponin) with at least one value above the 99th percentile of the upper reference limit together with evidence of myocardial ischemia with at least one of the following: Symptoms of ischemia for ≥ 20 minutes ECG changes indicative of new ischemia: new ST-T changes ≥0.1 mV or new left bundle branch block Development of pathological Q waves in the ECG; Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality.	2 years
Systemic arterial embolism	Acute vascular occlusion confirmed on ultrasound or angiography Adrenal hemorrhagic infarction (indicating adrenal vein thrombosis) - radiologic diagnosis on ultrasound or CT.	2 years
Death	Due to major arterial or venous thromboembolism within 30days of follow up and major and minor bleeding.	30 days of follow up

Collaborators and Investigators

• Sponsor: Ottawa Hospital Research Institute
• Investigators: Principal Investigator: Lisa Duffett, MSc, MD, Ottawa Hospital Research Institute

Publications and helpful links

General Publications

• Thygesen K, Alpert JS, White HD; Joint ESC/ACCF/AHA/WHF Task Force for the Redefinition of Myocardial Infarction. Universal definition of myocardial infarction. J Am Coll Cardiol. 2007 Nov 27;50(22):2173-95. doi: 10.1016/j.jacc.2007.09.011. No abstract available.
• Linkins LA, Dans AL, Moores LK, Bona R, Davidson BL, Schulman S, Crowther M. Treatment and prevention of heparin-induced thrombocytopenia: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012 Feb;141(2 Suppl):e495S-e530S. doi: 10.1378/chest.11-2303. Erratum In: Chest. 2015 Dec;148(6):1529.
• Raschke RA, Curry SC, Warkentin TE, Gerkin RD. Improving clinical interpretation of the anti-platelet factor 4/heparin enzyme-linked immunosorbent assay for the diagnosis of heparin-induced thrombocytopenia through the use of receiver operating characteristic analysis, stratum-specific likelihood ratios, and Bayes theorem. Chest. 2013 Oct;144(4):1269-1275. doi: 10.1378/chest.12-2712.
• Greinacher A, Ittermann T, Bagemuhl J, Althaus K, Furll B, Selleng S, Lubenow N, Schellong S, Sheppard JI, Warkentin TE. Heparin-induced thrombocytopenia: towards standardization of platelet factor 4/heparin antigen tests. J Thromb Haemost. 2010 Sep;8(9):2025-31. doi: 10.1111/j.1538-7836.2010.03974.x.
• Warkentin TE. How I diagnose and manage HIT. Hematology Am Soc Hematol Educ Program. 2011;2011:143-9. doi: 10.1182/asheducation-2011.1.143.
• Zwicker JI, Uhl L, Huang WY, Shaz BH, Bauer KA. Thrombosis and ELISA optical density values in hospitalized patients with heparin-induced thrombocytopenia. J Thromb Haemost. 2004 Dec;2(12):2133-7. doi: 10.1111/j.1538-7836.2004.01039.x.
• Lo GK, Sigouin CS, Warkentin TE. What is the potential for overdiagnosis of heparin-induced thrombocytopenia? Am J Hematol. 2007 Dec;82(12):1037-43. doi: 10.1002/ajh.21032.
• Warkentin TE. HIT paradigms and paradoxes. J Thromb Haemost. 2011 Jul;9 Suppl 1:105-17. doi: 10.1111/j.1538-7836.2011.04322.x.
• Warkentin TE, Greinacher A, Gruel Y, Aster RH, Chong BH; scientific and standardization committee of the international society on thrombosis and haemostasis. Laboratory testing for heparin-induced thrombocytopenia: a conceptual framework and implications for diagnosis. J Thromb Haemost. 2011 Dec;9(12):2498-500. doi: 10.1111/j.1538-7836.2011.04536.x. No abstract available.
• Warkentin TE, Sheppard JI, Moore JC, Sigouin CS, Kelton JG. Quantitative interpretation of optical density measurements using PF4-dependent enzyme-immunoassays. J Thromb Haemost. 2008 Aug;6(8):1304-12. doi: 10.1111/j.1538-7836.2008.03025.x. Epub 2008 May 17.
• Linkins LA, Bates SM, Lee AY, Heddle NM, Wang G, Warkentin TE. Combination of 4Ts score and PF4/H-PaGIA for diagnosis and management of heparin-induced thrombocytopenia: prospective cohort study. Blood. 2015 Jul 30;126(5):597-603. doi: 10.1182/blood-2014-12-618165. Epub 2015 Apr 29.
• Lo GK, Juhl D, Warkentin TE, Sigouin CS, Eichler P, Greinacher A. Evaluation of pretest clinical score (4 T's) for the diagnosis of heparin-induced thrombocytopenia in two clinical settings. J Thromb Haemost. 2006 Apr;4(4):759-65. doi: 10.1111/j.1538-7836.2006.01787.x.
• Schulman S, Kearon C; Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost. 2005 Apr;3(4):692-4. doi: 10.1111/j.1538-7836.2005.01204.x.

Study record dates

Study Major Dates

• Study Start (ACTUAL): November 23, 2018
• Primary Completion (ANTICIPATED): December 1, 2021
• Study Completion (ANTICIPATED): December 1, 2022

Study Registration Dates

• First Submitted: April 10, 2017
• First Submitted That Met QC Criteria: May 8, 2017
• First Posted (ACTUAL): May 11, 2017

Study Record Updates

• Last Update Posted (ACTUAL): February 24, 2021
• Last Update Submitted That Met QC Criteria: February 22, 2021
• Last Verified: February 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Hematologic Diseases; Blood Platelet Disorders; Thrombocytopenia
• Other Study ID Numbers: IRIS6428

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No