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 Table of Contents  
ORIGINAL ARTICLE
Year : 2016  |  Volume : 41  |  Issue : 2  |  Page : 50-55

Hyperfibrinolysis underlies abnormal hemostasis in patients with advanced liver cirrhosis


1 Department of Tropical Medicine, Faculty of Medicine, Minia University, Minia, Egypt
2 Department of Clinical Pathology, Faculty of Medicine, Minia University, Minia, Egypt

Date of Submission18-May-2015
Date of Acceptance11-Oct-2015
Date of Web Publication15-Jul-2016

Correspondence Address:
Zienab M Saad
El Minia, El Miia University Hospital, Tropical Medicine Departmet Postal Code 6111
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1110-1067.186398

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  Abstract 

Background Hemostasis is a dynamic process resulting from the balance between procoagulant and anticoagulant factors. The liver plays a key role in blood coagulation, being the site of synthesis of almost all coagulation factors and inhibitors. In addition to synthesis, the hepatic reticuloendothelial system is also involved in the clearance of activated coagulation factors as well as enzyme-inhibitor complexes. Plasma levels of fragment D-dimer represent an accurate marker of fibrinolytic activity. Thus, coagulation abnormality is a predictable feature of acute and chronic liver diseases.
Aim The aim of the study was to evaluate fibrinolytic activity in patients with various degrees of liver parenchymal damage and its relation to the synthetic function of hepatic coagulation.
Patients and methods We studied 40 patients with liver cirrhosis, who were classified into two groups according to Child-Pugh classification: group I, comprising patients with Child class A or B (n = 17), and group II, comprising patients with Child class C (n = 23). In addition, there was a control group (group III) (n = 15).
Results Platelet count was significantly low in group II compared with groups I and III (P = 0.001); platelet distribution width was significantly high in group II compared with groups I and III (P = 0.009). There was nonsignificant difference between the studied groups as regards the mean platelet volume (P = 0.4). Fibrinogen and factor VII were significantly decreased in group II when compared with group I and group III (P = 0.01 and 0.001, respectively). D-dimer was significantly increased in group II when compared with group I and group III (P = 0.04).
In group II (Child class C) there was significant positive correlation between fibrinogen level, prothrombin concentration, and factor VII (r = 0.53 and 0.58; P = 0.009 and 0.004, respectively) and significant negative correlation between fibrinogen level, activated partial thromboplastin time, and D-dimer concentration (r = −0.50 and −0.39; P = 0.01 and 0.05, respectively). There was significant negative correlation between D-dimer concentration and prothrombin concentration (r = −0.59; P = 0.003).
Conclusion Patients with liver cirrhosis suffer from complex coagulation changes. There is a state of hyperfibrinolysis in decompensated cirrhosis. Abnormal fibrinolytic activity is a major hemostatic defect in patients with liver parenchymal damage.

Keywords: D-dimer, factor VII, fibrinogen, liver cirrhosis, mean platelet volume, platelet distribution width


How to cite this article:
Saad ZM, Ghobrial AG, Ali LH, Saber MM, Mohamed SM. Hyperfibrinolysis underlies abnormal hemostasis in patients with advanced liver cirrhosis. Egypt J Haematol 2016;41:50-5

How to cite this URL:
Saad ZM, Ghobrial AG, Ali LH, Saber MM, Mohamed SM. Hyperfibrinolysis underlies abnormal hemostasis in patients with advanced liver cirrhosis. Egypt J Haematol [serial online] 2016 [cited 2019 Dec 14];41:50-5. Available from: http://www.ehj.eg.net/text.asp?2016/41/2/50/186398


  Introduction Top


Hemostasis is a dynamic process resulting from the balance between procoagulant and anticoagulant factors [1].

The liver plays a key role in blood coagulation, being the site of synthesis of almost all coagulation factors and inhibitors [2],[3]. In addition to synthesis, the hepatic reticuloendothelial system is also involved in the clearance of activated coagulation factors as well as enzyme-inhibitor complexes [2],[3]. Thus, coagulation abnormality is a predictable feature of acute and chronic liver disease (CLD) [1].

Decreased levels of most procoagulant factors [4] and thrombocytopenia [5] are the main hemostatic abnormalities associated with CLD. As a consequence, this condition was, until recently, considered a prototype of acquired coagulopathy. Patients are subjected to laboratory screening along with assessment of prothrombin time (PT) and activated partial thromboplastin time (APTT), and those with abnormal values are treated with plasma or procoagulant agents to correct the abnormalities and prevent hemorrhage during invasive procedures or to stop bleeding from the gastrointestinal tract [6].

Thrombocytopenia and thrombocytopathy usually complicate the clinical picture [7].

Fibrinolysis can be either a primary process or secondary to certain clinical situations. Secondary elevation in D-dimer is seen after major surgery or recent trauma, during sepsis, and as a manifestation of thromboembolic events [8]. Our study excluded such cases of acute illness. In the absence of such events elevated D-dimer is an indication of hyperfibrinolysis in the setting of cirrhosis and ascites.

This study was aimed to assess the platelet parameters and some coagulation parameters and fibrinolysis (D-dimer) in patients with liver cirrhosis. This may help to assess the hemostatic disturbance that occurs because of liver cirrhosis and the severity of coagulation defects.


  Patients and methods Top


A total of 40 cirrhotic patients (case groups) and 15 healthy individuals without liver disease (control group) were included in this study. These participants were selected from El Minia University Hospital (Minia, Egypt). In each case, a detailed history including age, sex, occupation, socioeconomic status, and personal and family history was taken, and thorough physical examination was performed. The primary criterion for inclusion was the presence of cirrhosis of the liver; all patients were hepatitis C virus positive. Diagnosis of cirrhosis of the liver was based on a combination of clinical features - namely, ascites and neurological disorders - and biochemical investigations - (raised serum bilirubin, reduced serum albumin, prothrombin concentration and INR) and abdominal ultrasound. Patients were classified according to Child-Pugh classification into group I, comprising patients of classes A and B (n = 17), and group II, comprising patients of class C (n = 23).

Exclusion criteria included renal impairments, diabetes mellitus, deep venous thrombosis (DVT), portal vein thrombosis, and history of antithrombotic therapy.

The laboratory investigations included evaluation of platelet count, platelet distribution width (PDW), mean platelet volume (MPV) (using an automated cell counter, Sysmex Kx-21N; TAO Medical Incorporation, Japan), plasma PT, APTT, factor VII (FVII) (using the Stago-Compact Hemostasis System 58986; Stago-Deficient FVII System, Diagnostica Stago, Asnieres, France), plasma fibrinogen level using the fully automated Stago-Compact Hemostasis System 58986 (Stago Fibri Prest System, Diagnostica Stago, Asnieres, France), and fibrin degradation products (D-dimer) (using Nyco Card; Axis-Shield Group, Oslo, Norway). The results were analyzed as mean and SD, and using the unpaired t-test with SPSS (version 17; SPSS Inc., Chicago, Illinois, USA) software.


  Results Top


The mean age in group I was 42 ± 1.9 years, that in group II was 45.3 ± 3.5 years, and that in group III (control) was 44.3 ± 3.6 years, with nonsignificant difference. Group I included seven male and 10 female patients, group II included 12 male and 11 female patients, and group III included nine male and six female patients ([Table 1]).
Table 1 Demographic and hemostatic data of the different studied groups


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Platelet count was significantly low in group II compared with groups I and III (P = 0.001).

PDW was significantly higher in group II compared with group I and group III (P = 0.009).

As regards MPV there was nonsignificant difference between the studied groups (P = 0.4).

APTT was significantly higher in group II compared with group I and group III (P = 0.001) ([Figure 1]).
Figure 1 Comparison between studied groups regarding mean value of prothrombin concentration (PC) and activated partial thromboplastin time (APTT).

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Prothrombin concentration (PC) was significantly lower in group II compared with group I and group III (P = 0.001) ([Figure 1]).

Fibrinogen level was significantly low in group II (class C cirrhosis) compared with group I (class A and B) and group III (control) (P = 0.01) ([Figure 2]).
Figure 2 Comparison between studied groups regarding mean value of fibrinogen concentration, factor VII (FVII), D-dimer.

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FVII (%) was significantly low in group II when compared with group I and group III (P = 0.001) ([Figure 2]).

D-dimer (mg/l) was significantly high in group II when compared with group I and group III (P = 0.04) ([Figure 2]).

In group I there was nonsignificant negative correlation between fibrinogen level and APTT and D-dimer concentration (r = −0.47 and −0.11; P = 0.06 and 0.65, respectively). There was nonsignificant positive correlation between fibrinogen level, PC, and FVII (r = 0.23 and 0.001; P = 0.37 and 0.99, respectively) ([Table 2]).
Table 2 Correlation between hemostatic parameters in group I


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There was nonsignificant negative correlation between FVII and APTT (r = −0.01; P = 0.96) and nonsignificant positive correlation between FVII and PC (r = 0.44; P = 0.07).

There was nonsignificant positive correlation between D-dimer concentration and APTT (r = 0.34; P = 0.17) and significant negative correlation between D-dimer concentration and PC (r = −0.50; P = 0.04) ([Table 2]).

In group II (Child-Pugh score C), there was significant negative correlation between fibrinogen concentration and APTT (r = −0.50; P = 0.01) ([Table 3]) and significant positive correlation between fibrinogen level and PC (r = 0.53; P = 0.009). In group II there was significant positive correlation between fibrinogen level and FVII (r = 0.58; P = 0.004), and a borderline significant negative correlation between fibrinogen level and D-dimer (r = −0.39; P = 0.05) ([Figure 3]).
Figure 3 Correlation between D-dimer and fibrinogen concentration among decompensated group II. r = −0.39, P = 0.05.

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Table 3 Correlation between hemostatic parameters in group II


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There was significant negative correlation between FVII concentration and APTT (r = −0.56; P = 0.005) and significant positive correlation between FVII concentration and PC (r = 0.83; P = 0.001) ([Table 3]). There was significant negative correlation between FVII and D-dimer (r = −0.44; P = 0.03) ([Table 3]), borderline significant positive correlation between D-dimer concentration and APTT (r = 0.40; P = 0.05), and significant negative correlation between D-dimer concentration and PC (r = −0.59; P = 0.003) ([Table 3] and [Figure 4]).
Figure 4 Correlation between D-dimer concentration and prothrombin concentration (PC) in group II. r = −0.59, P = 0.003

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  Discussion Top


Patients with liver cirrhosis commonly have multiple hemostasis defects, such as impaired hepatic synthetic function, resulting in decreased levels of clotting and fibrinolytic factors, in addition to decreased clearance effect of activated clotting and fibrinolytic factors and complexes, such as thrombin-antithrombin and plasmin-antiplasmin complexes [9].

The finding of high D-dimer plasma concentration in patients with liver cirrhosis, decompensated by ascites, suggests a major role of ascites in the pathogenesis of the hyperfibrinolytic state associated with liver failure [10].

In the present study platelet count was significantly lower in group II when compared with group I and group III. This is in agreement with Essawy et al. [11], who observed that a progressive decrease in platelet count was noticed in different groups of patients with CLD compared with controls. This was also in agreement with other investigators who noted a significant reduction in platelet count on comparing patients with controls [12],[13]. As regards the MPV there was nonsignificant difference between the studied groups, in contrast to the findings of Karagoz et al. [14], who found that MPV values were significantly higher in patients with advanced fibrosis and cirrhosis. They suggest MPV to be an independent predicting factor in assessing hepatic fibrosis [14].

As regards the MPV, the larger the size of the platelet, the more glycogen, adenine, nucleotide, and normal phosphates it contains and the higher its active functions. Smaller-sized platelets have lower functions. Blood platelet count, MPV, and other indices are indirect reflections of its parameters and activities [15].

As regards the PDW it was significantly higher in patients with advanced cirrhosis and liver cell failure compared with compensated cirrhosis and control. PDW reflects the variation in size of the platelets, which enhances the phagocytosis and destruction by hypersplenism [16].

In the present study, APTT was significantly increased in group II when compared with group I and group III. PC was significantly lower in group II compared with groups I and III. In accordance with our results, Gatt et al. [12] and Elsayed et al. [13] observed that low plasma levels of coagulation factors reflected by significantly prolonged coagulation screening tests (PT and APTT) were detected in all diseased groups compared with controls. Patients with CLD also showed significant prolongation with the advancement of the disease [12],[13].

In the present study, as regards fibrinogen level there was significant decrease in group II when compared with group I and group III.

Sohail et al. [17] reported reduction in plasma fibrinogen levels in the liver cirrhosis group. These results agreed with those of Elsayed et al. [13], who revealed that fibrinogen level was significantly decreased in all disease groups compared with the control group. These results disagreed with those of Gatt et al. [12], who reported increase in fibrinogen concentration in the cirrhotic group. This may be because fibrinogen is an acute-phase reactant and many patients with liver cirrhosis present with normal or high fibrinogen levels [18].

In the present study FVII (%) was significantly decreased in group II when compared with group I and group III. This is in agreement with the finding of other investigators who demonstrated that the reduced levels of FVII in advanced stages of liver disease - namely, cirrhosis and hepatocellular carcinoma (HCC) - can be attributed partly to decreased synthesis by the malfunctioning hepatocytes and, in part, to consumption during a process of intravascular coagulation that may complicate end stage liver disease (ESLD) [19].

In the present study D-dimer was significantly increased in group II when compared with group I and group III.

The data of this study show that fibrinolytic activity is higher in patients with decompensated cirrhosis (group II) of Child-Pugh class C who develop ascites as diagnosed by elevated levels of plasma fragment D-dimer than in patients of Child-Pugh class A or B who do not develop ascites or who have easily controlled ascites. These results are in agreement with those of Saray et al. [20].

Spadaro et al. [21] concluded that high D-dimers are associated either with the presence of ascites or with HCC. In patients with liver cirrhosis, high D-dimer levels in the absence of ascites require more careful monitoring for HCC. Depletion of ascetic fluid might prevent bleeding complications, especially if invasive procedures become necessary [21].

In the present study in group II there was significant positive correlation between fibrinogen level and PC, whereas there was significant negative correlation between fibrinogen level and APTT.

This agreed with the results of Chen et al. [22], who reported significant positive correlation between fibrinogen level and PC in decompensated liver cirrhosis.


  Conclusion Top


The hemostatic process is complex, resulting from interaction between the procoagulant and fibrinolytic factors. Patients with liver cirrhosis suffer from complex coagulation changes. There is a state of hyperfibrinolysis in decompensated cirrhosis. Abnormal fibrinolytic activity is a major factor in hemostatic defect in patients with liver parenchymal damage. The rise in D-dimers suggests increased fibrinolytic activity in these patients. This, together with decrease in platelet count and changes in platelet parameters, can guide the management of bleeding in patients with liver cell failure.

Recommendation

Further studies are needed to investigate the abnormalities in the components of the fibrinolytic system in patients with liver diseases.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

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