99

Hemostasis and Thrombosis in Major Liver Resection Andrea J. Cross, MBChB1

Saxon J. Connor, MBChB, FRACS1

1 Department of Surgery, Christchurch Hospital, Christchurch,

New Zealand

Address for correspondence Saxon J. Connor, MBChB, FRACS, Department of Surgery, Private Bag 4710, Christchurch Hospital, Christchurch 8001, New Zealand (e-mail: [email protected]).

Abstract Keywords

► liver resection ► hemostasis ► thrombosis

The liver plays an important role in the balance between hemostasis and thrombosis. Hepatic resection, particularly when performed in the presence of underlying parenchymal liver disease, can cause perturbation of this balance. This review summarizes the changes that occur in normal hemostasis and thrombosis before, during, and after nontransplant hepatic resection and, wherever possible, provides strategies for the perioperative management of bleeding and thrombosis.

Hepatic resection has become a routine procedure for the management of resectable primary and selected secondary malignancies of the liver. Early attempts at liver resection were associated with high morbidity and mortality, often secondary to massive intraoperative hemorrhage.1,2 It is now accepted that hepatic resection can be performed safely with contemporary series reporting a 4% incidence of major intraoperative hemorrhage, 12% rate of transfusion, 0.3% incidence of postoperative hemorrhage, and 2% mortality.3 This change in outcome has been due to an increased understanding of the underlying hemodynamics that contribute to hemorrhage during hepatic resection4 and the physiological responses that occur following hepatic resection.5 The aim of this review is to describe the physiological changes that occur in the coagulation system following hepatic resection excluding liver transplantation and provide an overview of the intraoperative interventions that can reduce the risk of hemorrhage during major hepatic resection.

Liver and Normal Hemostasis The balance between hemostasis and thrombosis is achieved via the interplay of procoagulant, anticoagulant, and fibrinolytic processes. While it is beyond the scope of this review to revise the physiology of coagulation in its entirety, the role of the liver in hemostasis is such that it participates in all of the aforementioned phases. The primary contribution of the liver to hemostasis is via the production of proteins, the details of

published online January 15, 2015

Issue Theme Thrombosis and Hemostasis Issues in Critically Ill Patients; Guest Editor, Marcel Levi, MD, PhD.

which are summarized in ►Table 1. In addition to synthetic functions, the reticuloendothelial system of the liver plays an important role in the clearance of activated clotting factors and the by-products of fibrin degradation.9

Preoperative Considerations Obstructive Jaundice In patients being considered for hepatic resection who present with coexisting obstructive jaundice, vitamin K deficiency occurs at a rate of 13 to 18% per day.10 This deficiency is due to the absence of bile in the gastrointestinal tract leading to malabsorption of fat. This results in decreased levels of the vitamin K–dependent factors, namely, the procoagulant factors II, VII, IX, and X and the anticoagulants proteins C, S, and Z, the timing of which is dependent on the relative half-lives of the coagulant factors (►Table 1). Vitamin K deficiency can cause prolongation of prothrombin time (PT) and activated partial thromboplastin time (aPTT), but other screening tests typically remain normal.9 Even so, a study by Çakır et al11 evaluated standard measures of coagulation as well as thromboelastography and platelet function using PFA-100 before and after relief of obstruction in 23 patients with obstructive jaundice mainly due to underlying malignancy. Although PT was prolonged in 56% of patients, this was not associated with an increase in bleeding risk as assessed by these functional assays. In fact, 19 of 23 patients (82%) were actually hypercoagulable on thromboelastography and this persisted after biliary drainage. Furthermore, the coagulation index was

Copyright © 2015 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.

DOI http://dx.doi.org/ 10.1055/s-0034-1398385. ISSN 0094-6176.

This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.

Semin Thromb Hemost 2015;41:99–107.

Hemostasis and Thrombosis in Major Liver Resection

Cross, Connor

Table 1 Proteins synthesized by the liver that function in homeostasis of coagulation Protein

Half-life

Function

• Fibrinogen

100 h

Activated by thrombin to form fibrin

• • • •

65 h 8h 24 h 36 h

Vitamin K–dependent clotting factors

• Factor V

15 h

A cofactor in the activation of thrombin

• Factor VIII

10 h

A cofactor in the activation of Factor X

• Factor XI • Factor XII

45 h 52 h

• Factor XIII

200 h

Stabilization of the fibrin clot

• Protein C

8–14 h (15 minutes if activated)

Vitamin K–dependent; rapidly activated by the binding of thrombomodulin to thrombin (IIa) to inactivate factors Va and VIIIa6

• Protein S

30–42 h

Vitamin K–dependent; a co-factor for the action of protein C7

• Protein Z

48 h

Vitamin K–dependent; interacts with protein Z–dependent protease inhibitor by acting to downregulate Factor Xa8

• Antithrombin III

72 h

Acts to inhibit thrombin

•Alpha-2-antiplasmin

72 h

Acts to inhibit plasmin

• Plasminogen

52 h

Binds to fibrin and tissue plasminogen activator to form plasmin which cleaves fibrin and releases fibrin degradation products

• Thrombopoietin

20–30 h

Regulation of platelet production

• ADAMTS-13

48–72 h

Cleavage of von Willebrand factor, to promote bleeding

Coagulation factors Factor Factor Factor Factor

II VII IX X

Anticoagulants

Fibrinolytic system

Platelet function

correlated with bilirubin such that higher levels of bilirubin were associated with increased hypercoagulability as measured by thromboelastography. This has also been demonstrated in those with obstructive jaundice secondary to benign biliary disease.12,13 It is generally accepted that vitamin K deficiency can be corrected with 10 mg of vitamin K given intravenously over 3 consecutive days and that coagulation factors can be replaced with administration of fresh frozen plasma (FFP).14 Although the intravenous route of vitamin K administration is associated with an increased risk of anaphylaxis, subcutaneous administration can result in inconstant absorption, and vitamin K given intramuscularly can result in major hematoma.14 In addition, in jaundiced patients undergoing major hepatic resection with a future liver remnant of 15 minutes may be tolerated by using hepatic preconditioning (10 minutes ischemia followed by 10 minutes reperfusion) before hepatic transection. Huntington et al35 identified 10 randomized controlled trials using a variety of inflow control techniques and control groups with only 2 of the 10 trials showing a reduction in blood loss in the treatment group. However, the possibility of increased complications in those undergoing inflow occlusion, particularly in those with abnormal hepatic parenchyma,35 was also observed. Thus, despite being widely used, the evidence that this technique

alone reduces blood loss during hepatic resection remains difficult to dissect due to heterogeneity across the trials. Hepatic venous outflow is provided by three hepatic veins which terminate into the inferior vena cava just below the diaphragm and several small caudate veins which terminate directly into the inferior vena cava. It is technically possible to control all venous outflow individually after full mobilization of the liver before parenchymal transection. Although total vascular exclusion (inflow and outflow control) can be performed for complex hepatic resections, this is rarely required for a standard hemihepatectomy as it has been shown to be associated with hemodynamic instability and increased complications particularly pulmonary emboli.41 Many hepatic surgeons would, however, use a selective approach to vascular exclusion when performing anatomical resections. The vascular inflow and outflow of the hemi liver to be resected can be controlled extrahepatically before parenchymal transection such that a demarcation can be seen along the principal plane of the liver (anatomical division between left and right hemi liver). Thus, the parenchymal transection can be performed through a predominantly avascular plane (►Fig. 2). The only remaining blood flow is retrograde flow from the middle hepatic venous tributaries. The evidence to support this being effective in reducing blood loss remains mixed,35 but this may reflect the heterogeneous nature of the trial designs. In terms of parenchymal transection, there are multiple devices and techniques. Sharp transection has long been abandoned in favor of crush-clamp techniques. Recently, hydro and ultrasonic dissection, staplers, ultrasonic sealants, and radiofrequency-assisted hepatic resection have all been proposed. Huntington et al35 concluded that the results remain

Fig. 2. A young trauma victim, who was involved in a high-speed car vs. truck collision, presented cardiovascularly unstable condition and was taken straight to the operating room (OR) for damage control laparotomy. Operative findings were of an isolated injury to right liver with split right lobe such that there was shear injury along the line of right hepatic vein (RHV). Hemorrhage could be controlled only with hemi-Pringle (inflow) to the right lobe (black arrow highlights absence of right portal pedicle). RHV injury was repaired. Injuries were closed and the patient was sent for trauma CT to determine if there were other injuries. Once the patient was warmed, acidosis reversed, and hematology and coagulation had been normalized, the patient returned to OR for right hepatectomy. The images show axial and coronal views of the liver at the level of porta highlighting the effect of inflow control. A clear demarcation can be seen down the line of the principal plane (white dotted line). The right lobe (R) is essentially devascularized allowing transection with minimal blood loss. Seminars in Thrombosis & Hemostasis

Vol. 41

No. 1/2015

This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.

102

Hemostasis and Thrombosis in Major Liver Resection

103

Changes to Normal Hemostasis and Thrombosis following Major Liver Resection Platelets and Their Function Several studies52–56 have evaluated the postoperative changes in platelet count following liver surgery. A small nonclinically significant reduction in platelet count occurs that corresponds to intraoperative blood loss but not residual liver volume.56 The platelet count returns to baseline levels between postoperative days 5 and 7.52,53 Although no studies have analyzed the effect of hepatic resection on platelet function as measured by platelet function analysis, two studies52,53 have analyzed changes to VWF following hepatic resection. Both studies52,53 demonstrated increased VWF in the postoperative period, with levels found up to four times higher than baseline and peaking at day 7.53 Kobayashi et al53 analyzed changes in the protein responsible for the cleavage of VWF, ADAMTS-13 (a disintegrin and metalloprotease with a thrombospondin type 1 motif, member 13, and the ratio of VWF:ADAMTS-13, elevated levels of which have previously been associated with arterial thrombosis.57 It was observed that levels of ADAMTS-13 were significantly lower following liver resection with the overall effect being that the VWF: ADAMTS-13 ratio was significantly elevated, indicative of a tendency toward clotting. Interestingly, in the three patients who developed thrombotic complications (portal vein thrombosis [PVT; n ¼ 1] inferior vena cava thrombosis [n ¼ 1], and cerebral infarction [n ¼ 1]), extremely high ratios of VWF to ADAMTS-13 had been measured before diagnosis.53 Kobayashi et al also found a correlation between lower residual liver volumes and higher VWF to ADAMTS-13 ratios. This indicates that the mechanism behind these changes is not simply loss of synthetic function because of a small residual liver volume. Soluble p-Selectin is a cell adhesion molecule that is active in platelet aggregation; thus, elevated levels lead to a procoagulant state. Bezeaud et al52 measured p-selectin levels following major hepatic resection and found that by the first postoperative day, levels had increased to almost double the preoperative levels and these elevations persisted to the 5th postoperative day. Overall, these changes to platelet function following major hepatectomy indicate a tendency toward clot formation.

Coagulation Studies53,56 looking at changes in PT following major liver resection have shown a prolongation of PT of up to 50% by the first postoperative day that gradually returned toward baseline thereafter. However, it should be noted that the degree of prolongation of PT is related to length of surgery,55 proportion of liver resected,55,56 and intraoperative blood loss.56 When PT is standardized as the INR,52,58 it is seen that there is a corresponding initial elevation on the first postoperative day of up to 1.5. This then gradually declines to return to close to baseline by the 10th postoperative day.58 aPTT levels have not been shown to change appreciably during the postoperative period.53,56 Levels of fibrinogen fall early in the first 24 hours post– liver resection.52,53,58,59 Following this, they increase by Seminars in Thrombosis & Hemostasis

Vol. 41

No. 1/2015

This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.

mixed and can be left to the individual surgeon’s preference. This has been supported by a Cochrane review42 which raised concerns about the possibility of radiofrequency techniques being associated with higher rates of adverse consequences, but otherwise levels of evidence to support superiority of any particular technique was poor. In the event of clinically significant hemorrhage following parenchymal transection, only one of six randomized controlled trials have shown a topical agent to be of benefit.35 In a trial by Koea et al,43 the application of a fibrin pad was shown to reduce intraoperative bleeding by 4 minutes as compared with manual compression with cellulose. The rate of success in those receiving a fibrin pad was 94% compared with 28% in the control group. The effect size was greater for those with abnormal parenchyma. However, caution must be advised with regard to use of modern expanding thrombotic agents, given the reported risk of major venous thrombosis.44 The understanding of a low central venous pressure (CVP) as the key component of reducing blood loss during hepatectomy was dramatically demonstrated by the early studies that first appeared in the English literature in the 1990s. One such example by Rees et al4 showed a reduction in the mean blood loss from 2,613 to 414 mL following the restriction of CVP to less than 5 mm Hg. Correspondingly, a dramatic reduction in transfusion rates, morbidity, and mortality were observed.45–47 This combined with the surgical techniques described earlier is now the standard of care for patients undergoing liver resection. The effect is to lower the retrograde flow of blood from the cava into the intrahepatic veins allowing easy occlusive control in the event of injury or avulsion. Techniques for achieving low CVP include nonoperative techniques such as restrictive approach to intravenous fluid, systemic vasodilators, reduced mechanical ventilation, Trendelenburg position, and epidural analgesia.35 Operative techniques described include infrahepatic caval clamping which, although effective, result in increased risk of pulmonary emboli.48 Whether partial infrahepatic caval clamping49 can achieve the same effect with lower risk of pulmonary emboli remains to be seen. Recently, the introduction of minimally invasive hepatic resection may help reduce blood loss by reducing hepatic venous bleeding through the positive pressure effect of the pneumoperitoneum50; however, the level of evidence remains low with conclusions being based on nine observational studies. Despite low CVP being an accepted standard of care for hepatic resection, a recent Cochrane review38 questioned the quality of evidence for cardiopulmonary interventions to decrease blood loss and subsequent allogenic blood transfusions during hepatic resection. The authors concluded that the level of evidence to support the nonoperative techniques listed earlier was poor. Only hemodilution seemed to reduce the risk of allogeneic transfusion. The authors concluded that there was a high risk of bias among the trials and considerable risk of both types I and II errors suggesting the need for further well-designed trials. It is, however, worth noting that the dramatic improvements in outcomes for patients undergoing hepatic resection achieved by the changes described earlier45–47 mean many hepatic surgeons would lack the equipoise for such trials.51

Cross, Connor

Hemostasis and Thrombosis in Major Liver Resection

Cross, Connor

between 25 and 50% of baseline levels to peak between days 3 and 5.52,53,58,60 Bezeaud et al52 also evaluated levels of proteins C and S and found a 50% reduction in levels of protein C which persisted at the 5th postoperative day and a 25% reduction in protein S which had returned to normal by the 5th postoperative day. The changes in ATIII levels and thrombin-ATIII (TAT) complex levels following liver resection have been well described.52,53,58,59,61 These studies52,58,59,61 demonstrate a reduction of ATIII by between 55 and 75% of baseline levels with nadir by the 2nd or 3rd postoperative day. The two studies that looked at TAT levels52,53 found up to ninefold increases that peaked in the immediate postoperative period and remained elevated beyond the 7th postoperative day. In one of these studies,52 higher concentrations of TAT in the first 48 hours were associated with an increased risk of thrombotic complications. Interestingly, while elevated PT and INR levels are supportive of an early hypocoagulability following liver resection, the changes in levels of fibrinogen, proteins C and S, ATIII and TAT favor a hypercoagulable state. As the INR does not account for changes in these other proteins, such measures may overemphasize hypocoagulation in the early postoperative period.

Fibrinolytic Pathway Alpha-2 antiplasmin (AP) is a potent inhibitor of plasmin and is thus an antifibrinolytic. Changes in AP and plasmin-α 2 antiplasmin (PAP) complexes in 48 patients undergoing partial hepatectomy have been studied.53,61 AP levels decreased slightly then returned to normal, but PAP complex levels were significantly elevated at 4 hours and 1 day following partial hepatectomy but returned to baseline levels by the 14th postoperative day. Meijer et al61 also analyzed changes in plasminogen, the enzyme responsible for fibrinolysis, its activator (tissue plasminogen activator [t-PA]), and its inhibitor (PAI). Plasminogen levels decreased to almost 60% of preoperative levels at day 3 and then slowly trended toward normal: this decrease was presumably due to rapid conversion of plasminogen to plasmin, as these authors also demonstrated a corresponding eightfold increase in concentrations of t-PA. t-PA levels remained elevated, albeit less so, up to 7 days following surgery. However, PAI peaked immediately following surgery then quickly returned to normal levels by the 2nd postoperative day. Overall, these results demonstrate a tendency toward fibrinolysis.

requirements, and the degree of lysis to guide usage of antifibrinolytics.62 While thromboelastography has been used to monitor hemostasis and thrombosis during orthotopic liver transplantation for almost 30 years, the thromboelastographic changes that occur following liver resection have only recently been described. Thromboelastography was compared with standard measures of hemostasis and thrombosis (platelet count, INR, aPTT, and ATIII) at baseline; end of surgery; and on the 1st, 3rd, 5th, and 10th postoperative days in 38 patients who underwent elective hepatectomy, with 50% of patients undergoing major hepatectomy.58 The authors reported that while the standard measures demonstrated early hypocoagulability (elevated INR, low ATIII), thromboelastography showed normocoagulability throughout the postoperative period. This was similar to the findings of Barton et al63 who evaluated thromboelastography in 40 patients undergoing liver resection (90% of whom underwent major hepatectomy) and found that time to clot formation at 5 hours after surgery was significantly shorter (i.e., hypercoagulable), but all other measures demonstrated normal coagulation until 5 days postoperatively. This indicates that the routine measurement of INR following liver resection may be overcalling the degree to which true hypocoagulability is present and this has important implications for the use of VTE prophylaxis.58,63 Furthermore, given that there were both major and minor liver resections undertaken in these studies, it might be beneficial in future studies to standardize thromboelastographic results against the functional future liver remnant to allow any differences in coagulation between these to be appreciated.

Role of Steroids It is thought that inflammation may play a role in complications following liver surgery, including thrombotic events.64–67 A recent meta-analysis67 found that while preoperative steroids were associated with significant reductions in the proinflammatory cytokine interleukin-6, there was only a trend toward fewer postoperative complications. One of these studies found that preoperative methylprednisone might attenuate some of the changes in hemostasis and thrombosis that occur following liver surgery.64 Specifically they found that administration of 500 mg of methylprednisone resulted in significantly higher levels of ATIII, as well as preservation of PT and fibrinogen, thus suggesting amelioration of the tendency toward hypercoagulability and fibrinolysis that can occur following liver surgery.

Postoperative Thrombosis

Thromboelastography

Deep Vein Thrombosis and Pulmonary Embolus

Understanding the total cumulative effect of hepatic resection on the coagulation system has been difficult. Thromboelastography is a point-of-care test that gives combined information regarding platelet function, coagulation, and fibrinolysis. It can thus be used to guide transfusion of specific products such that the clot strength can guide infusion of platelets, and time to clot formation provides information about the need for FFP, addition of heparinase to judge protamine

Because of the aforementioned changes in coagulation parameters, there has been a reticence by liver surgeons to use chemoprophylaxis in patients who had undergone hepatic resection assuming that these abnormalities were protective. However, analysis of data obtained by the American National Surgical Quality Improvement Program found that in 5,651 patients who underwent partial hepatectomy there was an overall rate of VTE of 2.9%, with 1.9% of patients

Seminars in Thrombosis & Hemostasis

Vol. 41

No. 1/2015

This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.

104

Hemostasis and Thrombosis in Major Liver Resection

Portal Vein Thrombosis PVT is an uncommon complication following nontransplant liver surgery. In a series of 5,000 patients undergoing abdominal surgery, 44 (0.9%) developed PVT and of these only 5 had undergone a liver resection.76 When it does occur, it is usually due to inadvertent portal vein injury or because reconstruction was undertaken as part of the resection.77,78 The treatment modality of choice depends on the proximity to surgery and whether anticoagulation can be safely used.

105

Where it cannot, thrombectomy is undertaken, and this has the advantage of allowing visual inspection of the reconstructed portal vein but carries the risk of recurrent thrombosis.78 Treatment with anticoagulants have been shown to achieve complete recanalization at rates of only 30 to 45%,79,80 but lifelong anticoagulation has demonstrated prevention of increasing clot burden.80

Summary The changes within the coagulation system following hepatic resection are complex and the true net effect can be difficult to assess. With increasing availability of complex real-time assessment of the coagulation system, it is becoming clearer that in fact many patients may be hypercoagulable as compared with baseline and in spite of derangement of traditional measures of coagulation suggesting a hypocoagulable state. Hepatic resection can now be performed safely, often with minimal blood loss due to an increased understanding of hepatic vascular hemodynamics and improved surgical techniques.

References 1 Foster JH. Survival after liver resection for cancer. Cancer 1970;

26(3):493–502 2 Ekberg H, Tranberg KG, Andersson R, et al. Determinants of

3

4

5

6 7 8 9 10

11

12

13

survival in liver resection for colorectal secondaries. Br J Surg 1986;73(9):727–731 Zimmitti G, Roses RE, Andreou A, et al. Greater complexity of liver surgery is not associated with an increased incidence of liverrelated complications except for bile leak: an experience with 2,628 consecutive resections. J Gastrointest Surg 2013;17(1): 57–64, discussion 64–65 Rees M, Tekkis PP, Welsh FK, O’Rourke T, John TG. Evaluation of long-term survival after hepatic resection for metastatic colorectal cancer: a multifactorial model of 929 patients. Ann Surg 2008; 247(1):125–135 Siu J, McCall J, Connor S. Systematic review of pathophysiological changes following hepatic resection. HPB (Oxford) 2014;16(5): 407–421 Esmon CT. The protein C pathway. Chest 2003;124(3, Suppl):26S–32S Esmon CT. Coagulation and inflammation. J Endotoxin Res 2003; 9(3):192–198 Vasse M. Protein Z, a protein seeking a pathology. Thromb Haemost 2008;100(4):548–556 Wada H, Usui M, Sakuragawa N. Hemostatic abnormalities and liver diseases. Semin Thromb Hemost 2008;34(8):772–778 Ferland G, Sadowski JA, O’Brien ME. Dietary induced subclinical vitamin K deficiency in normal human subjects. J Clin Invest 1993; 91(4):1761–1768 Çakır T, Cingi A, Yeğen C. Coagulation dynamics and platelet functions in obstructive jaundiced patients. J Gastroenterol Hepatol 2009;24(5):748–751 Ben-Ari Z, Panagou M, Patch D, et al. Hypercoagulability in patients with primary biliary cirrhosis and primary sclerosing cholangitis evaluated by thrombelastography. J Hepatol 1997; 26(3):554–559 Pihusch R, Rank A, Göhring P, Pihusch M, Hiller E, Beuers U. Platelet function rather than plasmatic coagulation explains hypercoagulable state in cholestatic liver disease. J Hepatol 2002;37(5): 548–555 Seminars in Thrombosis & Hemostasis

Vol. 41

No. 1/2015

This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.

developing a DVT and 1.3% a PE.68 Furthermore, the risk of developing VTE increased with the amount of liver resected such that in those who had a segmentectomy, the rate of VTE was 2.1%, compared with 5.8% in those having an extended hepatectomy.68 Despite this, Weiss et al69 recently surveyed American liver surgeons about their VTE prophylaxis use and 16% identified major resection as a factor that would make them less likely to use pharmacological agents. Mechanical strategies of VTE prophylaxis include the use of graduated compression stockings and intermittent pneumatic compression (IPC) devices. Both of these are thought to act by preventing venous distension and thus stasis in the lower limbs.70 In addition, IPC has been shown to increase fibrinolytic activity by increasing t-PA and PAI.71 Meta-analyses of the use of mechanical compression in surgical and medical patients showed that the risk of DVT was reduced by approximately two-thirds72,73 when used alone, or up to 50% when used with pharmacological adjuncts.72 The risk of PE was reduced by 20%.72 However, there are insufficient data in general surgical patients, particularly those undergoing liver surgery, to determine if IPC has an effect on the rates of symptomatic DVT and PE in this cohort.74 While the use of LMWH or low-dose unfractionated heparin for pharmacological VTE prophylaxis has been well established in other forms of abdominal surgery,74 no trials of their use specifically in liver surgery were identified. However, Weiss et al69 recently surveyed American liver surgeons and found that 98% use some form of VTE prophylaxis. Ninety-one percent of respondents used IPC regularly, but there was some variation in the use of pharmacological agents with 39% using LMWH and a further 62% preferring unfractionated heparin. Factors contributing to decreased use of pharmacological agents were elevated postoperative INR, thrombocytopenia, postoperative hepatic insufficiency, and large volumes of intraoperative blood loss.69 Recently, Tzeng et al75 analyzed the National Surgical Quality Improvement Program database and found that 29% of those patients developing VTE following liver resection did so after being discharged from hospital, with a mean time to representation of 14 days postoperatively. Of note, they found that prolonged operation time (>240 minutes), development of intra-abdominal infection, and return to theater as being significantly associated with late development of VTE.75 Thus, these would be indications for prolonged chemoprophylaxis on discharge. Interestingly, only 14% of surgeons surveyed by Weiss et al69 routinely discharged patients on pharmacological prophylaxis; yet, the above data would support consideration for prolonged prophylaxis in certain subgroups.

Cross, Connor

Hemostasis and Thrombosis in Major Liver Resection

Cross, Connor

14 Papadopoulos V, Filippou D, Manolis E, Mimidis K. Haemostasis

15

16

17

18

19

20

21

22

23

24

25

26 27 28

29

30

31

32

33

impairment in patients with obstructive jaundice. J Gastrointestin Liver Dis 2007;16(2):177–186 Kennedy TJ, Yopp A, Qin Y, et al. Role of preoperative biliary drainage of liver remnant prior to extended liver resection for hilar cholangiocarcinoma. HPB (Oxford) 2009;11(5):445–451 Lisman T, Caldwell SH, Burroughs AK, et al; Coagulation in Liver Disease Study Group. Hemostasis and thrombosis in patients with liver disease: the ups and downs. J Hepatol 2010;53(2):362–371 Tripodi A, Salerno F, Chantarangkul V, et al. Evidence of normal thrombin generation in cirrhosis despite abnormal conventional coagulation tests. Hepatology 2005;41(3):553–558 Nuttall GA, Brost BC, Connis RT, et al; American Society of Anesthesiologists Task Force on Perioperative Blood Transfusion and Adjuvant Therapies. Practice guidelines for perioperative blood transfusion and adjuvant therapies: an updated report by the American Society of Anesthesiologists Task Force on Perioperative Blood Transfusion and Adjuvant Therapies. Anesthesiology 2006;105(1):198–208 Lisman T, Leebeek FWG. Hemostatic alterations in liver disease: a review on pathophysiology, clinical consequences, and treatment. Dig Surg 2007;24(4):250–258 Mannucci PM. Abnormal hemostasis tests and bleeding in chronic liver disease: are they related? No. J Thromb Haemost 2006;4(4): 721–723 Massicotte L, Beaulieu D, Thibeault L, et al. Coagulation defects do not predict blood product requirements during liver transplantation. Transplantation 2008;85(7):956–962 O’Shaughnessy DF, Atterbury C, Bolton Maggs P, et al; British Committee for Standards in Haematology, Blood Transfusion Task Force. Guidelines for the use of fresh-frozen plasma, cryoprecipitate and cryosupernatant. Br J Haematol 2004;126(1):11–28 Massicotte L, Lenis S, Thibeault L, Sassine M-P, Seal RF, Roy A. Effect of low central venous pressure and phlebotomy on blood product transfusion requirements during liver transplantations. Liver Transpl 2006;12(1):117–123 Søgaard KK, Horváth-Puhó E, Grønbaek H, Jepsen P, Vilstrup H, Sørensen HT. Risk of venous thromboembolism in patients with liver disease: a nationwide population-based case-control study. Am J Gastroenterol 2009;104(1):96–101 Senzolo M, Sartori MT, Lisman T. Should we give thromboprophylaxis to patients with liver cirrhosis and coagulopathy? HPB (Oxford) 2009;11(6):459–464 Lee AYY, Levine MN. Venous thromboembolism and cancer: risks and outcomes. Circulation 2003;107(23, Suppl 1):I17–I21 Falanga A, Panova-Noeva M, Russo L. Procoagulant mechanisms in tumour cells. Best Pract Res Clin Haematol 2009;22(1):49–60 Falanga A, Marchetti M, Vignoli A. Coagulation and cancer: biological and clinical aspects. J Thromb Haemost 2013;11(2): 223–233 Lyman GH, Khorana AA, Falanga A, et al; American Society of Clinical Oncology. American Society of Clinical Oncology guideline: recommendations for venous thromboembolism prophylaxis and treatment in patients with cancer. J Clin Oncol 2007;25(34): 5490–5505 Srivastava A, Brewer AK, Mauser-Bunschoten EP, et al; Treatment Guidelines Working Group on Behalf of The World Federation Of Hemophilia. Guidelines for the management of hemophilia. Haemophilia 2013;19(1):e1–e47 Kokudo T, Uldry E, Degrauwe S, Demartines N, Halkic N. A successful case of right hepatectomy in a patient with von Willebrand disease. Haemophilia 2014;20(2):e191–e192 Buchanan GS, Rodgers GM, Ware Branch D. The inherited thrombophilias: genetics, epidemiology, and laboratory evaluation. Best Pract Res Clin Obstet Gynaecol 2003;17(3):397–411 Lille S, Blackstone R. Inherited thrombophilias: are they an important risk factor in bariatric and post-bariatric surgery? Bariatric Times 2008; Available at: http://bariatrictimes.com/inherited-

Seminars in Thrombosis & Hemostasis

Vol. 41

No. 1/2015

34

35

36

37

38

39 40

41

42

43

44

45

46

47

48

49

50

51

52 53

thrombophilias-are-they-an-important-risk-factor-in-bariatricand-post-bariatric-surgery/. Accessed January 13, 2015 Kujovich JL. Factor V Leiden Thrombophilia. In: Pagon RA, Adam MP, Ardinger HH, et al. eds. Gene Review, 2010. University of Washington, Seattle (WA). Available online at http://www.ncbi. nlm.nih.gov/books/NBK1368/ Huntington JT, Royall NA, Schmidt CR. Minimizing blood loss during hepatectomy: a literature review. J Surg Oncol 2014; 109(2):81–88 Gurusamy KS, Pamecha V, Sharma D, Davidson BR. Techniques for liver parenchymal transection in liver resection. Cochrane Database Syst Rev 2009;(1):CD006880 Gurusamy KS, Li J, Sharma D, Davidson BR. Pharmacological interventions to decrease blood loss and blood transfusion requirements for liver resection. Cochrane Database Syst Rev 2009; (4):CD008085 Gurusamy KS, Li J, Vaughan J, Sharma D, Davidson BR. Cardiopulmonary interventions to decrease blood loss and blood transfusion requirements for liver resection. Cochrane Database Syst Rev 2012;5(5):CD007338 Strasberg SM, Belghiti J, Clavien PA, et al. The Brisbane 2000 terminology of liver anatomy and resections. HPB 2000;2:333–339 Ishizaki Y, Yoshimoto J, Miwa K, Sugo H, Kawasaki S. Safety of prolonged intermittent pringle maneuver during hepatic resection. Arch Surg 2006;141(7):649–653, discussion 654 Belghiti J, Noun R, Zante E, Ballet T, Sauvanet A. Portal triad clamping or hepatic vascular exclusion for major liver resection. A controlled study. Ann Surg 1996;224(2):155–161 Simillis C, Li T, Vaughan J, Becker LA, Davidson BR, Gurusamy KS. Methods to decrease blood loss during liver resection: a network meta-analysis. Cochrane Database Syst Rev 2014;4(4):CD010683 Koea JB, Batiller J, Patel B, et al. A phase III, randomized, controlled, superiority trial evaluating the fibrin pad versus standard of care in controlling parenchymal bleeding during elective hepatic surgery. HPB (Oxford) 2013;15(1):61–70 Cauchy F, Gaujoux S, Ronot M, et al. Local venous thrombotic risk of an expanding haemostatic agent used during liver resection. World J Surg 2014;38(9):2363–2369 Rees M, Plant G, Wells J, Bygrave S. One hundred and fifty hepatic resections: evolution of technique towards bloodless surgery. Br J Surg 1996;83(11):1526–1529 Cunningham JD, Fong Y, Shriver C, Melendez J, Marx WL, Blumgart LH. One hundred consecutive hepatic resections. Blood loss, transfusion, and operative technique. Arch Surg 1994;129(10):1050–1056 Melendez JA, Arslan V, Fischer ME, et al. Perioperative outcomes of major hepatic resections under low central venous pressure anesthesia: blood loss, blood transfusion, and the risk of postoperative renal dysfunction. J Am Coll Surg 1998;187(6):620–625 Rahbari NN, Koch M, Zimmermann JB, et al. Infrahepatic inferior vena cava clamping for reduction of central venous pressure and blood loss during hepatic resection: a randomized controlled trial. Ann Surg 2011;253(6):1102–1110 Uchiyama K, Ueno M, Ozawa S, et al. Half clamping of the infrahepatic inferior vena cava reduces bleeding during a hepatectomy by decreasing the central venous pressure. Langenbecks Arch Surg 2009;394(2):243–247 Luo L-X, Yu Z-Y, Bai Y-N. Laparoscopic hepatectomy for liver metastases from colorectal cancer: a meta-analysis. J Laparoendosc Adv Surg Tech A 2014;24(4):213–222 Lochan R, Ansari I, Coates R, Robinson SM, White SA. Methods of haemostasis during liver resection—a UK national survey. Dig Surg 2013;30(4-6):375–382 Bezeaud A, Denninger MH, Dondero F, et al. Hypercoagulability after partial liver resection. Thromb Haemost 2007;98(6):1252–1256 Kobayashi S, Yokoyama Y, Matsushita T, et al. Increased von Willebrand Factor to ADAMTS13 ratio as a predictor of thrombotic complications following a major hepatectomy. Arch Surg 2012; 147(10):909–917

This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.

106

Cross, Connor

54 Shontz R, Karuparthy V, Temple R, Brennan TJ. Prevalence and risk

67 Richardson AJ, Laurence JM, Lam VWT. Use of pre-operative

factors predisposing to coagulopathy in patients receiving epidural analgesia for hepatic surgery. Reg Anesth Pain Med 2009;34(4): 308–311 Weinberg L, Scurrah N, Gunning K, McNicol L. Postoperative changes in prothrombin time following hepatic resection: implications for perioperative analgesia. Anaesth Intensive Care 2006; 34(4):438–443 Siniscalchi A, Begliomini B, De Pietri L, et al. Increased prothrombin time and platelet counts in living donor right hepatectomy: implications for epidural anesthesia. Liver Transpl 2004;10(9): 1144–1149 Matsukawa M, Kaikita K, Soejima K, et al. Serial changes in von Willebrand factor-cleaving protease (ADAMTS13) and prognosis after acute myocardial infarction. Am J Cardiol 2007;100(5):758–763 De Pietri L, Montalti R, Begliomini B, et al. Thromboelastographic changes in liver and pancreatic cancer surgery: hypercoagulability, hypocoagulability or normocoagulability? Eur J Anaesthesiol 2010;27(7):608–616 Tapper EB, Tanaka KA, Sarmiento JM. Evaluation of hemostatic factors in patients undergoing major hepatic resection and other major abdominal surgeries. Am Surg 2011;77(9):1188–1193 Giovannini I, Chiarla C, Giuliante F, Vellone M, Nuzzo G. Modulation of plasma fibrinogen levels in acute-phase response after hepatectomy. Clin Chem Lab Med 2004;42(3):261–265 Meijer C, Wiezer MJ, Hack CE, et al. Coagulopathy following major liver resection: the effect of rBPI21 and the role of decreased synthesis of regulating proteins by the liver. Shock 2001;15(4): 261–271 Luddington RJ. Thrombelastography/thromboelastometry. Clin Lab Haematol 2005;27(2):81–90 Barton JS, Riha GM, Differding JA, et al. Coagulopathy after a liver resection: is it over diagnosed and over treated? HPB (Oxford) 2013;15(11):865–871 Pulitanò C, Aldrighetti L, Arru M, et al. Preoperative methylprednisolone administration maintains coagulation homeostasis in patients undergoing liver resection: importance of inflammatory cytokine modulation. Shock 2007;28(4):401–405 Pulitanò C, Aldrighetti L, Arru M, et al. Prospective randomized study of the benefits of preoperative corticosteroid administration on hepatic ischemia-reperfusion injury and cytokine response in patients undergoing hepatic resection. HPB (Oxford) 2007;9(3): 183–189 Neal CP, Mann CD, Garcea G, Briggs CD, Dennison AR, Berry DP. Preoperative systemic inflammation and infectious complications after resection of colorectal liver metastases. Arch Surg 2011; 146(4):471–478

steroids in liver resection: a systematic review and meta-analysis. HPB (Oxford) 2014;16(1):12–19 Tzeng C-WD, Katz MHG, Fleming JB, et al. Risk of venous thromboembolism outweighs post-hepatectomy bleeding complications: analysis of 5651 National Surgical Quality Improvement Program patients. HPB (Oxford) 2012;14(8):506–513 Weiss MJ, Kim Y, Ejaz A, et al. Venous thromboembolic prophylaxis after a hepatic resection: patterns of care among liver surgeons. HPB (Oxford) 2014;16(10):892–898 Morris RJ, Woodcock JP. Evidence-based compression: prevention of stasis and deep vein thrombosis. Ann Surg 2004;239(2):162–171 Comerota AJ, Chouhan V, Harada RN, et al. The fibrinolytic effects of intermittent pneumatic compression: mechanism of enhanced fibrinolysis. Ann Surg 1997;226(3):306–313, discussion 313–314 Roderick P, Ferris G, Wilson K, et al. Towards evidence-based guidelines for the prevention of venous thromboembolism: systematic reviews of mechanical methods, oral anticoagulation, dextran and regional anaesthesia as thromboprophylaxis. Health Technol Assess 2005;9(49):iii–iv, ix–x, 1–78 Urbankova J, Quiroz R, Kucher N, Goldhaber SZ. Intermittent pneumatic compression and deep vein thrombosis prevention. A meta-analysis in postoperative patients. Thromb Haemost 2005; 94(6):1181–1185 Geerts WH, Bergqvist D, Pineo GF, et al; American College of Chest Physicians. Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008;133(6, Suppl):381S–453S Tzeng C-WD, Curley SA, Vauthey JN, Aloia TA. Distinct predictors of pre- versus post-discharge venous thromboembolism after hepatectomy: analysis of 7621 NSQIP patients. HPB (Oxford) 2013; 15(10):773–780 Leonardi MJ, Hollander LL, Pitt HA, et al. Acute Portomesenteric Venous Thrombosis Following Abdominal Surgery: Observe, Anticoagulate or Operate? Conference proceedings for The Society for Surgery of the Alimentary Tract; 2011 Sobhonslidsuk A, Reddy KR. Portal vein thrombosis: a concise review. Am J Gastroenterol 2002;97(3):535–541 Thomas RM, Ahmad SA. Management of acute post-operative portal venous thrombosis. J Gastrointest Surg 2010;14(3):570–577 Plessier A, Darwish-Murad S, Hernandez-Guerra M, et al; European Network for Vascular Disorders of the Liver (EN-Vie). Acute portal vein thrombosis unrelated to cirrhosis: a prospective multicenter follow-up study. Hepatology 2010;51(1):210–218 Amitrano L, Guardascione MA, Scaglione M, et al. Prognostic factors in noncirrhotic patients with splanchnic vein thromboses. Am J Gastroenterol 2007;102(11):2464–2470

55

56

57

58

59

60

61

62 63

64

65

66

68

69

70 71

72

73

74

75

76

77 78 79

80

Seminars in Thrombosis & Hemostasis

Vol. 41

No. 1/2015

107

This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.

Hemostasis and Thrombosis in Major Liver Resection

Copyright of Seminars in Thrombosis & Hemostasis is the property of Thieme Medical Publishing Inc. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.