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Ann Thorac Surg 2000;69:774-777
© 2000 The Society of Thoracic Surgeons

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Original Articles

Anticoagulative management of patients requiring left ventricular assist device implantation and suffering from heparin-induced thrombocytopenia type II

^a Department of Thoracic and Cardiovascular Surgery, Westfälische Wilhelms-Universität Münster, Münster, Germany
^b Department of Anesthesiology and Operative Intensive Care Medicine, Westfälische Wilhelms-Universität Münster, Münster, Germany
^c Department of Experimental and Clinical Hematology, Westfälische Wilhelms-Universität Münster, Münster, Germany

Address reprint requests to Dr Christiansen, Department of Thoracic and Cardiovascular Surgery, Westfälische Wilhelms-Universität Münster, Albert-Schweitzer-Str 33, 48149 Münster, Germany

	Abstract

Top Abstract Introduction Patients and methods Comment References

 
Background. Heparin-induced thrombocytopenia type II (HIT II) is a rare but life-threatening side effect of heparin therapy. We describe the perioperative anticoagulative management of patients tested positive for HIT II and requiring implantation of a left ventricular assist device (LVAD).

Methods. We report on 3 patients with a different perioperative anticoagulative management (preoperative, intraoperative, and postoperative anticoagulation with danaparoid-sodium; preoperative anticoagulation with recombinant hirudin, anticoagulation with danaparoid-sodium intraoperatively and postoperatively; preoperative anticoagulation with recombinant hirudin, intraoperative anticoagulation with heparin, and postoperative anticoagulation with danaparoid-sodium) and discuss the difficulties of the treatment.

Results. Anticoagulation with alternative drugs such as recombinant hirudin and danaparoid-sodium led to serious and life-threatening bleeding complications as well as to thromboembolic events in the first 2 patients. Therefore the third patient underwent LVAD implantation using heparin for intraoperative anticoagulation to avoid administration of high doses of recombinant hirudin or danaparoid-sodium. Despite very low anti-factor Xa activities, when using danaparoid-sodium postoperatively, the patient suffered from a bleeding complication on the 4th day after LVAD implantation requiring reexploration.

Conclusions. In selected cases (negative heparin-induced platelet aggregation (HIPA) test at the time of LVAD implantation and continuation of postoperative anticoagulation with recombinant hirudin or danaparoid-sodium), heparin may be used for LVAD implantation in HIT II patients to reduce bleeding complications.

	Introduction

Top Abstract Introduction Patients and methods Comment References

 
Thrombocytopenia is a well-known side effect of heparin therapy. Two types can be distinguished, but type II is the more serious one. In general, the incidence is low (0.5%) [1] but may be increased in operative critically ill patients (3%) [2] and may lead to life-threatening thromboembolic complications. Therefore, these patients require an alternative anticoagulative treatment.

There is no consensus about the proper anticoagulative management for patients with heparin-induced thrombocytopenia type II (HIT II) who have to undergo cardiac operation with extracorporeal circulation (ECC). Several options, such as anticoagulation with tedelparin [3], enoxaparin [4], ancrod [5], and prostacyclin analogues such as iloprost [6], have been reported. In addition to these reports there are some clues that danaparoid-sodium (DS) also may be useful in these patients [7–10]. Furthermore, recombinant hirudin (r-hirudin), a new anticoagulant with direct inhibition of thrombin, may be used. Unfortunately, only a few data dealing with the proper management exist [11].

As in patients suffering from HIT II, there is no consensus about the anticoagulative management of patients with left ventricular assist devices (LVAD) [1, 12, 13]; Copeland [14] has the opinion that it remains empirically until now.

We report on our experiences with 3 patients who required LVAD implantation due to end-stage heart failure and suffered from HIT II, and discuss the anticoagulative management.

	Patients and methods

Top Abstract Introduction Patients and methods Comment References

 
Patient 1
A 51-year-old man suffered from an ischemic heart disease, which had led to a high-grade left ventricular dilatation and dysfunction (ejection fraction 18%). The apex of the left ventricle was lined by a thrombus, which had developed under heparin therapy. Because of a drop in platelet counts a heparin-induced platelet aggregation (HIPA) test (Boehringer Mannheim, Mannheim, Germany) was performed and demonstrated antibodies against complexes of heparin and platelet factor 4 (extinction 0.348 after discontinuation of heparin therapy and 0.093 4 weeks later), so that the diagnosis of HIT II was confirmed. DS was used for further anticoagulation, because it was not cross-reacting in the HIPA test. Despite antiarrhythmic therapy the patient suffered from recurrent ventricular tachycardias, which led to a therapy-refractory cardiac decompensation with multiorgan dysfunction, so that an LVAD (Heartmate, Thermo Cardiosystems Inc, Woburn, MA) had to be implanted.

Implantation of the Heartmate LVAD was performed with DS as anticoagulant. Before the ECC was instituted, 8,125 units (U) of DS was administered intravenously and 7,500 U of DS was added to the pump prime. During ECC, 450 U DS/h was administered. This management resulted in antifactor Xa activities of 1.19 ± 0.29 U/mL before institution of ECC and 1.48 ± 0.18 U/mL during ECC. Removal of the left ventricular thrombus required the extension of the ventriculotomy for insertion of the inflow conduit parallel to the course of the left anterior descending coronary artery until the first diagonal branch. After removal of the thrombus, the Heartmate LVAD was implanted using the technique described by Scheld and associates [15]. Before termination of the ECC, appropriate vasodilator and catecholamine therapy were initiated for preservation of right ventricular function. An additional dose of 750 U of DS was administered at the end of the operation. Antifactor Xa activity declined to 0.36 U/mL on the 1st postoperative day and was adjusted with DS to 0.2 to 0.4 U/mL postoperatively. Total postoperative drainage was 2,100 mL. All tubes could be removed until the 3rd postoperative day.

After extubation the patient suffered again from recurrent ventricular tachycardias, which led to a reduction of pump flow, so that a cardioverter defibrillator lead had to be implanted. The lead was inserted using the Seldinger technique through the right subclavian vein and was connected to the external cardioverter defibrillator, which terminated all ventricular tachycardias occurring on the next days. Fifteen days after implantation of the Heartmate LVAD the patient underwent total orthotopic cardiac transplantation, again with DS as anticoagulant. Intravenous administration of 6,000 U of DS and addition of 7,500 U of DS to the pump prime led to an antifactor Xa activity of 1.21 ± 0.03 U/mL intraoperatively. A therapy-refractory right heart failure developed on the 1st postoperative day, so that a reperfusion was started for 3 hours with DS as anticoagulant again. Despite extensive reperfusion, weaning from ECC was not possible and a centrifugal pump (Bio-Medicus, Medtronic Inc, Anaheim, CA) was inserted as a right ventricular assist device through the right atrium and pulmonary artery. Antifactor Xa activities were adjusted to 0.52 ± 0.26 U/mL for the duration of centrifugal pump support. Furthermore, an intraaortic balloon pump (IABP) was implanted to augment myocardial perfusion and continuous venovenous hemofiltration had to be started because of an acute renal failure. Also an ileostomy was necessary for decompression of an acute megacolon. The IABP was removed 2 days later. After recovery of right heart function as assessed by echocardiography, the centrifugal pump was removed on the 6th day after cardiac transplantation. Despite stabilization of the patient’s general condition, he suffered from an acute abdomen once again, which required a second laparotomy on the 12th day after cardiac transplantation. Intraoperatively, thrombosis of the jejunal veins was identified as the cause of partial necrosis of the jejunum. This thrombosis had developed despite effective anticoagulation with DS (antifactor Xa activity 0.34 ± 0.11 U/mL). After jejunal resection, the patient did not recover from multiorgan failure and died on the 27th day after cardiac transplantation.

Patient 2
A 42-year-old woman suffered from a dilatative cardiomyopathy, which was diagnosed for the first time in May 1997 due to a rapid drop in her performance. After three cardiac decompensations, which were managed conservatively, the fourth one was therapy-refractory and led to an impairment of liver and kidney function as well as to a pulmonary congestion, so that an LVAD implantation (Novacor, Baxter Healthcare Corp, Oakland, CA) was necessary.

Because of a positive HIPA test (extinction 0.49 at the time of discontinuation of heparin therapy) anticoagulation was performed preoperatively with r-hirudin. Due to our lack of experience with r-hirudin in cardiac surgery we used DS as anticoagulant for Novacor implantation.

After intravenous administration of 125 U DS/kg of body weight and addition of 5,000 U of DS to the pump prime, antifactor Xa activity was 1.4 U/mL at the time of institution of ECC. Implantation was performed as described by Scheld and associates [15]. Because of a serious postoperative bleeding tendency (drainage loss > 300 mL/h) anticoagulation had to be terminated (antifactor Xa activity < 0.05 U/mL) and the coagulation status normalized. Nevertheless, three reexplorations were necessary on the first 3 postoperative days. The first reexploration revealed that a bleeding branch of the right coronary artery necessitating a suture ligature caused the hemorrhage. The other two reinterventions only showed a marked diffuse hemorrhage, so that the thorax cavity was lined by abdominal pads and the sternum was closed provisionally to improve hemostasis. After the bleeding tendency had decreased and the hemodynamics had stabilized on the 13th day after Novacor implantation, the thorax was closed definitively. Because the patient required prolonged ventilatory support, a tracheostomy was performed 18 days after LVAD implantation. The patient underwent successful weaning from mechanical ventilation 76 days after LVAD implantation. During this time the patient had to undergo another 11 reexplorations due to hemorrhages despite a normalized coagulation status without anticoagulation: three of the device pocket, two after cholecystectomy for cholecystitis, three of the left groin after vasopuncture, and three of the left upper leg due to a hemorrhage of the musculature. Furthermore, temporary continuous venovenous hemofiltration had to be instituted for acute renal failure. Anticoagulation was continued with DS (antifactor Xa activity 0.24 ± 0.09 U/mL) after recovery from all surgical procedures.

The patient is awaiting cardiac transplantation in a satisfying general condition on a normal ward with phenprocoumon as well as acetylsalicylic acid and dipyridamole for anticoagulation. Because of a negative HIPA test (extinction 0.17), the plan is to perform cardiac transplantation with heparin as anticoagulant for ECC and to continue postoperative anticoagulation with DS.

Patient 3
A dilatative cardiomyopathy with high-grade left ventricular dysfunction was diagnosed in a 34-year-old man for the first time in November 1997 and the patient was registered for cardiac transplantation. In May 1998 the left ventricular function deteriorated (ejection fraction 8%) and led to a secondary renal and hepatic malfunction, so that a Novacor LVAD was implanted as a bridge to transplantation.

Six months before Novacor implantation the HIPA test revealed positive results (extinction 1.25) and r-hirudin was used for preoperative anticoagulation. At the time of surgery the HIPA test was negative (extinction 0.19), so we decided to use heparin for anticoagulation (ACT > 400 seconds during ECC) because of the numerous bleeding complications in patient 2 and to continue anticoagulation with DS postoperatively.

Novacor implantation was performed as proposed by Scheld and associates [15]. After transfusion of several blood products bleeding tendency decreased, tubes were removed after a total drainage loss of 1,890 mL, and DS was introduced. Despite very low antifactor Xa activities (< 0.06 U/mL), anticoagulation with DS led to a bleeding complication: a cardiac tamponade required reexploration on the 4th postoperative day and the anticoagulative treatment was stopped immediately. As expected, the HIPA test showed an increase of extinction (0.776) on the 6th postoperative day due to heparin reexposure, but no thromboembolic events occurred. After hemostasis was secured, anticoagulation was started with acetylsalicylic acid and later with dipyridamole. The patient was referred to a normal ward on the 11th postoperative day and was discharged after the anticoagulative management was completed by phenprocoumon. Current follow-up is done on an outpatient basis.

	Comment

Top Abstract Introduction Patients and methods Comment References

 
There has been no consensus about the best anticoagulative management of LVAD patients. Usually heparin is used for anticoagulation intraoperatively and postoperatively. Postoperative anticoagulation is started if there is no longer any bleeding tendency.

In Heartmate LVAD patients postoperative anticoagulation consists of an intravenous heparin therapy and an oral treatment with acetylsalicylic acid and possibly dipyridamole. Heparin therapy is stopped after mobilization of the patient and long-term anticoagulation is done by acetylsalicylic acid and possibly dipyridamole.

As in Heartmate LVAD patients, postoperative anticoagulation in Novacor LVAD patients is done by heparin, acetylsalicylic acid, and possibly dipyridamole. Phenprocoumon and acetylsalicylic acid are used for long-term anticoagulation. Whether dipyridamole has an additional effect on inhibition of platelet aggregation when acetylsalicylic acid is administered has been obscure [14].

Despite all efforts to achieve an effective anticoagulation in LVAD patients, the risk of thromboembolic events is approximately 30% [13, 16]. Reasons are the contact between blood components and the foreign surfaces of the LVAD with activation of the coagulation system, altered rheologic conditions, and different velocities of blood flow besides insufficient anticoagulation and septic complications. Furthermore, thrombus formation may take place within the native heart [17].

In contrast to the Novacor LVAD, the Heartmate LVAD is lined by a textured inner surface, which promotes formation of a neointima. This development starts after 5 days with fibrin deposits on the inner surface which contain erythrocytes, leukocytes, and platelets. On day 13 mononuclear, mesenchymal, and giant cells are observed within a thick fibrin meshwork [18]. This neointima reduces the risk of thromboembolic complications in Heartmate LVAD patients to 2% [16], but nevertheless the coagulation system and fibrinolysis remain activated [16, 19].

All these problems require the most effective anticoagulation without increasing the risk of bleeding complications, especially fatal intracranial hemorrhages. This remains difficult in patients in whom the well-known anticoagulants heparin, phenprocoumon, acetylsalicylic acid, and dipyridamole may be used. The anticoagulative management is much more difficult in patients suffering from HIT II because heparin is contraindicated. Therefore, alternative anticoagulants have to be employed. Different treatment strategies for cardiac operation in HIT II patients are described [3–11], but there is no consensus about the optimal procedure. Furthermore, there are no reports on perioperative anticoagulation for LVAD implantation in patients suffering from HIT II.

The majority of experiences are reported on DS as an alternative anticoagulant in patients undergoing cardiac operation with ECC. However, there is no agreement about the lowest possible antifactor Xa activity suitable for cardiac surgery with ECC without the risk of blood coagulation. In fact, reported antifactor Xa activities during cardiac surgery vary between 0.7 and 2.9 U/mL [7–10]. The manufacturer recommends antifactor Xa activities between 1.5 and 2.0 U/mL for ECC. Furthermore, DS as a heparinoid shows cross-reactions in up to 25%, although it does not contain heparin fragments in contrast to low molecular weight heparins [20]. Today low molecular weight heparins are obsolete in HIT II patients because of cross-reactions in about 90%. The long half-life time of about 25 hours, which is prolonged in patients with an impaired renal function, and the lack of an antagonist are further disadvantages of DS. Also protamine fails to reverse the effects of DS.

Thus, the use of DS is associated with difficulties in avoiding blood coagulation within the ECC and a high incidence of postoperative bleeding complications requiring reexplorations and blood product transfusions [7, 9, 10]. Therefore, DS administration cannot be based on laboratory tests only, but also must be adapted to the patient’s clinical condition. For postoperative anticoagulation antifactor Xa activities ranging from 0.15 to 0.8 U/mL are recommended [1, 9, 20]. Furthermore, use of heparin-coated tubes or transfusion of heparin-containing drugs as well as blood products should be avoided.

Another alternative anticoagulant for heparin is r-hirudin. Advantages of r-hirudin compared with DS are the possibility to eliminate r-hirudin by hemofiltration and the shorter half-time, which is increased in patients with renal insufficiency. The disadvantages of r-hirudin are frequent bleeding complications and lack of experiences in most departments. Blood levels of r-hirudin may be monitored by the activated partial thromboplastin time.

Thus the best anticoagulative management for patients suffering from HIT II and requiring LVAD implantation remains unclear. Our first observations demonstrate that there is no close correlation between measured antifactor Xa activities and the bleeding tendency. On the one hand, patient 1 suffered from a thrombosis of the jejunal veins in which the antifactor Xa activity was 0.34 U/mL. On the other hand, 11 reexplorations were necessary in patient 2, although DS administration was stopped completely (antifactor Xa activities < 0.05 U/mL). Furthermore, the bleeding complication of patient 3 probably was not caused by DS antifactor Xa activities (< 0.06 U/mL). We cannot explain these great differences in detail, but it must be taken into consideration that the whole coagulation system is altered by the contact of blood with foreign surfaces (ECC, LVAD) [16, 19] and that other causes, such as hypertension and release of tissue factor pathway inhibitor by glycosaminoglycans [21], may contribute to hemorrhages.

Normally, heparin is contraindicated in patients with HIT II, but the HIPA test was negative at the time of operation in patient 3 so we decided to use heparin for LVAD implantation and to continue anticoagulation with DS postoperatively. This management was chosen to avoid the serious bleeding complications experienced in patient 2, and due to the consideration that thromboembolic complications may be prevented despite accelerated antibody production because complexes of heparin and platelet factor 4 are already eliminated when these antibodies occur.

In summary, we cannot derive a definite strategy for anticoagulation of patients suffering from HIT II and requiring LVAD implantation from our data because we are reporting on only 3 patients. The decision to perform the LVAD implantation with heparin as anticoagulant in patient 3 was considered carefully and cannot be recommended unreservedly. To avoid serious bleeding complications in cases in which DS or r-hirudin is used for LVAD implantation in patients suffering from HIT II, the following management may be helpful in selected cases. If the HIPA test is negative at the time of LVAD implantation, heparin may be used for the surgical intervention and postoperative anticoagulation continued with DS or r-hirudin. If the HIPA test is positive at the time of surgery, DS or r-hirudin should be used.

	References

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