Among all study subjects, 11 (11.2%) subjects developed at least one TE event during the study period and two patients’ experienced two TE events.
In terms of types of MCS devices, among the TE group, 7 (63.6%) patients had TAH, 2 (18.2%) had HM II, 1 (9.1%) had BIVAD, and 1 (9.1%) had HW. Among the non-TE group, 28 (32.2%) had TAH, 23 (26%) had HM II, 6 (6.9%) had BIVAD, and 30 (34.4%) had HW as shown on Table 3.
In terms of types of events, a total of 100 events were reviewed, including 13 (13%) TE events and 87 (87%) non TE events. Of the 87 non TE events, 28 (32.2%) occurred in patients with TAH, 30 (34.5%) in those with HM II, 23 (26.4%) in those with HW, and 6 (6.9%) in those with BiVAD. Of the 13 TE events, 8 (61.5%) events occurred in patients with TAH, 2 (15.4%) in those with BiVAD, 2 (15.4%) in those with HM II, and 1 (7.7%) in those with HW. The TE events included cerebral vascular accidents (61.5%), transient ischemic accident (7.7%), RVAD thrombosis (23.1%) and acute coronary event (7.7%)
Thromboelastography and Thromboelastography Platelet Mapping Parameters
The mean of all TEG parameters were either measured (R, α, MA) or calculated (G, CI) and compared between subjects with TE events and without TE events (when adequately anticoagulated) based on the type of MCS device (Table 4). A significantly higher CI was observed in the TE group compared with the non TE group in all four types of MCS devices (TE versus non-TE mean for TAH 3.12 vs. 1.12, HM II 2.79 vs. 1.74, HW 2.79 vs. 1.70 and for BiVAD 2.79 vs. 1.72). The CI value provides an indication of the global hemostatic state of a patient. It is derived and calculated from a linear combination of the kinetic parameters of clot development (R, K, angle) and clot strength (MA) CI = –0.6516Rc – 0.3772Kc + 0.1224MAc + 0.0759αc − 7.7922. Positive values above the range suggest overall hypercoagulability, whereas negative values below the range suggest overall hypocoagulability. The normal range for CI was calculated based on our validation studies for the laboratory. The normal CI range was found to be from −5.3 to 1.5. This range was developed from normal donors. The range of the CI values calculated for patients implanted with the different MCS devices without a TE event are presented in Table 4.
During TE events, a higher G and α were observed when compared with periods of non-TE events, with significant differences for those with HW, HM II, and BIVAD. A trend toward higher α, MA, G, and MA-ADP were observed in the TE group compared with the non TE group. There were no significant differences seen in MA-AA and INR between the two groups (Table 4).
Of the 87 non TE patients
- 26/87 (30%) were transplanted and 14/87 (16.1%) expired by > 1 year point.
- 23/87 (26.4%) were transplanted and 13/87 (14.9%) expired by 1 year point.
Of the 11 with TE patients
- 5/11 (45.5%) were transplanted and 2/11 (18.2%) expired by > 1 year point.
- 5/11 (45.5%) were transplanted and 1/11 (9.1%) expired by 1 year point
One of the largest TAH study describing anticoagulation protocol with a very low neurologic adverse event rate (0.016 event/patient-month) attributed their success to the single so-called “La Pitie” anticoagulation protocol that was required to be followed by all physicians taking care of device patients.5 According to that protocol, hemostatic status of a patient was analyzed through many coagulation assays that allows for very specific anticoagulation management.
Our hands-on experience with TAH started in 2012, when the first TAH heart was implanted at our Institution, which is quaternary care teaching center with state of art surgery service, postoperative intensive care units, and a specialized coagulation laboratory. Our MCSD team included experienced surgeons, cardiologists, anesthesiologists, hematologist-oncologist, coagulation expert (hematopathologist), pharmacist, physician assistants, and nurses as well as residents and fellows rotating through the service. In our hands TEG PM appeared to be single most useful real time assay of overall hemostasis changes including increased fibrinolysis. But despite continuous and in depth MCSD team training on how to interpret TEG PM, it was very difficult to decide how to adjust anticoagulation and antiplatelet therapy using all the described parameters.
Thrombelastography (TEG, Haemonetics) is a device that measures global viscoelastic properties of whole blood clot formation and lysis in one test. Currently, this technology has been used extensively in hemostasis monitoring during major surgeries, trauma, obstetrical complications, and management of deep vein thrombosis whereas its other assay, TEG PM, is used to monitor antiplatelet agent’s activity.10,11
This type of assay that uses whole blood better mimics the in vivo hemostatic processes that are described in the cell-based model of hemostasis. Interaction of TF expressing cells, platelets, coagulation factors, and inhibitors form the basis of the hemostatic balance. Therefore, we speculate that the TEG with TEG PM can be a more valuable tool in tailoring therapy for MCS D patients who have a high risk of developing major thrombosis or bleeding events.
Thromboelastography Platelet Mapping-Guided Anticoagulation Protocol
Despite data showing its clinical utility and because of its complexity in interpreting multiple variables, the initially suggested TEG PM-based anticoagulation protocol, was not followed by all who were involved in the MCSD patients care. For some of the patients, TEG PM was performed either sporadically or only immediately after a thrombotic or bleeding event. Even in our center, with specialized coagulation laboratory and a coagulation expert, esoteric coagulation assays are either not performed (thrombomodulin, platelet factor 4) or are available only on scheduled days (platelet aggregometry, antithrombin III).
These limitations have led to this pilot study with the objective of developing an individually-tailored anticoagulation protocol that is cost effective and standardized with a simple and easy to follow set of defined target parameters. The outlined protocol includes only four parameters (CI, INR, MA-AA, and MA-ADP) performed daily with two assays (TEG PM and INR).
The implantation of an MCSD induces a systemic inflammatory response that often leads to daily alterations of normal hemostasis as it is depicted in Figure 4. During the immediate postoperative and recovery period (especially during the first 2 weeks), the TEG PM assay may be a useful tool in preventing TE and or bleeding events in patients with durable MCS devices such as HW, HMII, and TAH. Once the patient is stabilized (Figure 5), TEG PM can be performed once or twice per week until discharge, and only if necessary (in case of bleeding and or clotting event) after the discharge. In our experience, infrequently observed TEG PM with high MA-A value requires another assay to assess aspirin response (platelet aggregometry).
Assessment of Anticoagulation Therapy Adequacy
The single most statistically significant TEG parameter in our study used to define overall normocoaguability is the CI, which is calculated from the R, K, α, and MA values from a kaolin-activated TEG assay. Our results support what others have found about the utility of the CI parameter for maintaining a patient within the normocoaguable range and free from a TE event.7 The University of Arizona group used nonactivated blood samples for TEG analysis (native TEG) to monitor their MCSD patients. The CI range for normocoagulability for their MCSD patients was calculated to be from 0.29 to +3.66.12 Their range was also shifted from the reference range provided by manufacturer. At our institution Kaolin-activated TEG analysis is performed. The range of CI values determined from normal donors was from −5.3 to 1.5 (mean −1.9 ± 1.7), which is different from manufacturer suggested range from −3 to 3. With the underlying hemostatic abnormality for MCSD patients being hypercoagulable, the range for a normocoagulable state (free from thrombotic events) in our pilot study was 0.19–2.09 for TAH, 0.67–2.76 for BiVAD, 1.27–2.22 for HM II, and 1.23–2.17 for HW groups. Based on our results, patients with HM II and HW devices should be maintained at a CI value ≤1.5, whereas patients on TAH devices should be maintained at a value ≤1.2. Because of the design of devices, patients with HM II and HW are at higher risk of hemorrhagic complications owing to von Willebrand factor multimer loss.3,4 For this reason, their targeted CI value is higher than for patients implanted with TAH. The validity of the proposed values will be evaluated in a larger study.
There was no significant difference observed in INR between the two groups, signifying that aggressive TEG R-targeted titration of anticoagulant therapy is not necessary. Instead, the patient should be kept within device-specific INR goal ranges to achieve adequate Vitamin K-dependent factors inhibition.
At an INR of >3.5, the activity levels of all four factors are usually less than 30%, which is below the hemostatic range.13 Further increase in warfarin dose may cause significant inhibition of Vitamin K-dependent factors (VII, II, IX, and X), but will have no effect on fibrinogen and factor VIII, both of which are acute phase reactants and are usually elevated leading to normal TEG R values despite a prolonged INR. In cases of elevated CI but therapeutic INR, it may be helpful to review other TEG parameters for possible hypercoagulable states such as (infection, inflammation) and should be treated accordingly.
Assessment of Antiplatelet Therapy Adequacy
Because of the predominant nature of TE events (cerebrovascular accidents), reactive thrombocytosis and platelet hyperactivity, focus should be on stabilization of their reactivity with antiplatelet agents. Because an MA-AA and MA-ADP value of 50 provides the lowest number for the normal range of MA in a thrombin-generated kaolin assay, an MA-AA and MA-ADP benchmark value of less than 50 appears to define normocoagulability in all MCS patients. In our experience, adequacy of the antiplatelet therapy cannot be assessed when MA-A value is elevated above 40 mm, platelet aggregometry may be used instead.
Assessment of Bleeding
Thromboelastography is a useful real time assay of overall hemostasis, especially in cases of complex coagulopathies. It allows a wider scope of detection to help identify bleeding cause (factors, including fibrinogen, platelets, or their combination) and guide appropriate blood products transfusion intraoperatively.
Fibrinolysis, either primary or secondary (both can be seen in patients on MCSD), presents clinically as bleeding and requires different approaches to manage, but it is not apparent with conventional coagulation assays. Thromboelastography can be used to help in detection of fibrinolysis based on the LY30 parameter, which is the amount of lysis seen 30 minutes after MA.
If the patient develops a GI bleed when MA-AA and MA-ADP are therapeutic and TEG is normocoaguable, acquired von Willebrand disease should be ruled out with appropriate work up, because TEG is not sensitive to detect this defect.
There were several limitations of this study including the small sample size (n = 98) and the disproportionate amount of subjects without TE events (n = 87) compared with those with at least 1 TE event (n = 11). With the limited number of patients who developed TE events, the interpretations of our results were only based on a total number of 13 TE events. For this reason, a one-to-one comparison between two groups based on types of MCSD could not be performed; rather the TE events group included all types of MCS devices, while non-TE events group was categorized based on the type of MCSD. Another limitation of our study was that some of the patients with TE events did not have their TEG PM assays collected before or on the day of the TE event. As a result, the TEG PM assay for these patients may not accurately reflect the true nature of their hypercoaguability at the time of the event. A larger study will be conducted at our Institution to evaluate the validity of this established protocol.
The healthcare team involved with the management of MCS patients normally comprises doctors of different subspecialties, pharmacists, physician assistants, and nurses. Therefore, a standardized yet individually-tailored anticoagulation protocol is imperative for successful patient outcomes. Laboratory tests that assess anticoagulation adequacy must be simple to interpret, cost effective, and have defined target parameters for normocoaguability. Based on our pilot study results, the CI, MA-AA, and MA-ADP are minimally required. Thromboelastography PM parameters that need to be assessed and correlated with device-specific INR ranges to help individualize a MCS patient’s antiplatelet and anticoagulation therapy.
The authors thank Mike Miller, Manager Haemonetics Hemostasis clinical resources, for his help in describing TEG and TEG PM Parameters.
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Keywords:Copyright © 2017 by the American Society for Artificial Internal Organs
thromboelastography platelet mapping; mechanical circulatory support devices; anticoagulation protocol; single institutional; normocoagulability definition