Fig. 21.1
The balance and rebalance of hemostasis in cirrhosis. Patients without liver disease maintain a balance of procoagulant and anticoagulant proteins. Patients with cirrhosis have decreased levels of both and other compensatory mechanisms but at steady state maintain an effective rebalance of hemostasis. Many factors, both extrinsic and intrinsic can lead to imbalance and bleeding or clotting disorders in patients with cirrhosis (Illustration by Anita Impagliazzo)
While the stable patient with cirrhosis is in a rebalanced state of hemostasis , the balance is tenuous and easily disturbed (Fig. 21.1). Many factors, both extrinsic (infection, surgery, other medical comorbidity or acute illness) and intrinsic (acute and chronic renal disease, mechanical sources of bleeding such as esophageal varices) can cause a loss of balance and result in various clinical disorders such as hemorrhage, portal vein thrombosis, venous thromboembolism (VTE) , or hyperfibrinolysis. Clinically available diagnostic tests are currently inadequate to fully describe the hemostasis system in an individual patient and we will discuss the options currently available to the practicing clinician in the next section.
Evaluation of the Coagulation Status of a Cirrhosis Patient
Plasma-Based Laboratory Studies
Table 21.1 summarizes some commonly available laboratory studies used in clinical practice.
Table 21.1
Diagnostic tests and the special considerations needed in patients with chronic liver disease
Diagnostic test | Special consideration in cirrhosis |
---|---|
International normalized ratio | Inaccurate due to variation with reagents and provides poor predictability for pre-procedure bleeding risk stratification |
Platelet count | Thrombocytopenia in portal hypertension is multifactorial in etiology. Levels greater than 55,000/mcL provide adequate primary hemostasis and allow for thrombin generation during coagulation. Levels greater than 100,000/mcL may be needed for acute bleeding |
Fibrinogen | Degradation products increase with severe cirrhosis due to persistent plasminogen activators. Normal plasma levels do not rule out a fibrinolysis disorder |
Factor VIII/protein C ratio | Mean ratio in cirrhosis found to be 0.8, but higher values indicate hypercoagulability. Can be an early clinical marker of clotting tendency |
International Normalized Ratio
The INR was developed in the 1980s to normalize variations in the prothrombin time (PT) and correct for the different reagents utilized in the coagulation laboratory [12]. The foundation for INR measurements is based on extrapolation from plasma testing in patients taking vitamin K antagonists, specifically warfarin. This extrapolation has proven to be inadequate for accurate bleeding risk assessment in cirrhosis patients, as many factors affect coagulation profiles in liver disease patients. Multiple studies show that the variation in INR measurements for cirrhosis patients is dependent on reagents used in the coagulation laboratory [13]. These variations can mislead practitioners and have far-reaching clinical implications, as they can affect model of end-stage liver disease (MELD) scores and liver transplant organ allocation [14]. An INR (liver) based on plasma from liver disease patients has proven to be more accurate; however, it lacks clinical validation and widespread availability [15]. While INR will remain a conventional measure of bleeding risk in the general population, caution should be taken when used to evaluate cirrhosis patients.
Platelets
It is reported that 76 % of chronic liver disease patients suffer from thrombocytopenia (platelet count < 150,000/mm3) [16]. The cause of thrombocytopenia is likely multifactorial with marrow suppression, portal hypertension, splenic sequestration, and reduction in thrombopoietin production, all contributing. Physiologic compensation in cirrhosis patients can lead to increased levels of vWF and thus increased platelet adhesion [4]. However, in vitro studies show that a minimum number of platelets (approximately 55,000/mcL) are needed to generate adequate thrombin production for clot formation [8, 15]. In the setting of adequate platelet numbers and thrombin availability, platelet function analyzers have shown a correction in hematocrit values that further promote the platelet and endothelium interaction [17].
Fibrinogen
Severity of liver disease inversely correlates with fibrinogen levels. Fibrin degradation products increase in the setting of severe cirrhosis [18]. In the setting of normal fibrinogen levels, cirrhosis patients may still experience decreased function due to dysfibrinogenemia. The cell turnover in cirrhosis can lead to production of immature fibrinogen, which contributes to the direct measurement of a fibrinogen level, but does not provide a functional component in hemostasis [19].
Factor VIII/Protein C Ratio
Factor VIII, a procoagulant, is often increased in cirrhosis due to its release from injured hepatocytes, as well as a relative deficiency in lipoprotein receptor-related protein, its regulator [20]. Conversely, protein C, an anticoagulant, is a protein that experiences decreased production in the setting of liver disease. This deficiency further potentiates a rise in Factor VIII levels due to the presence of a light chain binding site for protein C to inactivate and regulate Factor VIII levels [21]. Therefore, the measurement of these separate components can provide a ratio that correlates with the severity of liver disease [22]. Values in cirrhosis patients have a mean of 0.8, while controls possess a mean value of 0.66. In this manner, a Factor VIII level can differentiate between the presence of hepatic dysfunction from disseminated intravascular coagulation, which is associated with low levels of coagulation factors.
Global Coagulation Measurements
With the multifactorial nature of coagulation in liver disease, there is increasing evidence for the utility of global functional measurements of clot formation. Conventional measures evaluate each component of the blood involved in hemostasis separately; however, their interaction is essential to properly determine bleeding or clotting risk.
Thromboelastography (TEG)
This device measures the shear stress needed to oscillate a cuvette with whole blood around a stationary pin at a steady rate. As the blood coagulates from its liquid form, the force needed to maintain a steady rate slowly increases as the liquid blood solidifies. This incorporates the interaction of all the blood components as the clot is formed. This whole blood measurement in cirrhosis patients seems to provide a more accurate measurement of bleeding/clotting risk [23, 24], but its clinical utility outside of the operating room has not been proven.
Rotational Thromboelastometry (ROTEM®)
This technique of whole blood measurement is similar to TEG, but involves a rotating pin with a stationary cuvette. Commercially available devices using this technology include several different “channels” that add various activators and inhibitors to the process in order to isolate or enhance an individual component of the hemostasis system to allow detailed analysis. This technique has been studied in the setting of liver transplantation, and has been used to provide guidance with blood product use and utilization of platelets and fibrinogen [25–27].
Sonorheometry (SR)
TEG and ROTEM provide whole blood functional measurements on a macroscopic scale. The shearing effect of these devices could theoretically lead to clot disruption affecting the true measurement of clotting times. Sonorheometry uses pulsed ultrasound waves to measure red blood cell movement and its correlation with clot formation. This technique is still under investigation and currently in development [28] but holds promise as a clinically useful whole blood coagulation monitor.
Management of Specific Coagulation Disorders
Bleeding
The majority of bleeding encountered in cirrhosis patients requires treatment of portal hypertension by both medical and mechanical methods. Transfusion of blood products is usually an essential adjunct for resuscitation, but the consequences of overtransfusion should be considered. A practical approach to optimization during active bleeding includes a target transfusion goal of a hemoglobin of 7–8 g/dL [29]. Clinical in vivo studies are sparse, but maintaining platelet count above 55,000/mcL and fibrinogen levels above 100 mg/dL (with cryoprecipitate) are also recommended to support endogenous coagulation systems in actively bleeding patients [30].
Other therapies have been studied to control bleeding in cirrhosis patients. In patients with variceal bleeding, treatment with recombinant factor VIIa(rFVIIa) was no different than placebo in controlling bleeding [31]. Additional reports in the literature describe the use of rFVIIa for rescue therapy in severe and uncontrolled hemorrhage [32]. Currently, the routine use of rFVIIa is limited to specific clinical situations without proof of efficacy from clinical trials [33]. Evidence for the use of prothrombin complex concentrates (PCC) for rescue bleeding in cirrhosis is limited and mainly observational [34, 35]. Hyperfibrinolysis is characterized by delayed bleeding from prior puncture sites or profuse mucosal bleeding and can cause significant steady blood loss. Medications such as tranexamic acid and epsilon-aminocaproic acid are available to treat bleeding from hyperfibrinolysis. One study showed successful hemostasis with use of epsilon-aminocaproic acid in cirrhosis patients with subcutaneous and soft tissue hemorrhage [11]. While DDAVP may have a role in prophylaxis, investigators showed worse outcomes when DDAVP with terlipressin was administered to patients with acute variceal bleeding compared to terlipressin alone [36].
Bleeding complications in cirrhosis may occur from a variety of physiologic mechanisms that often coexist. As we begin to understand the coagulopathy of cirrhosis and recognize it as a “rebalanced” state, the practice of routine prophylaxis and transfusion should be reevaluated. Furthermore, caution is paramount when manipulating the coagulation system with transfusion or medications due to the risk of initiating unwanted thrombotic events.
Prophylaxis for Bleeding Events
The lack of literature supporting or refuting bleeding prophylaxis in cirrhosis generates uncertainty, causing clinicians to extrapolate recommended strategies from noncirrhosis patients. Guidelines exist for the prevention of bleeding in portal hypertensive-related complications [29, 37]. Recommendations for pre-procedural prophylaxis for percutaneous liver biopsy are relatively nonspecific, but suggest platelet transfusion in patients with platelet count less than 50,000–60,000/mcL [38]. Ultimately, the authors recommend that pre-procedural prophylaxis strategies to liver biopsy be developed specific to each clinical situation. There are no current standardized guidelines for pre-procedural bleeding prophylaxis for other procedures and variation in practice is common [39, 40].
Common tests, like PT and INR, do not accurately predict bleeding and cannot be used to gauge risk [41]. Even so, the practice of transfusing fresh frozen plasma (FFP) to “correct” the INR pervades. Current evidence suggests that this is generally ineffective and may be harmful [15, 42]. Liver transplantation is the most invasive procedure a cirrhosis patient will likely undergo. While improvements in surgical technique and anesthesia management have reduced intraoperative bleeding, this procedure is sometimes associated with massive hemorrhage. Clinical outcomes are directly related to transfusion requirement during the perioperative period [43]. Conventional tests to predict bleeding prior to transplant are generally ineffective [44]. Moreover, evidence is accumulating that avoidance of plasma transfusion and efforts to reduce portal pressures can decrease transfusion requirement and improve outcomes [45, 46].
Other considerations for bleeding prophylaxis include PCC, rFVIIa, vasopressin analogues (desmopressin), antifibrinolytics, and hemopoietic growth factors. PCC contain purified and concentrated coagulation factors II, VII, IX, X, protein C and S (25-fold higher concentration compared to plasma). Use of PCC for bleeding prophylaxis is attractive due to reduced transfused volume, but data are limited and thrombotic complications have been reported [35, 47]. Prophylactic use of rFVIIa has been studied in a variety of clinical situations including prior to liver biopsy, intracranial monitoring in acute liver failure , and liver transplantation [48–50]. Results are inconsistent and use of this agent is limited by expense and risk of thrombosis. DDAVP has been studied in two randomized controlled trials in cirrhosis with patients undergoing dental extraction and liver resection [51, 52]. In the study evaluating dental extraction with DDAVP alone versus prophylactic transfusion of FFP and platelets, there were no differences in bleeding episodes between treated and control groups. Another study evaluating the use of DDAVP versus placebo prior to hepatic resection showed that DDAVP did not decrease transfusion requirement although traditional coagulation parameters showed improvement. The use of aprotinin (an antifibrinolytic agent) has been shown to reduce blood transfusion requirements in patients undergoing liver transplant, but the agent has been withdrawn from the market in the USA and Europe due to observed thrombotic complications in cardiac surgery patients [53, 54]. Recently, eltrombopag (a thrombopoietin analogue) was shown to effectively increase platelet levels and reduce transfusions, but did not reduce bleeding events and was associated with thrombotic complications [16]. Furthermore, the necessity of empirically increasing platelet counts above the 75,000/mcL level used in this study is questionable and can result in a tendency toward hypercoagulability [13].
Clotting Events
As discussed above, the rebalancing of the hemostasis system in patients with cirrhosis is frequently disturbed. There is now significant evidence that many patients with cirrhosis have a tendency for thrombophilia [22]. Portal vein thrombosis (PVT) and its complications are highly prevalent in cirrhosis patients and are addressed in a separate chapter of this textbook. There is also strong empiric evidence from observational [55] and large-scale epidemiologic [56] studies that patients with cirrhosis are predisposed to VTE, both pulmonary embolism and non-splanchnic deep venous thrombosis. Unlike the venous thromboembolic events, observational data regarding arterial thrombosis (in the nontransplant setting) are less convincing. In nonalcoholic fatty liver disease (NAFLD) there are mounting data, both mechanistic [57, 58] and observational [59], for an increased risk for arterial events. This elevated risk is usually manifested as typical plaque rupture in cardiovascular or cerebrovascular ischemic events.
Outside of the realm of portal vein thrombosis, data for treatment of acute thrombotic events in cirrhosis patients are extremely limited and few definitive conclusions can be drawn from the literature. It is clear that hepatic synthetic dysfunction and impaired renal function, both of which are common in progressive cirrhosis patients, must be considered in dosing and scheduling of antihemostatic medications. Data are now accumulating on pharmacokinetics for many of these agents in cirrhosis patients including the low molecular weight heparins (LMWH) [60], rivaroxaban [61], dabigatran [62], and apixaban [63]. The use of the vitamin K antagonists is difficult because of the innate elevation in INR in patients with liver disease making the narrow therapeutic window difficult to reliably achieve. There is a definitive lack of data regarding the antiplatelet agents in cirrhosis patients, especially in the acute event management setting, aside from scant case reports and subgroup analyses of larger studies [64]. Safety data for therapeutic use of the anticoagulants are significantly lacking except for enoxaparin and the current lack of specific reversal agents make the direct acting anticoagulants (factor X or factor II inhibitors) less comforting despite their wide therapeutic window and easy dosing [65]. It is clear that none of the currently available laboratory tests are adequate to measure therapeutic efficacy or dosing although some research methods, most significantly thrombin generation assays [66], show promise in eventual clinical development. It should be stressed that as liver disease progresses, functional levels of antithrombin decrease remarkably and this may cause confusion and misinterpretation of traditional anti-Xa activity assays which can be useful in monitoring anticoagulant activity in the noncirrhosis patient [67]. Use of the anti-Xa assay in advanced liver disease can lead to the overdosage of many anticoagulants and should not be used to assess adequacy of anticoagulation in this population. The direct inhibitors of factor X may be monitored with this method but data on the clinical usefulness of this monitoring method are lacking.