Chemistry: analytical and immunological testing – Clotting or clotting factor level tests
Reexamination Certificate
2001-01-03
2003-10-14
Wallenhorst, Maureen M. (Department: 1743)
Chemistry: analytical and immunological testing
Clotting or clotting factor level tests
C600S369000, C073S064410, C702S019000
Reexamination Certificate
active
06632678
ABSTRACT:
BACKGROUND AND SUMMARY OF THE INVENTION
This invention relates to the determination of the activated clotting time (ACT) of blood or plasma, specifically for patients receiving the drugs heparin and aprotinin.
Heparin is an anticoagulant drug used during surgeries requiring the use of extracorporial circuits, such as cardiopulmonary bypass (CPB). Heparin prevents blood clots from forming while blood is flowing through the circuit. In order to ensure sufficient anticoagulation, doctors must be able to measure heparin's anticoagulant effect on blood. The anticoagulant effect of heparin is often managed using the activated clotting time (ACT) as determined by in vitro diagnostic tests. The ACT is prolonged after heparin administration. For example, without heparin, the ACT is generally about 120 seconds, while the ACT after heparin administration is typically beyond 480 seconds. An ACT of greater than 480 seconds is considered by many clinicians to be the minimum amount of heparin anticoagulation effect necessary for CPB surgery. The object of an ACT test is to indicate if adequate heparin has been administered to the patient in order to proceed with the surgical procedure without risk of forming blood clots.
Heparin is metabolized during surgery. Consequently, heparin must be administered both before and during CPB surgery in order to maintain a sufficient level of anticoagulation. Also, the anticoagulant effect of heparin varies from patient to patient. Therefore, different patients require different amounts of heparin, both before and during CPB surgery.
Several different tests are used throughout the world to manage heparin administration during CPB surgery. The most widely used tests for heparin management are the ACT, activated partial thromboplastin time (aPPT), and protamine titration of heparin. Of these tests, ACTs are the most common, least expensive, and most convenient way to manage heparin administration during a CPB surgical procedure. Heparin management protocols vary among medical institutions, but typically, when the ACT drops below a threshold time of typically 400 to 480 seconds, additional heparin is administered. ACT tests contain a contact activator to trigger clot formation. The two activators currently in general used for CPB surgery are diatomaceous earth (celite) and kaolin, a type of clay. Glass beads (silicon dioxide) are also used as a contact activator for ACT tests, although they are typically not used in CPB surgery because glass beads provide less contact activation than comparable amounts of celite or kaolin.
Several prior art instruments measure ACTs. Exemplary of these products are the Hemochron® 801 and Hemochron Jr. manufactured by International Technidyne Corporation, the Automated Coagulation Timer II and the Hepcon® Hemostasis Management System manufactured by Metronic HemoTec Inc., the Hemotec ACT manufactured by HemoTec, Inc., the Actalyke® manufactured by Array Medical, and the Sonoclot® Coagulation & Platelet Function Analyzer manufactured by Sienco, Inc. All of these instruments measure the time required to form a clot. Measurement time typically begins when the whole blood sample is mixed with an activator and ends when a clot is detected.
Aprotinin, manufactured under the name Trasylol® by Bayer Corporation, is a drug that has been shown to reduce blood loss after cardiopulmonary bypass (CPB) surey. Researchers do not completely understand the process or processes by which aprotinin achieves this reduction in bleeding. Aprotinin is a protease inhibitor neutralizing primarily plasmin and kallikrein. It also reduces glycoprotein loss in platelets, thereby preserving the platelets' ability to aggregate after CPB. The net effects of aprotinin administration reduce the need for post-operative blood transfusions and re-exploratory surgery to stop bleeding. Aprotinin may have additional effects on hemostasis via other mechanisms.
An undesirable and potentially dangerous side effect of aprotinin is that it prolongs celite activated ACT results in the presence of heparin. For example, a celite ACT on a heparinized patient may be 480 seconds. The same patient with the same amount of heparin plus aprotinin may have an ACT substantially over 700 seconds. The celite ACT result is not a useful measurement for the heparin anticoagulant effect in the presence of aprotinin because the aprotinin prolongs the ACT result. Managing heparin with celite ACT tests is not effective because, in the presence of aprotinin, the ACT is substantially delayed, creating a risk of under heparinization and subsequent clotting during surgery. Also, any time wasted waiting for a 700-second ACT is a significant operating room cost and should be avoided when possible.
Kaolin activated ACTs have been investigated as a preferred alternative to celite activated ACTs for use with patients receiving both heparin and aprotinin. Numerous publications state that kaolin ACTs are not prolonged by aprotinin. These publications include J. S. Wang et al., “Monitoring of Heparin-induced Anticoagulation with Kaolin-activated Clotting Time in Cardiac Surgical Patients Treated with Aprotinin,” Anesthesiology, 77:1080-1084, December 1992, and W. Dietrich et al., “Influence of Hi-dose Aprotinin on Anticoagulation, Heparin Requirement, and Celite and Kaolin Activated Clotting Time in Heparin-pretreated Patients Undergoing Open-Heart Surgery,” Anesthesiology, 88: 679-689, October 1995. The published research of kaolin activated ACTs appears to have been based on the assumption that all kaolin reagents perform similarly when used for ACTs. Each of these published studies investigated commercially available kaolin ACTs or custom kaolin ACTs using only one type of kaolin. The idea that the source or purity of kaolin may contribute to the stability of kaolin ACT results in the presence of heparin is never discussed.
The original development objective of the present inventors was to develop a kaolin ACT for use with the Sonoclot Analyzer in applications using aprotinin during CPB surgery. Based on published information, the initial assumption was that this development effort would be straightforward. The first kaolin formulations used USP grade kaolin, part number 5645 from Mallinckrodt Chemical, Inc., Kentucky, in a concentration that produced a desired heparin dose response to other commercial kaolin ACT tests. When this formulation was tested for aprotinin stability, an unexpected result was found; this kaolin ACT was found to perform similar to celite ACTs rather than published performance for kaolin ACTs. The ACT results were significantly prolonged by aprotinin when heparin was also present. Subsequent work by the present inventors showed that kaolin activated ACT tests are highly dependent on the source and purity of kaolin.
This research also exposed another unexpected concern; any alteration of kaolin ACT results due to aprotinin is highly patient variable. Using kaolin from ACT tests manufactured by International Technodyne, it was found that the ACT results on heparinized blood were unaffected by aprotinin for most samples. However, in approximately 10% of blood samples taken from the normal population, the ACT results on heparinized blood were substantially prolonged by aprotinin. This is a significant concern because the patients with heparinized blood samples that produce prolonged ACT results in the presence of aprotinin may receive significantly less heparin. These patients are at risk for under heparinization and subsequent clotting of the CPB circuit. Published performance data on kaolin ACTs reported only sample mean and standard deviations; this statistical analysis can miss individual patient variability that occurs only in a small percentage of the sample population. Kaolin ACT performance in the presence of aprotinin is described in more detail hereinafter.
The manufacturer of aprotinin recognizes that aprotinin may compromise ACT based heparin management. The aprotinin product insert recommends minimum ACTs while on CPB of 750 or 480 seconds for celite or kaoli
Aiken Jennifer C.
DeBiase Barbara A.
Henderson Jon H.
Hein William E.
Sienco, Inc.
Wallenhorst Maureen M.
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