Welcome to the February 2002 session of AACC's Expert Access Live on-line program. Today's program, Ecarin Clotting Time: A New Tool for Management of Heparin Induced Thrombocytopenia in Cardiac Surgery, is co-hosted by our experts Drs. Paula J. Santrach and Greg A. Nuttall who are now available on-line to answer your inquiries.

The Expert Access Live on-line program, is sponsored, in part, by a generous educational grant from the Bayer Corporation

Have there been any reported adverse reactions to hirudin?
Lima , Ohio

Paula J. Santrach, Greg Nuttall:The most commonly reported adverse effect is bleeding, especially from cannulation sites. Skin rash has also been reported. Some patients will develop anti-hirudin antibodies, which will enhance the anticoagulant effect of hirudin. Therefore, ongoing monitoring in these patients is important.

Thank you for your excellent presentation. You have given a very thorough explanation of the clinical evaluation for HIT type II, but do not explain how it differs from heparin-related transient thrombocytopenia. Could you please explain the distinction, particularly since you indicate the antibody titer for HIT II can drop below detectable level.
Los Angeles, CA

Paula J. Santrach, Greg Nuttall:Heparin-related transient thrombocytopenia (HIT type I) typically involves a mild decrease in platelet count („T30% decrease from baseline) that occurs in the first few days of heparin treatment. The thrombocytopenia does not progress and may resolve despite continued use of heparin. New or progressive thrombosis does not occur. This early decrease in platelet count may relate more to the patient¡¦s concurrent disease and other medical procedures rather than the heparin therapy itself. The diagnosis of HIT (HIT type II) is based on a combination of clinical features, laboratory test results, and elimination of other causes of thrombocytopenia. Mild to moderate thrombocytopenia occurs 5-10 days after the onset of therapy and often is „d50% decrease from baseline. Clinical features may include venous and/or arterial thromboembolism, heparin-induced skin lesions, acute systemic reactions to intravenous bolus heparin, warfarin-associated venous limb gangrene, and bilateral adrenal hemorrhagic infarction. Up to 10% of patients may have a negative immunoassay for heparin/PF4 antibodies, but platelet activation assays may be positive. Delayed onset HIT, with thrombocytopenia and thrombosis occurring up to 3 weeks after exposure to heparin, has also been described (Warkentin TE, Kelton JG. Ann Intern Med 2001; 135:502-506). In these patients, high-titer platelet-activating antibodies were detected and thrombotic complications were common.

You stated in your presentation that in HIT II patients develop thrombocytopenia 5-10 days after heparin is initiated. Is this for the primary response, and if so, what is the expected time for complications in an anamnestic response?
Denver, Colorado

Paula J. Santrach, Greg Nuttall: Patients with HIT (HIT II) typically exhibit a mild to moderate decrease in platelet count 5-10 days after the start of heparin therapy. If a patient has developed these antibodies as a result of heparin exposure in the last 100 days, thrombocytopenia may occur in 24-48 hours after re-exposure to heparin. This is probably due to the persistence of antibodies rather than a true anamnestic response. HIT antibodies tend to become undetectable a few months after the cessation of therapy. Clinical experience suggests that patients with a remote history of HIT and a negative antibody test may be received heparin therapy again without the redevelopment of HIT. An excellent article on the time course of patients with HIT is: Warkentin TE and Kelton JG. Temporal aspects of heparin-induced thrombocytopenia. NEJM 2001; 344:1286-1292.

If heparin can be neutralized easily with protamine, why is this process insufficent when performing CPB on patients with HIT II?
Salt Lake City, Utah

Paula J. Santrach, Greg Nuttall: Patients without heparin-induced thrombocytopenia can undergo CPB with heparin anticoagulation and protamine reversal. In contrast, patients with HIT who need CPB should not receive heparin, since they are at significant risk for life or limb threatening thromboembolic events associated with the heparin administration. They may be anticoagulated during CPB with hirudin and there is no antagonist available to reverse the effect of hirudin (protamine is ineffective). The typical heparin-based CPB protocol was included in the presentation so one could compare it to the protocol used with hirudin.

Can you estimate what the cost of this test to be compared to routine heparin monitoring?
Ithaca, NY

Paula J. Santrach, Greg Nuttall: The cost of the cards to perform the ECT are significantly more expensive than activated clotting time reagents. However, the ECT is much more reflective of the actual plasma hirudin concentrations and allows more precise monitoring to prevent bleeding or thrombosis during CPB. Fortunately, the number of patients requiring this type of monitor is very small. We have only treated 6 CPB patients with this therapy in the last 2 years and during that same time we performed ~5000 CPB procedures. We refer you to the manufacturers for precise cost information.

What is the laboratory's role in the coordination/performance, etc of this test?
Wilmington, Delaware

Paula J. Santrach, Greg Nuttall: The ECT must be performed at the point of care because of the required rapid turnaround time in order to adjusted the hirudin infusion. At our facility, the laboratory is involved in performing the preoperative titration curves usually the day before surgery. During surgery, a lab technician is present in the operating room to perform the test. This may not be the model for other facilities. We believe that this is an opportunity for surgery and the lab to work together to provide the service. Ideally, the lab has the most expertise to do the preoperative studies while surgical personnel (anesthesia or perfusion) may perform the test in the operating room. Preoperative studies are important at least in the first few cases to make sure that everyone involved understands how patients respond to this drug.

On the topic of assessing patients for CPB, I am hearing conflicting information about the utility of the bleeding time test. Some say it is archaic and no longer in use, but I know of some major institutions that still use it. At your institution is this test still performed, or what has replaced it?
Knoxville Tennessee

Paula J. Santrach, Greg Nuttall: Our facility still offers the bleeding time test. It is not routinely used to assess patients prior to CPB. It is used predominantly during a hemostatic consultation when there is a specific history or concern that a particular patient has a bleeding disorder.

Are there alternative anticoagulants to hirudin in patients with HIT II?
Charlottesville, VA

Paula J. Santrach, Greg Nuttall: Hirudin is the anticoagulant that has been studied most extensively as an alternative to heparin for CPB. Other drugs that been tried are argotroban, the glycoprotein IIb/IIIa inhibitor tirofiban, and low molecular weight heparin. All of these agents share similar weaknesses as compared to hirudin: There is no specific antagonist, monitoring is difficult, and ideal dosing protocols are not well established. There are case reports and small series using these other drugs in the literature.

What percentage of the population would you estimate to have HIT II? What in a patient's medical history, other than prior thrombocytopenia due to heparin, would be an indicator for this condition?
Hartford, Connecticut

Paula J. Santrach, Greg Nuttall: Up to 50% of surgical patients and 20% of medical patients treated with heparin will develop heparin/PF4 antibodies. However, only 1-5% will develop clinical HIT. In the patient's history, the combination of heparin associated thrombocytopenia and the relevant clinical features (thrombembolism, etc) and the appropriate test results are the criteria for the diagnosis.

Is Pharmanetics (Bayer) still waiting for FDA clearance for the ECT or will it remain just an HDE test? Do you still recommend running a dose response curve for each patient before beginning the surgery and use of hirudin? Why do you run a response curve on neat patient plasma in addition to the 1:1 patient:pool, since the 1:1 is what will be used during monitoring?
Madison WI

Paula J. Santrach, Greg Nuttall: We do recommend running a dose response curve for each patient before beginning the surgery and the use of hirudin. Prior to CPB, one can use the undiluted plasma to perform the ECT. However, once on CPB, it is necessary to use diluted plasma. Initially, we ran both for educational purposes - now we simply run the studies with the diluted plasma. We would refer you to Pharmanetics for the answer to the question about whether or not they will be pursuing FDA clearance.

Please give additional details describing your ecarin time assay. After mixing with normal plasma, do you test on the TAS system?
Birmingham, Alabama

Paula J. Santrach, Greg Nuttall: After mixing with normal plasma, one drop of the patient's diluted sample is placed in the sample well of the ECT card which previously has been placed in the TAS analyzer. The analyzer then detects the endpoint and provides the result in seconds.

Do you feel patients should be pre-screened routinely for HIT II?
Galveston, TX

Paula J. Santrach, Greg Nuttall: No, the incidence of clinical HIT is extremely low yet the presence of clinically insignificant antibodies may be as high as 20-50% depending on the patient population. With routine screening, one would have to figure out what to do with patients with "false positive" test results. And using hirudin for the CPB anticoagulant has significant risk for excessive bleeding post bypass.

Do you have experience with the ECT assay using a standard clot-based laboratory instrument?
Birmingham, Alabama

Paula J. Santrach, Greg Nuttall: No, we have only used the ECT with the TAS analyzer. The test has been previously performed in other institutions using a lab-based instrument. However, the turnaround time would be a significant issue - CPB monitoring requires rapid results in order to adjust the hirudin infusion to avoid hemorrhage or thrombosis.

In patients who have unsuspected HIT II but undergo CPB with heparin, how is the thrombocytopenia treated?
Vancouver, Canada
 
Paula J. Santrach, Greg Nuttall: If a patient with unsuspected HIT II undergoes CPB with heparin, we can think of two possible scenarios. 1. There may be no discernable impact during surgery, since moderate thrombocytopenia is common during and following CBP. Postoperatively, the patient may then exhibit signs and symptoms of thromboembolic phenomena. Treatment would then center on preventing further thromboembolic events through alternative anticoagulation. 2. During CPB, intravascular and/or intracardiac clot formation may be detected despite adequate heparin anticoagulation. Therapy in this circumstance centers on clot removal and prevention of additional clot formation. In both scenarios, it is the thrombotic complications that are of prime importance, not the platelet count. However, you might also see a dramatic drop in the platelet count and resulting excessive hemorrhage. Following protamine reversal of heparin, platelet transfusion might be required to control bleeding.

If a patient has heparin induced thrombocytopenia and needs to undergo another procedure, ie. dialysis, that would usually require heparin, what would be recommended anticoagulant?
New Orleans, Louisiana

Paula J. Santrach, Greg Nuttall: Alternative anticoagulants that have been used for coverage of other procedures include danaparoid, argatroban, and lepirudin. Each has somewhat different characteristics that will influence its applicability depending on the clinical situation. Danaparoid has potent anti-Xa activity with a half-life of 24 hours and primary elimination through the kidney. Argatroban is a reversible direct thrombin inhibitor whose half-life is only 40 minutes and primary route of elimination is through the liver. Lepirudin is an irreversible direct thrombin inhibitor with a half-life of 1.5 hours and renal clearance. Although danaparoid may show some cross-reactivity with heparin, that is not seen with either argatroban and lepirudin. We recommend that one review the literature specific for the clinical procedure/indication in order to determine the options for anticoagulation. Standardized protocols are not available.

You indicate that HIT patients develop IgG antibodies presumably in the 5-10 day range. Is there an IgM produced sooner that could be used to detect this condition sooner?
Chapel Hill, NC

Paula J. Santrach, Greg Nuttall: The heparin-PF4 antibody test that we perform will detect IgG, IgA, and IgM. Some of the published studies suggest that it is the IgG that interacts with the Fc receptors on the patient’s platelets resulting in the clinical syndrome. Since the test is usually not performed until there is a clinical suspicion, there may not be much of an advantage in being able to detect IgM. False positives are also likely to be encountered if asymptomatic patients are tested. On the other hand, there are isolated reports of IgM and IgA being involved. So probably the best approach is to be able to detect all three types of immunoglobulin and to reserve testing for those patients with a clinical picture suggestive of HIT.

Thank you for joining us for this month's Expert Access Live on-line program. Mark your calendars for our next session on March 5 when Dr. James Westgard will present, Six Sigma Quality: Performance Metrics vs Laboratory Myths.

See you next month

We would like to thank the Bayer Corporation for their generous support of the Expert Access Live-on-Line program.