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Brief Communication

Prothrombin Complex Concentrate Use in Durable and Short-Term Left Ventricular Assist Device Implantation

Barac, Yaron D.*; Nevo, Adam*; Jawitz, Oliver*; Hashmi, Nazish K.; Henkel, Peter; Blue, Laura J.*; Kelly, Joseph§; Patel, Chetan B.§; Daneshmand, Mani A.*; Schroder, Jacob N.*; Milano, Carmelo A.*; Welsby, Ian

Author Information
doi: 10.1097/MAT.0000000000000937

Durable left ventricular assist devices (LVADs) therapy is used in advanced heart failure (HF) patients as either a bridge to transplantation or as a destination therapy, whereas short-term LVADs are used to treat cardiogenic shock or as a bridge to decision. Regardless of the LVAD type, implantation is associated with a high risk of bleeding with up to 30% of patients returning to the operating room for surgical bleeding.1,2

Prothrombin complex concentrates is used for emergency reversal of oral anticoagulation therapy,3 despite its efficacy, a serious concern with the use of prothrombin complex concentrates (PCC) is thromboembolism, which is greater in LVAD patients, with pump thrombosis being the most threatening complication. Thus, although some trials have shown promise in the use of PCC to control bleeding complications in cardiac surgery,4 there is still limited data on the use of PCC in LVAD patients. Because ventricular assist device thrombosis is a major adverse event, we investigated the safety of low dose PCC use in the management of bleeding post LVAD implantation comparing durable to short-term LVADs.

Methods

Study Protocol

Following Institutional Review Board approval, a retrospective chart review of the patients who had undergone LVAD implantation from January 2014 to June 2017 was performed. Adults greater than 18 who had received Profilnine/Kcentra (Grifols Biologicals Inc.) for bleeding in the up to 12 hours post-operation were included. Postoperative variables included thrombotic complications e.g. cerebrovascular accident (CVA), deep vein thrombosis, pulmonary emboli (PE) as well as pump thrombosis. Patient charts were reviewed from admission till 1 year post discharge. Categorical variables were compared with each other using a χ2, test and continuous variables were compared with the Wilcoxon rank sum test.

Post Cardiopulmonary Bypass Transfusion Algorithm

In case of refractory bleeding after discontinuation of cardiopulmonary bypass and reversal of heparin with protamine, the chest was packed and coagulopathy was corrected in accordance with the institutional perioperative cardiovascular transfusion algorithm (Figure 1, and (see Supplemental Digital Content, http://links.lww.com/ASAIO/A382). If bleeding persisted despite aggressive transfusion, PCC was administered at a dose of 10–15 U/kg.

Figure 1
Figure 1:
The duke cardiac surgical intraoperative transfusion algorithm; modified from Ghadimi et al.10—Supp. 1.

Results

Patient Demographics

Five-hundred thirty patients undergone LVAD implantation (435 durable LVADs) at our institution between January 2014 and June 2017 and were retrospectively analyzed. Prothrombin complex concentrates was used in 27 cases. Low dose PCC was either given at the end of the operation or upon arrival to the ICU (Table 1).

Table 1
Table 1:
Demographic Data and Patient Characteristics

Adverse Events

We monitored the patients for short and long-term survival as well as development of pump thrombosis, CVA, and PE up to 1 year post the surgery and found a statistically significant difference between the groups. Of the 21 patients treated with Durable LVADs and PCCs, there was no pump thrombosis in none of the LVAD pumps, there was however a pump thrombosis in one of the RVADs in these patients. No PE or CVA was detected in any of these patients. Seventeen of 21 patients of this group survived beyond 90 days. However, of the patients treated with short-term LVADs and PCCs, three patients had pump thrombosis events which required extracorporeal pump replacements, two patients developed a PE and none suffered from CVA while being treated with heparin and having a therapeutic partial thromboplastin time the majority of the time; three of six patients survived beyond 90d.

Discussion

Following previous work that showed the safety of vitamin K antagonism reversal and the use of PCC in bleeding LVAD patients,5 we set out to examine whether the risk of thrombosis, following PCC administration, was dependent on the type of LVAD in use and the time of use e.g. immediately post implantation. We were able to demonstrate a statistical difference in pump thrombosis incidence between the cohort groups; while durable LVAD patients suffered no sequala following the use of PCC post implantation, this was not the case in short-term LVADs, with patients suffering from both pump thrombosis as well as PE.

Bleeding post LVAD implantation is a well-known adverse event and is contributed to several factors, ranging from liver dysfunction e.g. synthesis of coagulation factors because of right ventricle overload, anticoagulation treatment as well, and acquired Von-Willibrand syndrome because of mechanical sheer stress similar to Heyde syndrome.6 Thus, novel tools to address postimplantation bleeding are constantly being evaluated. Prothrombin complex concentrates is considered superior to fresh frozen plasma (FFP),2,3 for numerous reasons but also due to the fact that it requires considerably lower volumes than FFP to achieve its effect, which may prevent right ventricular overload. Thus, PCC might prove to be especially suitable to use in LVAD patients, who are at increased risk of right ventricle failure.1

Our study agrees with previous findings on PCC safety of use in cases where warfarin reversal was needed or use due to excessive post-operation bleeding.7–9 However, in our cohort, the patient population that was supported by a short-term LVAD was different, they were younger and usually supported due to an acute event thus making them an Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) 1 profile type of patient; while age was not shown to be a risk factor for thrombosis in the literature, INTERMACS 1 patient profile was.1 Thus, the combination of the previously mentioned patient profile, short-term LVAD and PCC use should be used with caution, pending publications of larger series.

To the best of our knowledge, no study thus far examined the use of PCC in short-term LVADs or the use of PCC at the time of implantation of Heartware or HeartMate III. We conclude that in our patient population the use of low dose PCC did not induce pump thrombosis, CVA, or PE in the durable LVAD cohort. However, we cannot conclude whether the PCC was responsible for the short-term LVAD cohort reported thrombotic complications in the short-term LVAD cohort because of the lack of a control group. Future prospective trials with a larger treatment groups, are warranted in order to further validate the findings of this study.

References

1. Kirklin JK, Pagani FD, Kormos RL, et al. Eighth annual INTERMACS report: Special focus on framing the impact of adverse events. J Heart Lung Transplant 2017.36: 1080–1086
2. John R, Lee S. The biological basis of thrombosis and bleeding in patients with ventricular assist devices. J Cardiovasc Transl Res 2009.2: 63–70
3. Leissinger CA, Blatt PM, Hoots WK, Ewenstein B. Role of prothrombin complex concentrates in reversing warfarin anticoagulation: A review of the literature. Am J Hematol 2008.83: 137–143
4. Song HK, Tibayan FA, Kahl EA, et al. Safety and efficacy of prothrombin complex concentrates for the treatment of coagulopathy after cardiac surgery. J Thorac Cardiovasc Surg 2014.147: 1036–1040
5. Jennings DL, Jacob M, Chopra A, Nemerovski CW, Morgan JA, Lanfear DE. Safety of anticoagulation reversal in patients supported with continuous-flow left ventricular assist devices. ASAIO J 2014.60: 381–384
6. Makris M, Greaves M, Phillips WS, Kitchen S, Rosendaal FR, Preston EF. Emergency oral anticoagulant reversal: The relative efficacy of infusions of fresh frozen plasma and clotting factor concentrate on correction of the coagulopathy. Thromb Haemost 1997.77: 477–480
7. Brown CS, Zemrak WR, Dyer KJ, Rolfe S. Low-dose prothrombin complex concentrate in patients with left ventricular assist devices. ASAIO J 2018 [Epub ahead of print].
8. Rimsans J, Levesque A, Lyons E, et al. Four factor prothrombin complex concentrate for warfarin reversal in patients with left ventricular assist devices. J Thromb Thrombolysis 2018.46: 180–185
9. Bradford CD, Stahovich MJ, Dembitsky WP, Adamson RM, Engelbert JJ, Perreiter AS. Safety of prothombin complex concentrate to control excess bleeding during continuous flow LVAD insertion. ASAIO J 2015.61: 509–513
10. Ghadimi K, Levy JH, Welsby IJ. Perioperative management of the bleeding patient. Br J Anaesth 2016.117(suppl 3): iii18–iii30
Keywords:

left ventricular assist device; pump thrombosis; prothrombin complex concentrates

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