Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving blood clotting factor
Reexamination Certificate
1996-01-11
2002-10-29
Gitomer, Ralph (Department: 1627)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving blood clotting factor
C436S069000
Reexamination Certificate
active
06472161
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to a technique for determining and measuring clotting related conditions in blood. More particularly, this invention relates to a new and improved technique for determining blood clot lysis conditions. In addition the present invention pertains to determining blood clot lysis times quickly and consistently with a high degree of sensitivity, to detecting thrombolysis or pathological fibrinolysis, to measuring the effect of therapeutically administered thrombolytic and anti-fibrinolytic agents, and to developing dose response information for the therapeutic administration of thrombolytic and anti-fibrinolytic agents, among other things.
BACKGROUND OF THE INVENTION
Fibrinolysis is the process in which blood clots are dissolved. Fibrinolysis is the final step in the natural reparative process which follows blood clot formation, as when a blood clot which was previously formed in response to blood vessel damage is subsequently dissolved after the damage has been repaired. Fibrinolysis may also be induced by the therapeutic administration of thrombolytic agents. Thrombolytic agents are administered to avoid the complications of pulmonary embolism resulting from lower limb venous thrombosis and to minimize the cell destruction of myocardial infarctions, gangrene and stroke caused by arterial thrombosis, among other reasons.
Whether or not cell destruction can be minimized after physiological events such as myocardial infarctions, stroke or gangrene may depend, in part, upon the existence of pathological or therapeutically induced thrombolysis. In order to eliminate or minimize such cell destruction in an individual who has undergone or is undergoing a stroke, heart attack or similar event, it would be helpful to ascertain quickly whether the individual's clot lysis ability is within a normal range of lytic response times. By comparing the individual's specific lytic response time to the average lytic response time of a normal, non-pathogenic individual, a treating physician could determine whether the patient's specific lytic response capability needs to be treated or otherwise taken into consideration.
Under conditions when arterial or venous thrombosis has occurred or is likely to occur, such as during and after surgery, it becomes critical that the treating physician have reliable information available about an individual's fibrinolytic processes. For example, clot formation is especially likely to occur during cardiac surgery utilizing extra-corporeal passage of blood. Although clotting during cardiac surgery may be minimized through use of heparin or other anticoagulants, a surgical patient's natural lytic ability can help avoid surgical complications by dissolving any clots that form. If a particular surgical patient's lytic ability is impaired, a physician may administer thrombolytic agents to maintain a particular level of lytic activity and to avoid the possibility of permanent and disabling clot formation occurring during surgery. To maintain a desired level of lytic activity, it would be helpful to detect whether the administration of a thrombolytic agent had the desired effect upon the surgical patient.
It would be further helpful for treating physicians to be able to quickly and accurately monitor a patient's total lytic activity, i.e. lysis resulting from both natural fibrinolytic activity and physiological responses to the therapeutic administration of thrombolytic agents. It would also be helpful to be able to distinguish changes to properties of clotted blood caused by lytic activity from changes to properties of clotted blood caused by other therapeutically administered agents or by pathological or other conditions, such as, for example, changes related to disseminated intravascular coagulation. In order to monitor blood condition changes caused by lytic activity, a test which evaluates changes to a sample of clotted blood in which lysis is allowed to proceed and compares those changes with changes to a sample of clotted blood in which lysis is suppressed would prove useful. However, no such test is currently known to be available. Such a test might be based upon plasmin and plasminogen activity in the sample of blood. Plasminogen is a naturally occurring blood component and is a precursor of plasmin. Plasmin is an enzyme which degrades fibrin into soluble products. One way in which the body promotes fibrinolytic activity and in which thrombolytic agents increase lytic activity is by stimulating plasmin and plasminogen activators to cause the formation of plasmin from plasminogen. If an inhibitor of plasmin and plasminogen activators is added to a sample of blood, then the effects of previously administered thrombolytic agents and naturally stimulated fibrinolytic activity are suppressed. The addition of an inhibitor of plasmin and plasminogen allows the lytic activity to be monitored in such a way to evaluate the overall contribution to clot lysis from plasmin.
In addition to the current limitations on measuring the effect of therapeutically administered thrombolytic agents, physicians have been hampered by an inability to prescribe individualized doses of thrombolytic or anti-fibrinolytic agents tailored to the unique physiological responses of a particular patient. Currently, no known tests are commercially available to determine the dose response to thrombolytic and anti-fibrinolytic agents. In the absence of such dose response data, a standardized dose is usually prescribed. A standardized dose may be either inadequate or excessive for a particular patient because of variations in body size, blood volume, blood chemistry and pathological or surgical conditions.
Currently there are methods available to measure some characteristics of clot lysis, as exemplified by U.S. Pat. No. 4,276,383 to Leighton, et al. However, many prior art techniques are subject to certain technical problems. Generally, the known clot lysis measuring methods are expensive to perform, produce relatively inconsistent results, and are not suited to providing information responsive to real-time surgical or emergency conditions. Some of these prior methods tend to be cumbersome, such as when clots must be pre-formed under special conditions outside of the vessel or chamber in which clot lysis testing later occurs. These prior methods often require special collection and processing procedures, thus limiting the use of blood or plasma samples collected only for clot lysis testing. These prior methods are also susceptible to inconsistent results because they require sample mixing procedures which often involve repeated manual inversion or other manual manipulation of the testing chamber. Manual mixing can result in incomplete or variable mixing of the sample and reagents, resulting in either incomplete activation or deactivation of the components which would otherwise block or promote the clotting or lysing reactions to be measured.
It is against this background that the below described significant improvements and advancements have evolved in the field of measuring clotting- and lysing-related conditions in blood.
SUMMARY OF THE INVENTION
A significant aspect of the present invention relates to evaluating a clot lysis condition in a sample of blood. A clot is formed in the sample of blood and thereafter the clot is lysed. The time to lyse the clot relative to the time in which the clot was formed is measured to determine the lysis condition. By measuring the clot lysis relative to the clot formation, the information available from the clot lysis condition is more accurate and more directly related to actual conditions.
Other significant aspects of the invention relate to the types of tests which can be performed by evaluating the clot lysis condition. A test to determine the existence and effect of any previously administered thrombolytic agent in the sample of blood is achieved by testing two similar samples of blood. One sample contains an inhibitor of plasmin and plasminogen activator. The inhibitor inhibits the
Gitomer Ralph
Hogan & Hartson LLP
Petersen Steven C.
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