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Nmr Methods for Monitoring Blood Clot Formation

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(19) *EP003321373B1* (11) EP 3 321 373 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: C12Q 1/56 (2006.01) 15.01.2020 Bulletin 2020/03 (21) Application number: 17001484.9 (22) Date of filing: 13.07.2012 (54) NMR METHODS FOR MONITORING BLOOD CLOT FORMATION NMR-VERFAHREN ZUR ÜBERWACHUNG DER BLUTGERINNSELBILDUNG PROCÉDÉS DE RMN DESTINÉS À SURVEILLER LA FORMATION D’UN CAILLOT SANGUIN (84) Designated Contracting States: • THAYER, Edward, Chris AL AT BE BG CH CY CZ DE DK EE ES FI FR GB Woodinville, WA 98077 (US) GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR (74) Representative: Bösl, Raphael Konrad Patentanwälte (30) Priority: 13.07.2011 US 201161507307 P Isenbruck Bösl Hörschler PartG mbB 21.09.2011 US 201161537396 P Prinzregentenstraße 68 23.09.2011 US 201161538257 P 81675 München (DE) 17.11.2011 US 201161560920 P 08.02.2012 US 201261596445 P (56) References cited: 18.04.2012 US 201261625945 P WO-A1-2010/051362 (43) Date of publication of application: • BLINC A ET AL: "PROTON NMR STUDY OF THE 16.05.2018 Bulletin 2018/20 STATE OF WATER IN FIBRIN GELS, PLASMA, AND BLOOD CLOTS", MAGNETIC RESONANCE (62) Document number(s) of the earlier application(s) in IN MEDICINE, JOHN WILEY & SONS, INC, US, vol. accordance with Art. 76 EPC: 14, no. 1, 1 April 1990 (1990-04-01), pages 105-122, 12812054.0 / 2 732 046 XP000141595, ISSN: 0740-3194 • BRYANT R G ET AL: "MAGNETIC RELAXATION (73) Proprietor: T2 Biosystems, Inc. IN BLOOD AND BLOOD CLOTS", MAGNETIC Lexington, MA 02421 (US) RESONANCE IN MEDICINE, JOHN WILEY & SONS, INC, US, vol. 13, no. 1, 1 January 1990 (72) Inventors: (1990-01-01), pages 133-144, XP000103637, ISSN: • LOWERY, Thomas, Jay 0740-3194 Belmont, MA 02478 (US) • CLARK R A ET AL: "Acute hematomas: effects of • PAPKOV, Vyacheslav deoxygenation, hematocrit, and fibrin-clot Waltham, MA 02453 (US) formation and retraction on T2 shortening", • MASSEFSKI, Walter, W. RADIO, RADIOLOGICAL SOCIETY OF NORTH Sharon, MA 02067 (US) AMERICA, INC, US, vol. 175, no. 1, 1 April 1990 • DHANDA, Rahul (1990-04-01) , pages 201-206, XP009171040, Dorchester, MA 02124 (US) ISSN: 0033-8419, DOI: 10.1148/RADIOLOGY.175.1.2315481 Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 3 321 373 B1 Printed by Jouve, 75001 PARIS (FR) EP 3 321 373 B1 Description Background of the Invention 5 [0001] The invention features methods for monitoring rheological changes in an aqueous sample. [0002] Blood is the circulating tissue of an organism that carries oxygen and nutritive materials to the tissues and removes carbon dioxide and various metabolic products for excretion. Whole blood consists of a pale yellow or gray yellow fluid, plasma, in which are suspended red blood cells, white blood cells, and platelets. [0003] An accurate measurement of hemostasis, i.e., the ability of a patient’s blood to coagulate and dissolve, in a 10 timely and effective fashion is crucial to certain surgical and medical procedures. Accelerated (rapid) and accurate detection of abnormal hemostasis is also of particular importance in respect of appropriate treatment to be given to patients suffering from hemostasis disorders and to whom it may be necessary to administer anti-coagulants, antifibri- nolytic agents, thrombolytic agents, anti-platelet agents, or blood components in a quantity which must clearly be de- termined after taking into account the abnormal components, cells or "factors" of the patient’s blood which may be 15 contributing to the hemostasis disorder. [0004] Hemostasis is a dynamic, extremely complex process involving many interacting factors, which include coag- ulation and fibrinolytic proteins, activators, inhibitors and cellular elements, such as platelet cytoskeleton, platelet cyto- plasmic granules and platelet cell surfaces. As a result, during activation, no factor remains static or works in isolation. Thus, to be complete, it is necessary to measure continuously all phases of patient hemostasis as a net product of whole 20 blood components in a non-isolated, or static fashion. To give an example of the consequences of the measuring of an isolated part of hemostasis, assume that a patient developed fibrinolysis, which is caused by the activation of plasminogen into plasmin, an enzyme that breaks down the clot. In this scenario, a byproduct of this process of fibrinogen degrading product behaves as an anticoagulant. If the patient is tested only for anticoagulation and is treated accordingly, this patient may remain at risk due to not being treated with antifibrinolytic agents. 25 [0005] The end result of the hemostasis process is a three-dimensional network of polymerized fibrinogen fibers (i.e., fibrin), which together with platelet glycoprotein IIb/IIIa (GPIIb/IIIa) receptor bonding forms the final clot. A unique property of this network structure is that it behaves as a rigid elastic solid, capable of resisting deforming shear stress of the circulating blood. The strength of the final clot to resist deforming shear stress is determined, in part, by the forces exerted by the participating platelets. 30 [0006] Platelets have been shown to affect the mechanical strength of fibrin in at least two ways. First, by acting as node branching points, they significantly enhance fibrin structure rigidity. Secondly, by exerting a "tugging" force on fibers, by the contractility of platelet actomyosin, a muscle protein that is a part of a cytoskeleton-mediated contractibility apparatus. The force of this contractility further enhances the strength of the fibrin structure. The platelet receptor GPIIb/IIIa appears crucial in anchoring polymerizing fibers to the underlying cytoskeleton contractile apparatus in acti- 35 vated platelets, thereby mediating the transfer of mechanical force. [0007] Thus, the clot that develops and adheres to the damaged vascular system as a result of activated hemostasis and resists the deforming shear stress of the circulating blood is, in essence a mechanical device, formed to provide a "temporary stopper," that resists the shear force of circulating blood during vascular recovery. The kinetics, strength, and stability of the clot, that is its physical property to resist the deforming shear force of the circulating blood, determine 40 its capacity to do the work of hemostasis, which is to stop hemorrhage without permitting inappropriate thrombosis. [0008] Platelets play a critical role in mediating ischemic complications in prothrombotic (thrombophilic) patients. The use of GPIIb/IIIa inhibitor agents in thrombophilic patients or as an adjunct to percutaneous coronary angioplasty (PTCA) is rapidly becoming the standard of care. Inhibition of the GPIIb/IIIa receptor is an extremely potent form of antiplatelet therapy that can result in reduction of risk of death and myocardial infarction, but can also result in a dramatic risk of 45 hemorrhage. The reason for the potential of bleeding or non-attainment of adequate therapeutic level of platelet inhibition is the weight-adjusted platelet blocker treatment algorithm that is used in spite of the fact that there is considerable person-to-person variability. This is an issue in part due to differences in platelet count and variability in the number of GPIIb/IIIa receptors per platelet and their ligand binding functions. To be clinically useful, an assay of platelet inhibition must provide rapid and reliable information regarding receptor blockade at the bedside thereby permitting dose modifi- 50 cation to achieve the desired anti-platelet effect. [0009] There is a need for a method and apparatus for rapid, reliable, quantitative, point-of-care test for monitoring therapeutic platelet blockade, and for measuring the efficacy of anti-platelet agents, continuously and over the entire hemostasis process from initial clot formation through lysis. 55 Summary of the Invention [0010] The invention is as defined by the appended claims. [0011] It is described a method of monitoring a rheological change in an aqueous sample by: (i) measuring a signal 2 EP 3 321 373 B1 characteristic of the NMR relaxation rate of water in the sample to produce NMR relaxation data; (ii) determining from the NMR relaxation data a magnetic resonance parameter value or set of values being characteristic of the rheological change in the sample; and (iii) comparing the result of step (ii) to a predetermined threshold value. [0012] In a related aspect, it is described a method of monitoring a rheological change in an aqueous sample including: 5 (i) making a series of magnetic resonance relaxation rate measurements of water in the sample; (ii) transforming the measurements using an algorithm that distinguishes two or more observable water populations within the sample, wherein each observable water population has a distinct relaxation rate and a distinct signal intensity at one or more time points during the rheological change; and (iii) on the basis of the relaxation rate or signal intensity for at least one of the two or more observable water populations, monitoring the rheological change in the sample. 10 [0013] It is described a method of monitoring a rheological change in an aqueous sample including: (i) making a series of measurements of water in the sample, wherein the measurements distinguish two or more observable water populations within the sample, and each observable water population has a distinct signal and/or signal intensity at one or more time points during the rheological change; and (ii) on the basis of the signal and/or signal intensity observed for at least one of the two or more observable water populations, monitoring the rheological change in the sample.
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