Perioperative thromboprophylaxis in liver transplant patients

Table 1 Balance of antihemostatic and prohemostatic drivers in the cirrhotic patient

	Anti-hemostatic drivers	Pro-hemostatic drivers
Primary hemostasis	Abnormal platelet function	Elevated vWF
	Thrombocytopenia	Reduced ADAMTS 13
	Decreased production of thrombopoietin	Platelet hyperreactivity
Coagulation	Reduced synthesis of factors II, V, VII, IX, X, and XI	Elevated factor VIII
	Vitamin K deficiency	Reduced anticoagulant protein C, protein S, antithrombin III
	Hypo-dysfibrinogenemia	Procoagulant changes in fibrin structure
Fibrinolysis	Low α2-antiplasmin,	Low plasminogen
	factor XIII, and TAFI	High PAI
	Elevated tPA

vWF: Von Willebrand factor; TAFI: Thrombin-activatable fibrinolysis inhibitor; t-PA: Tissue plasminogen activator; PAI: Plasminogen activator inhibitor; ADAMTS13: A disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13.

Table 2 Different thromboprophylaxis protocols for postoperative arterial and venous thrombosis in liver transplant patients

Authors	Type of study	Drug used	Target population	Number Pts	PVT	HAT	Bleeding	Observations
Blasi 2016[61]	Retrospective study No controls	Enoxaparin not routinely, unless intraoperative. thrombectomy or the patient was under anticoagulant treatment before LT. No thromboprophylaxis if the platelets are under 30 × 109/L.	Adult LT	328	8 (2.4%)	NA	Not reported	5/8 patients with PVT did not receive prophylaxis, and the other 3 received it days after LT or in only a few doses
Kaneko 2005[71]	Prospective study No controls	Dalteparin administration adjusted with reference to the ACT (130-160 s)	Adult Living-donor LT	128	1 PVT (0.78%) and 1 (0.78%) PVT + HAT	2 HAT (1.5%) and 1 HAT + PVT (0.78%)	11 (8.5%) surgical revisions and 8 (6.25%) patients with hemorrhages complications treated conservatively	High hemorrhage complication rate in this series indicates that a lower target ACT range may be preferable in the second post-operative week.
Gad 2016[74]	Retrospective study No controls	Heparin infusion up to 180-200 units/kg/day adjusted with reference to the ACT (target levels, 180-200 s) and/or the aPTT (target levels, 50-70 s).	Adult and pediatric living-donor LT	186	5 (2.3%)	4 HAT (1.8%) 4 HAT and PVT (1.8%)	4 (1.8%)	Pre-LT PVT may deserve more intensive anticoagulation therapy
Sugawara 2002[76]	Prospective study No Controls	LMWH, ATIII, prostaglandin E1 (0.01 g/kg/h) and a protease inhibitor	Adult Living-donor LT	172	4 (2.3%) both PVT + HAT	7 (4.0%)	Not considered	The authors’ strategy against HAT is aimed to correct the imbalance between the coagulation and anticoagulation systems
Mori 2017[80]	Prospective study No controls	Heparin infusion at the dose of 5 U/kg/h during the first week after LT	Adult Living-donor LT	282 total patients; 48 patients with pre-existing PVT; number of patient with thromboprophylaxis not cited	8 (17%)	NA	Not considered	The basic protocol after LDLT does not provide anticoagulant therapy. Only patients with good coagulation (INR) < 1.5 or slow portal flow (velocity < 10 cm/s) and intraoperative portal reconstruction for PVT were administered intravenous heparin. The aim of this study was to determine the risk factors that influence the incidence of DVT/PE and the effectiveness of prophylaxis
Yip 2016[73]	Retrospective case control study	Subcutaneous heparin (5000 U) every 8 h	Adult LT	999 total patients; 288 patients with thromboprophylaxis from 2011	Not considered	Not considered	NA	The aim of this study was to determine the risk factors that influence the incidence of DVT/PE and the effectiveness of prophylaxis
Uchikawa 2009[75]	Prospective case control study	Continuous i.v. Dalteparin infusion administered in the anhepatic phase to maintain the ACT levels from 140 to 150 seconds (Gr.A) vs continuous i.v Dalteparin infusion administered immediately after the operation and adjusted depending on clinical findings (Gr.B)	Adult Living-donor LT	42 total patients (10 vs 32)	0 % in Gr. B 5 (15.6%) in Gr. A	0 % in Gr. B 5 (15.6%) in Gr. A	0% in Gr. B 1 (3.1%) in Gr. A	The study evaluated the advantage of ACT as a reliable tool for bedside monitoring of LMWH anticoagulant effects during and following LDLT
Stange 2003[72]	Retrospective study No controls	UFH 5000 IU over 24 h beginning 6 h postoperatively, for 14 d	Adult Living-donor LT	1192	Not evaluated	14 (1.17%)	3 (0.2%) bleeding episodes not apparently related to UFH	The authors analyzed the incidence, clinical presentation, therapeutic options, and outcome of hepatic artery thrombosis (HAT)
Wolf DC, 1997[77]	Retrospective case control study	81 mg oral aspirin in adult and 40 mg in children from postoperative day 1	Adult and pediatric LT	499 total patients (354 vs 175)	Not evaluated	10 (2.9%) vs 6 (3.6%) in the not treated group	89 (16.8%) gastrointestinal bleeding 66 treated vs 23 not treated patients	The spontaneous or invasive maneuver-related bleeding episodes were more frequent in the treated group
Vivarelli 2007[78]	Retrospective case control study	100 mg aspirin	Adult LT	838 total patients (236 treated vs 592 not treated)	Not evaluated	1/236 (0.4%) treated patients vs 13/592 (2.2%) not treated patients	0%	The aim of this study was to determine the safety and efficacy of aspirin therapy on late HAT
Shay 2013[79]	Retrospective case control study	325 mg aspirin	Adult LT	469 total patients (165 treated vs 304 not treated)	6/304 (2%) not treated patients vs 1/165 patients treated (0.6%)	15/304 patients (4.9%) vs 5/165 (3%) patients overall HAT (early and late) in the control and treated group	Similar bleeding rates between the two groups	The aim of this study was to determine the safety and efficacy of early aspirin therapy on clinical outcomes

LT: Liver transplant; PVT: Portal vein thrombosis; HAT: Hepatic artery thrombosis; ACT: Activated clotting time; aPTT: Activated partial thromboplastin time; DVT: Deep vein thrombosis; PE: Pulmonary embolism; LMWH: Low-molecular-weight heparin; UFH: Unfractionated heparin.

Table 3 Possible conditions warranting thromboprophylaxis in the postoperative period of liver transplant recipients

Living-donor liver transplant and split liver

Surgical difficulties and complex vessel reconstruction

Presurgical portal vein thrombosis

Intraoperative portal or hepatic artery thrombectomy

Hypoplastic portal vein

Jump graft artery reconstruction

Cholestatic recipient diseases and Budd-Chiari disease

Non-alcoholic fatty liver disease/non-alcoholic steatohepatitis

Small or multiple recipient arteries

Low portal or arterial blood flow intraoperatively