Imbalance of the coagulation-anticoagulation-fibrinolytic system: Pathogenesis and therapeutic approaches in progressive liver injury

Abstract

The coagulation-anticoagulation-fibrinolysis system is essential for normal hemostasis, and its key components are predominantly synthesized in the liver. During the progression of liver injury, reduced synthesis and increased consumption of coagulation factors occur concurrently, leading to an imbalance between coagulation and anticoagulation, and the establishment of an unstable rebalanced state. At the systemic level, these derangements tend to manifest as a relative hypocoagulable phenotype with elevated bleeding tendency. In contrast, the intrahepatic microcirculation, characterized by tissue factor exposure and sluggish portal perfusion, preferentially promotes local prothrombotic changes and accumulation of coagulation factors, particularly during advanced cirrhotic stages, resulting in a regionally hypercoagulable milieu despite systemic coagulation instability. Combined with the reduced synthesis of anticoagulant factors, these changes may create a prothrombotic, low-flow microenvironment within the intrahepatic and portal venous compartments, which is closely associated with intrahepatic microcirculatory disturbances and portal vein thrombosis. Given the bidirectional interplay between this dynamic imbalance and liver injury progression, a thorough understanding of the underlying regulatory mechanisms and the development of targeted interventions are paramount for mitigating liver injury. To gain deeper insights into the evolution of the coagulation-anticoagulation-fibrinolysis system in the context of advanced chronic liver disease/cirrhosis and portal microcirculatory or thrombotic complications, we searched MEDLINE, PubMed Central, and Bookshelf via PubMed to identify relevant literature on the coagulation-anticoagulation-fibrinolysis system and liver injury, and discuss corresponding therapeutic strategies.

Key Words: Coagulation-anticoagulation-fibrinolysis system; Liver injury; Rebalanced state; Intrahepatic microcirculatory disturbance; Portal vein thrombosis; Coagulopathy; Therapeutic strategies

Core Tip: During the progression of liver injury, an imbalance in the coagulation-anticoagulation-fibrinolysis cascade results in a complex hemostatic state: Systemic hypocoagulability with bleeding tendency vs intrahepatic and portal hypercoagulability with thrombotic risk. This dichotomy drives microcirculatory dysfunction, portal vein thrombosis, and disease aggravation. This review summarizes the dynamics of these changes, their pathological implications, and therapeutic interventions, offering a theoretical backing for the management of liver injury.

INTRODUCTION

The liver synthesizes the vast majority of coagulation, anticoagulation, and fibrinolytic factors; consequently, coagulation dysfunction is a core manifestation of liver injury. Hepatic impairment disrupts the homeostasis of the coagulation-anticoagulation-fibrinolysis system, and the subsequent compensatory regulations lead to the development of an unstable rebalanced state[1]. This regained equilibrium is inherently fragile and intimately correlated with the progression of liver disease[2].

During liver injury, impaired synthetic function leads to decreased levels of most coagulation factors and reduced thrombin generation. This results in a hypocoagulable state in the peripheral circulation, increasing the risk of systemic hemorrhage. Concurrently, due to the reduced synthesis of anticoagulant factors and fibrinogen, coupled with the localized enrichment of coagulation factors and sluggish blood flow within the injured liver, the hepatic parenchyma and portal venous system exhibit a propensity for hypercoagulation[3]. These prothrombotic characteristics not only contribute to intrahepatic microcirculatory disturbances and portal vein thrombosis but also predispose patients to systemic thromboembolic complications. As liver disease progresses, these divergent alterations become amplified: Patients present with an unstable rebalanced coagulation phenotype featured by peripheral hypocoagulability and elevated bleeding risk, whereas the intrahepatic microenvironment shifts toward a progressive hypercoagulable state especially in cirrhosis at advanced ChildPugh stages. However, it is important to note that liver disease progression is a complex process; currently, the precise relationship between the rebalancing of the coagulation-anticoagulation-fibrinolysis system and the advancement of liver injury remains to be fully elucidated.

In this review, we summarize the dynamic changes in this system in the context of advanced chronic liver disease/cirrhosis and portal microcirculatory or thrombotic complications. We aim to provide novel theoretical insights to facilitate the prevention and treatment of advanced liver disease.

PERIPHERAL COAGULATION-ANTICOAGULATION-FIBRINOLYSIS IMBALANCE IN LIVER INJURY

Coagulation system and liver injury

During the blood coagulation process, coagulation factors are sequentially activated by thrombin, which ultimately converts fibrinogen into fibrin. This cascade can be divided into several distinct steps: Initiation via the extrinsic and intrinsic pathways, formation of the prothrombinase complex through the common pathway, activation of thrombin, and subsequent fibrin generation. In patients with liver disease, declining hepatic function leads to reduced synthesis or functional abnormalities of key coagulation factors, namely, factors I, II, V, VII, IX, X, XI, and FXII (coagulation factors are henceforth abbreviated as FI, FII, FV, etc., while activated coagulation factors are designated FVIIa, FXa, etc.).

Extrinsic coagulation pathway: Tissue factor (TF), also known as coagulation FIII, serves as the primary initiator of the extrinsic coagulation pathway. Encoded by the F3 gene, TF is a transmembrane glycoprotein that functions as a receptor for coagulation FVII. The resultant TF-FVIIa complex activates FX, thereby initiating the extrinsic coagulation cascade[4,5]. Under physiological conditions, TF is constitutively expressed in extravascular tissues, such as fibroblasts and smooth muscle cells, but remains absent in intact vascular endothelial cells and circulating blood, thereby preventing pathological thrombosis[6]. However, TF expression can be induced by various stimuli, including endothelial injury, inflammatory cytokines [e.g., tumor necrosis factor-α, interleukin-6 (IL-6)], endotoxins, and oxidative stress[7]. In end-stage liver disease, TF expression is upregulated due to endothelial damage, inflammation, and monocyte activation, thereby promoting the activation of the extrinsic coagulation pathway[8].

Coagulation FVII, also known as proconvertin, is synthesized exclusively in the liver and requires activation to form a complex with TF[9]. As the vitamin K-dependent coagulation factor with the shortest half-life[10], FVII requires γ-carboxylation to achieve full biological activity[11]. In acute and chronic liver diseases, impaired hepatocyte function leads to a significant reduction in FVII synthesis, and vitamin K deficiency results in the production of non-functional des-γ-carboxy FIX; both mechanisms contribute to decreased FVII levels, and the degree of this decline correlates positively with the severity of liver disease[12]. With a half-life of approximately 3-6 hours, FVII reflects liver injury earlier than other coagulation factors such as FII and FX; thus, it is the most sensitive coagulation factor in liver disease, and holds significance for evaluating the severity of hepatic dysfunction and patient prognosis[13].

Ca²⁺, also referred to as FIV, serve as essential cofactors in multiple steps in the coagulation cascade. They participate in the formation and stabilization of the TF-FVIIa complex, activation of prothrombin, conversion of fibrinogen, and platelet activation[14,15]. The liver is responsible for converting vitamin D into 25-hydroxyvitamin D. In severe liver disease, impaired hepatic conversion capacity may lead to marked hypocalcemia (ionized calcium < 1.0 mmol/L), which delays thrombin generation and prolongs prothrombin time (PT)/activated partial thromboplastin time (APTT), thereby contributing to bleeding[16,17]. Consequently, although patients with liver disease may develop calcium metabolism disorders that indirectly affect coagulation, these alterations are not considered a major contributor to bleeding in this population.

Intrinsic coagulation pathway: FXII, also known as the contact factor or Hageman factor, is synthesized primarily by hepatocytes, with additional contributions from megakaryocytes and endothelial cells[18,19]. This serine protease zymogen is a single-chain glycoprotein with a molecular weight of 80 kDa and a half-life of approximately 48-72 hours[20,21]. FXII can be activated via the contact pathway, whereby exposure to negatively charged surfaces or molecules triggers its autoactivation[22]. It can also be activated by proteases such as plasmin and thrombin as well as by surfaces provided by platelets and polymorphonuclear leukocytes[23]. Upon activation, FXIIa converts FXI to FXIa, initiating the intrinsic coagulation pathway and indirectly promoting thrombin generation[24]. FXIIa also activates prekallikrein to generate kallikrein, which in turn catalyzes the conversion of plasminogen into active plasmin. Plasmin degrades abnormally formed fibrin in the body, thereby maintaining the dynamic homeostasis of the coagulation–fibrinolytic system and preventing excessive thrombus formation or worsening bleeding tendency[25,26].

In addition, FXII participates in inflammatory regulation by generating bradykinin via the kallikrein–kinin system, modulating vascular permeability, and recruiting to sites of injury[27]. Studies have shown that FXII plays an important role in the propagation phase of pathological thrombus formation, but is not essential for normal hemostasis[28]. FXII levels are consistently reduced in liver disease[29]. In acute hepatitis, FXII may remain mildly decreased or within the normal range due to the acute-phase response counteracting reduced synthesis. In cirrhosis, diminished hepatic synthetic function leads to a significant reduction in FXII. In liver failure, massive hepatocyte necrosis results in extremely low FXII levels and an increased risk of bleeding[30]. However, despite decreasing FXII levels during the progression of liver injury, the level of FXIIa rises; consequently, the risk of thrombosis may still increase[31].

FXI is also a serine protease zymogen with unique structural and functional characteristics within the coagulation cascade. It plays an important yet non-essential core regulatory role in the intrinsic coagulation pathway, and serves as a key molecule maintaining the initiation and amplification of normal coagulation while preventing bleeding or abnormal thrombosis[32,33]. FXI is primarily synthesized and secreted by hepatic parenchymal cells, classifying it as a typical liver-dependent coagulation factor. It is also synthesized by megakaryocytes and stored in platelet α-granules for on-demand release. This dual synthetic origin endows FXI with more flexible responsiveness in coagulation regulation[34,35]. Compared with most other coagulation factors, FXI has a relatively long half-life of approximately 40-80 hours, and exhibits slower metabolic clearance and greater stability; consequently, it serves as an important indicator of hepatic synthetic function[36]. The activation of FXI proceeds via two complementary pathways that jointly regulate the coagulation process with precision. The traditional contact system–dependent activation pathway involves the activation of FXI by FXIIa during the initiation phase of the intrinsic coagulation cascade. This process requires high-molecular-weight kininogen as a cofactor and a catalytic surface provided by negatively charged substances such as collagen or glass, representing the classic trigger of the intrinsic pathway[29]. In contrast, the thrombin feedback–dependent activation pathway allows thrombin (FIIa) to directly activate FXI. This interaction occurs primarily on the platelet surface and is mediated by the glycoprotein Ib-IX-V complex, establishing a thrombin–FXI positive feedback loop that markedly amplifies localized coagulation and enhances thrombus stability[37]. Plasma FXI levels correlate strongly with hepatic functional status, and serve as a sensitive indicator of coagulation function in patients with liver disease. In acute hepatitis, because hepatocellular injury is usually mild and FXI has a long half-life, the transient reduction in synthesis has a limited impact on plasma levels; consequently, FXI levels typically remain mildly decreased or within the normal range[30]. In cirrhosis, widespread hepatocyte degeneration, necrosis, and fibrosis severely compromise overall hepatic synthetic capacity, leading to a marked reduction in FXI levels[38,39]. In Child-Pugh class C cirrhosis, FXI activity may drop below 30%, and is frequently accompanied by overt coagulation dysfunction. Regrettably, FXI appears not to be responsible for thrombosis and the progression of cirrhosis, and no association was found between low FXI levels and bleeding events[40].

FIX, also known as plasma thromboplastin, is a key component of the intrinsic coagulation pathway. It is primarily synthesized by the liver and classified as a vitamin K–dependent coagulation factor[41]. With a half-life of approximately 1824 hours-intermediate between those of FVII and FII-FIX can be activated to its active form, FIXa, by either FXIa or the TF-FVIIa complex. Subsequently, together with FVIIIa, Ca²⁺, and phospholipids, FIXa forms the tenase complex, which converts FX to FXa and drives the propagation of the coagulation cascade[42]. In patients with cirrhosis or liver failure, extensive hepatocellular damage leads to a marked reduction in FIX synthesis; however, due to its longer half-life compared with FVII, the decline in FIX is less pronounced[43]. In the early stage of acute hepatitis, FIX levels may remain largely normal, but they gradually decrease as hepatocyte necrosis progresses and synthetic capacity declines[44]. Additionally, in cholestatic liver disease, impaired bile excretion causes malabsorption of vitamin K, resulting in the production of abnormal PIVKA-IX and reduced FIX activity[45]. In disseminated intravascular coagulation, widespread microthrombosis leads to massive consumption of FIX, causing a significant reduction in its plasma levels[46].

FVIII, also known as the antihemophilic factor, acts as a key cofactor that accelerates the activation of FX by FIXa and promotes thrombin generation, playing a pivotal role in the intrinsic coagulation pathway[47]. FVIII is synthesized primarily by liver sinusoidal endothelial cells, with minor expression in tissues such as the spleen and lymph nodes, and has a half-life of approximately 8-12 hours[48]. Due to its poor intrinsic stability and susceptibility to proteolytic degradation, FVIII requires non-covalent binding to von Willebrand factor (vWF) to form a stable complex[39,49]. vWF is a plasma multimeric glycoprotein with a molecular weight of approximately 250 kDa that participates in platelet adhesion and coagulation, and plays an essential role in hemostasis. vWF constitutes about 99% of the FVIII–vWF complex, whereas FVIII: C accounts for only 1%. This binding configuration not only protects FVIII from inactivation mediated by activated protein C (APC), but also prevents its premature incorporation into the tenase complex[50]. FVIIIa undergoes rapid inactivation, and its clearance is primarily mediated by the uptake and degradation of the FVIII–vWF complex via low-density lipoprotein receptor-related protein expressed on hepatocytes and vascular endothelial cells[51]. Evidence from a rat model of metabolic dysfunction-associated steatohepatitis indicates that FVIII levels remain normal or mildly elevated during acute liver injury[52]. In acute liver failure, although FVIII levels may rise, the concomitant decline in FV is more pronounced; consequently, the FVIII/FV ratio serves as an important prognostic indicator[53,54]. In cirrhosis, markedly elevated FVIII levels are closely associated with an increased risk of portal vein thrombosis.

Common coagulation pathway: FX, also known as Stuart-Prower factor, is a central zymogen in the coagulation cascade and marks the entry point of the common coagulation pathway. FX is a vitamin K-dependent glycoprotein synthesized by the liver, and has a half-life of approximately 40–60 hours-longer than FVII and FIX, but shorter than FII[55]. FX is activated to FXa via either the intrinsic pathway (FIXa–FVIIIa complex) or the extrinsic pathway (TF-FVIIa complex). Subsequently, FXa assembles with FVa, Ca²⁺, and phospholipids into the prothrombinase complex. The prothrombinase complex can be generated via either the intrinsic or the extrinsic coagulation pathway; however, in vivo studies demonstrated that the extrinsic pathway plays a pivotal initiating role in physiological hemostasis[56]. The prothrombinase complex converts prothrombin (FII) into thrombin (FIIa), which in turn, activates FVIII, FV, FXI, and FXIII, thereby establishing a positive feedback loop that amplifies coagulation[57]. In patients with liver disease, reduced FX levels represent one of the key factors underlying coagulation dysfunction, and hold significant value in assessing disease severity and patient prognosis[38]. In acute liver failure, FX levels can drop markedly within 24-48 hours, often reflecting the extent of hepatocellular necrosis. In cirrhosis patients, persistent FX reduction correlates negatively with Child–Pugh and Model for End-stage Liver Disease (MELD) scores[58]. Decreased FX levels are also observed in primary biliary cholangitis, biliary obstruction, and disseminated intravascular coagulation[59].

FV is synthesized primarily by the liver and serves as a key cofactor in the coagulation cascade, facilitating the conversion of prothrombin (FII) to thrombin and thereby amplifying the coagulation signal[55]. FVa is degraded by APC, which helps prevent excessive thrombus formation[60]. In animal models of severe liver diseases (such as cirrhosis and acute liver failure) or during severe infections, FV synthesis declines markedly, and widespread microthrombosis increases its consumption, leading to reduced thrombin generation and prolongation of PT and APTT. An FV level < 30% serves as a marker of poor prognosis in acute liver failure[61]. Compared with FVII, FV has a longer half-life (12-36 hours), yet it still decreases significantly in end-stage liver disease.

FII, also known as prothrombin, serves as a marker of long-term coagulation disorders in liver disease due to its relatively long half-life of 60-72 hours[59]. FII is a vitamin K-dependent coagulation factor that is synthesized and secreted by hepatocytes[62]; it has the second highest plasma concentration among all coagulation factors, ranking only after fibrinogen (FI). Although coagulation begins slowly, the generation of trace thrombin triggers multiple positive feedback mechanisms that rapidly accelerate the process. Thrombin facilitates fibrinogen-to-fibrin conversion; activates FV, FVIII, FXI, FXIII, and platelets; and promotes further thrombin generation[63]; it also binds thrombomodulin on endothelial cells to APC for anticoagulation and activates thrombin-activatable fibrinolysis inhibitor (TAFI). In liver injury, decreased synthetic capacity and vitamin K metabolic disturbances result in deficient prothrombin secretion and breakdown of hemostatic function[44]. Thus, declining prothrombin levels reflect the severity of liver disease.

FI is typically produced in hepatocytes and directly reflects hepatic synthetic function. It is a key coagulation protein composed of three pairs of different subunits (α, β, γ). Under normal conditions, fibrinogen is cleaved by the protease thrombin to form polymerized fibrin molecules, which promote clot stabilization through the cross-linking of activated platelets[64]. Abnormally low expression of FI impairs blood clot formation and predisposes to bleeding tendency or hemorrhage[65]. However, FI levels do not always decrease in liver disease. In fact, plasma FI levels are elevated in the early stage of disease in most patients with acute hepatitis, and fibrinogen levels may also be increased in patients with mild-to-moderate cirrhosis, as it is an acute-phase reactant. In most patients with chronic liver disease, FI levels are normal or elevated, but decrease in patients with acutely decompensated cirrhosis[66], indicating a predisposition to bleeding tendency or hemorrhage.

FXIII, also known as fibrin-stabilizing factor, is the final step in the coagulation cascade, and its changes in liver disease have significant implications for hemostatic function. FXIII is a tetramer (A₂B₂) composed of two A subunits (FXIII-A) and two B subunits (FXIII-B), of which FXIII-B is mainly synthesized by hepatocytes and serves as a carrier protein. After being activated by thrombin, FXIIIa exhibits transglutaminase activity, and can catalyze the crosslinking and polymerization of fibrin monomers to form a fibrin network[67]. In summary, FXIII plays a role in stabilizing fibrin clots, enhancing antifibrinolytic capacity, and promoting wound healing. In liver disease, FXIII consistently decreases in parallel with FXII, and the extent of its decline becomes more pronounced as the liver disease progresses[30].

Anticoagulation system and liver injury

Under physiological conditions, the coagulation and anticoagulation systems maintain a state of dynamic equilibrium. The anticoagulation system consists of three categories of physiological anticoagulants: Serine protease inhibitors, the protein C (PC) system, and tissue factor pathway inhibitor (TFPI).

Serine protease inhibitor family: Serine protease inhibitors mainly include antithrombin (AT), heparin cofactor II (HCII), and protein C inhibitor. Synthesized primarily by hepatocytes, AT regulates the proteolytic activity of procoagulant enzymes in both the intrinsic and extrinsic pathways. Due to its relatively short half-life of approximately 2.5 days, AT serves as a sensitive indicator of early coagulation abnormalities in liver disease[68,69]. Deficiency of AT is a common cause of venous thrombosis[70,71]. AT, a single-chain glycoprotein, is the principal plasma serine protease inhibitor, circulating at concentrations of 150–350 mg/L; it primarily inhibits FIIa, FIXa, FXa, FXIa, and FXIIa, with FXa being its main target[72]. In cirrhotic portal hypertension, blood stasis and endothelial injury activate coagulation; however, massive consumption of AT to neutralize FIIa and FXa, along with impaired synthesis due to hepatocellular damage, leads to a significant reduction in AT levels and predisposes patients to a hypercoagulable state. Thus, AT activity is an independent factor influencing the prognosis of patients with severe liver disease[73]. Studies have found that AT levels decrease progressively with the severity of liver disease, being significantly lower in patients with advanced cirrhosis or acute-on-chronic liver failure than in those with uncomplicated chronic hepatitis B[74,75]. Beyond its fundamental anticoagulant function, AT can bind to heparan sulfate proteoglycans (HSPGs) on vascular endothelial cells to trigger potent anti-inflammatory signaling responses, thereby inducing prostacyclin synthesis[76]. However, when liver disease is complicated by infection, inflammatory cytokines (such as IL-6) promote coagulation activation, leading to further AT consumption[77]. Furthermore, following proteolytic cleavage by coagulation proteases and/or spontaneous conversion to a latent conformation, AT loses its anti-inflammatory activity as well as its high-affinity interactions with heparin and HSPGs[78,79]. However, the low-affinity heparin conformational isomers of AT can still bind specific HSPGs via unknown mechanisms, thereby triggering potent pro-apoptotic and anti-angiogenic activities[76]. Additionally, protein glycosylation disorders in liver disease may lead to structural abnormalities in AT, resulting in reduced heparin-binding affinity and attenuated anticoagulant efficacy[80]. In conclusion, as liver disease advances, the decline in AT levels may exacerbate the hypercoagulable state.

HCII is synthesized primarily in the liver, with very low expression levels in other tissues[81]. In normal human plasma, HCII concentrations range from 70-130 g/L, and its half-life is approximately 2-3 days. Unlike AT, which possesses distinct reactivity toward various thrombotic targets, HCII specifically inhibits the proteolytic activity of thrombin, upon activation by heparin or dermatan sulfate. HCII is also known by several alternative names, including AT BM (reflecting its “moderate” binding to heparin), dermatan sulfate cofactor, and human Leuserpin-2 (owing to the unique leucine residue at the P1 position of the reactive site). Similar to other serine protease inhibitors, HCII consists of nine helices (A–I), three β-sheets (A–C), and a reactive center loop. While the basic structure of serine protease inhibitors contains approximately 400 amino acids, certain members may possess additional N-terminal, C-terminal, or internal insertion loops[82]. The inhibitory mechanism of serine protease inhibitors arises from their specific structural arrangement[83,84]. In its native conformation, a serine protease inhibitor does not adopt the most thermodynamically favorable conformation. Upon encountering its target protease, the scissile bond within the reactive center loop of the serine protease inhibitor is cleaved, forming a covalent complex with the protease. The protease is subsequently translocated to the opposite pole, converting the serine protease inhibitor to its lowest thermodynamic state and resulting in the inactivation of both the inhibitor and the target protease[85,86]. Although HCII contains all the standard serine protease inhibitor domains and inhibits proteases as described above, it possesses several unique features that distinguish it from other serine protease inhibitors and influence the specificity and activity of its cofactor binding.

HCII, AT, and several other thrombin-inhibiting serine protease inhibitors require cofactors to achieve physiologically relevant rates of inhibition[87]. HCII, AT, and certain other serpins utilize glycosaminoglycans (GAGs)-unbranched, sulfated polysaccharide chains composed of repeating disaccharide units-to enhance their protease inhibition efficiency[81]. Although both HCII and AT can be activated by the GAGs heparin and heparan sulfate, HCII is unique among serine protease inhibitors in its ability to employ dermatan sulfate as a cofactor[88]. In addition to heparin, heparan sulfate, and dermatan sulfate, several other polyanions-such as polysulfates, polyphosphates, and polycarboxylates-can accelerate the inhibitory effect of HCII on thrombin. In vitro, GAGs facilitate the inhibition mediated by both AT and HCII. During the progression of liver disease, declining hepatic synthetic function leads to reductions in AT and HCII levels, resulting in inadequate thrombin inhibition and a potential risk of microthrombosis[30].

Protein C system: The PC system plays a pivotal role in anticoagulation, and comprises PC, protein S (PS), and thrombomodulin. Alongside AT, PC is one of the two major anticoagulant factors. Both PC and PS are vitamin K–dependent natural anticoagulant proteins synthesized primarily by the liver, and serve a central function in maintaining the coagulation–anticoagulation balance[89]. PC exists in plasma as a zymogen. Upon dissociation from sites of injury, thrombin binds to thrombomodulin on normal vascular endothelial cells, thereby activating PC and establishing the thrombin-thrombomodulin–PC system[90]. APC proteolytically inactivates FVIIIa and FVa, and suppresses the activation of FX and prothrombin, thereby preventing the coagulation process from spreading to adjacent normal vascular regions[91]. PS acts as a cofactor for APC, dramatically enhancing the latter’s ability to inactivate FVIIIa and FVa[92]. In liver parenchymal injuries such as cirrhosis and liver failure, the synthesis of PC and PS declines due to impaired hepatic function, with the magnitude of reduction correlating with the severity of liver disease. PC/PS activities decrease progressively with the severity of liver disease; in patients with Child–Pugh class C, these activities may drop to only 20%-40% of normal values[93]. During cirrhosis-associated portal vein thrombosis or sepsis, PC and PS are massively consumed owing to their role in suppressing thrombin generation. In liver disease complicated by cholestasis or malnutrition, vitamin K deficiency leads to insufficient γ-carboxylation of PC and PS, thereby impairing their functional activity. Given that FVIIIa and FVa serve as rate-limiting factors for FX and prothrombin activation, the inactivation of FVIIIa and FVa by PC constitutes a key mechanism of its anticoagulant effect[94,95]. The thrombin–thrombomodulin complex also activates TAFI, thereby modulating the fibrinolytic balance[90]. Consequently, reduced synthesis and/or functional abnormalities of PC, PS, and thrombomodulin may disrupt the rebalanced hemostatic state in liver disease, thereby exacerbating the disease progression.

TFPI: TFPI, synthesized primarily by vascular endothelial cells, megakaryocytes, and platelets, is a key regulator of the extrinsic coagulation pathway. By binding to and inhibiting FXa, TFPI not only blocks the activity of the extrinsic coagulation pathway (i.e., TF–FVIIa–FXa complex) and the prothrombinase complex (composed of FXa, FVa, and Ca²⁺), but also indirectly modulates the function of the downstream prothrombinase complex (FXa-FVa), ultimately suppressing thrombin generation. Additionally, spliced TFPI isoforms (α, β, and δ) are expressed by vascular and extravascular cells, where they regulate thrombosis and hemostasis as well as the cellular signaling of TF complexes via protease-activated receptors. The proteolytic processing of TFPI plays a significant role in modulating the physiological functions of the extrinsic coagulation pathway in host defense and hemostasis[96]. Human TFPI consists of a peptide chain containing three Kunitz-type domains. Its structure comprises an N-terminal acidic region followed by three tandem Kunitz-type protease inhibitor domains-designated Kunitz domain 1 (K1), Kunitz domain 2 (K2), and Kunitz domain 3 (K3)-and a highly basic C-terminal region[97]. The TFPI family comprises two members: TFPI-1 and TFPI-2. Emerging evidence indicates that, beyond their established roles in coagulation, TFPI-1 and TFPI-2 are also involved in angiogenesis, cancer progression, host defense against pathogens, and innate immunity[98]. Although structurally similar to TFPI-1, TFPI-2 functions as a weak inhibitor of the TF/FVIIa complex. The unique role of TFPI at the initiation phase of the extrinsic coagulation pathway has been well established[99]. Although the precise contribution of TFPI to hemostasis remains controversial, it undoubtedly plays a central and highly effective role in downregulating coagulation. Initially, in response to vascular injury, TF binds to FVII in a 1:1 stoichiometric complex in the presence of Ca²⁺, prompting the auto-cleavage of FVII into FVIIa within the resultant TF–FVII/FVIIa complex. The TF-FVIIa complex subsequently activates FIX and FX to FIXa and FXa, respectively[100]. TFPI then inactivates the TF-FVII/FVIIa complex in an FXa-dependent manner, thereby blocking the early stages of the plasma coagulation cascade[101]. Notably, the extrinsic tenase complex (TF-FVIIa-Ca²⁺) can directly activate FVIII in conjunction with nascent FXa, counteracting the inhibitory control exerted by TFPI. Consequently, TFPI-mediated inhibition of the TF-FVIIa complex ensures that minor procoagulant stimuli do not trigger uncontrolled thrombin generation[96]. Initially, TFPI interacts with activated FXa to form a TFPI–FXa complex. This complex then engages the TF-FVIIa complex via the K1 domain of TFPI, resulting in the formation of an inactive quaternary complex (TF-FVIIa-FXa-TFPI)[102]. The formation of this quaternary complex ultimately inhibits the activation of FX catalyzed by the TF-FVIIa complex. Within the coagulation initiation pathway, nascent FXa generated by TF-FVIIa can transiently evade the slow inhibition by TFPI and specifically activate FVIII via FV[103]. PS acts as a cofactor for TFPI. Upon binding to the quaternary complex, PS localizes TFPI to the phospholipid membrane surface, facilitating the interaction between the K2 domain of TFPI and the serine protease domain of FXa, thereby enhancing the inhibitory function of K2.

Fibrinolytic system and liver injury

The fibrinolytic system plays a pivotal physiological role in maintaining vascular patency through the degradation of fibrin, the core structural component of thrombi. Given its central position in hemostatic regulation, key enzymes within this system have emerged as actionable targets for pharmacological intervention across a spectrum of disorders. Notably, Wang et al[104] exploited a plasmin-responsive release system to achieve site-specific delivery of an antifibrinolytic agent to hemorrhagic foci in intracerebral hemorrhage, thereby demonstrating the translational potential of targeting fibrinolytic activity in the management of hemorrhagic disorders. This system consists of plasminogen, plasminogen activators, plasmin, and fibrinolytic inhibitors, operating under multi-level fine-tuned regulation[105,106]. The initiation of fibrinolysis depends on the conversion of plasminogen to plasmin by plasminogen activators. Plasmin then degrades fibrin and destabilizes clots, ultimately producing d-dimer and fibrin/fibrinogen degradation products. Fibrinolytic inhibitors prevent excessive fibrinolysis.

Plasminogen, plasmin, and plasminogen activators: Plasminogen is a central precursor protein in the fibrinolytic system, playing a pivotal role in maintaining vascular patency, tissue repair, and immune regulation[107,108]. Synthesized primarily by the liver, plasminogen circulates at plasma concentrations of 60-250 g/L, with a half-life of approximately 2.2 days[109]. Structurally, it contains five “kringle domains” that mediate binding to fibrin and cell surface receptors (such as annexin A2)[110,111].

Plasmin is the central effector protease of the fibrinolytic system, generated by the activation of hepatic-derived plasminogen via tissue-type plasminogen activator (t-PA) or urokinase-type plasminogen activator (u-PA). Its primary function is to degrade fibrin clots, thereby dissolving thrombi and maintaining vascular patency; it also plays a key role in physiological processes such as tissue remodeling and wound healing[112]. The activity of plasmin is subject to precise regulation by its inhibitors, primarily α₂-antiplasmin and other fibrinolytic inhibitors, ensuring the maintenance of a dynamic equilibrium between hemostasis and fibrinolysis[113]. In liver disease, the presence of plasmin may contribute to the paradoxical coexistence of thrombosis and hemorrhage. On the one hand, as liver disease progresses, the declining hepatic synthesis of plasminogen theoretically weakens fibrinolytic potential, predisposing to localized thrombus formation; on the other hand, the more prominent clinical issue is often secondary hyperfibrinolysis[114]. The liver synthesizes various fibrinolytic inhibitors, including TAFI and α₂-antiplasmin; as liver function deteriorates, the levels of these inhibitors decrease significantly, attenuating the negative regulation of plasmin. Furthermore, impaired hepatic clearance of t-PA results in relatively elevated t-PA levels, further promoting plasmin generation. This imbalance leads to uncontrolled plasmin activity and excessive fibrin degradation, representing a key mechanism underlying the bleeding diathesis in patients with liver disease. However, while hyperfibrinolysis precipitates hemorrhage, it may also indirectly promote sustained thrombin generation by lysing newly formed, unstable microthrombi, thereby establishing a vicious cycle. Consequently, the imbalance of the fibrinolytic system constitutes one of the core links in the pathogenesis of coagulation dysfunction in liver disease, and balancing the risks of thrombosis and hemorrhage remains a formidable challenge[115].

Plasminogen activators comprise t-PA and u-PA. t-PA is synthesized and stored in vascular endothelial cells, and released upon stimulation by stress, thrombin, or hemodynamic shear stress, with its activity regulated by plasminogen activator inhibitor-1 (PAI-1). t-PA preferentially activates fibrin-bound plasminogen, enhancing its efficiency by approximately 1000-fold to ensure localized fibrinolysis. In patients with severe liver disease, the synthesis of fibrinolytic inhibitors and their inhibitory capacity are reduced, while the clearance of activated t-PA is significantly impaired. This leads to the disruption of coagulation and anticoagulation mechanisms, resulting in an imbalance that favors a hypercoagulable state, thereby contributing to the formation of portal vein thrombosis and microcirculatory dysfunction. u-PA is secreted by renal tubular epithelial cells, monocytes, and other cell types, and exists primarily as a single-chain precursor known as pro-u-PA[116]. u-PA is involved in cellular migration processes, such as wound repair and tumor metastasis, and facilitates the activation of cell surface–bound plasminogen via the u-PA receptor[117].

Fibrinolytic inhibitors: Fibrinolytic inhibitors are key regulatory factors that maintain the dynamic equilibrium between fibrinolysis and coagulation. By suppressing plasminogen activation or neutralizing plasmin activity, they prevent the bleeding risk associated with excessive fibrinolysis. Major members of this system include α₂-antiplasmin, PAI-1, and TAFI[118].

α₂-Antiplasmin is the principal physiological inhibitor of fibrinolysis. Its primary function is to rapidly neutralize newly formed plasmin, thereby preventing excessive activation of the fibrinolytic system[119]. Synthesized by the liver as a 70-kDa single-chain glycoprotein belonging to the serine protease inhibitor (Serpin) family, α₂-antiplasmin circulates at a plasma concentration of approximately 60-70 mg/L with a half-life of about 2.5 days[120,121]. Importantly, its plasma levels correlate closely with the severity of liver disease, as assessed by Child-Pugh or MELD scores, so it serves as a sensitive indicator of failing hepatic synthetic function. As liver disease progresses to advanced stages accompanied by a marked decline in α₂-antiplasmin levels, the inhibition of plasmin is attenuated, leading to relatively hyperactive fibrinolytic activity[122,123]. This results in the premature and excessive dissolution of fibrin, disrupting the already fragile hemostatic balance and compromising the formation of stable thrombi at vascular injury sites. Consequently, this manifests as prolonged bleeding time, with a significant increase in the risk of post-procedural, surgical, or spontaneous hemorrhage.

PAI-1 is a 50-kDa single-chain glycoprotein belonging to the Serpin family. It is derived from vascular endothelial cells, adipocytes, and platelets, and is released upon activation[124]. Circulating PAI-1 levels fluctuate widely (10-50 ng/mL) and exhibit a short half-life of approximately 10 minutes. Functionally, PAI-1 forms irreversible complexes with t-PA and u-PA, thereby blocking plasminogen activation. It plays roles in thrombus stabilization and regulation of cell migration. In the early stages of chronic liver injury, inflammatory responses and cellular stress upregulate PAI-1 expression[125]. Elevated PAI-1 levels strongly suppress t-PA and u-PA, leading to reduced plasmin generation. Evidence from animal models proves this impairs extracellular matrix degradation, and by influencing pathways such as transforming growth factor-β, directly promotes the activation and survival of hepatic stellate cells, thereby accelerating collagen deposition and hepatic fibrogenesis[126]. As liver disease progresses to cirrhosis, however, the role of PAI-1 appears to become more complex. While persistently high PAI-1 levels may sustain fibrosis, PAI-1 levels may paradoxically drop absolutely or relatively during decompensation due to global liver synthetic failure[127]. Simultaneously, impaired hepatic clearance leads to the accumulation of t-PA. This disrupted PAI-1/t-PA ratio precipitates hyperfibrinolysis, serving as a critical mechanism for fatal bleeding events, including esophageal and gastric variceal rupture[114,128].

TAFI primarily functions to inhibit plasminogen binding; specifically, TAFIa removes C-terminal lysine residues from fibrin, thereby blocking the binding sites for the kringle domains of plasminogen and reducing plasmin generation[129]. It regulates fibrinolysis by inducing a delay in the activation of the fibrinolytic system following the initiation of coagulation, thereby ensuring thrombus stability[130]. Furthermore, TAFI exerts anti-inflammatory effects by suppressing complement activation and bradykinin production[131,132]. Similar to platelet function, these fibrinolytic activators and inhibitors are aberrant in patients with severe liver disease, leading to a state of hyperfibrinolysis accompanied by an increased risk of clinical bleeding. However, the extent to which fibrinolytic dysfunction contributes to clinically significant hemorrhage in severe liver disease remains unclear.

Platelets and liver injury

Platelet-associated abnormalities constitute a pivotal mechanism in the disruption of microcirculatory homeostasis during liver injury. The interplay among thrombocytopenia, platelet dysfunction, elevated vWF levels, and diminished ADAMTS13 activity forms a complex bidirectional regulatory network. This network concurrently modulates systemic hemorrhagic risk and localized procoagulant activity, creating a unique clinical paradox in hepatic dysfunction.

Platelet-influencing factors: From the perspective of hemorrhagic risk, portal hypertension-induced hypersplenism precipitates thrombocytopenia, thereby directly compromising the formation of primary hemostatic plugs. Concurrently, the intrinsic signaling pathway impairment and deficient secretory capacity of platelets in chronic liver disease culminate in platelet dysfunction, further diminishing thrombus stability. Furthermore, inadequate hepatic synthesis of ADAMTS13 coupled with the massive release of vWF leads to the accumulation of ultra-large vWF multimers (ULVWF). This accumulation persistently induces non-specific platelet adhesion and activation, accelerating platelet consumption and depleting granular reserves. Such mechanisms exacerbate both quantitative deficiency and functional exhaustion of platelets, ultimately elevating the risk of mucocutaneous oozing and variceal hemorrhage[133,134].

Conversely, regarding procoagulant and thrombotic pathogenesis, hepatic sinusoidal endothelial injury triggers excessive vWF release. Concurrently, hepatic-derived ADAMTS13 levels decline, impairing the degradation of ULVWF. Within the low-shear microenvironment of the hepatic sinusoids and portal vein, ULVWF persistently binds to platelet membrane GP I b receptors, inducing excessive activation and degranulation of residual platelets. This process facilitates the release of adenosine diphosphate (ADP), thromboxane A₂, and procoagulant platelet-derived microparticles, which provide phospholipid surfaces for coagulation complex assembly and amplify the coagulation cascade[135]. Moreover, activated platelets further exacerbate sinusoidal endothelial injury, promoting subsequent vWF release and establishing a positive feedback loop between endothelial damage and platelet activation. Additionally, vWF binds and stabilizes FVIII against degradation. When superimposed upon impaired hepatic synthesis of anticoagulant proteins and localized portal venous stasis, these alterations predispose patients to intrahepatic microthrombosis and portal vein thrombosis[136]. The platelet-vWF-ADAMTS13 signaling axis exhibits a characteristic bidirectional paradoxical effect: At the systemic level, thrombocytopenia and functional exhaustion confer a hemorrhagic diathesis, whereas within the localized microenvironment of the portal vein and hepatic sinusoids, ULVWF-driven aberrant platelet activation induces a localized hypercoagulable state. This mechanistic duality elucidates the unique clinical phenotype wherein hemorrhagic events and portal vein thrombosis concurrently manifest in a subset of patients with cirrhosis[137].

In summary, patients with severe liver disease exhibit a rebalanced hemostatic state that predisposes to a hypercoagulable state within the portal venous system. Interacting with altered portal hemodynamics, endothelial injury, and other pathogenic factors, this hypercoagulability renders these patients highly susceptible to portal vein thrombosis and microcirculatory dysfunction. Table 1 summarizes the alterations in key factors of the coagulation–anticoagulation–fibrinolysis system in liver disease.

Table 1 Changes in factors in the coagulation-anticoagulation-fibrinolysis system in liver disease.

Factors	Factors contributing to bleeding	Factors contributing to coagulation
Coagulation factors	Reduced procoagulant factors	Reduced anticoagulant factors. Increased factor VIII
Anticoagulant factors	Increased tissue factor pathway inhibitor	Reduced heparin cofactor II. Reduced antithrombin. Reduced protein C. Reduced thrombomodulin
Fibrinolytic pathway	Increased t-PA. Reduced TAFI. Reduced antiplasmin	Increased PAI-1 (more than t-PA). Reduced plasminogen
Platelets	Platelet dysfunction. Thrombocytopenia	Increased vWF. Reduced ADAMTS13

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

REBALANCE OF COAGULATION–ANTICOAGULATION–FIBRINOLYSIS AND LIVER INJURY PROGRESSION

Bleeding tendency in peripheral circulation

The dynamic equilibrium among the coagulation, anticoagulation, and fibrinolysis systems is fundamental to maintaining hemostatic–anticoagulant balance and preventing abnormal bleeding or thrombosis. These three components mutually restrict and coordinately regulate each other to ensure a steady state of the hemostatic function. As the primary site for the synthesis of most clotting factors, physiological anticoagulant proteins, and fibrinolytic regulatory molecules, the liver plays a central role in this network. During the progression of chronic liver disease, the hemostatic–anticoagulant imbalance leads to an overall shift toward a hypocoagulable state and hyperfibrinolysis in the peripheral circulation, clinically manifesting as a significant hemorrhagic tendency, which constitutes a characteristic pathophysiological alteration in the course of chronic liver disease[138].

During the progression of liver injury, the reduction in coagulation factor synthesis is a key determinant of the hypocoagulable state and the elevated bleeding risk observed in the peripheral circulation. Levels of hepatic-derived coagulation factors-including FI, FII, FV, FVII, FX, and FXI-decline significantly during the liver injury progression, impairing both the extrinsic and intrinsic coagulation pathways. This results in insufficient thrombin generation and defective fibrin polymerization, preventing the formation of stable, effective fibrin clots and leading to the marked impairment of hemostatic function. Although the synthesis of major anticoagulant proteins, such as PC, PS, and AT III, is also reduced, the decline in coagulation factors is far more profound. Given their shorter half-lives, accelerated clearance, and increased consumption, defects in the coagulation system outweigh those in the anticoagulation system. Consequently, the overall hemostatic balance shifts toward a state of relative anticoagulant predominance[139].

Building on this foundation, aberrant hyperfibrinolysis further amplifies the bleeding tendency. In liver injury, impaired hepatic clearance of t-PA coupled with insufficient synthesis of PAI-1 leads to excessive plasmin generation, and persistent degradation of fibrin and fibrinogen. This results in the premature lysis of loosely formed thrombi. Additionally, hyperfibrinolysis accelerates the consumption of coagulation factors and platelets, establishing a vicious cycle characterized by “hypocoagulability-hyperfibrinolysis–exacerbated bleeding”[140,141]. Clinically, this manifests as cutaneous and mucosal ecchymoses, gingival bleeding, and epistaxis. In severe cases, it can precipitate life-threatening complications such as rupture of esophageal and gastric varices, and disseminated intravascular coagulation.

Although current research has established a close association between the imbalance of the coagulation–anticoagulation–fibrinolysis system and bleeding risk in liver disease, there remains a lack of systematic elucidation regarding its spatiotemporal dynamic regulatory network, extrahepatic compensatory mechanisms, and crosstalk with inflammation, lipid metabolism disorders, and intestinal barrier dysfunction. Therefore, deeply deciphering the underlying molecular regulatory pathways and identifying intervention targets capable of precisely correcting this rebalance hold significant theoretical and clinical value for mitigating bleeding risk in severe liver disease and improving long-term prognosis[142,143].

Hepatic microcirculatory dysfunction and portal vein thrombosis

The liver possesses a highly specialized blood supply system. The portal vein collects deoxygenated blood from the splenic and superior mesenteric veins, while the hepatic artery receives oxygenated blood from the aorta. Both converge at the hepatic sinusoids, where exchange occurs before draining into the hepatic veins and ultimately returning to the systemic circulation. Liver sinusoidal endothelial cells constitute the sinusoidal barrier, and serve as a critical hub for bidirectional material exchange between the bloodstream and hepatocytes[144], while also participating in the maintenance of hepatic microcirculatory homeostasis[143,145]. Blood stasis, endothelial injury, platelet hyperactivation, and a hypercoagulable state collectively constitute the key driving mechanisms underlying hepatic microcirculatory dysfunction and portal vein thrombosis, and these interactions form a complex network.

The inherent structural characteristics of the hepatic microcirculation-specifically the narrow caliber of hepatic sinusoids and high flow resistance-coupled with the anatomical features of the portal venous system (wherein the main portal vein exhibits lower flow velocities than the peripheral veins)-establish a physiological basis for sluggish blood flow. It is worth noting that blood stasis is not only a consequence of a hypercoagulable state but also an upstream trigger for endothelial damage and platelet activation. Furthermore, in patients with hepatic fibrosis, cirrhosis, or acute-on-chronic liver failure, the capillarization of sinusoidal endothelial cells leads to reinforcement of the sinusoidal mechanical barrier and elevated portal pressure. This, in turn, further reduces flow velocity and may even induce flow vortices (or turbulence). Blood stasis directly promotes the local enrichment of coagulation factors and platelets, preventing effective dilution by circulating blood flow. Simultaneously, it reduces the efficiency of hepatic clearance of activated coagulation factors, thereby creating conditions conducive to thrombus formation. Furthermore, low shear stress directly induces endothelial dysfunction and a procoagulant phenotype via downregulation of eNOS and upregulation of ROS production[146]. Clinically, when portal vein velocity falls below 15 cm/s in patients with cirrhosis, the incidence of portal vein thrombosis increases significantly, fully corroborating the critical pathogenic role of sluggish flow[147].

Endothelial cells serve as central regulators of microcirculatory function; however, persistent endoplasmic reticulum stress and oxidative stress exacerbate endothelial injury[148]. Vascular endothelial damage leads to abnormally elevated levels of vWF. As a key molecule in the hemostatic system, vWF binds coagulation factors via intermolecular interactions, thereby increasing the local concentration of coagulation factor proteins within the liver. Under physiological conditions, vWF and collagen within the vessel wall are sequestered by intact endothelial cells, thereby strictly suppressing their platelet-aggregating potential. Following vascular injury, exposed subendothelial collagen binds to vWF, inducing a conformational change that unmasks additional platelet-binding sites. Subsequently, vWF mediates the firm adhesion of platelets to the subendothelial matrix and triggers their activation—manifested as morphological spreading and degranulation-leading to the release of procoagulant mediators such as ADP and thromboxane A₂ (TXA₂). It is worth adding that damaged hepatic sinusoidal endothelial cells can release extracellular vesicles carrying procoagulant cargo, such as TF and PS-exposing microparticles. These extracellular vesicles not only directly activate the coagulation cascade, but can also be taken up by platelets, further amplifying the platelet activation signal[149]. These mediators further enhance platelet adhesion and aggregation, leading to the formation of primary platelet aggregates that establish a structural foundation for coagulation cascade activation and stable thrombus formation. The activated coagulation cascade generates thrombin, which catalyzes the conversion of fibrinogen into fibrin. In vivo studies have demonstrated that fibrin undergoes cross-linking to form an insoluble meshwork on the surface of aggregated platelets, entrapping additional platelets and red blood cells, ultimately resulting in the formation of a stable mixed thrombus[150,151]. The microenvironmental imbalance induced by endothelial injury involves two forms of programmed cell death-apoptosis and ferroptosis. Ferroptosis is an iron-dependent, non-apoptotic form of cell death driven by lipid peroxidation. In the context of liver disease, excessive accumulation of free iron catalyzes the massive generation of ROS via the Fenton reaction, which attacks polyunsaturated fatty acids in the membrane of hepatic sinusoidal endothelial cells, triggering a lipid peroxidation chain reaction. This ultimately leads to the loss of endothelial integrity and the exposure of procoagulant surfaces[152]. An in vivo animal experiment confirmed that inhibition of ferroptosis (e.g., via iron chelators or lipid peroxidation inhibitors) has been demonstrated to alleviate hepatic sinusoidal endothelial injury and hypercoagulability[153]. A disintegrin and metalloproteinase with thrombospondin type 1 motif 13 (ADAMTS13), synthesized by the liver, specifically cleaves ULVWF, thereby restricting excessive vWF-mediated platelet adhesion and aggregation. Under hepatic pathological conditions, deficient ADAMTS13 synthesis leads to the accumulation and impaired degradation of ultra-large-molecular-weight vWF, significantly potentiating platelet adhesion, activation, and aggregation. Patients with severe liver disease exhibit significantly elevated platelet activation markers[154]. The underlying mechanism is closely associated with ADAMTS13 deficiency, abnormally elevated vWF levels, and the formation of abnormally stable platelet–vWF complexes. Concurrently, massive platelet consumption leads to a sharp decline in platelet count; this process stimulates the extensive release of platelet activation factors, which further amplifies platelet activation signals and accelerates the formation and deposition of platelet-rich microthrombi.

Platelet hyperactivation serves as the core executing link connecting intrahepatic microcirculatory dysfunction and portal vein thrombosis, with its mechanisms operating throughout the entire course of chronic liver disease and playing serving as a critical “bridge” in decompensation events. Recent clinical studies have confirmed that patients with cirrhotic portal vein thrombosis exhibit significant upregulation of platelet activation, showing significantly higher proportions of CD62p-positive and CD63-positive platelets than cirrhosis patients without portal vein thrombosis[155]. Moreover, the degree of platelet activation is positively correlated with the incidence of portal hypertension-related complications and thrombus burden. Furthermore, after correction for platelet count, the platelet-fibrin clot strength (G-value) has been identified as an independent risk factor for portal vein thrombosis in decompensated cirrhosis[156]. A prospective analysis was conducted on 107 patients with cirrhosis[157]. Flow cytometry confirmed abnormal expression of platelet protease activation receptor (PAR)-1, PAR-4, and activation markers. Notably, epinephrine-induced platelet activation independently increased the risk of non-neoplastic portal vein thrombosis and thrombosis, whereas elevated hepatic venous pressure gradient was identified as the primary risk factor for portal hypertensive bleeding[157]. Collagen-induced platelet-aggregation rates and plasma soluble P-selectin levels are also significantly elevated in patients with portal vein thrombosis[158]. These clinical findings establish platelet activation as an independent risk factor for thrombotic events in cirrhosis. Furthermore, a positive feedback amplification loop exists between platelet hyperactivation and endothelial injury. Activated platelets release platelet-derived microparticles and chemokines that can further damage hepatic sinusoidal endothelial cells, which in turn release more procoagulant extracellular vesicles under pathological conditions, establishing a vicious cycle of “endothelial injury–platelet activation–re-injury”[159].

Furthermore, upregulated vWF binds to FVIII via non-covalent interactions, shielding FVIII from rapid proteolytic degradation. Concurrently, levels of PC and AT III are reduced due to decreased hepatic synthesis and increased consumption during coagulation, leading to a marked decline in their capacity to inactivate coagulation factors[160,161]. Together, these dual mechanisms prolong the procoagulant effects of FVIII and other coagulation factors, thereby contributing to and reinforcing the establishment of hepatic microcirculatory dysfunction and a hypercoagulable state within the portal venous system.

The maintenance and amplification of the hypercoagulable state are inseparable from the profound interplay among inflammation, coagulation, and cell death. During the progression of chronic liver injury, inflammation, endoplasmic reticulum stress, and oxidative stress promote the upregulation of TF expression in hepatocytes and endothelial cells. The excessive exposure of TF facilitates the formation of the TF–FVIIa complex, which initiates the extrinsic coagulation pathway. Additionally, this complex can indirectly activate the intrinsic pathway by activating FXII and FXI. These two pathways converge on the common coagulation pathway, ultimately leading to the activation of the prothrombinase complex. This complex activates prothrombin to thrombin, which further catalyzes the conversion of fibrinogen into fibrin, thereby initiating the coagulation cascade. These pathological alterations render the portal venous system hypercoagulable, increasing the risk of portal vein thrombosis. Furthermore, TF recruits and promotes the adhesion of platelets and leukocytes to the vascular wall, resulting in a low-shear-rate blood-flow state and the release of chemokines. Neutrophil extracellular traps, induced by chemokines and characterized by a scaffold-like structure, facilitate the adhesion of blood clots and contribute to thrombotic diseases. Beyond mobilizing immune cells to sites of liver injury, chemokines activate key signaling pathways (such as NF-κB and MAPK), triggering the cascade amplification of inflammatory responses. This represents a critical mechanism underlying hepatic microcirculatory dysfunction. This dysfunction further promotes hepatocyte apoptosis, thereby inducing hepatic fibrosis and facilitating the development of portal hypertension. Additionally, a study has revealed that the hepatic fibrinolytic system is suppressed under pathological conditions, characterized by elevated levels of PAI-1[162]. Of note, an in vivo animal study confirmed that PAI-1 not only inhibits fibrinolysis but also promotes platelet adhesion and aggregation through integrin signaling pathways, thereby simultaneously amplifying thrombotic risk at both the procoagulant and anti-fibrinolytic levels[163,164]. This imbalance-marked by hypercoagulability coupled with weakened fibrinolysis-jointly drives the extensive formation of plateletrich microthrombi. The hypercoagulable state in the liver can exacerbate hepatic tissue hypoxia; the oxidative stress triggered by hypoxia then further aggravates liver injury[165,166]. Hypoxia-inducible factor 1α plays a central role in this process: It not only upregulates the expression of TF and PAI-1 but also induces the expression of ferroptosis-related proteins, thereby tightly coupling hypoxia, hypercoagulability, and cell death[167]. Without timely intervention, hypoxia and hypercoagulability establish a vicious cycle that ultimately leads to disease progression.

In summary, blood stasis and endothelial injury initiate the disruption of the structure and function of the hepatic microcirculation. This leads to slowed perfusion, local retention of procoagulant factors, decreased synthesis of anticoagulants, and the formation of platelet microthrombi. It is worth noting that endothelial injury can give rise to ferroptosis and the release of procoagulant extracellular vesicles. Platelet activation, which is under autophagic control, further aggravate endothelial injury. In addition, inflammation and neutrophil extracellular traps play a pivotal role in both amplifying the coagulation cascade and maintaining the hypercoagulable state. Through the synergistic action of these factors, a hypercoagulable state is established within the hepatic microcirculation and the portal venous system. The hypercoagulable state directly initiates the coagulation cascade within the stagnant microcirculation and portal vein. This enhancement of coagulation likely expands the territory of microthrombi, ultimately promoting the formation of either microthrombi or portal vein thrombosis. Ferroptosis and neutrophil extracellular trap formation together define a “silent hub” that orchestrates endothelial injury, platelet activation, and hypercoagulability, serving as a key determinant of the disease trajectory in hepatic microcirculatory dysfunction. The resulting thrombi further obstruct blood flow and mechanically injure the endothelium, establishing a pathological vicious cycle. Consequently, hepatic microcirculatory dysfunction and portal blood flow obstruction are exacerbated. In severe cases, this can lead to increased ascites formation and rupture of esophageal and gastric varices, thereby accelerating the progression of liver injury.

Therefore, future therapeutic paradigms for hepatic microcirculatory dysfunction and portal vein thrombosis should not be limited to traditional anticoagulant and antiplatelet agents, but rather should incorporate a comprehensive repertoire of mechanisms, ranging from hemodynamic restoration and endothelial protection (e.g., ferroptosis inhibition) to autophagy modulation and neutrophil extracellular trap blockade.

STRATEGIES FOR TARGETED THERAPY

Laboratory parameters

In patients with cirrhosis, accurate assessment of coagulation–anticoagulation–fibrinolysis function and related global parameters is crucial for monitoring disease progression and determining prognosis.

Coagulation status is routinely assessed via standard coagulation tests, which often reveal prolonged PT, APTT, and elevated international normalized ratio (INR) in patients with cirrhosis. However, these tests overlook the concurrent reduction in anticoagulant proteins, and do not necessarily correlate with an increased bleeding risk; furthermore, PT/INR values exhibit significant inter-laboratory variability[168]. While a reduced platelet count elevates bleeding risk, it fails to reflect platelet function[169,170]. Both thrombin–thrombin-antithrombin complex and thrombin generation assay can be utilized to assess coagulation status in cirrhosis patients, and elevated levels may indicate a potential risk of thrombosis. However, owing to the lack of standardized detection methodologies, inconsistent reference ranges, and significant inter-laboratory variability, their clinical utility in evaluating bleeding or thrombotic risk in cirrhosis remains controversial, necessitating further studies to validate their prognostic value[171]. Assays for coagulation factor activity provide a more accurate assessment of individual factor function; however, they fail to comprehensively reflect the overall coagulation status. vWF reflects the functional status of vascular endothelial cells, and elevated levels indicate an increased risk of thrombosis; however, it fails to comprehensively reflect the overall coagulation status. Regarding the anticoagulant system, commonly used indicators such as AT and PC/PS are reduced in cirrhosis, suggesting heightened thrombotic risk, yet these markers also do not provide a complete picture of the hemostatic state[168]. Within the fibrinolytic system, elevated d-dimer levels are associated with disease severity and poor prognosis. However, these markers exhibit poor specificity, and are susceptible to confounding factors such as inflammation and infection. While hepatic impairment typically leads to decreased fibrinogen levels, a study has reported normal or even elevated fibrinogen levels in certain patients, necessitating further validation through larger datasets[172]. Similarly, elevated levels of PAI-1 and α2-antiplasmin suggest an increased thrombotic risk in cirrhosis model mice[173]; however, their utility is limited by poor specificity and vulnerability to inflammatory and infectious states[174]. Thromboelastography (TEG) is a functional coagulation assay based on the principle of blood viscoelasticity, enabling dynamic and visualized monitoring of the entire cascade-from the initiation of coagulation and clot formation to fibrinolysis. It holds significant clinical value in the assessment of thrombosis and hemorrhage risks as well as in guiding personalized component transfusion. In contrast to conventional coagulation tests, such as PT and APTT, which merely provide static and isolated coagulation indicators in vitro, TEG utilizes whole blood samples to simulate physiological temperature and hemodynamic shear conditions in vitro. It continuously, and in real-time, records the complete kinetics of clot generation, cross-linking, reinforcement, and fibrinolytic degradation, thereby comprehensively reflecting the overall equilibrium of the body’s coagulation, anticoagulation, and fibrinolysis systems[175].

In view of the inherent limitations of currently available assays, the precise evaluation of coagulation status and the monitoring of treatment responses in cirrhosis continue to pose considerable difficulties in clinical settings. Looking ahead, there is an urgent need to establish integrated and user-friendly diagnostic systems and to develop novel detection tools, with the aim of facilitating rapid disease staging, accurate identification of therapeutic windows, and robust prognostic assessment, ultimately providing more actionable objective evidence to inform clinical decision-making.

Existing therapeutic approaches

The liver serves as the central organ for synthesizing the majority of coagulation factors, anticoagulant proteins (e.g., PC, PS, and AT), and regulatory molecules of the fibrinolytic system. During liver injury, the synchronous reduction of these components theoretically establishes a fragile rebalancing of hemostasis. However, as the disease progresses, multiple factors disrupt this equilibrium, leading to severe derangement of the coagulation–fibrinolysis system. Furthermore, patients with severe liver disease frequently develop thrombocytopenia, primarily attributable to congestive splenomegaly induced by portal hypertension[176]. It is important to emphasize that beyond mere quantitative reduction and functional defects that elevate bleeding risk, various platelet abnormalities also predispose to pathological thrombosis[177]. Portal hypertension induces blood stasis and endotoxemia, which stimulate vascular endothelial cells to express TF and initiate coagulation. Concurrently, reduced ADAMTS13 activity facilitates the formation of platelet microaggregates[178]. Collectively, these pathological alterations act in concert to precipitate thrombotic events, with portal vein thrombosis being the most frequent manifestation, significantly impacting patient prognosis. Conversely, the exacerbation of bleeding risk is intimately associated with thrombocytopenia/platelet dysfunction, hyperfibrinolysis (resulting from attenuated fibrinolytic inhibition due to reduced TAFI synthesis), and acquired von Willebrand syndrome. Crucially, the prothrombotic and pro-hemorrhagic mechanisms are not mutually independent; rather, they are intricately interwoven and exist in a relationship of reciprocal causation. For instance, compensatory hyperfibrinolysis, while precipitating hemorrhage, concurrently lyses newly formed microthrombi and releases TF-rich microparticles, thereby further promoting coagulation activation and establishing a vicious cycle[179]. Consequently, clinical management necessitates the individualized assessment of the risk-benefit ratio between thrombosis and bleeding under rigorous monitoring of hemostatic function, ensuring the prudent selection of anticoagulant or hemostatic therapeutic strategies. Given that patients with cirrhosis face a dual risk of both hemorrhage and thrombosis, with the underlying mechanisms being intricately linked and dynamically evolving, anticoagulant therapy should not be deemed an absolute contraindication in their clinical management. Instead, therapeutic strategies involving anticoagulation or hemostasis must be cautiously selected through an individualized assessment of the risk-benefit ratio, predicated on rigorous monitoring of hemostatic function (including conventional coagulation parameters, TEG/rotational thromboelastography (ROTEM), and thrombin generation assays). This paradigm has served as a fundamental cornerstone for the recent conceptual shift in the anticoagulation management of portal vein thrombosis in cirrhosis.

Hemostatic therapy: Patients with severe liver disease frequently exhibit a bleeding diathesis due to multiple factors, including reduced synthesis of coagulation factors, thrombocytopenia or platelet dysfunction, and hyperfibrinolysis. Contrary to conventional paradigms, the hemorrhagic risk in patients with cirrhosis is not solely attributable to a diminished anticoagulant capacity. Rather, it ensues from the disruption of a “fragile rebalancing” that emerges following the derangement of procoagulant and anticoagulant hemostatic mechanisms. Consequently, hemorrhage management should not rely on the indiscriminate administration of procoagulant agents; instead, it must be guided by individualized assessments of hemostatic function. Currently, the cornerstone of treatment lies in aggressively managing the underlying etiology (e.g., antiviral therapy for hepatitis B/C, alcohol abstinence, and immunomodulatory therapy) and administering hepatoprotective agents to improve liver function. However, pending the recovery of hepatic function, hemorrhagic events necessitate stratified and precise hemostatic interventions.

For deficiencies in vitamin Kdependent coagulation factors, appropriate vitamin K supplementation combined with fresh frozen plasma infusion is recommended. Notably, patients with cirrhosis frequently exhibit impaired absorption or utilization of vitamin K. In cases where the response to vitamin K is suboptimal, fresh frozen plasma remains the first-line therapeutic option; however, the associated clinical benefits demonstrate significant inter-individual variability[180]. If the fibrinogen level falls below 1.0 g/L, supplementation with fibrinogen concentrate or cryoprecipitate should be administered[12]. A fibrinogen level > 1.2 g/L may optimize clot formation in advanced liver disease[181]. However, excessive fibrinogen supplementation may elevate the risk of thrombosis. Consequently, target levels should be dynamically adjusted based on comprehensive assessments of both bleeding status and thrombotic risk. Studies have suggested that growth factors derived from platelets may contribute to the promotion of liver regeneration, and that platelet transfusion may ameliorate certain hepatic function parameters in a subset of patients with cirrhosis[182]. It is imperative to emphasize that hemorrhagic risk is dictated not merely by platelet quantity but more critically by platelet function. Patients with cirrhosis frequently exhibit platelet-function defects, such as diminished aggregation rates induced by ADP or collagen. Consequently, even when platelet counts exceed 50 × 10⁹/L, bleeding may still occur due to “functional thrombocytopenia”. Conversely, some thrombocytopenic patients present with concurrent ADAMTS13 deficiency and aberrantly elevated vWF levels. In these individuals, despite thrombocytopenia, platelets may be hyperfunctional, conferring a prothrombotic risk; thus, platelet transfusion in such scenarios may be more detrimental than beneficial. Therefore, prior to deciding on platelet transfusion, it is recommended to conduct assessments of platelet aggregation function or viscoelastic hemostatic assays (e.g., TEG or ROTEM) when feasible. In patients with markedly elevated d-dimer levels, and definitive evidence of hyperfibrinolysis, tranexamic acid can be administered as an antifibrinolytic agent to achieve hemostasis. However, vigilance is warranted: The elevation of d-dimer in patients with cirrhosis may stem from hyperfibrinolysis, but could also originate from low-grade disseminated intravascular coagulation or microthrombosis. The indiscriminate administration of antifibrinolytic agents may “freeze” microthrombi within the microcirculation, thereby exacerbating the thrombotic burden in the portal venous system and precipitating or worsening portal vein thrombosis. Therefore, antifibrinolytic therapy should be reserved for cases where viscoelastic hemostatic assays (TEG/ROTEM) indicate hyperfibrinolysis (e.g., elevated LY30). Furthermore, such treatment should be administered at low doses for a short duration, accompanied by rigorous monitoring for thrombotic events. While targeted drugs such as FXa inhibitors and thrombin inhibitors appear to be relatively safe and effective in patients with stable cirrhosis, further investigation is required in those with more advanced liver disease[181]. For patients presenting with ruptured esophageal and gastric varices, the first-line treatment involves endoscopic variceal ligation or sclerotherapy, combined with somatostatin analogs or vasopressin. Concurrently, proton pump inhibitors should be administered to maintain an optimal pH level conducive to coagulation stability. In cases of refractory hemorrhage, transjugular intrahepatic portosystemic shunt (TIPS) placement or splenectomy may be considered. Furthermore, nonsteroidal anti-inflammatory drugs and antiplatelet agents are contraindicated; unnecessary invasive procedures should be avoided whenever possible. Additionally, active correction of hypothermia and acidosis constitutes a critical component of effective hemostatic management.

Anticoagulation therapy: Antithrombotic therapy in patients with progressive liver injury presents a formidable challenge, as the coagulation system exhibits a bidirectional disorder, wherein bleeding diathesis and thrombotic complications may coexist within the same patient or undergo dynamic transitions. Clinical management necessitates an individualized decision-making process that integrates the specific thrombotic phenotype (main portal vein, branch, or microvascular thrombosis), bleeding risk (stratified by liver function class, platelet count and function, and the severity of portal hypertension), and hepatic functional reserve.

Common thrombotic manifestations in advanced liver injury include portal vein thrombosis, mesenteric vein thrombosis, hepatic vein thrombosis, deep vein thrombosis/pulmonary embolism, and the microthrombi associated with disseminated intravascular coagulation. Low-molecular-weight heparin (LMWH) is the first-line agent for anticoagulation therapy. By enhancing the activity of AT III, LMWH inactivates FXa and FIIa, thereby suppressing the coagulation cascade. Compared with unfractionated heparin, LMWH exhibits higher anti-FXa activity, with an anti-FXa to anti-FIIa ratio ranging from 2:1 to 4:1. This property facilitates effective anticoagulation while mitigating the risk of bleeding[183]. Its predominant effect of FXa inhibition, coupled with its weaker anti-FIIa activity, allows for the potent inhibition of blood coagulation, with both prophylactic and therapeutic effects against thrombosis. LMWH exhibits a rapid onset of action and does not necessitate routine coagulation monitoring in patients with stable cirrhosis. However, its clinical utility is limited by a short half-life and the inconvenience associated with subcutaneous administration. Upon achieving clinical stability following initial treatment with LMWH, a transition to warfarin therapy may be considered. Warfarin, a vitamin K antagonist, exerts its anticoagulant effect by inhibiting the hepatic synthesis of vitamin K-dependent coagulation factors (FII, FVII, FIX, and FX)[184]. Furthermore, warfarin inhibits the synthesis of PC and PS, thereby blocking the coagulation cascade, prolonging clotting time, and suppressing thrombus formation. Warfarin has a slow onset of action and requires coagulation factor depletion; however, the associated bleeding can be corrected with vitamin K and fresh frozen plasma transfusion. It is also characterized by a narrow therapeutic window, significant interindividual variability in effective doses required to achieve the same therapeutic effect, and a high risk of bleeding, necessitating regular INR monitoring. When pharmacological therapy proves ineffective, TIPS placement or liver transplantation should be considered[185]. TIPS directly reduces portal venous pressure, thereby creating a “low-pressure” milieu that facilitates subsequent endoscopic interventions or anticoagulation therapy. Conversely, liver transplantation serves as the definitive therapeutic modality for both portal vein thrombosis and the underlying liver disease.

Rivaroxaban is a direct FXa inhibitor with high oral bioavailability, achieving peak plasma concentrations within 2-4 hours after administration. Its pharmacokinetic profile is consistent between healthy subjects and patient populations. The pharmacodynamic effect is closely correlated with plasma concentration, and rivaroxaban has been approved for use across a broad spectrum of thromboembolic disorders[186]. Rivaroxaban is characterized by its rapid oral onset, stable and predictable anticoagulant effect, and the absence of a requirement for routine coagulation monitoring. Thrombomodulin is a transmembrane glycoprotein expressed on the surface of vascular endothelial cells. In the physiological state, thrombomodulin binds to thrombin, inducing a conformational change that abrogates thrombin’s ability to cleave fibrinogen and activate platelets, thereby neutralizing its procoagulant properties. In pathological states, the exogenous administration of thrombomodulin serves to bolster this endogenous anticoagulant mechanism. Although this therapeutic strategy holds theoretical merit for cirrhosis patients presenting with disseminated intravascular coagulation or microthrombosis, robust clinical evidence remains scarce. It is noteworthy that the entire course of antithrombotic therapy necessitates rigorous monitoring of coagulation function. The therapeutic targets should be maintained at an INR > 1.5 (the target INR range for warfarin therapy is 2.0-3.0; this may be appropriately relaxed to 2.0-2.5 in patients with cirrhosis), an APTT of 1.5-2.5 times the normal reference value (when using ordinary heparin; the value of APTT monitoring is limited when LMWH is employed), and a platelet count above 50 × 10⁹/L, while closely observing for any signs of active bleeding. Should a bleeding tendency emerge (enlargement of skin ecchymoses, gingival bleeding, melena, hematuria, etc.), anticoagulation therapy must be discontinued, and the cause and severity of bleeding evaluated immediately.

Clinically utilized antiplatelet agents primarily include cyclooxygenase (COX) inhibitors and purinergic receptor Y12 (P2Y12) antagonists. The former category, comprising aspirin and aluminum magnesium acetylsalicylate, irreversibly inhibits platelet COX-1, thereby blocking the conversion of arachidonic acid to TXA₂. As TXA₂ is a potent mediator of platelet aggregation and vasoconstriction, its diminished synthesis significantly suppresses platelet adhesion and aggregation, exerting the pharmacologic effects of antiplatelet therapy and arterial thrombosis prevention. Low-dose aspirin can be administered for long-term maintenance therapy. However, its drawbacks include a direct irritant effect on the gastrointestinal mucosa, which predisposes patients to epigastric pain, gastric ulcers, and even lethal gastrointestinal hemorrhage in patients with portal hypertensive gastropathy or esophageal and gastric varices due to cirrhosis. Furthermore, as aspirin acts solely on the platelet pathway exerting no direct inhibitory effect on the coagulation cascade, its efficacy in preventing venous thromboembolism and atrial fibrillation-related thromboembolism is limited. Both clopidogrel and ticagrelor belong to the class of P2Y12 receptor antagonists. P2Y12 is a G protein-coupled receptor. Upon platelet activation, ADP is released, and following the specific binding of ADP to the P2Y12 receptor, downstream intracellular signaling pathways are initiated, mediating platelet adhesion, activation, and aggregation, and amplifying the thrombotic process[187]. A study demonstrated that among patients with Child-Pugh class A or B cirrhosis and 12 healthy controls, all of whom received clopidogrel, the peak plasma concentration of the parent drug was higher in the cirrhosis patients; however, exposure to its major metabolite, inhibition of platelet aggregation, and prolongation of bleeding time did not differ significantly from those in the healthy controls, and no serious bleeding events were reported[188]. These findings suggest a promising role for clopidogrel in patients with cirrhosis. However, the clinical use of clopidogrel and ticagrelor in other settings involves adverse bleeding events affecting the gastrointestinal tract, brain, and skin, and caution is therefore warranted[189]. For patients with Child-Pugh class C (decompensated) cirrhosis, data are still limited, so more cautious evaluation is warranted. Table 2 summarizes key interventions for cirrhosis-associated thrombotic events and synthesizes the clinical evidence supporting each treatment modality.

Table 2 Summary of blood products and/or pharmacological recommendations for thrombosis in cirrhosis.

	Choice of agent	Statement	Limitations
Anticoagulation agents	LMWH	Monitor anti-FXa activity; evaluate anticoagulation efficacy	Short half-life; subcutaneous injection
	Warfarin	Inhibits vitamin K-dependent coagulation factor synthesis	Monitor INR to guide anticoagulation therapy; high bleeding risk
	Rivaroxaban	Inhibits FXa	Contraindicated or not recommended in severe hepatic impairment (Child-Pugh class C)
Antiplatelet agents	Aspirin or aspirin-magnesium-aluminum	Inhibits COX-1; blocks thromboxane A₂ formation. Suppresses platelet aggregation	Irritation of the gastrointestinal mucosa
	Clopidogrel or ticagrelor	Irreversibly inhibits the P2Y12 receptor on platelets and exerts antithrombotic activity	Risk of bleeding events

LMWH: Low-molecular-weight heparin; FXa: Activated factor X; INR: International normalized ratio; COX-1: Cyclooxygenase-1; P2Y12: Purinergic receptor Y12.

CONCLUSION

During the progression of liver injury, the imbalance of the coagulation-anticoagulation-fibrinolysis system results in a dual pathological state: Hypocoagulability in the peripheral circulation with a bleeding tendency, and hypercoagulability in the intrahepatic and portal venous system predisposing to thrombosis. This dual abnormality not only aggravates intrahepatic microcirculation disturbance but also markedly increases the risk of portal vein thrombosis, thereby accelerating the progression of liver disease. This paper summarizes the alterations of relevant factors in coagulation-anticoagulation-fibrinolysis system during liver disease progression, discusses the underlying pathological mechanisms, and suggests suitable intervention strategies, aiming to provide new insights for subsequent mechanistic research and lay a theoretical foundation for blocking liver disease progression as well as precisely optimizing clinical hemostasis and anticoagulation strategies.

Blood stasis, endothelial cell injury, platelet hyperactivation, and a hypercoagulable state collectively constitute the key driving mechanisms underlying intrahepatic microcirculatory dysfunction and portal vein thrombosis. Comprehensive assessment of these pathological alterations-coupled with early, individualized intervention—may represent an effective strategy for mitigating microcirculatory impairment and preventing thrombosis within the portal system.

During the progression of liver injury, the synthesis of coagulation factors (FI, FII, FV, FVII, FX, and FXI) is diminished, accompanied by a state of hyperfibrinolysis. This combination results in a systemic hypocoagulable tendency and a significantly elevated risk of hemorrhage. Concurrently, the reduced expression of anticoagulant proteins (including PC and AT III), coupled with the upregulated expression of FVIII and vWF-along with the involvement of endoplasmic reticulum stress, oxidative stress, and inflammatory responses-collectively drives a local hypercoagulable state within the liver and portal venous system. This pathological shift is not only intimately associated with intrahepatic microcirculatory dysfunction and portal vein thrombosis but is also closely linked to peripheral bleeding events, thereby synergistically accelerating the progression of liver injury. Therefore, in-depth exploration of the dynamic characteristics of the coagulation–anticoagulation–fibrinolysis system during liver injury progression, along with targeted modulation of its key links, holds significant potential for the prevention and treatment of hepatic damage. This review aims to elucidate the patterns of evolving compensatory and pathological alterations of this system in the context of liver injury and to establish a theoretical foundation for targeting key factors within this system as a therapeutic strategy.

Currently, our understanding of the precise regulatory mechanisms governing hemostatic rebalance in liver injury is limited. Consequently, future investigations should prioritize the identification and characterization of potential risk factors within the coagulation–anticoagulation–fibrinolysis system. Furthermore, with the continuous innovations in genomics and proteomics technologies, and the deepening integration of multidisciplinary approaches, systematic analysis of the dynamic changes in these factors during liver injury progression can facilitate the further elucidation of the underlying molecular mechanisms. This endeavor promises to provide novel insights for clinical precision medicine, and is anticipated to result in emergence of new strategies for the treatment of liver diseases, particularly, refractory liver conditions.

The present review is a narrative review. We acknowledge the limitations of a non-systematic literature search and selective citation, which may have introduced potential selection bias and may not have captured all relevant studies. However, our goal is to provide a comprehensive overview of the systematic analysis of dynamic changes in the factors involved in liver injury progression as well as current therapeutic measures.