Chemistry: analytical and immunological testing – Composition for standardization – calibration – simulation,... – Blood serum or blood plasma standard or control
Reexamination Certificate
2002-01-16
2004-06-08
Wallenhorst, Maureen M. (Department: 1743)
Chemistry: analytical and immunological testing
Composition for standardization, calibration, simulation,...
Blood serum or blood plasma standard or control
C436S008000, C436S069000, C436S079000, C422S067000, C422S073000, C600S369000, C073S064410
Reexamination Certificate
active
06746872
ABSTRACT:
BACKGROUND OF THE INVENTION
A variety of blood and plasma coagulation tests have been developed for diagnosis of coagulation disorders, monitoring of patient anti-coagulation therapies, screening of patients for coagulation ability prior to surgery, and other uses. Such tests include, for example, the prothrombin time (PT), partial thromboplastin time (PTT), activated partial thromboplastin time (APTT), thrombin clotting time (TCT), activated clotting time (ACT), fibrinogen assays, and other tests.
The prothrombin time or PT test is the most frequently used coagulation test, and is typically employed to monitor patients undergoing oral anticoagulation therapies with drugs such as warfarin or coumadin. The PT evaluates the extrinsic coagulation pathway factors by measuring the ability of a patient's recalcified plasma or capillary blood to clot when mixed with thromboplastin. Accurate monitoring of patients is required to regulate drug dosage and avoid massive bleeding or recurrence of thrombosis. Prothrombin time assays typically involve exposing a patient blood sample to thromboplastin, and then monitoring the time required for gelling or clotting of the blood or plasma. The thromboplastin may be present in a liquid reagent mixable with blood, or may be in the form of a chemical pre-dried on a test strip to which blood is applied, or arranged in other test format. The development of clotting is the—onset of the thromboplastin reaction, and the onset time may be detected optically, electrically, by viscosity change, or other techniques.
Non-uniformity of PT test results can lead to dosage control problems for patients. The variation in PT has long been recognized as a serious problem, and the World Health Organization (WHO) has developed standards for establishment of uniformity of PT tests. The International Sensitivity Index (ISI) is a correction factor for the response of different thromboplastins to oral anticoagulants (L. Poller, “The Prothrombin Time”, WHO 1998). The ISI value depends upon a calibration of an individual PT test against a reference preparation such as the WHO International Reference Preparation (IRP). The ISI must be determined for every commercial lot of PT test devices to provide a compensation for non-uniformity of test systems.
Prothrombin times obtained using different coagulation tests can be compared by the calculation called the International Normalized Ratio (INR). The INR provides a compensation for system-to-system variations in the determination of PT, and is calculated by dividing the PT time by the Mean Normal Prothrombin Time (MNPT) of a defined normal subject population and raised to the power of ISI. Different types of PT tests may generate different PT results from the same sample, but the INR values for the different tests should be comparable. The ISI is a part of the INR calculation to correct for the difference in sensitivity of the PT test system. The ISI is derived from the slopes of the calibration lines of the log of reference PT values versus testing PT values obtained from 20 normal (non-anti-coagulated) subjects and sixty stabilized patients undergoing long-term orally administered anti-coagulation therapy. The MNPT value is typically obtained by calculating the geometric mean of testing PT from 20 normal subjects used in the ISI determination.
The calibration of coagulation tests in the manner recommended by the WHO is a relatively complex and expensive procedure. Calibration of each commercial lot of PT tests requires capillary blood samples from a group of at least 80 donors with wide range of INR. Since the aging blood samples cannot be used in PT tests, fresh blood samples typically must be obtained from donors for each new commercial lot of PT tests. The acquisition of blood samples in this manner is costly and requires obtaining numerous patient consents for blood drawing for evaluation of each commercial lot of PT tests.
One attempt to overcome the aforementioned difficulties has been use of commercially available “calibration” plasmas that are derived from pools of normal and anti-coagulated blood donors and which can be stored frozen. Five to seven different levels or types of calibration standards are generally required, depending upon the particular test to be calibrated. However, many coagulation tests are based on optical detection of blood coagulation in a test strip, which allows quick and easy PT testing by individual patients using “finger stick” blood samples in non-clinical settings. Such coagulation tests cannot effectively detect coagulation in plasma alone, and the effectiveness of calibration plasmas as control standards for coagulation tests has thus been limited.
There is accordingly a need for calibration and control compositions and methods for coagulation tests that are simple and inexpensive to use, which do not require large blood or plasma donor pools, and which are usable with optical detection systems. The present invention satisfies these needs, as well as others, and generally overcomes the deficiencies found in the background art.
SUMMARY OF THE INVENTION
The invention provides control compositions, methods, devices and kits for use in the calibration of coagulation tests. The subject control compositions comprise, in general terms, particles capable of aggregating in plasma, and calcium ions. The composition may additionally comprise plasma. The plasma may comprise a citrated calibration plasma derived from a pool of known anti-coagulated human blood donors, citrated control plasma derived from diluting or depleting pooled normal plasma, or other plasma. The particles may comprise polymeric beads having a plurality of charged groups on surfaces thereof which undergo non-specific binding to proteins present in the plasma. The calcium ions may be in the form of a solution of Ca
++
ion such as a calcium halide solution or solution of other soluble calcium salt. The compositions, in certain embodiments, may comprise a solution or suspension of particles capable of aggregation in citrated plasma, a solution of calcium ions that can be combined with the suspension of particles, and citrated plasma that can be mixed with the combined calcium ion solution and particle suspension.
The subject compositions may further comprise one or more optical contrast enhancers to facilitate optical detection of plasma coagulation. The optical contrast enhancers may comprise one or more particulate pigments and/or a soluble dye or dyes. —The optical contrast enhancer(s) may be dissolved and/or suspended in a solution with the calcium ions. The particles or polymeric beads may also include a dye or pigment for contrast enhancement. The subject compositions may further comprise hemoglobin to facilitate particle aggregation in plasma. Various components of the control compositions may be stored separately prior to use to maximize shelf life. The compositions may additionally comprise an antifreeze to facilitate low-temperature storage of the compositions or components thereof.
The subject methods comprise, in general terms, providing calcium ions and particles capable of—aggregation in plasma, combining the calcium ions and particles with plasma to form a control composition, and applying or introducing the control composition to at least one coagulation test. The methods may further comprise monitoring coagulation of the control composition. The methods may additionally comprise determining a relationship between coagulation time of the control composition and the coagulation time of at least one whole blood sample associated with the plasma used in the control composition. The method may further comprise determining a relationship between a coagulation time for the control composition obtained from the coagulation test, and a coagulation time using a reference test. The method may still further comprise determining a calibration curve or assigning a calibration for the coagulation test. In certain embodiments, the method may comprise providing a first control component including calcium ions, pro
Chow Herbert
Earp Brian
Hartmann Christa
Zheng Xiang Yang
Bozicevic Field & Francis LLP
LaSalle Carol M.
LifeScan, Inc.
Wallenhorst Maureen M.
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