Hemostasis activation in patients with liver cirrhosis

doi:10.1016/0049-3848(95)91614-Q

Thrombosis Research

Volume 77, Issue 3, 1 February 1995, Pages 271-278

https://doi.org/10.1016/0049-3848(95)91614-Q Get rights and content

Abstract

In patients with liver cirrhosis a decrease of the coagulant potential is well-documented and has been linked to the high bleeding tendency among these patients. Wether the decrease of the coagulant potential is only due to a reduced hepatic synthesis of coagulation factors or also to its consumption by disseminated intravascular coagulation is debatable. We investigated hemostasis activation markers thrombin-antithrombin III complexes (TAT), fibrin degradation products (D-Dimer) and plasmin-α2-antiplasmin complexes (PAP) in 41 outpatients with liver cirrhosis (Child-Pugh index 1 n=18, 2 n=15, 3 n=8). Compared to controls similar in terms of age and sex, TAT, D-Dimer and PAP was elevated in the whole group of patients. A progressive increase of D-Dimer and PAP from Child 1 to 3 indicates a relationship between the severity of cirrhosis and the amount of hemostasis activation. Investigation of the natural anticoagulant potential showed significant decreases of antithrombin III (AT III), protein C, and protein S, most pronounced in Child 3 patients. Statistical analysis revealed significant negative correlations between levels of D-Dimer and both AT III and protein C, indicating that hemostasis activation is linked to the loss of anticoagulant potential.

References (18)

K Huber et al.
Hepatic synthesis and clearance of components of the fibrinolytic system in healthy volunteers and in patients with different stages of liver cirrhosis
Thromb Res
(1991)
F Marongiu et al.
α2-antiplasmin and disseminated intravascular coagulation in liver cirrhosis
Thromb Res
(1985)
T.C Vukovich et al.
Quantitative determination of human protein C
Thromb Res
(1988)
K.H Zurborn et al.
Immunological and functional determination of the protease inhibitors, protein C and antithrombin III, in liver cirrhosis and in neoplasia
Thromb Res
(1988)
J.M. Carr
Disseminated intravascular coagulation in Cirrhosis
Hepatology
(1989)
O.D. Ratnoff et al.
The natural history of Laennec's cirrhosis of the liver: an analysis of 386 cases
Medicine
(1942)
D.A. Kelly et al.
Haemostatic problems in liver disease
Gut
(1986)
N Aoki et al.
The α2-plasmin inhibitor levels in liver disease
Clin Chim Acta
(1978)
S Coccheri et al.
Significance of plasma fibrinopeptide A and high molecular weight fibrinogen in patients with liver cirrhosis
Brit J Haematol
(1982)

There are more references available in the full text version of this article.

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Acute pulmonary embolism (PE) can occur as a manifestation of an underlying cancer and be of paraneoplastic aetiology. A previously unknown cancer is sometimes diagnosed after the acute PE diagnosis. The identification of a group of patients with elevated probability of having an occult cancer underlying PE was never performed. We aimed to determine predictors of occult cancer in acute PE. Our hypothesis was that the D-dimer levels would be a predictor of cancer.
We retrospectively analysed a cohort of patients hospitalized with acute PE. Exclusion criteria: <18 years, venous embolism only of veins other than pulmonary territory or when the embolism was considered chronic, and no image confirmation of acute PE. Patients were grouped according to the timing of cancer diagnosis: 1) known concomitant active cancer, 2) cancer diagnosed during acute PE admission or in the following 2 years and, 3) no known cancer during the 2-year follow-up since PE diagnosis. Predictors of concomitant cancer were determined using a logistic regression analysis. Multivariate models were built.
We studied 562 patients; median age was 72 years and 219 (39.0 %) were men. In 223 (39.7 %) of the patients the PE was of central arteries and 61.4 % presented with bilateral PE. PE was considered unprovoked at time of discharge in 47.7 %. Median (interquartile range) D-dimer level was 7.98 (3.30–14.99) μg/mL. A total of 126 (22.4 %) patients were in group 1, 47 in group 2 (cancer diagnosed after the diagnosis of acute PE and up to 2 years) and 389 patients were in group 3. Elevated D-dimer levels were independently associated with already known cancer. D-dimer were independent predictors of future cancer diagnosis: OR = 1.07 ((95 % CI: 1.01–1.14) per each 5 ng/mL increase; for patients with D-dimer >15.0 μg/mL the OR of future cancer was 2.10 (1.05–4.18). If only patients with unprovoked PE upon admission (n = 307) were to be considered results were similar considering D-dimer; anaemia also predicted unknown cancer [OR = 2.13 (1.08–4.16)].
Patients with D-dimer >15 μg/mL presented a >2-fold higher risk of being diagnosed with a cancer condition in the upcoming 2 years. D-dimer may help clinicians in identifying which patients are at higher risk of occult cancer.
The portal vein in patients with cirrhosis is not an excessively inflammatory or hypercoagulable vascular bed, a prospective cohort study
2022, Journal of Thrombosis and Haemostasis
Citation Excerpt :
We detected no local increase in NET markers in portal nor in hepatic plasma, suggesting there is not (at least) a direct link between local inflammation and NETs in portal hypertension in cirrhotic patients. TAT, PAP, and D‐dimers, which are markers of activation of coagulation and fibrinolysis, have been shown to be elevated in patients with cirrhosis compared with healthy controls.28 Although our results indicate elevated levels of these markers in portal plasma compared with hepatic and peripheral plasma, on careful inspection, levels of these markers are clearly the lowest in the HV.
A hypercoagulable state is not associated with development of portal vein thrombosis in cirrhosis, as we previously demonstrated. However, some groups demonstrated elevated levels of inflammatory markers and activation of hemostasis in the portal vein (PV) compared to posthepatic veins, but because the liver is involved in clearance of these markers, we hypothesize that interpretation of these data is not straightforward.
To determine whether the PV has particular proinflammatory/hypercoagulable characteristics by comparing plasma sampled in the PV, hepatic vein (HV), and the systemic circulation.
Plasma samples from 51 cirrhotic patients with portal hypertension undergoing transjugular intrahepatic portosystemic shunt placement, were taken from the PV, HV, and jugular vein (JV). Markers of inflammation (lipopolysaccharide, tumor necrosis factor‐α, interleukin‐6, thiobarbituric acid‐reactive substances), neutrophil‐extracellular‐traps (cfDNA, MPO‐DNA), endothelial damage (von Willebrand factor [VWF]), and hemostasis were determined and compared among the three vascular beds.
Markers of inflammation were slightly, but significantly higher in the PV than in the HV and systemic circulation. VWF and markers of hemostasis were modestly elevated in the PV. Levels of multiple markers were lower in the HV compared with the PV and systemic circulation. Higher model for end‐stage liver disease score was associated with a more prothrombotic state in all three sample sites.
In contrast to published studies, we did not detect a clear proinflammatory or prothrombotic environment in the PV of cirrhotic patients. Many markers are lowest in the HV, indicating that the low levels of these markers in the HV, at least in part, reflect clearance of those markers in the liver.
Thrombotic risk factors in patients with liver cirrhosis: Correlation with MELD scoring system and portal vein thrombosis development
2009, Journal of Hepatology
Citation Excerpt :
In a previous study, TRFs were found to be independently associated with the extent of fibrosis in patients with chronic hepatitis [10]. The results obtained in the present study confirm several earlier reports showing that haemostatic tests could be of great practical value in the assessment of hepatocyte function in liver disease [6,13,27,40,41]. Not surprisingly, our study showed that the reduction in the level of antithrombotic proteins is strongly related to the severity of liver cirrhosis according to the MELD scoring system.
Prognostic scores currently used in cirrhotic patients do not include thrombotic risk factors (TRFs). Predicting factors of portal vein thrombosis (PVT) development are still unknown. We wanted to describe TRFs as a function of liver disease severity using the MELD score and assess the role of local and systemic TRFs as predictors of PVT development in cirrhotic patients.
One hundred consecutive patients with liver cirrhosis were included in the study. TRFs, D-dimers, MELD score, portal vein patency and flow velocity were evaluated in all subjects at baseline and every 6 months thereafter. Variables able to predict PVT development within 1 year were identified by means of multiple logistic regression.
The plasma levels of protein C and antithrombin were lower and the concentration of D-dimers was higher in patients with advanced disease. Plasma levels of antithrombin, protein C and protein S resulted significantly lower in PVT group at univariate analysis, but reduced portal vein flow velocity was the only variable independently associated with PVT development.
Lower concentrations of natural coagulation inhibitors are frequently detected in patients with liver cirrhosis. A reduced portal flow velocity seems to be the most important predictive variable for PVT development in patients with cirrhosis.
The use of D-dimer in specific clinical conditions: A narrative review
2009, European Journal of Internal Medicine
Citation Excerpt :
More co-morbidity can also be expected in patients admitted to the hospital (inpatients), providing a sample with elevated D-dimer levels. Factors that can contribute to a higher level of D-dimer are extensive inflammation, malignancy, surgery and liver disease [32–35]. Hospitalized patients are also at higher risk for developing VTE with an increased mortality rate [36].
The use of D-dimer in combination with a clinical decision rule has been widely investigated in pulmonary embolism and deep venous thrombosis. Although it has been shown to be safe in excluding venous thromboembolism, the clinician is often faced with specific situations in which the use of D-dimer is controversial. We review the best available evidence on these patients. We conclude that it is not safe to use D-dimer testing in patients with symptoms of a venous thromboembolism for over 14 days, patients receiving therapeutic heparin treatment and patients with suspected deep venous thrombosis during oral anticoagulant therapy. In these populations the levels of D-dimer can be lower then expected giving rise to false-negative results. It is safe to use D-dimer testing in combination with a clinical decision rule in patients of all ages, patients presenting with a suspected recurrent venous thromboembolism or inpatients with suspected pulmonary embolism. As patients with recurrent venous thromboembolism, elderly patients and inpatients have higher levels of D-dimer, D-dimer testing has a low specificity and the need for additional radiological testing is increased.
Hypercoagulation in Liver Disease
2009, Clinics in Liver Disease
Citation Excerpt :
Congenital genetic defects in protein C, protein S, antithrombin III, and prothrombin production are well-known causes of inappropriate thrombosis. It has been documented that in patients with cirrhosis, serum levels of all of these proteins can be low because of decreased production.1,2 The procoagulant factors prothrombin, V, VII, IX, X, and XI13 are also commonly low in patients who have liver disease.
The coagulopathy of liver disease is complex and often unpredictable. Despite clear evidence of an increased tendency for bleeding in patients who have cirrhosis, many circumstances also promote local and systemic hypercoagulable states. The consequences of hypercoagulability include the obvious morbidity and mortality of portal vein thrombosis, deep vein thrombosis, and pulmonary embolism, but possibly also include other end-organ syndromes, such as portopulmonary hypertension, hepatorenal syndrome, and spontaneous bacterial peritonitis. A more subtle contribution also could be responsible for progression of early fibrosis to decompensated cirrhosis. Future research is needed to elucidate specific mechanistic pathways that might lead to local hypercoagulation and the clinical interventions that might prevent morbidity and mortality related to hypercoagulation in patients who have cirrhosis.
Hypercoagulation and thrombophilia in liver disease
2008, Journal of Thrombosis and Haemostasis
A complex balance exists between endogenous procoagulants and the anticoagulant system in liver disease patients. Hypercoagulable events occur in cirrhosis patients despite the well‐known bleeding diathesis of liver disease. These events may be clinically evident, such as in portal vein thrombosis or pulmonary embolism, but these conditions may also be a silent contributor to certain disease states, such as portopulmonary hypertension or parenchymal extinction with liver atrophy as well as thrombosis of extracorporeal circuits in dialysis or liver assist devices. Moreover, liver disease‐related hypercoagulability may contribute to vascular disease in the increasingly common condition of non‐alcoholic fatty liver disease. Despite the incidence of these problems, there are few widely accessible and practical laboratory tests to evaluate the risk of a hypercoagulable event in cirrhosis patients. Furthermore, there is little research on the use of commonly accepted anticoagulants in patients with liver disease. This article is a result of an international symposium on coagulation disorders in liver disease and addresses several areas of specific interest in hypercoagulation in liver disease. Critical areas lacking clinical information are highlighted and future areas of research interest are defined with an aim to foster clinical research in this field.

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PaperHemostasis activation in patients with liver cirrhosis

Abstract

Thromb Res

Thromb Res

Thromb Res

Thromb Res

Disseminated intravascular coagulation in Cirrhosis

Hepatology

The natural history of Laennec's cirrhosis of the liver: an analysis of 386 cases

Medicine

Haemostatic problems in liver disease

Gut

The α2-plasmin inhibitor levels in liver disease

Clin Chim Acta

Significance of plasma fibrinopeptide A and high molecular weight fibrinogen in patients with liver cirrhosis

Brit J Haematol

Paper
Hemostasis activation in patients with liver cirrhosis