Ann Thorac Surg 2008;85:1453-1456. doi:10.1016/j.athoracsur.2007.10.039
© 2008 The Society of Thoracic Surgeons
Case Reports
Hemostasis Management in Pediatric Mechanical Circulatory Support
Kerstin Seibel, MDa,
Pascal Berdat, MDb,
Colette Boillat, PhDc,
Bendicht Wagner, MDa,
Zacharias Zachariou, MDc,
Ulf Kessler, MDc,*
a Pediatric Intensive Care Unit, Inselspital, Bern, Switzerland
b Department of Cardiovascular Surgery, Inselspital, Bern, Switzerland
c Department of Pediatric Surgery, Inselspital, Bern, Switzerland
Accepted for publication October 9, 2007.
* Address correspondence to Dr Kessler, Inselspital, University of Medicine, Department of Surgical Pediatrics, Berne, 3010, Switzerland (Email: ulf.kessler{at}insel.ch).
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Abstract
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In a 9-year-old boy, bridging to transplantation was successful with an external biventricular device, the Berlin Heart Excor (Berlin Heart, Berlin, Germany), during a 7-month period. Main long-term complications consisted of infection and hypercoagulability with clotting inside the chambers necessitating six pump exchanges, but without thromboembolic events. This report reviews hemostasis monitoring and management of long-term mechanical circulatory support.
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Introduction
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Despite growing experience with mechanical circulatory support, infection and hemostatic complications remain common.
During insertion and explantation of ventricular assist devices (VADs), bleeding due to multifactorial hypocoagulability is a major problem [1]. While on support, hypercoagulability regularly leads to thrombosis inside the pumps and thromboembolic events [2]. Chronic inflammation, infection, and contact to foreign surfaces play a major role in platelet and coagulation activation [1, 3]. However, even though a combined anticoagulation and antiplatelet regimen is part of the post-implantation routine with most VADs, the risk of thromboembolic events remains generally high [2].
Means for specific coagulation monitoring (including the platelet and plasmatic component in a state of hypocoagulability and hypercoagulability) are barely evaluated to date. Fries and colleagues [4] recently demonstrated the usefulness of modified thromboelastography (TEG) and specific platelet function testing in mechanical circulatory support.
Pump thrombosis within the newly developed Berlin Heart Excor (Berlin Heart, Berlin, Germany) has reportedly been a rarer event compared with former models of circulatory support (eg, the Incor (Berlin Heart), an implantable nonpulsatile flow pump) [5].
This report reviews the hemostatic management including routine plasmatic tests, TEG, and specific platelet function analysis in a child with a Berlin Heart Excor during 7 months. We believe that this is the first report describing early thrombosis of a Berlin Heart, despite full anticoagulation therapy with reduced plasmatic coagulation and suppressed platelet function.
We report a 9-year-old boy requiring mechanical circulatory support for end-stage heart failure due to arrhythmogenic right ventricular dysfunction. In this patient, a biventricular assist device (ie, the Berlin Heart Excor, consisting of two extracorporeal polyurethane blood pumps with heparin coated surfaces) was implanted through a median sternotomy. Inflow and outflow connections lead from each blood chamber to the inlet and outlet cannulas (Fig 1).
Prior to implantation, the patient was in cardiogenic shock with multiorgan dysfunction, including coagulopathy with an international normalized ratio of 2.0 and a fibrinogen level of 1.2 g/L (Dade-Behring Coagulation System [Dade-Behring, Marburg, Germany]), and a platelet count of 84 G/l (Sysmex XT-2000 [Toa Medical Electronics, Kobe, Japan]). Because echocardiography showed right ventricular thrombi, low-dose continuous heparin therapy was introduced 7 days before implantation of the device. At the end of the operation, heparin was reversed with a total dose of 20,000 units of protamine, yielding an activated partial thromboplastin time of 89 seconds. However, due to postoperative intrathoracic hemorrhage, the boy required a re-sternotomy on postoperative day 2, as well as large amounts of fresh frozen plasma, red blood cell transfusions, and platelet transfusions. The bleeding stopped after the second intervention and the causes were considered to be both surgical and nonsurgical. Thereafter, anticoagulation therapy was started with intravenous heparin aiming for an activated partial thromboplastin time level of 60 to 80 seconds. Bleeding from wounds persisted until day 8, and then the chest tubes were able to be removed. Heparin was replaced by oral phenprocoumon with an overlap period of 1 week and additional aspirin since day 18 after implantation. Despite effective anticoagulation with an international normalized ratio above 2.0 and an activated partial thromboplastin time of 125 seconds, there was evidence of extensive thrombus formation inside the pumps after postoperative day 14. According to a modified TEG (RoTEM [Pentapharm, Munich, Germany]) and multiple electrode platelet aggregometry (Multiplate [Dynabyte, Munich, Germany]), platelet aggregation was significantly reduced, but the contribution of fibrinogen to clotting was strongly increased (Fig 2). In accordance, his plasma fibrinogen level was permanently elevated between 5 and 7 g/L since day 7 post-implantation.
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Fig 2. Modified thromboelastography (TEG) (RoTEM [Pentapharm, Munich, Germany]) and multiple electrode platelet aggregometry (MEA) (Multiplate [Dynabyte, Munich, Germany]). (aPTT = activated partial thromboplastin time; INR = international normalized ratio.)
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After initial implantation of the VAD, the boy also suffered from catheter-related sepsis with Staphylococcus epidermidis. He was treated with antibiotics, and the central venous line was removed. However, C-reactive protein (CRP) (Hitachi 917 [Boehringer Mannheim, Mannheim, Germany]) remained between 100 and 230 mg/L for 3 weeks and between 20 and 60 mg/L until the first change of the device 4 weeks post-implantation due to clot formation. Although colonization of the device was detected by positive cultures of S. epidermidis from the pump clots of the first pump exchange and from wound swabs 3 weeks thereafter, ongoing or intermittent bacterial sepsis could not definitely be ruled out. However, regularly repeated blood cultures remained sterile.
One week after the first complete device exchange (both chambers), C-reactive protein level normalized spontaneously. After decrease of serum fibrinogen to values between 2 and 4 mg/L and initiation of dipyridamole as an additional antiplatelet agent, fibrin deposits in the pumps grew slower. Immunohistologic examination showed fibrin as a major component of the clot (not shown). There were no thromboembolic complications. However, another two right pump and two left pump exchanges were required due to ongoing thrombus formation in the outlet, and less markedly in the inlet cannula underneath the polyurethane valve (Fig 3).
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Fig 3. Early visible clot, with the circle shown indicating the growing clot situated at the predilection area below the polyurethane valve.
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After 7 months on circulatory support, the patient finally underwent successful heart transplantation. Perioperative hypocoagulability due to fibrinogen deficiency, as observed in modified thromboelastography, could effectively be corrected with fibrinogen concentrate. There were no further perioperative or postoperative complications, except infections under immunosuppression and bilateral diaphragm paralysis, probably due to mechanical trauma to the phrenic nerve during surgery. The boy was discharged 4 weeks after transplantation. Recovery of diaphragm function on the right occurred; however, function on the left remained poor. Meanwhile, 17 months later he still suffers from mild dyspnea on exertion, but he has resumed most normal activities of daily living.
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Comment
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Despite the growing use of VADs, there is no consensus on perioperative and long-term hemostasis management. Although bleeding and hypocoagulability are the main complications during insertion and explantation of VADs [1, 2], pump thrombosis and infection mandating pump exchange are frequently seen during long-term VAD support [1, 6].
Our observation of pump thrombosis by 4 weeks, and repeated thrombosis after another 5 to 6 weeks, but without thromboembolic complications in a child with Berlin Heart Excor, contradicts reports on other pulsatile VADs in pediatric use (eg, the Thoratec VAD [Thoratec Corp, Pleasonton, CA]) that describe thromboembolism but not pump thrombosis [7, 8]. Dewald and colleagues [1] reported on 1 of 8 patients with a perivalvular thrombus with a Novacor left ventricular assist system (Novacor Division, Baxter Healthcare Corp, Oakland, CA) who died from thromboembolic complication and sepsis, without telling about the interval between implantation and the onset of complications. There is only a low number of reports on long-term experience with the Berlin Heart Excor. The initial results are encouraging, with suspicion on thrombus-related pump dysfunction in 3 of 15 patients, but with absence of visual thrombus deposition in all explanted devices [5]. Thus, besides the quality of surface coating, fluid dynamic factors may mainly contribute to thrombus formation. Perivalvular flow turbulence might trigger thrombus generation, even if polyurethane valves have a lower thrombogenicity than mechanical valves. As observed in the present case, the predilection areas for recurrent thrombosis were located underneath the polyurethane valves of both chambers. Different factors may have contributed to the fact that the patient did not embolize in spite of thrombosis. However, possible interpretations and explanations remain hypothetical.
Platelet activation and a constantly activated inflammatory state and endothelial activation play a pivotal role in the pathophysiology of hypercoagulability in the use of VADs [3]. Even if persistently high levels of fibrinogen have been observed throughout the post-implantation period [3], the role of fibrinogen in thrombosis and failure of assist devices has not been clarified yet.
Recurrent or persistent infection may also contribute to refractoriness to anticoagulation. Biofilm formation, thrombus development, and recurrent bacteremia from other sources facilitate bacterial colonization. In addition, in implant-associated chronic inflammatory states, resolution of chronic infection is very difficult. In the present case, we have observed a continuous state of inflammation, possibly influenced by recurrent infection, elevation of fibrinogen up to 7 g/L, and progressive thrombus formation. Blocking platelet function by cytochalasin in TEG allowed differentiation of the particular contributions of platelets and fibrinogen to clot formation, demonstrating an increased fibrinogen activity in this child.
Because of continuous platelet activation, antiplatelet therapy with aspirin and dipyridamole, in addition to phenprocoumon, has been recommended in adults. In the present pediatric case, only aspirin was used until the first exchange of the pump. However, although platelet aggregation seemed to be completely blocked by aspirin, and aspirin resistance was ruled out by Multiplate analysis, aspirin alone may not be sufficient. The addition of another antiplatelet agent, such as dipyridamole might be helpful to prevent clot formation. However, ongoing pump thrombosis was observed even when dipyridamole was introduced and fibrinogen level decreased to a normal range at the same time. Thus, it remains unclear to which extent platelets or fibrinogens were causative for thrombus formation. Finally, especially in pediatric patients on long-term support, the relation between thrombosis, pump designs, and flow dynamics remains uncertain.
We used thromboelastography, because on the one hand it is a fast and reliable means of whole blood bedside coagulation monitoring, and on the other hand, the manufacturer of the Berlin Heart strongly suggests its use. We believe TEG helped us to differentiate between the contribution of platelets and fibrinogen to clot strength. This report only treats partial aspects of the large field of long-term management of patients on assist devices. Therefore, diagnostic and therapeutic deductions should be drawn with caution.
Clot lysis using recombinant tissue plasminogen activator (rtPA) may be an elegant method to avoid potential morbidity associated with repeated device changes. However, because this procedure bears the risks of thrombus embolization or bleeding and because of our limited experience using recombinant tissue plasminogen activator for clot lysis in VAD patients, we chose not to use recombinant tissue plasminogen activator in this patient.
The present case demonstrates that mechanical circulatory support with an extracorporeal assist device requires extensive coagulation monitoring including TEG and platelet function tests for adjustment of anticoagulation therapy. Development of standardized diagnostic and therapeutic coagulation management protocols (in the use of VADs) and refinements in antithrombotic designs and artificial surfaces of VADs may reduce the necessity of VAD replacements and thrombotic complications in the future.
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Acknowledgments
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The authors thank Sharon Dahl for checking and correcting the English text.
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References
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- Dewald O, Schmitz C, Diem H, et al. Platelet activation markers in patients with heart assist device Artif Organs 2005;29:292-299.[Medline]
- Portner PM, Jansen PG, Oyer PE, Wheeldon DR, Ramasamy N. Improved outcomes with an implantable left ventricular assist system: a multicenter study Ann Thorac Surg 2001;71:205-209.[Abstract/Free Full Text]
- Houel R, Mazoyer E, Boval B, et al. Platelet activation and aggregation profile in prolonged external ventricular support J Thorac Cardiovasc Surg 2004;128:197-202.[Abstract/Free Full Text]
- Fries D, Innerhofer P, Streif W, et al. Coagulation monitoring and management of anticoagulation during cardiac assist device support Ann Thorac Surg 2003;76:1593-1597.[Abstract/Free Full Text]
- Schmid C, Tjan TD, Etz C, et al. First clinical experience with the Incor left ventricular assist device J Heart Lung Transplant 2005;24:1188-1194.[Medline]
- Rothenburger M, Wilhelm MJ, Hammel D, et al. Treatment of thrombus formation associated with the MicroMed DeBakey VAD using recombinant tissue plasminogen activator Circulation 2002;106:I189-I192.[Medline]
- Minami K, Knyphausen E, Suzuki R, et al. Mechanical ventricular circulatory support in children; bad Oeynhausen experience Ann Thorac Cardiovasc Surg 2005;11:307-312.[Medline]
- Reinhartz O, Copeland JG, Farrar DJ. Thoratec ventricular assist devices in children with less than 1.3 m2 of body surface area ASAIO J 2003;49:727-730.[Medline]
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Abstract
Introduction
