Arterial Function and Atherosclerosis in Essential Thrombocythemia

NCT03828422 | Completed Results

• 1 other identifier: TP20180038
• Study Type: observational
• Target: 82
• Locations: 0 countries
• Sites: N/A

Brief Summary

The aim of the study is to examine (a) whether patients with JAK2 V617F positive ET in comparison to age-and sex-matched, apparently healthy control subjects show more advanced progression of arterial stiffness, pulse-wave velocity and coronary calcium score in a 4 year observation period, and (b) whether the burden of JAK2 V617F mutation correlates with the measured vascular parameters. All subjects will be examined twice. The first visit already took place between the years 2014 - 2015 and the second visit will take place between 2018-2019. All participants will have signed their informed consent before entering the study. Each visit will consist of completing a structured questionnaire (on personal and family medical history, risk factors for CVD and medication), physical examination, donating a blood sample for laboratory tests and undergoing carotid ultrasound and coronary calcium measurement oft the extent of coronary artery calcification. At the first and the second examination the JAK2 V617F allele burden, i.e. the percentage of mutated alleles, will be determined from genomic DNA in peripheral blood.

Conditions

Atherosclerosis

Keywords

essential thrombocythaemia; JAK2 V617F mutation burden; preclinical atherosclerosis; arterial stiffness; endothelial function; coronary artery calcium score

Outcome Measures

Primary Outcomes (6)

• Carotid Artery Stiffness (Expressed by Beta-stiffness Index ) in JAK2 V617F Positive ET Patients in Comparison to Healthy Control Subjects in a 4-year Period (From Baseline to Year 4).

  4-year change carotid artery in Beta-stiffness Index measured in JAK2 V617F positive ET patients in comparison to healthy control subjects. All measurements were performed by echo-tracking ultrasound of the common carotid artery. Echo-tracking of the common carotid artery wall was used to assess arterial stiffness expressed by the β-stiffness index. Measurement swere done at the common carotid artery 2 cm proximal to the bulb on both sides. The β-stiffness index was calculated as: β = ln (P\_max / P\_min) / \[(D\_max - D\_min / D\_min)\] (P\_max = the systolic blood pressure, P\_min = the diastolic pressure; D\_max = the maximum arterial diameter and D\_min = the minimal arterial diameter). In the adult population, the values of β range from 4 - 10 and increase with age. A larger value of β means increased arterial stiffness, i.e., a worse outcome.

  From Baseline (in 2014-2015) to Year 4 (in 2018-2019)

• Carotid Artery Stiffness (Expressed by the Pulse Wave Velocity) in JAK2 V617F Positive ET Patients in Comparison to Healthy Control Subjects in a 4-year Period (From Baseline to Year 4).

  4-year change in carotid artery pulse wave velocity (PWV) measured in JAK2 V617F positive ET patients in comparison to healthy control subjects. All measurements were performed by echo-tracking ultrasound of the common carotid artery. Measurements were done at the common carotid artery 2 cm proximal to the bulb on both sides. PWV was calculated from the beta stiffness index (β, for description see above), as follows: PWV = √ ((β x P\_min) / 2ρ)); ρ = 1050 kg/m³. PWV increases with arterial stiffness, a larger value means a worse outcome. PWV in adults ranges from 3 m/s to 12 m/s; values are strongly age dependent.

  From Baseline (in 2014-2015) to Year 4 (in 2018-2019)

• Change of Carotid Artery Plaque Score in JAK2 V617F Positive ET Patients in Comparison to Healthy Control Subjects in a 4-year Period.

  Change in carotid plaque score (i.e., the number of carotid artery segments with detected plaques, reported on a scale from 0-6) in a 4 year observation period. A carotid plaque score 0 means that the common carotid, internal carotid and exteranal carotid artery on both sides are free from plaques. A score of 6 means that the common carotid, internal carotid and external carotid artery on both sides have plaques detected by ultrasound.

  From Baseline (in 2014-2015) to Year 4 (in 2018-2019)

• Change of Coronary Calcium Burden in JAK2 V617F Positive ET Patients in Comparison to Healthy Control Subjects in a 4-year Period.

  Change in the Agatston coronary artery calcium score in a 4 year observation period. Agatston score denotes the number of coronary artery calcifications weighted for the intensity of calcification. Grading of coronary artery disease (CAD) based od Agatston score goes as follows: no CAD = score 0, minimal CAD = score 1-10, mild CAD = score 11-100, moderate CAD = score 101-400, svere CAD = score \> 400.

  From Baseline (in 2014-2015) to Year 4 (in 2018-2019)

• Change of Digital Endothelial Function, Expressed as Reactive Hyperemia Index and Augmentation Index (AI), in JAK2 V617F Positive ET Patients in Comparison to Healthy Control Subjects in a 4-year Period.

  4-year change in Reactive Hyperemia Index (RHI) and 4-year change Augmentation Index (AI). RHI was calculated by the formula: RHI = (A/B) / (C/D) where A is the post-occlusion pulse wave amplitude (PWA) of the occluded hand, B the baseline PWA of the occluded hand, C the post-occlusion PWA of the contralateral hand, and D the baseline PWA of the contralateral hand. A higher RHI means better endothelial function (= good outcome). RHI in patients ranges from1-3. Arbitrarily, normal RHI is defined as =\> 1.67, and abnormal RHI as RHI =\< 1.66. The AI was determined from the shape of the arterial pulse wave by the EndoPAT 2000 software which distinguished between the primary pulse wave (P1) and the reflected pulse wave (P2) by the formula: AI = ((P2-P1)/P1) x 100. The results were normalized to a heart rate of 75/min. A higher AI means greater arterial stiffness (= bad outcome). AI \>0.4 is abnormal.

  From Baseline (in 2014-2015) to Year 4 (in 2018-2019)

• The JAK2 V617F Mutation Burden in Patients With JAK2 V617F Positive ET.

  Change in JAK2 V617F mutation burden in the 4-year observation period. Ipsogen JAK2 MutaQuant Kit, Qiagen (USA) was used for the detection of JAK2 V617F mutation and quantification of its burden in genomic DNA, which was extracted from granulocytes in peripheral blood. Real-time quantitative polymerase chain reaction (qPCR) was used with double-dye oligonucleotide hydrolysis principle. The JAK2 V617F burden was defined as the percentage of JAK2 V617F mutated alleles in total genomic DNA.

  At baseline (in 2014- 2015) and at the second visit (in 2018-2019)

Study Arms (2)

patients with essential thrombocythemia

* essential thrombocythemia with JAK2 V617F positive mutation * patients from the Department of Haematology at University Medical Centre Ljubljana, Slovenia, who were diagnosed with JAK2 V617F positive ET between 2011 and 2014 * no personal history of clinically manifest atherosclerotic vascular disease (myocardial infarction, angina pectoris, peripheral arterial disease, aortic disease, transient ischemic attack or ischemic stroke) * all signed the informed consent * examined twice, the first time in the years 2014-2015 and for the second time in the years 2018-2019 * blood for laboratory tests * imaging and functional examination: ultrasound examination, EndoPat plethysmography, coronary artery calcium scanning

Diagnostic Test: imaging

control group

* the control group is selected among healthy employees of the University Medical Centre Ljubljana and their relatives * they are matched with the patient group for age and sex distribution and classical risk factors for cardiovascular disease * no personal history of clinically manifest atherosclerotic vascular disease (myocardial infarction, angina pectoris, peripheral arterial disease, aortic disease, transient ischemic attack or ischemic stroke) * all signed the informed consent * blood for laboratory tests * examined twice, the first time in the years 2014-2015 and for the second time the in years 2018-2019 * imaging and functional examination: ultrasound examination, EndoPat plethysmography, coronary artery calcium scanning

Diagnostic Test: imaging

Interventions

imaging DIAGNOSTIC_TEST

Also known as: EndoPat plethysmography, coronary artery calcium scanning, blood laboratory tests, ultrasound examination

control group; patients with essential thrombocythemia

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Probability Sample

Study Population

Expected patient group: 40 patients (14 male and 26 female) with JAK2 V617F positive ET without clinically apparent cardiovascular disease. Average age 55,05 (13,48); ITM 25,22 (3,65); systolic blood pressure 138 (124-150) mmHg; diastolic blood pressure 81 (74-85) mmHg; Framingham risk score for CHD 6,84%. Expected control group: 42 individuals (16 male and 26 female) who were age and sex matched with the patient group. Average age 59,16 (12,03); ITM 27,27 (4,64); systolic blood pressure 132 (125-141) mmHg; diastolic blood pressure 81 (76-86) mmHg; Framingham risk score for CHD 7,20%.

You may qualify if:

• patients with JAK2 V617F positive essential thrombocythemia
• age-and sex-matched apparently healthy control subjects

You may not qualify if:

• personal history of any atherosclerotic vascular disease (myocardial infarction, angina pectoris, peripheral arterial disease, aortic disease, transient ischemic attack or ischemic stroke)
• chronic kidney disease stage 3 and above
• known cancer
• chronic inflammatory disease
• autoimmune disease
• pregnancy

Sponsors & Collaborators

• University Medical Centre Ljubljana: lead

Related Publications (2)

• Vrtovec M, Anzic A, Zupan IP, Zaletel K, Blinc A. Carotid Artery Stiffness, Digital Endothelial Function, and Coronary Calcium in Patients with Essential Thrombocytosis, Free of Overt Atherosclerotic Disease. Radiol Oncol. 2017 Jan 14;51(2):203-210. doi: 10.1515/raon-2017-0006. eCollection 2017 Jun.

  PMID: 28740456 RESULT

• Anzic Drofenik A, Vrtovec M, Bozic Mijovski M, Sever M, Preloznik Zupan I, Kejzar N, Blinc A. Progression of coronary calcium burden and carotid stiffness in patients with essential thrombocythemia associated with JAK2 V617F mutation. Atherosclerosis. 2020 Mar;296:25-31. doi: 10.1016/j.atherosclerosis.2020.01.001. Epub 2020 Jan 11.

  PMID: 32005002 RESULT

Biospecimen

Retention: SAMPLES WITH DNA

The ipsogen JAK2 MutaQuant Kit, Qiagen (ZDA) (Ref: No. 673523) will be used for the detection and quantification of JAK2 V617F/G1849T allele in genomic DNA extracted from peripheral blood of patients and also control subjects. A SNP specific primer that selectively amplifies JAK2 V617F allele will be used with a real-time qPCR instrument which accurately quantifies the PCR products.

MeSH Terms

Conditions

Atherosclerosis; Thrombocythemia, Essential

Interventions

Diagnostic Imaging

Condition Hierarchy (Ancestors)

Arteriosclerosis; Arterial Occlusive Diseases; Vascular Diseases; Cardiovascular Diseases; Blood Coagulation Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Thrombocytosis; Blood Platelet Disorders; Myeloproliferative Disorders; Bone Marrow Diseases; Hemorrhagic Disorders

Intervention Hierarchy (Ancestors)

Diagnostic Techniques and Procedures; Diagnosis

Limitations and Caveats

* the relatively small number of participants (patients were recruited from a single tertiary medical centre) * the subjects were not examined at precisely the same time interval between both visit

Results Point of Contact

• Title: dr. Aleš Blinc, MD, PhD
• Organization: University Medical Centre Ljubljana

ales.blinc@kclj.si

+38615227124

Study Officials

• Ales Blinc, MD

  University Medical Centre Ljubljana

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: observational
• Observational Model: CASE CONTROL
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Ales Blinc, MD, PhD, Head, Dept of Vascular Diseases

Study Record Dates

• First Submitted: January 23, 2019
• First Posted: February 4, 2019
• Study Start: January 1, 2014
• Primary Completion: August 1, 2021
• Study Completion: August 5, 2021
• Last Updated: November 4, 2021
• Results First Posted: November 4, 2021

Record last verified: 2021-10