REVIEWS Procoagulant therapeutics in liver disease: a critique and clinical rationale Neeral L. Shah, Nicolas M. Intagliata, Patrick G. Northup, Curtis K. Argo and Stephen H. Caldwell Abstract | The complex nature of haemostasis in patients with liver disease can result in bleeding and/ or thrombosis. These opposing outcomes, which have multiple contributing factors, can pose diagnostic and therapeutic dilemmas for physicians. With the high rate of haemorrhagic complications in patients with cirrhosis, we examine the various procoagulants available for use in this population. In this Review, we describe the clinical and current rationale for using each of the currently available procoagulants —vitamin K, fresh frozen plasma (FFP), cryoprecipitate, platelets, recombinant factor VIIa (rFVIIa), antifibrinolytics, prothrombin concentrate complexes (PCC), desmopressin and red blood cells. By examining the evidence and use of these agents in liver disease, we provide a framework for targeted, goal-directed therapy with procoagulants. Shah, N. L. et al. Nat. Rev. Gastroenterol. Hepatol. 11, 675–682 (2014); published online 15 July 2014; doi:10.1038/nrgastro.2014.121
Introduction
Division of Gastroenterology and Hepatology, PO Box 800708, University of Virginia, Charlottesville, VA 22908, USA (N.L.S., N.M.I., P.G.N., C.K.A., S.H.C.).
The proper balance of procoagulant and antihaemostatic factors in healthy individuals leads to haemostasis, which prevents inappropriate bleeding or clotting. Although many cell types and organs are involved in this process, the liver produces the majority of proteins that regulate haemostasis. This balance usually remains intact in patients with liver disease, albeit in a much more precarious and fragile state.1 Traditionally, liver disease has been associated with a bleeding tendency, but mounting evidence has uncovered a coexistent propensity to develop thrombosis in certain circumstances.2 The complex nature of this coagulation system has led to uncertainty in the clinical realm regarding treatment. Although many studies in this field have considerably advanced our understanding of the coagulop athy of liver disease, in vitro studies have relied upon measures and tests that do not account for the multitude of in vivo interactions. Consequently, the results of many studies cannot necessarily be used directly by clinicians and underlying, entrenched dogmas become difficult to change. Furthermore, many available products were originally designed and intended for use in other bleeding diatheses and so it is often unclear which agent is useful for a particular circumstance in patients with liver diseases. With an increased understanding of the physiology of therapeutics, the following sections provide a greater understanding of treatment for bleeding or clotting in patients with liver disease. Examining procoagulants and the clinical rationale can ultimately prove essential in the treatment of the 20–40% of patients with cirrhosis who present to healthcare providers with bleeding episodes due to haemostatic abnormalities.3,4
Correspondence to: N.L.S. [email protected]
Competing interests The authors declare no competing interests.
Vitamin K
Vitamin K is mainly found in green leafy vegetables and is absorbed in the small intestine after ingestion. Vitamin K is involved in post-translational modification of coagulation factors within the liver. For example, the conversion of glutamic acid to gamma-carboxyglutamic acid is dependent on vitamin K. This conversion takes place in the liver and is hindered in the setting of vitamin K deficiency or in the presence of vitamin K antagonists.5 Low levels of vitamin K are often found in patients with liver disease who are malnourished, which most commonly occurs in those who are actively using alcohol.6 Low levels of vitamin K result in decreased production of procoagulation factors II, VII, IX, and X and anti coagulation factors, protein C and protein S. Repletion of vitamin K attempts to correct this imbalance by restoring normal levels of this essential component involved in the generation of coagulation factors. However, a study exploring the effect of vitamin K repletion in patients with cirrhosis showed that it resulted in only a slight improvement in prothrombin time and activated partial thromboplastin time and only a modest improvement in vitamin‑K‑dependent protein levels.7 In one study of patients with liver disease and vitamin K deficiency, almost 90% were found to produce pro thrombin in an ‘under-carboxylated’ state, known as ‘prothrombin induced by vitamin K absence’ (PIVKA II).8 PIVKA II has also been studied for its prognostic value in hepatocellular carcinoma screening. Alpha‑fetoprotein‑L3 and PIVKA II levels were shown to be sensitive markers for hepatocellular carcinoma detection when used in combination. 9 Although the clinical significance of vitamin K repletion to ameliorate PIVKA II is unclear as mentioned previously, studies have shown only a modest decrease in PIVKA II levels with the administration of vitamin K.7 In theory, vitamin K repletion should result in
NATURE REVIEWS | GASTROENTEROLOGY & HEPATOLOGY © 2014 Macmillan Publishers Limited. All rights reserved
VOLUME 11 | NOVEMBER 2014 | 675
REVIEWS Key points ■■ International normalized ratio values in liver disease might be falsely elevated, thus caution should be taken when using this value to consider fresh frozen plasma repletion ■■ Cryoprecipitate should be used in the setting of fibrinogen deficiency for proper clot formation ■■ Platelet transfusion to at least 50,000/dL can result in adequate thrombin production in the setting of liver disease ■■ In cirrhosis patients with chronic inflammation, hyperfibrinolysis can be present and can be treated with antifibrinolytics to promote clot stabilization ■■ The knowledge of the coagulation profile for cirrhosis patients is rapidly evolving, future studies might provide further insight into other procoagulant therapies
more complete carboxylation of prothrombin and proper production of coagulation proteins. Even with the high prevalence of vitamin K deficiency in patients with liver disease, evidence about the overall benefit of vitamin K repletion on the coagulation pro file of these patients is scant. Nevertheless, in clinical scenarios suggestive of vitamin K deficiency, repletion, preferably by intravenous delivery, would aid in pro coagulant factor production. Notably, studies have shown that oral vitamin K replacement is not as reliable as intravenous repletion owing to variable levels of gut absorption of this vitamin.10
Fresh frozen plasma
FFP is derived from donated blood products that have been centrifuged and separated from cellular components (Figure 1). FFP contains all coagulation factors that are essential to clot formation (that is, factors II, V, VII, VIII, IX, X and XI).11 Repletion of coagulation factors with FFP bypasses the need for vitamin K carboxylation in the liver for coagulation factor formation. The presence of coagulation factors can be measured using prothrombin time, which was first developed by A. J. Quick for use in the setting of vitamin K antagonists.12 Prothrombin time and the subsequently derived standardized result reported as the international normalized ratio (INR) have been widely used for the measurement of coagulation in disease. However, mounting evidence has shown that the INR is not an accurate marker of bleeding risk in patients with cirrhosis and has wide inter-laboratory variation.13,14 Nonetheless, as an elevated INR is commonly found in patients with liver disease, an inordinate amount of FFP is often used in patients with cirrhosis for prophylaxis without evidence of utility.3 Studies have shown the importance of using global coagulation measures on whole-blood samples rather than plasma alone, which is used in INR calculations. Thromboelastography is a whole-blood test that can provide more information on coagulation profiles in patients with liver disease than conventional parameters, such as the INR, which are often used as arbitrary targets to direct FFP administration.15 Routine use of FFP in clinical practice is based on insufficient evidence and is unlikely to cause significant correction of the liver coagulopathy. FFP infusions that are often used clinically, infrequently correct the coagulation profiles in patients with cirrhosis.16 In fact, caution should be taken in patients with cirrhosis and portal 676 | NOVEMBER 2014 | VOLUME 11
hypertension because the increased volume of blood after FFP transfusion will increase portal pressure in a linear fashion.17,18 Therefore, the risk of exacerbating portal hypertension and transfusion-related lung injury argues against routine use of FFP in this population, especially for targeting the INR.
Cryoprecipitate
Cryoprecipitate is what remains of frozen plasma after it has thawed. This insoluble residue contains factor VIII, fibronectin, von Willebrand factor (vWF) and fibrinogen (Figure 1), which are vital factors involved in coagulation. Fibrinogen is composed of six polypeptide chains (two α, β and γ chains each) that are normally assembled in hepatocytes. The protease thrombin subsequently cleaves fibrinogen to form fibrin molecules, which are then incorporated into a polymerization process for clot formation. Compared with healthy individuals, patients with endstage liver disease and cirrhosis might have lower levels of fibrinogen or impaired aggregation of fibrin monomers to properly form clots.19 In the setting of liver dysfunction, reduced fibrinogen levels might have a role in the impairment of coagulation.20 Cryoprecipitate or fibrinogen con centrate transfusions can supply ‘normal’ fibrinogen, but exact target values for fibrinogen are still unknown. Although the quantity of measureable fibrinogen might be adequate, the functionally abnormal fibrinogen (dysfibrinogenemia) in liver disease is still not readily measureable. Therefore, fibrinogen values obtained from the laboratory will not give an accurate assessment of the fibrinogen function in the setting of bleeding.19 Within these limitations and to ensure there is adequate functional fibrinogen available, our group uses a fibrinogen target level of 100–120 mg/dL in the setting of bleeding or pre-procedural prophylaxis. However, target levels for asymptomatic patients or prophylaxis in patients with liver disease remain unclear.21
Platelets
Platelet levels are assessed in a complete blood count from whole blood anticoagulated with ethylenediaminetetra acetic acid and can be used in the assessment of potential haemostasis. Platelets are essential for primary haemo stasis—that is, the formation of a platelet plug at the site of endothelial injury. Furthermore, platelet phospholipid surfaces and calcium potentiate tenase complexes (factors VIII and IX) and prothrombinase complexes (factors V and X), stimulate further platelet recruitment and clot formation. In patients with cirrhosis, platelet levels are often reduced owing to portal hypertension causing splenic seques tration, decreased production of the platelet growth factor (thrombopoietin) from the liver and increased platelet destruction (due to mechanisms similar to autoimmunemediated reactions such as immune thrombocytopenic purpura).22 Nevertheless, even in the setting of thrombocytopenia, patients with cirrhosis have preserved primary haemostasis. As a possible compensatory mechanism for decreased platelet levels, uncleaved vWF proteins levels are increased, which has been documented in patients with
www.nature.com/nrgastro © 2014 Macmillan Publishers Limited. All rights reserved
REVIEWS
Whole blood bag
Satellite bag
Hard spin
Coagulation factors II, VII, VIII, IX, X, XI Separate
FFP
Concentrated coagulation factors II, VII, IX, X, XII, protein C, protein S
PCC
PRBC Slow thaw Hard spin
FFP
Separate
Fibrinogen von Willebrand Factor (vWF) Cryosupernatant
Cryoprecipitate
Figure 1 | Procoagulant blood products derived from whole blood. Whole blood is centrifuged to separate PRBCs from plasma. The plasma can be used to derive three different blood products often used to aid in coagulation; FFP, PCC and cryoprecipitate. These products are often frozen for storage and thawed at the time of use. FFP is unaltered plasma that contains coagulation factors II, VII, VIII, IX, X and XI. PCC are distilled from plasma and contains the same factors as FFP but in a concentrated form. Finally, cryoprecipitate is an insoluble residue formed from thawed plasma and contains fibrinogen and von Willebrand factor. Abbreviations: FFP, fresh frozen plasma; PCC, prothrombin complex concentrate; PRBC, packed red blood cell.
cirrhosis.23 The increase in levels of large-multimer-sized vWF is thought to occur partly due to a decrease in the production of a vWF regulatory protein, ADAMTS13.24 Furthermore, in vitro studies have demonstrated that the presence of endotoxins in patients with cirrhosis might damage the endothelium and result in the release of vWF.25 The overall increase in the concentration of uncleaved vWF promotes adhesion of platelets to the subendothelial wall for primary haemostasis.23 The quantity of platelets is important for primary haemostasis to be achieved; however, the quality of platelet function could be just as crucial. The high prevalence of renal dysfunction in patients with liver disease—due to diuretic use or hepatorenal syndrome—can negatively affect platelet function because of underlying uraemia.26 The presence of uraemia reduces platelet aggregation and
binding capacity, thereby affecting the functional capacity of clot formation.27 Platelets are involved in thrombin (factor II) generation at the amplification phase of haemostasis to promote the activation of coagulation factors. Inherent thrombin production capacity might be limited when cirrhosis occurs alongside severe thrombocytopenia; however, it has been demonstrated that correcting platelet levels to >50,000/dL enables adequate thrombin production and >100,000/ dL might result in normalization of the capacity of platelets to generate thrombin.28 Therefore, correction of platelet levels by transfusion might be recommended as the first of many steps to promote thrombin production and primary haemostasis (Figure 2), with target levels of ≥50,000/dL, especially in the setting of active bleeding or during high‑risk invasive procedures.
Recombinant factor VIIa
rFVIIa was initially developed for use in patients with haemophilia who experienced active bleeding during invasive procedures.29 Although rFVIIa was shown to normalize prothrombin times for nonbleeding patients with cirrhosis, the effect on actual bleeding risk was not as clearly demonstrated.30 A randomized controlled trial in 2004 studying patients with Child–Pugh B and C stage cirrhosis with variceal bleeding showed a benefit of rFVIIa administration on control of bleeding, but no change in mortality compared with patients treated with placebo.31 The same research group performed a similar study in 2008 and demonstrated that treatment with rFVIIa had no benefit in controlling bleeding and did not affect mortality risk.32 As demonstrated by these studies and other case series of patients with cirrhosis and active variceal bleeding, results relating to the use of rFVIIa in achieving haemostatic control have differed, but the cost and risk of thrombotic complications remains.31,33,34 The use of rFVIIa as a ‘rescue’ agent in cases of ongoing haemorrhage to transiently gain control of a situation, such as to enable clearing the field for endoscopic banding, has yet to be adequately tested. Anecdotal experience in that situation varies widely even among the co-authors of this paper. In patients with acute liver failure the use of rFVIIa prior to intracranial pressure monitoring is often debated. A case report demonstrated the correction of the INR with rFVIIa at a dose of 40 μg/kg before placement of an intra cranial pressure monitor.35 However, previous comparative case series have shown that INR correction does not neces sarily correlate with a difference in bleeding complications or survival rates for patients with fulminant hepatic failure.36 The lack of significant differences could be due to the fact that despite having an elevated INR in the setting of acute liver failure, these patients often possess normal haemostatic profiles when measured using global tests such as thromboelastography, reinforcing the inadequate assessment of coagulation by INR in acute liver disease.37 Therefore, owing to the cost of treatment, the potential thrombotic complications and the lack of clear benefit, further studies are needed to guide our use of rFVIIa in patients with liver disease.38 Finally, the assessment of
NATURE REVIEWS | GASTROENTEROLOGY & HEPATOLOGY © 2014 Macmillan Publishers Limited. All rights reserved
VOLUME 11 | NOVEMBER 2014 | 677
REVIEWS Liver
Vitamin K
FFP PCC
Coagulation factors Coagulation cascade
Vascular cell rFVIIa Fibrinogen
TF
FVII
TF
Fxa
Cryoprecipitate Platelets
FVII
Thrombin
Fx
Prothrombin
von Willebrand Factor Fibrin degradation products
DDVAP Fibrin
Antifibrinolytics
Figure 2 | Site and mechanism of action for procoagulant blood products. Vitamin K repletion bypasses consumption in a malnourished state and is a cofactor in post-translational modification of coagulation factors in the liver. FFP or PCC provides passive repletion of coagulation factors to initiate the coagulation cascade. rFVIIa, a potent procoagulant, provides activated factor VIIa to avoid the need for coagulation activation. Cryoprecipitate repletes stores of fibrinogen to provide a substrate for clot formation. Desmopressin can stimulate the release of von Willebrand Factor to counteract platelet dysfunction. Finally, antifibrinolytics block the degradation of the fibrin clot to promote clot stability. Abbreviations: DDVAP, desmopressin; FFP, fresh frozen plasma; PCC, prothrombin complex concentrate; rFVIIa, recombinant factor VIIa; TF, tissue factor.
rFVIIa efficacy on the basis of INR correction is a possible flaw in earlier study designs. Future studies using global functional tests of whole blood might help to clarify the true effect of rFVIIa on coagulation.
Antifibrinolytic agents
When clotting occurs, the regulatory process that controls the amount of clot formation is called fibrinolysis (Figure 2). The presence of cirrhosis can affect the balance of clot stability and controlled fibrinolysis. Some patients with liver disease might experience hyperfibrinolysis, in which clot breakdown is accelerated.39 Fibrinolysis is promoted by tissue plasminogen activator, but can be countered by antagonists, specifically thrombin- activatable fibrinolysis inhibitor and plasminogen activator inhibitor.40 Patients with end-stage liver disease might produce low levels of the fibrinolysis inhibitors, which would promote more rapid clot breakdown, but conflicting results are reported in the literature.41,42 Clinically, fibrinolysis is important in patients who have decompen sated cirrhosis presenting with ascites because body cavity fluids, such as saliva and ascites, have fibrinolytic 678 | NOVEMBER 2014 | VOLUME 11
properties that might affect haemostasis after procedures such as paracentesis or dental extractions.43 Antifibrinolytic medications include derivatives of the amino acid lysine, which prevent plasmin formation thereby inhibiting clot lysis and promoting clot stabilization. The two forms of antifibrinolytic agents that are most commonly used are 4‑(aminomethyl) cyclohexanecarboyxylic acid (transexamic acid) and 6‑aminohexanoic acid (aminocaproic acid). Although point-of-care wholeblood assays such as thromboelastography or thrombo elastometry hold promise, there are currently no widely available laboratory measurements that can quantify the effect of fibrinolysis in patients who are bleeding. Other techniques of whole-blood measurements (thrombo elastography, sonorheometry and clot lysis times) might provide some insight into this aspect of clot stabilization and have shown increased rates of fibrinolysis in patients with cirrhosis. Even with whole-blood assays much work needs to be done to provide reliable and quickly available indices and parameters of coagulation. The use of anti fibrinolytic agents is currently directed by clinical recognition of hyperfibrinolysis in the setting of delayed bleeding or exposure of the clot to fibrinolytic fluids (that is ascites and saliva). Antifibrinolytic agents should be used with caution, as demonstrated by the market withdrawal of aprotinin; in May 2008, a cardiovascular study was stopped prematurely as aprotinin reduced the risk of massive bleeding, but led to a higher than expected mortality rate, probably due to the resulting hypercoaguability.44 On the other hand, safe use of aminocaproic acid has been reported in patients with cirrhosis and a more recent meta-analysis has called into question the originally proposed dangers of aprotinin.45,46 When hyperfibrinolysis is strongly suspected on the basis of clinical findings or confirmed by whole-blood assays, our own experience is in agreement that aminocaproic acid is fairly safe. When delayed bleeding occurs and hyperfibrino lysis is suspected, dosing with antifibrinolytic agents intravenously—or by topical application using soaked gauze during dental procedures—could promote clot stabilization and be life saving.47 Intravenous dosing consists of an initial loading dose and then subsequent utilization of a continuously infused maintenance dose. Use of antifibrinolytic agents should be considered in patients who have delayed bleeding episodes or when fibrinolytic bodily fluids are present.
Prothrombin concentrate complexes
PCC are derived from human plasma and contain concentrated liver-derived vitamin-K-dependent coagulation factors (in a ‘balanced’ form contain factor II, VII, IX and X along with protein C and protein S) to prevent activation of the factors (Figure 1).48 Initially developed to provide a supportive agent for coagulation in patients with a congenital deficiency (such as haemophilia), PCC have also been studied in the emergency reversal of action of vitamin K antagonists. Current guidelines recommend the use of PCC rather than FFP in patients with major bleeding related to vitamin K antagonists.49 A desirable feature of PCC is the reduced volume required for
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REVIEWS transfusion when compared with FFP because it has a 25-fold higher concentration of factors.48 Experience with PCC in the USA is limited and currently only one PCC formula containing four factors (Kcentra®, CSL Behring, King of Prussia, PA, USA) is FDA approved for use in the correction of bleeding related to vitamin K antagonists. Although effective at reversing INR in patients on vitamin K antagonists, Kcentra® carries an FDA label warning patients of a potential increased risk of thrombosis.50 The risk of thrombosis with PCC administration in patients with liver disease has been documented in early reports.51 Whether exogenous manipulation of procoagulation and anticoagulation factors with PCC will lead to improved outcomes in patients with cirrhosis remains uncertain. Several studies have examined the efficacy and safety of PCC in prophylaxis or rescue therapy for bleeding related to vitamin K antagonists, including four studies evaluating PCC in patients with chronic liver disease.52–55 These studies mainly examined the effect of PCC on coagulation parameters assessed by post-infusion changes in coagulation factor levels, change in prothrombin time or other indirect measures. As discussed previously, coagulation factor levels and prothrombin time or INR might not provide an accurate global assessment of bleeding risk in patients with cirrhosis, thus the clinical relevance of these studies is questionable. In patients with cirrhosis who are actively bleeding, PCC has been shown to achieve successful clinical haemostasis; however, the effect was transient and only provided a bridge to more‑definitive surgical therapy.54 A major contributing factor to bleeding in patients with cirrhosis is portal hypertension. As substantially lower volumes are required when using PCC compared with FFP, PCC represents an attractive alternative in patients with cirrhosis and bleeding or for prophylaxis when undergoing major surgery. Currently, a multicentre trial evaluating PCC versus placebo during liver transplantation is being conducted in the Netherlands (PROTON trial, NTR3174).56 The investigators hypothesize that use of PCC, due to its smaller repletion volume, will decrease overall blood loss and transfusion requirement as compared with use of a placebo infusion. The role of PCC in prophylaxis or rescue therapy for bleeding in patients with chronic liver disease is currently undefined. Further studies, like the current PROTON trial, are needed before routine usage of this product can be recommended in this population. As INR does not predict bleeding risk in patients with cirrhosis, surrogate markers of efficacy (thromboelastography or thrombin generation assay) should be used when studying the effects of PCC. Caution must remain because it is not known whether a disturbance of the fragile balance in the coagulation system in cirrhosis could place patients at an increased risk of thrombosis.
Desmopressin
Desmopressin (1-deamino‑8-D-arginine vasopressin) is a synthetic analogue of human antidiuretic hormone. Historically, desmopressin has been used for the treatment of inherited bleeding disorders such as von Willebrand
disease (caused by a deficiency in vWF) and mild forms of haemophilia A (caused by a deficiency in factor VIII), as well as in acquired disorders such as uraemic bleeding and thrombocytopenia. vWF acts as a carrier protein binding to factor VIII and promoting platelet adhesion at sites of vessel injury. In a randomized, double-blind placebo-controlled trial, desmopressin shortened bleeding time in patients with uraemia by increasing levels of factor VIII as they are bound to vWF multimers.57 As acute kidney injury and uraemia are common in hospitalized patients with cirrhosis, desmopressin represents an attractive agent to support haemostasis. Desmopressin has been studied in patients with chronic liver disease with conflicting results.58–63 In studies examining the effects on coagulation parameters, desmopressin is associated with increasing levels of factor VIII, vWF and improvement in measures such as bleeding time and prothrombin time.58,59,63 Other studies have examined the role of desmopressin by evaluating clinical outcomes comparing the administration of desmopressin with administration of FFP in patients with cirrhosis who were undergoing dental extractions.61 Prior to extraction, intranasal administration of desmopressin was as effective for post-extraction (24–48 h) bleeding and the need for red blood cell transfusions as FFP and platelet trans fusion. Furthermore, desmopressin was noted to be safer and more cost-effective than FFP.61 However, this study lacked a placebo arm and whether either intervention is actually necessary for prophylaxis is unclear. By contrast, a study evaluating the use of desmopressin prior to hepat ectomy found that although levels of factor VIII and vWF significantly increased in patients receiving desmopressin compared with placebo (P 50,000/dL or higher depending on the clinical scenario ■■ Control any infection to reduce endogenous heparinoids ■■ Control uraemia to prevent further platelet dysfunction ■■ Use conservative replacement to maintain low volumes and avoid exacerbating portal hypertension ■■ Measure fibrinogen and replete with cryoprecipitate if a value of
Introduction
Division of Gastroenterology and Hepatology, PO Box 800708, University of Virginia, Charlottesville, VA 22908, USA (N.L.S., N.M.I., P.G.N., C.K.A., S.H.C.).
The proper balance of procoagulant and antihaemostatic factors in healthy individuals leads to haemostasis, which prevents inappropriate bleeding or clotting. Although many cell types and organs are involved in this process, the liver produces the majority of proteins that regulate haemostasis. This balance usually remains intact in patients with liver disease, albeit in a much more precarious and fragile state.1 Traditionally, liver disease has been associated with a bleeding tendency, but mounting evidence has uncovered a coexistent propensity to develop thrombosis in certain circumstances.2 The complex nature of this coagulation system has led to uncertainty in the clinical realm regarding treatment. Although many studies in this field have considerably advanced our understanding of the coagulop athy of liver disease, in vitro studies have relied upon measures and tests that do not account for the multitude of in vivo interactions. Consequently, the results of many studies cannot necessarily be used directly by clinicians and underlying, entrenched dogmas become difficult to change. Furthermore, many available products were originally designed and intended for use in other bleeding diatheses and so it is often unclear which agent is useful for a particular circumstance in patients with liver diseases. With an increased understanding of the physiology of therapeutics, the following sections provide a greater understanding of treatment for bleeding or clotting in patients with liver disease. Examining procoagulants and the clinical rationale can ultimately prove essential in the treatment of the 20–40% of patients with cirrhosis who present to healthcare providers with bleeding episodes due to haemostatic abnormalities.3,4
Correspondence to: N.L.S. [email protected]
Competing interests The authors declare no competing interests.
Vitamin K
Vitamin K is mainly found in green leafy vegetables and is absorbed in the small intestine after ingestion. Vitamin K is involved in post-translational modification of coagulation factors within the liver. For example, the conversion of glutamic acid to gamma-carboxyglutamic acid is dependent on vitamin K. This conversion takes place in the liver and is hindered in the setting of vitamin K deficiency or in the presence of vitamin K antagonists.5 Low levels of vitamin K are often found in patients with liver disease who are malnourished, which most commonly occurs in those who are actively using alcohol.6 Low levels of vitamin K result in decreased production of procoagulation factors II, VII, IX, and X and anti coagulation factors, protein C and protein S. Repletion of vitamin K attempts to correct this imbalance by restoring normal levels of this essential component involved in the generation of coagulation factors. However, a study exploring the effect of vitamin K repletion in patients with cirrhosis showed that it resulted in only a slight improvement in prothrombin time and activated partial thromboplastin time and only a modest improvement in vitamin‑K‑dependent protein levels.7 In one study of patients with liver disease and vitamin K deficiency, almost 90% were found to produce pro thrombin in an ‘under-carboxylated’ state, known as ‘prothrombin induced by vitamin K absence’ (PIVKA II).8 PIVKA II has also been studied for its prognostic value in hepatocellular carcinoma screening. Alpha‑fetoprotein‑L3 and PIVKA II levels were shown to be sensitive markers for hepatocellular carcinoma detection when used in combination. 9 Although the clinical significance of vitamin K repletion to ameliorate PIVKA II is unclear as mentioned previously, studies have shown only a modest decrease in PIVKA II levels with the administration of vitamin K.7 In theory, vitamin K repletion should result in
NATURE REVIEWS | GASTROENTEROLOGY & HEPATOLOGY © 2014 Macmillan Publishers Limited. All rights reserved
VOLUME 11 | NOVEMBER 2014 | 675
REVIEWS Key points ■■ International normalized ratio values in liver disease might be falsely elevated, thus caution should be taken when using this value to consider fresh frozen plasma repletion ■■ Cryoprecipitate should be used in the setting of fibrinogen deficiency for proper clot formation ■■ Platelet transfusion to at least 50,000/dL can result in adequate thrombin production in the setting of liver disease ■■ In cirrhosis patients with chronic inflammation, hyperfibrinolysis can be present and can be treated with antifibrinolytics to promote clot stabilization ■■ The knowledge of the coagulation profile for cirrhosis patients is rapidly evolving, future studies might provide further insight into other procoagulant therapies
more complete carboxylation of prothrombin and proper production of coagulation proteins. Even with the high prevalence of vitamin K deficiency in patients with liver disease, evidence about the overall benefit of vitamin K repletion on the coagulation pro file of these patients is scant. Nevertheless, in clinical scenarios suggestive of vitamin K deficiency, repletion, preferably by intravenous delivery, would aid in pro coagulant factor production. Notably, studies have shown that oral vitamin K replacement is not as reliable as intravenous repletion owing to variable levels of gut absorption of this vitamin.10
Fresh frozen plasma
FFP is derived from donated blood products that have been centrifuged and separated from cellular components (Figure 1). FFP contains all coagulation factors that are essential to clot formation (that is, factors II, V, VII, VIII, IX, X and XI).11 Repletion of coagulation factors with FFP bypasses the need for vitamin K carboxylation in the liver for coagulation factor formation. The presence of coagulation factors can be measured using prothrombin time, which was first developed by A. J. Quick for use in the setting of vitamin K antagonists.12 Prothrombin time and the subsequently derived standardized result reported as the international normalized ratio (INR) have been widely used for the measurement of coagulation in disease. However, mounting evidence has shown that the INR is not an accurate marker of bleeding risk in patients with cirrhosis and has wide inter-laboratory variation.13,14 Nonetheless, as an elevated INR is commonly found in patients with liver disease, an inordinate amount of FFP is often used in patients with cirrhosis for prophylaxis without evidence of utility.3 Studies have shown the importance of using global coagulation measures on whole-blood samples rather than plasma alone, which is used in INR calculations. Thromboelastography is a whole-blood test that can provide more information on coagulation profiles in patients with liver disease than conventional parameters, such as the INR, which are often used as arbitrary targets to direct FFP administration.15 Routine use of FFP in clinical practice is based on insufficient evidence and is unlikely to cause significant correction of the liver coagulopathy. FFP infusions that are often used clinically, infrequently correct the coagulation profiles in patients with cirrhosis.16 In fact, caution should be taken in patients with cirrhosis and portal 676 | NOVEMBER 2014 | VOLUME 11
hypertension because the increased volume of blood after FFP transfusion will increase portal pressure in a linear fashion.17,18 Therefore, the risk of exacerbating portal hypertension and transfusion-related lung injury argues against routine use of FFP in this population, especially for targeting the INR.
Cryoprecipitate
Cryoprecipitate is what remains of frozen plasma after it has thawed. This insoluble residue contains factor VIII, fibronectin, von Willebrand factor (vWF) and fibrinogen (Figure 1), which are vital factors involved in coagulation. Fibrinogen is composed of six polypeptide chains (two α, β and γ chains each) that are normally assembled in hepatocytes. The protease thrombin subsequently cleaves fibrinogen to form fibrin molecules, which are then incorporated into a polymerization process for clot formation. Compared with healthy individuals, patients with endstage liver disease and cirrhosis might have lower levels of fibrinogen or impaired aggregation of fibrin monomers to properly form clots.19 In the setting of liver dysfunction, reduced fibrinogen levels might have a role in the impairment of coagulation.20 Cryoprecipitate or fibrinogen con centrate transfusions can supply ‘normal’ fibrinogen, but exact target values for fibrinogen are still unknown. Although the quantity of measureable fibrinogen might be adequate, the functionally abnormal fibrinogen (dysfibrinogenemia) in liver disease is still not readily measureable. Therefore, fibrinogen values obtained from the laboratory will not give an accurate assessment of the fibrinogen function in the setting of bleeding.19 Within these limitations and to ensure there is adequate functional fibrinogen available, our group uses a fibrinogen target level of 100–120 mg/dL in the setting of bleeding or pre-procedural prophylaxis. However, target levels for asymptomatic patients or prophylaxis in patients with liver disease remain unclear.21
Platelets
Platelet levels are assessed in a complete blood count from whole blood anticoagulated with ethylenediaminetetra acetic acid and can be used in the assessment of potential haemostasis. Platelets are essential for primary haemo stasis—that is, the formation of a platelet plug at the site of endothelial injury. Furthermore, platelet phospholipid surfaces and calcium potentiate tenase complexes (factors VIII and IX) and prothrombinase complexes (factors V and X), stimulate further platelet recruitment and clot formation. In patients with cirrhosis, platelet levels are often reduced owing to portal hypertension causing splenic seques tration, decreased production of the platelet growth factor (thrombopoietin) from the liver and increased platelet destruction (due to mechanisms similar to autoimmunemediated reactions such as immune thrombocytopenic purpura).22 Nevertheless, even in the setting of thrombocytopenia, patients with cirrhosis have preserved primary haemostasis. As a possible compensatory mechanism for decreased platelet levels, uncleaved vWF proteins levels are increased, which has been documented in patients with
www.nature.com/nrgastro © 2014 Macmillan Publishers Limited. All rights reserved
REVIEWS
Whole blood bag
Satellite bag
Hard spin
Coagulation factors II, VII, VIII, IX, X, XI Separate
FFP
Concentrated coagulation factors II, VII, IX, X, XII, protein C, protein S
PCC
PRBC Slow thaw Hard spin
FFP
Separate
Fibrinogen von Willebrand Factor (vWF) Cryosupernatant
Cryoprecipitate
Figure 1 | Procoagulant blood products derived from whole blood. Whole blood is centrifuged to separate PRBCs from plasma. The plasma can be used to derive three different blood products often used to aid in coagulation; FFP, PCC and cryoprecipitate. These products are often frozen for storage and thawed at the time of use. FFP is unaltered plasma that contains coagulation factors II, VII, VIII, IX, X and XI. PCC are distilled from plasma and contains the same factors as FFP but in a concentrated form. Finally, cryoprecipitate is an insoluble residue formed from thawed plasma and contains fibrinogen and von Willebrand factor. Abbreviations: FFP, fresh frozen plasma; PCC, prothrombin complex concentrate; PRBC, packed red blood cell.
cirrhosis.23 The increase in levels of large-multimer-sized vWF is thought to occur partly due to a decrease in the production of a vWF regulatory protein, ADAMTS13.24 Furthermore, in vitro studies have demonstrated that the presence of endotoxins in patients with cirrhosis might damage the endothelium and result in the release of vWF.25 The overall increase in the concentration of uncleaved vWF promotes adhesion of platelets to the subendothelial wall for primary haemostasis.23 The quantity of platelets is important for primary haemostasis to be achieved; however, the quality of platelet function could be just as crucial. The high prevalence of renal dysfunction in patients with liver disease—due to diuretic use or hepatorenal syndrome—can negatively affect platelet function because of underlying uraemia.26 The presence of uraemia reduces platelet aggregation and
binding capacity, thereby affecting the functional capacity of clot formation.27 Platelets are involved in thrombin (factor II) generation at the amplification phase of haemostasis to promote the activation of coagulation factors. Inherent thrombin production capacity might be limited when cirrhosis occurs alongside severe thrombocytopenia; however, it has been demonstrated that correcting platelet levels to >50,000/dL enables adequate thrombin production and >100,000/ dL might result in normalization of the capacity of platelets to generate thrombin.28 Therefore, correction of platelet levels by transfusion might be recommended as the first of many steps to promote thrombin production and primary haemostasis (Figure 2), with target levels of ≥50,000/dL, especially in the setting of active bleeding or during high‑risk invasive procedures.
Recombinant factor VIIa
rFVIIa was initially developed for use in patients with haemophilia who experienced active bleeding during invasive procedures.29 Although rFVIIa was shown to normalize prothrombin times for nonbleeding patients with cirrhosis, the effect on actual bleeding risk was not as clearly demonstrated.30 A randomized controlled trial in 2004 studying patients with Child–Pugh B and C stage cirrhosis with variceal bleeding showed a benefit of rFVIIa administration on control of bleeding, but no change in mortality compared with patients treated with placebo.31 The same research group performed a similar study in 2008 and demonstrated that treatment with rFVIIa had no benefit in controlling bleeding and did not affect mortality risk.32 As demonstrated by these studies and other case series of patients with cirrhosis and active variceal bleeding, results relating to the use of rFVIIa in achieving haemostatic control have differed, but the cost and risk of thrombotic complications remains.31,33,34 The use of rFVIIa as a ‘rescue’ agent in cases of ongoing haemorrhage to transiently gain control of a situation, such as to enable clearing the field for endoscopic banding, has yet to be adequately tested. Anecdotal experience in that situation varies widely even among the co-authors of this paper. In patients with acute liver failure the use of rFVIIa prior to intracranial pressure monitoring is often debated. A case report demonstrated the correction of the INR with rFVIIa at a dose of 40 μg/kg before placement of an intra cranial pressure monitor.35 However, previous comparative case series have shown that INR correction does not neces sarily correlate with a difference in bleeding complications or survival rates for patients with fulminant hepatic failure.36 The lack of significant differences could be due to the fact that despite having an elevated INR in the setting of acute liver failure, these patients often possess normal haemostatic profiles when measured using global tests such as thromboelastography, reinforcing the inadequate assessment of coagulation by INR in acute liver disease.37 Therefore, owing to the cost of treatment, the potential thrombotic complications and the lack of clear benefit, further studies are needed to guide our use of rFVIIa in patients with liver disease.38 Finally, the assessment of
NATURE REVIEWS | GASTROENTEROLOGY & HEPATOLOGY © 2014 Macmillan Publishers Limited. All rights reserved
VOLUME 11 | NOVEMBER 2014 | 677
REVIEWS Liver
Vitamin K
FFP PCC
Coagulation factors Coagulation cascade
Vascular cell rFVIIa Fibrinogen
TF
FVII
TF
Fxa
Cryoprecipitate Platelets
FVII
Thrombin
Fx
Prothrombin
von Willebrand Factor Fibrin degradation products
DDVAP Fibrin
Antifibrinolytics
Figure 2 | Site and mechanism of action for procoagulant blood products. Vitamin K repletion bypasses consumption in a malnourished state and is a cofactor in post-translational modification of coagulation factors in the liver. FFP or PCC provides passive repletion of coagulation factors to initiate the coagulation cascade. rFVIIa, a potent procoagulant, provides activated factor VIIa to avoid the need for coagulation activation. Cryoprecipitate repletes stores of fibrinogen to provide a substrate for clot formation. Desmopressin can stimulate the release of von Willebrand Factor to counteract platelet dysfunction. Finally, antifibrinolytics block the degradation of the fibrin clot to promote clot stability. Abbreviations: DDVAP, desmopressin; FFP, fresh frozen plasma; PCC, prothrombin complex concentrate; rFVIIa, recombinant factor VIIa; TF, tissue factor.
rFVIIa efficacy on the basis of INR correction is a possible flaw in earlier study designs. Future studies using global functional tests of whole blood might help to clarify the true effect of rFVIIa on coagulation.
Antifibrinolytic agents
When clotting occurs, the regulatory process that controls the amount of clot formation is called fibrinolysis (Figure 2). The presence of cirrhosis can affect the balance of clot stability and controlled fibrinolysis. Some patients with liver disease might experience hyperfibrinolysis, in which clot breakdown is accelerated.39 Fibrinolysis is promoted by tissue plasminogen activator, but can be countered by antagonists, specifically thrombin- activatable fibrinolysis inhibitor and plasminogen activator inhibitor.40 Patients with end-stage liver disease might produce low levels of the fibrinolysis inhibitors, which would promote more rapid clot breakdown, but conflicting results are reported in the literature.41,42 Clinically, fibrinolysis is important in patients who have decompen sated cirrhosis presenting with ascites because body cavity fluids, such as saliva and ascites, have fibrinolytic 678 | NOVEMBER 2014 | VOLUME 11
properties that might affect haemostasis after procedures such as paracentesis or dental extractions.43 Antifibrinolytic medications include derivatives of the amino acid lysine, which prevent plasmin formation thereby inhibiting clot lysis and promoting clot stabilization. The two forms of antifibrinolytic agents that are most commonly used are 4‑(aminomethyl) cyclohexanecarboyxylic acid (transexamic acid) and 6‑aminohexanoic acid (aminocaproic acid). Although point-of-care wholeblood assays such as thromboelastography or thrombo elastometry hold promise, there are currently no widely available laboratory measurements that can quantify the effect of fibrinolysis in patients who are bleeding. Other techniques of whole-blood measurements (thrombo elastography, sonorheometry and clot lysis times) might provide some insight into this aspect of clot stabilization and have shown increased rates of fibrinolysis in patients with cirrhosis. Even with whole-blood assays much work needs to be done to provide reliable and quickly available indices and parameters of coagulation. The use of anti fibrinolytic agents is currently directed by clinical recognition of hyperfibrinolysis in the setting of delayed bleeding or exposure of the clot to fibrinolytic fluids (that is ascites and saliva). Antifibrinolytic agents should be used with caution, as demonstrated by the market withdrawal of aprotinin; in May 2008, a cardiovascular study was stopped prematurely as aprotinin reduced the risk of massive bleeding, but led to a higher than expected mortality rate, probably due to the resulting hypercoaguability.44 On the other hand, safe use of aminocaproic acid has been reported in patients with cirrhosis and a more recent meta-analysis has called into question the originally proposed dangers of aprotinin.45,46 When hyperfibrinolysis is strongly suspected on the basis of clinical findings or confirmed by whole-blood assays, our own experience is in agreement that aminocaproic acid is fairly safe. When delayed bleeding occurs and hyperfibrino lysis is suspected, dosing with antifibrinolytic agents intravenously—or by topical application using soaked gauze during dental procedures—could promote clot stabilization and be life saving.47 Intravenous dosing consists of an initial loading dose and then subsequent utilization of a continuously infused maintenance dose. Use of antifibrinolytic agents should be considered in patients who have delayed bleeding episodes or when fibrinolytic bodily fluids are present.
Prothrombin concentrate complexes
PCC are derived from human plasma and contain concentrated liver-derived vitamin-K-dependent coagulation factors (in a ‘balanced’ form contain factor II, VII, IX and X along with protein C and protein S) to prevent activation of the factors (Figure 1).48 Initially developed to provide a supportive agent for coagulation in patients with a congenital deficiency (such as haemophilia), PCC have also been studied in the emergency reversal of action of vitamin K antagonists. Current guidelines recommend the use of PCC rather than FFP in patients with major bleeding related to vitamin K antagonists.49 A desirable feature of PCC is the reduced volume required for
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REVIEWS transfusion when compared with FFP because it has a 25-fold higher concentration of factors.48 Experience with PCC in the USA is limited and currently only one PCC formula containing four factors (Kcentra®, CSL Behring, King of Prussia, PA, USA) is FDA approved for use in the correction of bleeding related to vitamin K antagonists. Although effective at reversing INR in patients on vitamin K antagonists, Kcentra® carries an FDA label warning patients of a potential increased risk of thrombosis.50 The risk of thrombosis with PCC administration in patients with liver disease has been documented in early reports.51 Whether exogenous manipulation of procoagulation and anticoagulation factors with PCC will lead to improved outcomes in patients with cirrhosis remains uncertain. Several studies have examined the efficacy and safety of PCC in prophylaxis or rescue therapy for bleeding related to vitamin K antagonists, including four studies evaluating PCC in patients with chronic liver disease.52–55 These studies mainly examined the effect of PCC on coagulation parameters assessed by post-infusion changes in coagulation factor levels, change in prothrombin time or other indirect measures. As discussed previously, coagulation factor levels and prothrombin time or INR might not provide an accurate global assessment of bleeding risk in patients with cirrhosis, thus the clinical relevance of these studies is questionable. In patients with cirrhosis who are actively bleeding, PCC has been shown to achieve successful clinical haemostasis; however, the effect was transient and only provided a bridge to more‑definitive surgical therapy.54 A major contributing factor to bleeding in patients with cirrhosis is portal hypertension. As substantially lower volumes are required when using PCC compared with FFP, PCC represents an attractive alternative in patients with cirrhosis and bleeding or for prophylaxis when undergoing major surgery. Currently, a multicentre trial evaluating PCC versus placebo during liver transplantation is being conducted in the Netherlands (PROTON trial, NTR3174).56 The investigators hypothesize that use of PCC, due to its smaller repletion volume, will decrease overall blood loss and transfusion requirement as compared with use of a placebo infusion. The role of PCC in prophylaxis or rescue therapy for bleeding in patients with chronic liver disease is currently undefined. Further studies, like the current PROTON trial, are needed before routine usage of this product can be recommended in this population. As INR does not predict bleeding risk in patients with cirrhosis, surrogate markers of efficacy (thromboelastography or thrombin generation assay) should be used when studying the effects of PCC. Caution must remain because it is not known whether a disturbance of the fragile balance in the coagulation system in cirrhosis could place patients at an increased risk of thrombosis.
Desmopressin
Desmopressin (1-deamino‑8-D-arginine vasopressin) is a synthetic analogue of human antidiuretic hormone. Historically, desmopressin has been used for the treatment of inherited bleeding disorders such as von Willebrand
disease (caused by a deficiency in vWF) and mild forms of haemophilia A (caused by a deficiency in factor VIII), as well as in acquired disorders such as uraemic bleeding and thrombocytopenia. vWF acts as a carrier protein binding to factor VIII and promoting platelet adhesion at sites of vessel injury. In a randomized, double-blind placebo-controlled trial, desmopressin shortened bleeding time in patients with uraemia by increasing levels of factor VIII as they are bound to vWF multimers.57 As acute kidney injury and uraemia are common in hospitalized patients with cirrhosis, desmopressin represents an attractive agent to support haemostasis. Desmopressin has been studied in patients with chronic liver disease with conflicting results.58–63 In studies examining the effects on coagulation parameters, desmopressin is associated with increasing levels of factor VIII, vWF and improvement in measures such as bleeding time and prothrombin time.58,59,63 Other studies have examined the role of desmopressin by evaluating clinical outcomes comparing the administration of desmopressin with administration of FFP in patients with cirrhosis who were undergoing dental extractions.61 Prior to extraction, intranasal administration of desmopressin was as effective for post-extraction (24–48 h) bleeding and the need for red blood cell transfusions as FFP and platelet trans fusion. Furthermore, desmopressin was noted to be safer and more cost-effective than FFP.61 However, this study lacked a placebo arm and whether either intervention is actually necessary for prophylaxis is unclear. By contrast, a study evaluating the use of desmopressin prior to hepat ectomy found that although levels of factor VIII and vWF significantly increased in patients receiving desmopressin compared with placebo (P 50,000/dL or higher depending on the clinical scenario ■■ Control any infection to reduce endogenous heparinoids ■■ Control uraemia to prevent further platelet dysfunction ■■ Use conservative replacement to maintain low volumes and avoid exacerbating portal hypertension ■■ Measure fibrinogen and replete with cryoprecipitate if a value of
