Coagulopathy and transfusion therapy in pediatric liver transplantation

Table 1 Hemostatic differences in the pediatric population

Parameters	Defects	Activity	Time to normalization
Procoagulant factors
Factors II, VII, IX, X (vitamin K-dependent)	↓ quantity	↓	6 mo
Fibrinogen	Dysfunctional	↓	1 yr
Platelet	Hyporesponsiveness	↓	2-4 wk
vWF	↑ quantity/Hyperfunction	↑	/
Factor VIII	↑ quantity	↑	/
Anticoagulant factors
AT-III	↓ quantity/dysfunctional	↓	6 mo
Heparin Cofactor II	↓ quantity	↓	6 mo
TFPI	↓ quantity	↓	6 mo
α2-antiplasmin	↓ quantity	↓	6 mo
α1-antitrypsin	↓ quantity	↓	6 mo
C 1 esterase inhibitor	↓ quantity	↓	6 mo
Protein C	↓ quantity	↓	6 mo
Protein S	↓ quantity	↓	6 mo
α2-macroglobulin	↑ quantity	↑	6 mo

Table 2 Liver transplantation phases and coagulation status

Liver transplantation phases	Coagulation status
Pre-existing coagulation disorders	Developmental hemostasis
	Rebalanced hemostasis in chronic disease
	Unpredictable effect in acute liver failure
Liver transplantation surgery	Coagulopathy of surgical trauma
Pre-anhepatic phase	Surgical challenge
Anhepatic phase	Hyperfibrinolysis (lack tPa clearance)
Reperfusion phase
	Ischemic-reperfusion syndrome
	Heparin-like effect
	tPa release
After liver transplantation surgery	Tendency to thrombotic state (days 1-14 after liver transplantation)
	Recovery of coagulation activity in 1 mo

Table 3 Factors implicated in rebalancing

System	Increases	Decreases
Clotting cascade	Factor VIII	Procoagulation factors V, VII, IX, X, XI, prothrombin
		Vitamin K-dependent procoagulation factors II, VII, IX , X
		Vitamin K-dependent anticoagulation factors protein C and protein S; anticoagulant proteins synthesized by the liver such as protein Z, protein Z-dependent protease inhibitor, antithrombin, heparin cofactor II, and alpha-2-macroglobulin
		Fibrinogen and dysfibrinogenemia
Clot lysis	Tissue plasminogen activator (tPA) (due to enhanced release by the activated endothelium and/or by reduced hepatic clearance)	Plasminogen, antiplasmin (alpha-2 plasmin inhibitor or alpha-2 PI), thrombin-activatable fibrinolysis inhibitor (TAFI), and factor XIII
	Levels of plasminogen activator inhibitor (PAI-1)
Platelet	Plasma von Willebrand factor (vWF; main platelet vessel wall adhesive protein)	Thrombocytopenia and thrombocytopathy (usually from hypersplenism, altered levels of thrombopoietin metabolism, antiplatelet antibodies and defective platelet aggregation)
		ADAMTS-13 (vWF cleaving protease)

Table 4 Reference parameters for Thromboelastogram in healthy and pathologic pediatric populations

Ref.	Type of patient	Age	n	R, min	k, min	Alpha, 0	MA, mm	Lys30, %	Note
Rajwal et al[113]	Healthy	1-15 yr	14	17.4 ± 3.6	7.6 ± 1.4	31.2 ± 4.8	52.6 ± 6.4	0.8 ± 1.0	Native blood
				7.7 ± 2.6	3.1 ± 1.4	55 ± 10.5	57.6 ± 3.7	1.9 ± 1.2	recalcified blood
Pivalizza et al[114]	Healthy	< 13 mo	25	10.1 ± 3.1	2.4 ± 0.5	74.2 ± 3.5	70.2 ± 6.1	3.4 ± 2.9	Celite as activator
		13-24 mo	33	9.8 ± 3.3	2.5 ± 0.6	73.2 ± 3.1	70.2 ± 4.7	2.1 ± 1.3
		25-48 mo	24	10.5 ± 3.0	2.7 ± 0.7	71.2 ± 4.2	68.4 ± 5.2	2.1 ± 1.4
		49 mo-9 yr	29	9.6 ± 2.5	2.8 ± 0.6	72.9 ± 4.2	70.5 ± 3.3	2.0 ± 1.1
Edwards et al[112]	Healthy	Newborn	59	5.3 ± 1.3	1.6 ± 0.4	67.2 ± 4.5	61.8 ± 4.6	0.7 ± 0.7	Cord blood, recalcified blood
		8.7 ± 2.6 yr	44	8.7 ± 2.6	2.1 ± 0.7	61.6 ± 7.1	59.6 ± 4.2	0.2 ± 1.3	Recalcified blood
Chan et al[29]	Healthy	< 1 yr	24	7.7 (4.5-11.6)	1.8 (1.2-2.3)	66.5 (58.8-73.4)	67.2 (60.7-73.2)	3.8 (0.3-8.4)	Mean and 2.5%-97.5%
		1-5 yr	24	8.3 (5.7-10.9)	2.0 (1.4-3.3)	63.6 (53.8-70.3)	65.2 (57.6-71.3)	3.0 (0.2-7.8)
		6-10 yr	26	7.8 (5.3-11.0)	2.0 (1.4-2.8)	63.9 (54.3-70.7)	65.0 (57.3-72.8)	3.3 (0.2-6.2)
		11-16 yr	26	6.9 (3.8-11.1)	1.9 (1.2-2.9)	65.1 (54.9-73.2)	66.5 (56.8-74.4)	3.7 (0.5-8.0)
Brenn et al[115]	Cerebral palsy	15 ± 3 yr	15	4.8 ± 1.0	1.6 ± 0.6	68 ± 8	65 ± 8		Patients undergoing spinal fusion surgery
	Idiopathic scoliosis	14 ± 1.5 yr	15	5.0 ± 0.6	1.3 ± 0.4	71 ± 5	70 ± 4
Kang et al[55]	Cirrhotic undergoing liver transplant	9 mo-7 yr	8	9.6 ± 6.2			46.9 ± 11.5		Baseline
				7.4 ± 2.8			47.3 ± 7.9		Anhepatic phase
				10.1 ± 2.4			46.1 ± 9.7		30' after reperfusion
				9.2 ± 3.2			49.9 ± 8.8		90' after reperfusion

R: Reaction time for the time from placement of blood in the cup until the clot formation; k: Coagulation time, the time between TEG trace elevation from 2 to 20 mm; Alpha: Alpha angle, the slope of the TEG trace describing the kinetics of clot formation; MA: Maximum amplitude as an indicator of clot stability and firmness; Lys30: Clot lysis expressed as an amplitude reduction at 30 min after MA. TEG: Thromboelastogram.

Table 5 Reference parameters for rotational thromboelastogram in healthy and pathologic pediatric populations

Ref.	Type of patient	Age	n	CT, s	CFT, s	MCF, mm	CLI60, %	Note
Strauss et al[28]	Pre-term	Newborn	47	185 (108-357)	80 (52-183)	57 (42-66)		Median (MIN-MAX)
	Full term		184	194 (98-588)	76 (34-208)	60 (39-71)
Oswald et al[111]	Healthy	0-3 mo	51	184 (105-285)	44 (27-88)	66 (54-73)		InTEM median (2.5%-97.5%)
		4-12 mo	55	172 (76-239)	60 (37-100)	63 (52-73)
		13-24 mo	54	161 (99-207)	61 (42-112)	64 (50-72)
		2-5 yr	70	170 (99-239)	60 (40-94)	63 (53-73)
		6-10 yr	79	168 (97-212)	64 (48-93)	62 (53-69)
		11-16 yr	50	171 (128-206)	68 (45-106)	62 (54-71)
		0-3 mo	51	48 (38-65)	57 (30-105)	62 (54-74)	87 (71-94)	ExTEM median (2.5%-97.5%)
		4-12 mo	55	53 (37-77)	72 (44-146)	60 (46-71)	86 (71-95)
		13-24 mo	54	55 (37-73)	75 (46-139)	60 (46-72)	88 (77-94)
		2-5 yr	70	56 (46-97)	72 (41-109)	61 (52-70)	86 (74-93)
		6-10 yr	79	57 (43-74)	77 (49-114)	60 (53-68)	87 (70-97)
		11-16 yr	50	59 (44-91)	81 (53-115)	62 (53-72)	88 (76-94)
Oasthaus et al[116]	Normal	211 ± 116 d	17	177 ± 28	60 ± 21	64 ± 6		InTEM (mean ± SD)
	Acyanotic	134 ± 61 d	17	178 ± 41	70 ± 16	61 ± 4
	Cyanotic	135 ± 132 d	17	194 ± 43	105 ± 68	56 ± 6
	Normal	211 ± 116 d	17	51 ± 6	71 ± 25	62 ± 6	94 ± 2	ExTEM (mean ± SD)
	Acyanotic	134 ± 61 d	17	50 ± 5	88 ± 22	59 ± 6	93 ± 2
	Cyanotic	135 ± 132 d	17	68 ± 40	141 ± 99	54 ± 9	91 ± 4
Haizinger et al[117]	ASA I	0-1 mo	6	179 ± 17	56 ± 23	68 ± 7	91 ± 2	InTEM (mean ± SD)
	ASAIII-IV cardiac		17	332 ± 207	127 ± 184	62 ± 10	93 ± 3
	ASA I	1-3 mo	6	166 ± 25	45 ± 9	69 ± 3	89 ± 2
	ASAIII-IV cardiac		6	257 ± 95	78 ± 47	61 ± 6	91 ± 2
	ASA I	3-6 mo	6	183 ± 22	49 ± 22	67 ± 7	90 ± 3
	ASAIII-IV cardiac		6	187 ± 29	53 ± 11	69 ± 4	94 ± 3
	ASA I	6-12 mo	6	172 ± 11	60 ± 17	63 ± 8	89 ± 2
	ASAIII-IV cardiac		6	196 ± 55	61 ± 11	66 ± 3	92 ± 4
	ASA I	0-1 mo	6	35 ± 12	65 ± 31	65 ± 9	91 ± 2	ExTEM (mean ± SD)
	ASAIII-IV cardiac		17	55 ± 62	119 ± 119	54 ± 10	92 ± 4
	ASA I	1-3 mo	6	35 ± 9	65 ± 12	64 ± 2	90 ± 4
	ASAIII-IV cardiac		6	35 ± 7	98 ± 43	54 ± 7	91 ± 2
	ASA I	3-6 mo	6	33 ± 9	75 ± 33	65 ± 9	89 ± 3
	ASAIII-IV cardiac		6	34 ± 15	79 ± 29	63 ± 5	94 ± 4
	ASA I	6-12 mo	6	45 ± 19	96 ± 39	59 ± 9	89 ± 2
	ASAIII-IV cardiac		6	36 ± 11	85 ± 17	58 ± 5	92 ± 3

CT: Clotting time, “r” time in TEG; CFT: Clot formation time, “k” time in TEG; MCF: Maximum clot firmness, MA in TEG; CLI60: Final clot lysis index at 60 min = LY A60 in TEG; INTEM and EXTEM are two different activated baseline analyses. ROTEM: Rotational thromboelastogram; TEG: Thromboelastogram.

Table 6 Measures to reduce bleeding complications and transfusions during liver transplantation

Surgical phase	Procedure
Pre-operative	Erythropoietin
	Supplemental iron and folic acid
Intraoperative	Low CVP (fluid restriction, phlebotomy, vasopressors, Pringle maneuver)
	Acute intraoperative hemodilution
	Low transfusional trigger
	Drugs (rFVIIa, antifibrinolytics)
	Blood salvage
	Surgical technique
	TEG/ROTEM
Postoperative	Low transfusional trigger
	Minimize blood sampling
	Erythropoietin
	Supplemental iron and folic acid

CVP: Central venous pressure; rFVIIa: Activated recombinant factor VII; TEG: Thromboelastogram; ROTEM: Rotational thromboelastogram.