Chemistry: analytical and immunological testing – Clotting or clotting factor level tests
Patent
1993-08-18
1997-02-04
Weinstein, Steven
Chemistry: analytical and immunological testing
Clotting or clotting factor level tests
436 63, 436164, 422 73, 422 99, 422102, G01N 3386
Patent
active
055997180
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
This invention relates to an in vitro method of measuring the thrombolytic activity of whole blood, in particular it relates to a method for measuring the lysis of an occlusive platelet-rich thrombus formed in vitro under conditions which simulate those in vivo and an apparatus for implementation of the method.
The ability to measure the thrombolytic activity of blood is extremely important, for example, it is now considered that whether or not spontaneous thrombolysis can occur in a patient is a main determinant of whether or not a patient will survive an acute myocardial infarction. (Swan, H. J. C. Acute Myocardial Infarction: A failure to timely, spontaneous thrombolysis. Journal of the American College of Cardiology 13:1435-37 (1989).) Furthermore, excessive thrombolysis which can occur during cardiopulmonary bypass is regarded as the main cause of severe bleeding after a successful operation.
Furthermore, thrombolytic therapy, i.e. the treatment of patients with thrombolytic agents, for example, tissue type plasminogen activator (t-PA) or streptokinase which simulate the natural thrombolysis, is at present the most efficient method of treating life-threatening arterial thrombotic disorders. The efficiency (patency-rate) and side effects, i.e. bleeding, of thrombolytic therapy are dose-related. Moreover, the amount of thrombolytic agent needed for a particular patient is found to vary widely, depending on a number of factors. A technique is therefore required to allow rapid and ready monitoring of the effect on a patient of the therapy.
There are many known techniques for measuring fibrinolysis. Overall fibrinolysis assays such as the lysis time of plasma proteins, e.g. euglobulin and fibrinogen, whole plasma or whole blood are laborious and time-consuming and therefore rarely used in clinical practice. Fibrinolytic status is normally assessed by the factorial approach, whenever at least half a dozen plasma variables are measured. While the list of the necessary variables is constantly increasing, the assessment of the overall status from the individual variables is extremely difficult.
In contrast to fibrinolysis, there is no technique of thrombolysis measurement in use in clinical practice. Thrombolysis, i.e. disintegration of an arterial thrombus, consisting of a mass of tightly packed blood cells of which the main are platelets but some are white cells is essentially different from fibrinolysis. Due to inhibitors released from the platelet mass, such a thrombus can be much more resistant to lysis than a plasma clot.
In order to measure thrombolysis in-vitro, a thrombus must first be formed. For the measurement to be meaningful, i.e. to give an accurate indication of the real in vivo situation, the thrombus must be formed in a physiologically relevant manner.
The conditions therefore should be an accurate reproduction of those found in vivo. In particular, it is now considered that one of the most relevant factors which initiates a thrombotic event are the haemodynamic forces, i.e. shear-stress. During formation of the thrombus, thrombin is generated which, together with shear-forces, plays the decisive role in the process. Thrombin amplifies platelet aggregation and by forming fibrin, confers structural stability to the thrombus.
Accordingly, for formation to be achieved in a physiologically relevant manner, the blood sample in which the thrombus is formed should be non-anticoagulated, as thrombin does not form in anticoagulated blood. Also, thrombus formation should be initiated entirely by shear-forces, as employing other thrombogenic stimuli makes the test irrelevant to physiology.
The Applicant is aware of only two known methods for measuring thrombolysis, described respectively in European Patent Application 0129425 and International Patent Application PCT/GB87/00633. In the methods described in both these applications, thrombi are formed in small holes punched in polyethylene tubing through which blood is perfused. Thrombolysis of the blood can be measured by caus
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Tran Lien
Weinstein Steven
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