One thing is sure. We have to do something. We have to do the best we know how at the moment…; If it doesn’t turn out right, we can modify it as we go along.
Franklin D. Roosevelt
The use of mechanical circulatory support (MCS), including extracorporeal membrane oxygenation (ECMO), ventricular assist devices (VADs), and the total artificial heart (TAH) has revolutionized the care of children and adults with respiratory or cardiac failure with successful bridging to organ recovery, transplantation, or destination therapy. All forms of MCS are vexed by continued thrombotic and hemorrhagic complications, among other limiting factors. In this issue, a series of studies explore anticoagulation management approaches attempting to ameliorate the hemostatic imbalances induced by MCS implantation and provides the framework for researchers to ask specific questions about our approach to biocompatibility for MCS.
ARE WE EFFECTIVELY DESIGNING OUR DEVICES TO MITIGATE SHEAR-INDUCED EMBOLIC PHENOMENON?
Serious complications often occur and are more common in specific types of MCS. Consequently, the type of MCS chosen for a patient is influenced by the suspected duration of support. For example, after 20 days of ECMO support, serious complications occur including vasomotor instability, capillary leak syndrome, bleeding, and multisystem organ failure.1 Although longer-term support can be carried out by implanting a TAH or a VAD, serious complications occur in patients, the most feared being ischemic and hemorrhagic stroke. The activation of the coagulation system leading to thrombosis of the ECMO components (circuit, oxygenator), the TAH or VAD and subsequent stroke may be related to type of device, component composition, shear force generated, and patient-related factors.1 Although antithrombotic therapy is administered to rebalance hemostasis and decrease thrombotic events, the ideal regimen and most effective management strategy is not known.
Mechanical circulatory support exposes the coagulation system to foreign material and supraphysiologic shear forces. Biomaterials cause activation of FXII, which leads to thrombin and fibrin generation. Shear stress changes many aspects of the hematologic system, which may either promote thrombus formation or bleeding. Elevated levels of plasma-free hemoglobin and lactate dehydrogenase suggest that high levels of shear can damage red blood cells. Device implantation also causes activation of the vascular endothelium and increased circulating endothelial cells expressing tissue factor.2,3 Tissue factor is the primary cellular activator of coagulation and may be involved in the prothrombotic state found in left ventricular assist device (LVAD) patients. In addition, exposure to shear force results in activation of platelets, which then participate in thrombus formation.4 Platelet membrane fragments, or microparticles, contain phosphatidylserine, an essential component for initiation of coagulation. Phosphatidylserine and activation of the complement pathway by generated thrombin promotes development of an inflammatory state that can result in further cell damage.3,4 In contrast, the degradation of high molecular weight von Willebrand Factor (VWF) multimers by supraphysiologic shear forces in the presence of ADAMTS13 may influence the development of gastrointestinal bleeding. Emerging evidence suggests that MCS also stimulates release of angiopoietin II, which may underlie altered angiogenesis and contribute to bleeding risk.5
Activation of the coagulation system also occurs in ECMO with important similarities to VADs. Hastings et al.6 conducted a thorough examination of ECMO circuits following support of children, observing thrombi in nearly all circuits. Thrombi most frequently occurred at the tubing connector junctions (TCJs) and in the oxygenator, presumed to be embolized from elsewhere in the circuit. Computational fluid mechanical modeling showed that the TCJs had low shear and recirculation. Histologic analysis showed the clots to be fibrin rich. Thus, they hypothesized that improving hemodynamics and anticoagulation regimens may decrease thrombosis. Interestingly, this finding is consistent with observations of thrombus on device surfaces with areas of recirculation in pulsatile and continuous flow VADs.7,8 Thus, both extrema of the shear spectrum contribute MCS complications that require further study to improve both the design of devices and how to manage anticoagulation in the setting of suboptimal flow conditions.
ARE WE UTILIZING THE MOST EFFECTIVE ANTITHROMBOTIC STRATEGIES?
In vivo modulators of hemostasis prevent excessive activation of coagulation (antithrombin [AT], protein C and S, tissue factor pathway inhibitor [TFPI], α2macroglobulin, thrombin activatable fibrinolytic inhibitor, thrombomodulin, endothelial protein C receptor [EPCR], and platelet activation [ectonucleotidase, prostacyclin, nitrous oxide]). However, these are sometimes unable to sufficiently modulate thrombin production in MCS and antithrombotic therapy is necessary to normalize hemostasis. Current antithrombotic agents used in MCS include anticoagulants (unfractionated heparin [UFH] or warfarin) and antiplatelet agents (APs), most commonly acetylsalicylic acid (ASA).9–11 Inherent challenges exist with the use of each of these agents. Although UFH has a short half-life, complications include heparin-induced thrombocytopenia (HIT), release of TFPI, and interference with platelet function.12 The mechanism of action of UFH is to increase the inhibitory activity of AT by 1,000 fold. Children physiologically have lower levels of AT than adults, which can be further decreased in illness.13 Consequently, achieving an anticoagulant effect with UFH in children can be challenging and replacement of AT has been described and used to increase the anticoagulant effect of UFH. Tzanetos et al.14 estimate the safety of this approach in a retrospective study. They demonstrate that use of recombinant AT in pediatric ECMO to keep AT levels >80% was not associated with increased bleeding. Low AT levels did not correlate to thrombotic events, but on average, patients only spent 5.2 hours with AT levels <80%. A comparative study of outcomes between patients with and without AT supplementation would be required to determine the efficacy of AT supplementation.
In MCS patients, there may be clinical situations where UFH is contraindicated but the safety of withholding anticoagulation has not been evaluated. Chung et al.15 demonstrated that in a select group of adult patients undergoing ECMO with thrombocytopenia (platelet count <50,000/mm3), ongoing bleeding, or ACTs >230 sec (target range 170–230 sec), there were no adverse thrombotic events despite no administration of UFH for more than 3 days. This cohort likely represents a mixture of patients with decreased platelet and/or coagulation protein, those with vasculopathies, and patients with increased platelet and factor consumption. Further investigation of this subgroup of patients supported on ECMO without anticoagulation may yield insight for enhanced anticoagulation strategies in other ECMO-supported populations. Particularly, given that thrombosis has been described with increasing doses of UFH without anticoagulant response or if HIT develops.16 In this clinical scenario, alternate agents such as parenteral direct thrombin inhibitors (argatroban or bivalirudin) have been used in the absence of safety and efficacy data.1,11,17
ARE WE UTILIZING EFFECTIVE LABORATORY TESTING TO MEASURE HEMOSTASIS IN MCS?
Currently, laboratory tests guiding AT therapy in MCS measure drug levels/effects in patient plasma samples devoid of cellular components which participate in vivo in hemostasis. Warfarin, used post stabilization in TAH and VAD patients, has unique challenges affecting therapeutic management, especially in the MCS population. This agent is a narrow therapeutic index drug with a long half-life (7 days) and affected by diet, medication additions or changes, and adherence.18 Drug effect is monitored using a prothrombin time (PT) converted to an international normalized ratio (INR) to account for different laboratory testing conditions (reagents and machines). The ideal INR range for a TAH or VAD patient is unknown; however, recent data in VAD patients demonstrated that INRs less than 2.5 is associated with an increased rate of Heartmate II (HMII) and Heartware ventricular assist device (HVAD) pump thrombosis.19,20 The time within the therapeutic range (TTR) estimates the quality of warfarin management and is related to adverse outcome events in other cohorts of patients (e.g., deep venous thrombosis).21 Previous studies have shown very low TTRs in LVAD patients that have been improved with pharmacist-managed warfarin.22 Differences in bleeding or thrombotic outcomes were not found in their small cohort. Using center-specific target, INR therapeutic ranges (HeartMate II [HMII] [therapeutic INR range 2–2.5] and HVAD (therapeutic INR range 2–3]), Halder et al.23 retrospectively found their LVAD patients’ TTR was 52%, similar to real world but not clinical trial management of patients with deep venous thrombosis or atrial fibrillation.21,24 Median INR 30 days preceding a bleeding or thrombotic event was 2.7 and 2.2, respectively. Patients with bleeding were more likely to be on low dose ASA and spend more time above the therapeutic range. Given the nature of dosing, testing, and time to therapeutic response in an outpatient setting, a difference of 0.5 INR is difficult to titrate. This highlights the potentially important aspect of a temporally integrated measurement, such as the TTR to delineate risk for adverse bleeding or thrombotic events.
In addition to cell-free methodology, whole blood can be stimulated to measure activation of hemostasis, thrombin generation, clot formation, and breakdown (global hemostasis). The use of viscoelastic testing of clot strength, thromboelastography (TEG), or thromboelastometry (ROTEM) might allow for tailored AT therapy in patients and potentially decrease the incidence of adverse events. This prospect was especially attractive for monitoring the effects of APs, which are most commonly used in TAH and VADs. In adult VAD patients, APs are administered in a fixed dose with no monitoring of effect. In the pediatric EXCOR study, the antiplatelet effect of aspirin and dipyridamole was monitored using TEG, with platelet mapping (PM).25 Studies have subsequently identified specific challenges with the TEG/PM,26 thus use of alternative methods to manage APs including multiplate, verify now, and classical platelet aggregation, despite validation of testing, has ensued.
Volod et al.27 retrospectively compared TEG testing in adult patients receiving AT therapy, with and without a thromboembolic event (TE) implanted with a TAH, Thoratec paracorporeal ventricular assist device (PVAD) biventricular device, HMII or HVAD. Results demonstrated a significantly increased coagulation index (CI), an index derived and calculated from the kinetic parameters of clot development (R, K angle) and clot strength (MA) in patients with a TE compared with those without, for each device. Based on these results, the investigators recommended a target CI, which can be manipulated by altering antithrombotic therapy, for each specific device. They concluded that CI was useful in guiding antithrombotic management, along with the INR (measured close to an event) as a reflection of warfarin effect, to achieve normal hemostasis and avoid adverse events. Further larger prospective studies are required to establish the safety and efficacy of global hemostatic testing in MCS to guide management.
Stroke remains one of the most feared complications of MCS resulting in mortality and morbidity. Despite the use of antithrombotic therapy, the rate of stroke remains high in children25,28–30 and adults.19,30 The mechanisms of thrombosis and stroke are not fully understood in MCS and will require a multidisciplinary approach to elucidate. However, many complicating factors exist. Components of ECMO vary between clinical centers which may result in variable amounts of hemostatic activation due to different biomaterials.17 In addition, the VADs implanted are composed of different biomaterials and generate different shear conditions and exposure times. Finally, development of inflammation most certainly plays a role.31,32 These differences present challenges to unraveling mechanisms of thrombosis which are integral to determining the “ideal” antithrombotic regimen to prevent adverse events.
Retrospective studies6,14,15,23,27 are important in that they provide a platform from which prospective studies can be designed and completed. However, to definitively determine safety and efficacy of AT therapy and management, mechanisms of thrombosis must be determined followed by prospective studies testing antithrombotic regimens, both in adults and children. Children have a number of developmental differences including developmental hemostasis with age-related differences in hemostatic proteins, altered pharmacokinetics/pharmacodynamics, clearance and metabolism of pharmacotherapeutic agents, and challenging venous access to administer and monitor drugs, which preclude the use of adult guidelines for antithromboitc therapy.33
Albert Einstein said, “We cannot solve our problems with the same level of thinking that created them.” Prospective adult and pediatric studies are urgently needed to guide antithrombotic management in MCS. The number of unique challenges in the MCS patients mandates multidisciplinary experts to be involved in study design. Systematically testing various regimens or strategies will allow the most effective management to be determined and will result in decreased adverse events and improved patient quality of life. Similarly, there remains a critical need to design and develop MCS devices, which require less antithrombotic therapy to avoid complications. As it has been for over six decades, the ASAIO community is at the crux of physicians, nurses, perfusionists, and engineers who, working in concert, can continue to innovate and collaborate to bring improved medical therapies from the bench to the bedside.
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