Trends in Coagulation Testing


Vol. 21 • Issue 1 • Page 20

Coagulation

The famous newspaper columnist, George F. Will, has been credited with saying, “The future has a way of arriving unannounced.” For the clinical scientist, the urgent need for change in response to advances in anticoagulation therapy certainly seems to fit this quote. Even though test methods have not changed greatly in the last decade, we have made great strides with information handling and automation developed in response to advanced regulatory, workflow and clinical demands for healthcare delivery. Considering the magnitude of these changes as the tip of the iceberg, we should assume that changes in drug therapies and delivery methods will also drive the need for modifications in lab testing at the same rapid pace.

Current methods for coagulation testing and drug monitoring, new anticoagulant drugs, potential new methods for measurement, recent guidance from the FDA regarding companion drug testing and what the future holds for the coagulation field are explored here.

Today’s Methods

Clinical coagulation testing is performed using a combination of clotting, chromogenic and immunologic assays to screen for abnormalities in the normal hemostatic system. These abnormalities may be the result of anticoagulant therapy, underlying genetic mutations or acquired pathologies. Oftentimes, two or more of these phenomena will coexist, requiring the use of multiple screening and confirmatory tests that are sensitive to various analytes while being insensitive to others.

For example, drugs are prescribed to prevent blood clots or thromboses in at-risk patients. To date, the most prescribed anticoagulant drugs, warfarin and heparin, require laboratory monitoring to maintain adequate therapeutic targets. Monitoring methods used are the prothrombin time (PT) and the activated partial thromboplastin time (aPTT), respectively.

However, there has been a trend to use the chromogenic anti-Xa method to monitor heparin. Though the drugs are potent and their effects predictable for some patients, there are others in whom compliance, variations in genetic makeup or coexisting pathologies prevent these drugs from working adequately. Thus, coagulation tests specific for the drug must be run frequently for clinicians to ensure patients are adequately anticoagulated. Both classes of anticoagulants are readily accessible and, even when the cost of monitoring is included, inexpensive. Once hospital labs, pharmacists and clinicians have validated a cohesive set of practices in line with clinical guidelines, they establish a comfort level that enables them to safely prescribe these drugs routinely in a cost-effective manner.

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New Demands

The varied challenges of maintaining therapeutic ranges in patients on warfarin and heparin have driven the need for intensive monitoring of these traditional anticoagulants. These same challenges have also driven the need to develop alternate methods of anticoagulation. New drugs, classified by their target of action, are direct thrombin inhibitors (DTIs) or synthetic anti-Xa drugs. They specifically inhibit either thrombin or factor Xa (Figure).

In contrast, the older anticoagulants, warfarin and heparin, are indirect coagulation inhibitors and inhibit multiple components of the coagulation cascade. Partly because of their specific target within the coagulation cascade, these newer drugs have been shown in some clinical studies to be safe for use without routine monitoring in most patients.1

Hurdles to Cross

The DTI and anti-Xa drugs have been approved by the FDA for various indications, including atrial fibrillation and knee replacements. Even accounting for the benefit of requiring little or no lab monitoring, these new drugs are much more expensive. In addition, there are no commercial lab tests labeled for IVD that allow clinicians to assess patient compliance, possible overdose or drug clearance issues. While these drugs have been demonstrated to be safe and effective, there are patients in whom they may cause increased risk of bleeding, such as those with decreased liver or kidney function who may have reduced drug clearance or the elderly.

If clinicians choose to use traditional coagulation tests to evaluate hemostasis in patients who are taking these drugs, they will quickly realize that classical coagulation tests are all affected in one way or another; these drugs have potent effects on critical coagulation pathway components required for clotting tests to work as expected. In addition, there are no antidotes readily available that could neutralize the effects of the drugs either in the lab tests or in patients found to be bleeding or in need of emergency surgery. For patients who need to be evaluated for bleeding or clotting, coagulation testing practices will need to be adapted and clinicians will need to be aware of patients who are taking these drugs so they can bridge the patients to a different, more traditional therapy, or not perform the tests at all.

The Lab’s Challenge

Until diagnostic test manufacturers can develop, validate and obtain marketing clearance on new tests for the new classes of anticoagulants, labs may choose to develop and validate their own test methods for determination of drug concentrations or activity. They also will need to determine what these concentrations mean in the larger context of patient safety and outcomes. The drug package inserts provide some guidance on this issue, but these processes will take time and understanding as well as people and resources to validate the newly developed tests.

This new anticoagulation challenge is rooted in the “5 Rights:” The clinician needs the tools to provide the right drug to the right patient in the right concentration at the right time and to measure the effects of the drug using the right test. New draft guidelines from the FDA have guided drug and diagnostic manufacturers in this area. The guidelines explicitly describe conditions under which a companion test is required for a given drug. With this in hand, manufacturers can work together to help clinicians ensure that safe and effective therapies are available. These commercial developments and updated guidelines will ensure that new anticoagulant drugs will produce the best outcomes.

Dr. Riley is manager, Research Use Products, Diagnostica Stago Inc., and an ADVANCE industry advisory board member.

Reference

Samama and Guinet. Laboratory assessment of new anticoagulants. Clin Chem Lab Med 2011;49(5): 761-772.

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