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Monitoring Platelet Function in Children With Ventricular Assist Devices

The Devil Is in the Details

Massicotte, M. Patricia*; Kreuziger, Lisa Baumann

doi: 10.1097/MAT.0000000000000948
Invited Commentaries
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From the *Department of Pediatric Cardiology, Stollery Childrens Hospital, University of Alberta, Edmonton, Alberta

Blood Research Institute, Versiti, Medical College of Wisconsin, Milwaukee, Wisconsin.

Submitted for consideration December 2018; accepted for publication in revised form December 2018.

Disclosure: Dr. Massicotte is a consultant for the National Institutes of Health/National Heart Lung Blood Institute (NHLBI) funded study, the PumpKIN study: Ventricular assist devices in children. Dr Baumann Kreuziger has no conflicts of interest.

Correspondence: M. Patricia Massicotte, Department of Pediatric Cardiology, 3–539 ECHA, Stollery Childrens Hospital and University of Alberta, Edmonton, Alberta. E-mail: mm41@ualberta.ca.

Ventricular assist device (VAD) implantation results in activation of the coagulation system and cellular components because of foreign biomaterials and shear stress generated by the pump.1 Antithrombotic therapy is given to mitigate this activation; however, stroke and device thrombosis occur. The most effective antithrombotic agents and how to manage their pharmacologic effects remain uncertain.

Most device studies have been specifically designed to measure safety and efficacy of the device itself. Antithrombotic regimens were designed based upon extrapolation from regimens used in other devices. Current guidelines for management of antithrombotic agents in patients with VADs include treatment with anticoagulant (unfractionated heparin [UFH], low molecular weight heparins [LMWHs], and vitamin K antagonists [VKA; e.g. warfarin]) and antiplatelet agents (acetylsalicylic acid [asa], dipyridamole, and clopidogrel).2 Universally accepted laboratory testing exists for anticoagulants, the activated partial thromboplastin time (aPTT) for UFH and/or the antifactor Xa for UFH and LMWH, and the international normalized ratio (INR) for warfarin. Only the INR has been standardized between laboratories, however, and the measurement of platelet inhibition in patients with a VAD receiving antiplatelet therapy remains controversial.

In children, the EXCOR, an extracorporeal pulsatile flow device, was studied prospectively and included detailed antithrombotic therapy and management guidelines.3 Investigators accepted that the antithrombotic therapy guidelines were based on expert opinion with knowledge of developmental hemostasis and published safety and efficacy data in children. Study centers were allowed to deviate from the guidelines if clinically necessary.4 Patients were bridged with UFH to either VKA if greater than 12 months of age or LMWH if less than 12 months of age with specific laboratory targets for each agent.3 Platelet inhibition by asa and dipyridamole was measured using thromboelastography (TEG) with platelet mapping (PM) (Haemonetics, Braintree, MA).3 Platelet receptor agonists arachidonic acid and adenosine diphosphate (ADP) were used to measure platelet inhibition by asa and dipyridamole, respectively.

The clinical utility of the TEG and PM testing has been questioned because of variable test results and up to 30% of tests being uninterpretable.5,6 These technical challenges include lack of reproducibility and activation of platelets by the heparin anticoagulant in the platelet mapping assay. The American College of Pathology completed proficiency testing of PM in 2014 in approximately 150 coagulation laboratories which confirmed variability between tests.6 Thus, validity of the TEG and PM results must be confirmed by visually examining the generated curves and deemed acceptable as per certain criteria, in order to accept the parameters calculated by the machine.

Recognizing the limitations of the TEG PM, in a retrospective study, Ferguson et al.7 compared antiplatelet effect of asa, dipyridamole, and/or clopidogrel using TEG/PM and multiple electrode platelet aggregometry (MEA) on a multiplate analyzer. The MEA measures platelet aggregation through impedance (Figure 1B), whereas the TEG PM compares the maximum amplitude of the clot tracing with and without a platelet agonist (Figure 1A). Sixty-six paired samples from nine children with either a pulsatile (EXCOR) or a continuous flow VAD (Centrimag, Abbott Laboratories, Abbott Park, Illinois or Heartware, Heartware Inc, Framingham,MA) were tested. Asa and clopidogrel resistance was much higher when using the TEG PM; in children treated with greater than or equal to 5 mg/kg/d asa, TEG PM demonstrated that 72% measurements were subtherapeutic compared with 11% of MEA tests. A dose response was seen with clopidogrel and MEA ADP induced aggregation but not with TEG/PM % ADP inhibition.7 Additionally, there was no association with dipyridamole dose and ADP inhibition. There was significantly less individual variability between samples using MEA.7 This study shows that the MEA in children is a more reproducible test compared with TEG PM when measuring platelet function.

Figure 1

Figure 1

Suboptimal antiplatelet therapy could explain the high incidence of stroke in the EXCOR IDE study. Children with the EXCOR were titrated using TEG PM to platelet inhibition of greater than 70% with asa and dipyridamole and may have not had optimal platelet inhibition.8 The antiplatelet therapy dose increased over time with a large variation in dosing in the cohorts (asa: 0.5–24.7 mg/kg/d; median 2.8–7.0 mg/kg/d; dipyridamole 0.4–16.1 mg/kg/d; median 2.8–7.0).8 The MEA reported less variability which could lead to more standardized antiplatelet dosing.7 However, Ferguson et al.7 demonstrated more children were considered therapeutic using MEA. If clinicians were using MEA test results to determine dose escalation, overall lower doses of antiplatelet agents may be used.

Improved clinical outcomes by adjusting antiplatelet dosing based upon laboratory testing has not been proven to date. Very large randomized studies in adults undergoing percutaneous coronary intervention have not shown decreased myocardial infarction or stent thrombosis when antiplatelet doses were modified based upon testing.9–11 The study by Ferguson et al.7 reported three children with neurologic events. The platelet testing before the ischemic events in two children were not reported, but one was off aspirin due to epistaxis at the time of the event. The child with a hemorrhagic stroke had antiplatelet therapy escalated due to recurrent VAD thrombosis. Therefore, the management of antiplatelet agents in two of the three cases was based upon clinical events and may not have been modifiable by using platelet assays.

Other investigators have moved away from laboratory monitoring of antiplatelet therapy. The Stanford protocol12 uses weight-based antiplatelet dosing and titrates to maximum dose if no bleeding. A significantly decreased incidence of stroke has been reported (0.8 vs 4.9 per 1,000 patient-days). The median doses of asa and dipyridamole were 4.4 and 2.3 times higher than in the EXCOR study with less dosing variability between patients.12 In addition, clopidogrel was added to the antiplatelet therapy regimen. Larger studies in other centers are needed to confirm the efficacy of the Stanford regimen.

Ferguson et al.7 provide valuable information supporting the use of MEA to measure platelet function in children with a VAD. The question remains as to whether testing platelet function in all children with a VAD has clinical utility or if a weight-based dosing strategy provides better patient outcomes. The MEA is not widely available or able to be run on standard laboratory equipment. Before hospitals are tasked with purchasing and integrating this assay into clinical practice, correlation of laboratory testing with clinical outcomes is needed (Figure 1). Prospective studies using the Stanford protocol12 compared with laboratory testing for platelet inhibition are necessary to determine the “best” antithrombotic regimen that correlates to less bleeding and thrombotic events. Once an effective algorithm is established, perhaps further individualized approaches could be considered including targeting children with an inherited thrombophilia or high levels of nonspecific acute phase reactants such as Factor VIII (FVIII) or fibrinogen for increased antithrombotic therapy. Finally, the broader question remains; are we using antithrombotic therapy that minimizes bleeding but prevents thrombosis. Studies using new agents targeting other platelet receptors and alternative anticoagulants are in development.

“The greater our knowledge increases the more our ignorance unfolds.”

—John F. Kennedy

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