Blood conservation strategies in liver transplantation: Past, present, and future

Table 1 Phase-integrated, three-pillar, 9 matrix framework spanning the pre-, intra-, and post-transplant periods

Phase of care	Pillar 1: Red cell mass optimization	Pillar 2: Blood loss minimization	Pillar 3: Anemia tolerance optimization
Pre-transplant	Screen all candidates for anemia early in transplant evaluation. Identify and correct iron, vitamin B12, and folate deficiencies. Treat inflammation- or renal-related anemia where feasible. Avoiding unnecessary pre-transplant transfusions that may increase sensitization and complications	Perform structured bleeding risk assessment (portal hypertension, coagulopathy, thrombocytopenia). Optimize coagulation status without prophylactic plasma or platelet transfusion. Plan surgical and anesthetic strategies anticipating high-risk bleeding	Assess cardiopulmonary reserve and end-organ function. Optimize oxygen delivery (nutrition, respiratory function, cardiac status). Educate the team on restrictive transfusion thresholds
Intra-operative	Avoiding prophylactic or trigger-based transfusion without physiologic indication. Using goal-directed transfusion guided by viscoelastic testing. Preserve autologous red cell mass wherever feasible	Employ meticulous surgical technique and low-CVP anesthesia. Use antifibrinolytics when indicated. Apply viscoelastic coagulation monitoring (TEG/ROTEM) to guide hemostatic therapy. Consider cell salvage where appropriate	Accept lower hemoglobin levels with stable hemodynamics and adequate oxygenation. Maintain normothermia, acid-base balance, and adequate perfusion. Base transfusion decisions on physiologic parameters rather than laboratory values alone
Post-transplant	Support erythropoiesis through nutritional supplementation. Treat ongoing anemia causes (renal dysfunction, inflammation, infection). Minimize phlebotomy-related blood loss	Monitor closely for surgical site bleeding and coagulopathy. Avoid routine correction of abnormal coagulation tests without clinical bleeding. Use targeted hemostatic therapy if bleeding occurs	Follow restrictive transfusion strategies in the ICU and ward. Optimize oxygenation, ventilation, and hemodynamic support. Avoid transfusion-related complications that may impair graft function

CVP: Central venous pressure; ICU: Intensive care unit; TEG: Thromboelastography; ROTEM: Rotational thromboelastometry.

Table 2 Reticulocyte production index integrated approach for anemia

RPI < 2	RPI > 2
Hypoproliferative	Adequate production
Workup:	Look for bleeding/hemolysis
Iron studies, B12/folate	Transfusion strategies
Treat deficiency	Bleeding management
Recheck RPI	Transplant readiness, optimize Hb

RPI = [(HCT/45) × RET%]/maturation time. RPI: Reticulocyte production index; Hb: Hemoglobin; B12: Vitamin B12.

Table 3 Pre-operative phase screening and optimization

Pre LT screening	Optimization
Uniform-anemia threshold (Hb < 13 g/dL)[29-31]	Recent literature supports revising the definition of preoperative anemia for patients undergoing high–blood-loss surgery. Although traditional criteria use sex-specific hemoglobin thresholds, evidence shows that a preoperative hemoglobin level below 13 g/dL is associated with higher transfusion rates, morbidity, and mortality irrespective of sex. Therefore, a hemoglobin cutoff of 13 g/dL is recommended to define preoperative anemia in both men and women in this surgical setting
Serial Hb monitoring to be advised only when indicated[32,33]	Standardized order sets that mandate routine blood draws, despite limited evidence supporting their clinical utility may lead to unnecessary investigations, increased healthcare costs, and iatrogenic blood loss, without demonstrable improvement in patient outcomes or reductions in length of hospital stay therefore, needs to be avoided
Detailed bleeding and transfusion history[34-36]	National blood collection and utilization survey report 2007, indicates that approximately 40%-70% of all red blood cell transfusions occur in surgical patients. Consequently, a thorough understanding of the etiology and clinical impact of anemia, along with available therapeutic strategies, is essential during preoperative assessment and optimization
Iron studies (ferritin, TSAT, serum iron, TIBC)[37-40]	Serum ferritin- Reflects body iron stores. Low in true iron deficiency. Dysregulated iron status (deficiency or overload) correlates with increased post-transplant mortality. TSAT: Percentage of transferrin bound with iron. (< 16%-20%) strong indicator of iron deficiency. Serum iron: Circulating iron bound to transferrin. Decreased in IDA. Varies with inflammation; needs context with TSAT/TIBC. TIBC: Total iron-binding capacity of transferrin. Increases in absolute deficiency
Ferritin with CRP[41]	Serum ferritin to C-reactive protein (SF/CRP) ratio ≤ 6 serves as a straightforward and reliable marker of iron deficiency, even in patients with significant systemic inflammation or comorbid conditions
Reticulocyte index[42]	RPI based algorithm can be followed to treat the anemia
Vitamin B12 and folate levels[43]	Folate and vitamin B12 deficiencies were independently and strongly associated with preoperative anemia, together contributing to nearly one-third of the overall anemia burden. The frequent coexistence of multiple deficiencies, along with considerable variability across surgical populations, highlights the importance of adopting comprehensive but population-tailored diagnostic and supplementation approaches
Renal function tests[44]	Renal dysfunction both pre-existing and post-transplant directly impairs erythropoietin production, iron utilization, and red cell survival, thereby contributing to preoperative and postoperative anemia in OLT patients. The high incidence of post-OLT renal failure, particularly severe renal impairment requiring RRT, limits physiological tolerance to anemia and increases transfusion requirements. PBM strategies that identify renal dysfunction early enable optimization of anemia management (e.g., correction of iron deficiency, avoidance of unnecessary phlebotomy, and judicious transfusion), thereby reducing reliance on allogeneic blood products in a population already vulnerable to anemia
Hepcidin measurement[45,46]	Hepcidin, a key regulator of iron homeostasis synthesized in the liver, is dysregulated in cirrhosis, with elevated levels reflecting inflammation-mediated iron restriction and suppressed levels indicating true iron deficiency due to reduced hepatic synthetic capacity. Evidence demonstrating that low baseline hepcidin reliably identifies iron deficiency and correlates with iron absorption capacity despite inflammatory confounding, is therefore highly applicable to OLT candidates. Measurement of baseline hepcidin may allow differentiation between true iron deficiency and functional iron sequestration, enabling identification of patients likely to benefit from targeted oral or intravenous iron therapy while avoiding ineffective or potentially harmful empirical supplementation
Hypersplenism assessment (imaging + cytopenias)[47,48]	Identifying hypersplenism pretransplant is clinically important. Hypersplenism-related thrombocytopenia contributes to perceived bleeding risk and often prompts prophylactic transfusion, despite limited correlation between platelet count alone and bleeding in cirrhosis. Early recognition allows for individualized planning, including avoidance of unnecessary platelet transfusions, consideration of thrombopoietin receptor agonists in selected patients, and reliance on viscoelastic testing to guide intraoperative hemostatic therapy
Sarcopenia assessment (CT-based)[49,50]	Sarcopenia reflects chronic malnutrition, systemic inflammation, hormonal dysregulation, and reduced physical reserve factors that directly impair tolerance to anemia and surgical stress. Patients with sarcopenia have reduced cardiopulmonary and metabolic reserve, making them less able to compensate for perioperative blood loss or anemia and more likely to require transfusion click or tap here to enter text
Frailty assessment (Liver Frailty Index)[51]	Sarcopenia serves as a marker of frailty and diminished physiologic reserve, both of which are associated with higher postoperative morbidity, prolonged ICU stay, and mortality outcomes that are also independently linked to increased transfusion exposure
Predictive transfusion risk models, other predictors include CTP-A/hemoglobin concentration, INR, and total time of graft ischemia are preoperative variables associated with blood requirements during OLT and in the subsequent days[52-55]	Higher Child-Turcotte-Pugh class, lower hemoglobin concentration, elevated INR, and prolonged total graft ischemia time are linked to increased transfusion needs during surgery and in the early postoperative period. In addition, higher MELD scores, extended cold and warm ischemia times, prior abdominal surgery, and longer operative duration have been identified as independent predictors of intraoperative massive transfusion, commonly defined as the requirement for ten or more units of packed red blood cells. Lower platelet counts and increasing MELD scores particularly driven by elevated INR and bilirubin have also been correlated with greater blood component utilization during OLT, although the overall predictive accuracy of these models remains limited
Measurement of the hepatic venous pressure gradient (HVPG)[56]	Stratification of patients based on HVPG identifies distinct bleeding risk profiles, with lower risk observed in patients with HVPG values below 16 mmHg, substantially higher risk at values ≥ 16 mmHg, and a very high bleeding risk when HVPG reaches or exceeds 20 mmHg. Incorporating HVPG into the pretransplant anaesthetic assessment enables proactive, PBM-aligned perioperative planning click or tap here to enter text

Hb: Hemoglobin; PBM: Patient blood management; TSAT: Transferrin saturation; TIBC: Total iron-binding capacity; CRP: C-reactive protein; SF/CRP: Serum ferritin-to-C-reactive protein ratio; RPI: Reticulocyte production index; IDA: Iron deficiency anemia; OLT: Orthotopic liver transplantation; RRT: Renal replacement therapy; CT: Computed tomography; INR: International normalized ratio; MELD: Model for end-stage liver disease; CTP: Child-Turcotte-Pugh; ICU: Intensive care unit.

Table 4 Traditional and newer methods of coagulation assessment in liver disease and liver transplantation

Assessment method	What It measures?	Key findings	Clinical utility	Major limitations	Ref.
Prothrombin time (PT)	Extrinsic and common pathway clotting factors	Prolonged due to reduced procoagulant factor synthesis	Historically used to assess bleeding risk	Does not account for reduced anticoagulants; poor bleeding predictor	[88,89]
International normalized ratio (INR)	Standardized PT (warfarin-based)	Elevated despite thrombotic risk	Not validated for bleeding risk	Misleading INR	[90-92]
Platelet count	Platelet quantity	Thrombocytopenia common but bleeding unpredictable	Baseline assessment	Does not reflect platelet function	[93]
aPTT	Intrinsic pathway (kaolin-based)	Often prolonged; kaolin-based activation	Screening test	Poor correlation with actual coagulation status	[94]
Fibrinogen (Clauss)	Functional fibrinogen level	May be low, normal, or high depending on disease stage	Guides cryoprecipitate use	Does not detect dysfibrinogenemia	[95]
D-dimer	Fibrin degradation	Often elevated regardless of bleeding	Marker of fibrinolysis	Poor specificity in cirrhosis	[89]
Static plasma-based testing	Traditional labs (combined)	Fail to predict bleeding vs thrombosis	Preoperative screening	Cannot reflect “rebalanced hemostasis”	[96]

aPTT: Activated partial thromboplastin time; D-dimer: Fibrin degradation product D-dimer; Clauss: Clauss method for fibrinogen measurement.

Table 5 Topical and mechanical hemostatic agents

Sub-class	Works on	Feature	Limitation	Ref.
Fibrin-based liquid adhesives: Tisseel, evicel	Broad oozing surfaces, vascular anastomoses, coagulopathic patients	Provide fibrinogen + thrombin: Fibrin clot formation	Air embolism with spray, intravascular thrombosis, viral transmission risk	[130,131]
Fibrin patches/sponges: TachoSil, evarrest, fibrin pad	Severe bleeding, liver resection, cardiac surgery	Adhesive + mechanical scaffold prevents streaming effect	Severe bleeding, liver resection, cardiac surgery	[132-135]
Thrombin-only agents: Human thrombin, bovine thrombin, recombinant thrombin	Adjunct to surgical hemostasis	Converts fibrinogen to fibrin	Immunogenicity, thrombosis, viral risk (plasma-derived)	[13,137]
Flowable gelatin and thrombin: Floseal, surgiflo	Rapid hemostasis across specialties	Mechanical matrix + active clot formation	Swelling, infection, compression injury	[138-141]

Table 6 Topical synthetic hemostatic agents

Sub-class	Works on	Feature	Limitation	Ref.
Cyanoacrylates (Octyl-2, Butyl-2)	Moisture-induced polymerization forming tissue adhesion	Rapid sealant, waterproof, sutureless closure; used for skin wounds and variceal embolization	Embolic risk if intravascular; toxic degradation products; unsuitable for mucosa, joints, avulsed tissue, or vascular anastomoses	[142-144]
Microporous polysaccharide hemospheres	Absorb fluid to concentrate platelets and clotting proteins	Accelerates endogenous clotting; reduces time to hemostasis	Ineffective in severe coagulopathy; limited efficacy in high-pressure bleeding	[145]
PEG hydrogel (CoSeal)	Cross-linked hydrogel sealing tissue planes	Sealant and anti-adhesion barrier; non-exothermic, low inflammation; reduces pericardial adhesions	Swelling may compress adjacent structures; poor adhesion to renal parenchyma	[146]
Glutaraldehyde cross-linked albumin (BioGlue)	Protein cross-linking forming rigid adhesive scaffold	Strong adhesion to tissue and synthetic grafts; useful in vascular/cardiac surgery	Tissue toxicity, stenosis risk; avoided in young patients	[147-149]
Synthetic hemostatic nanomolecules	Cationic interaction enhances platelet aggregation	Rapid hemostasis in experimental liver and trauma models	Predominantly preclinical; limited human safety data	[149-151]

Table 7 External hemostatic dressings

Sub-class	Works by	Feature	Limitation	Ref.
Fibrinogen-based dressings	Direct fibrin clot formation independent of host coagulation	Effective even in hypothermia and coagulopathy; useful for open wounds	Limited availability; biological product considerations	[152]
Zeolite-based dressings (QuikClot®, ACS)	Absorb water to concentrate clotting factors and cells	Rapid hemostasis in trauma; effective in junctional hemorrhage	Exothermic reaction; thermal injury, difficult removal, ineffective in arterial bleeding	[153-155]
Clay-based dressings	Surface charge–mediated activation of intrinsic pathway	Thermally stable; high surface area, ion exchange capability	Variable swelling, material-specific inflammatory risk	[156]
Kaolin-based dressings (QuikClot Combat Gauze®)	Contact activation of intrinsic coagulation (factors XII, XI)	No exothermic injury; strong clinical evidence; standard military use	Limited efficacy in massive arterial bleeding	[157]
Smectite-based dressings (e.g., WoundStat®)	Water absorption and intrinsic pathway activation	High absorption, swelling, and viscosity; effective hemostasis	Severe inflammation, tissue necrosis; difficult removal; withdrawn from use	[158]
Chitin/chitosan-based dressings	Electrostatic interaction with erythrocytes and platelets (coagulation-independent)	Effective in coagulopathy, antimicrobial, biocompatible	Expensive; shellfish allergy concern; requires training for optimal use	[159,160]
Polyelectrolyte complexes (chitosan-based PECs)	Electrostatic polymer interactions accelerating coagulation	Rapid clotting; antimicrobial activity; good tissue compatibility	Largely experimental; limited human clinical data	[161]
Chitosan bandages (HemCon®)	Mechanical sealing and tissue adhesion	Proven antimicrobial properties	Requires hands-on training, adhesion may be difficult in emergencies	[162]