الفهرس 
Fibrinolytic SystemOnly 14 pages are availabe for public view
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Abstract
The liver plays a major role in haemostasis; as most of the coagulation factors, anticoagulant proteins and components of the fibrinolytic system are synthesized by hepatic parenchymal cells, the liver is also responsible for removal of activated clotting and fibrinolytic factors and this is mediated through the hepatic reticuloendothelial system. The liver is a highly vascularized organ with vital venous systems draining through the parenchyma, liver diseases can affect abdominal blood flow and predispose patients to significant bleeding problems.
Hepatocellular damage in patients with severe liver disease can lead to abnormalities in the production and function of coagulation and fibrinolytic factors, disrupting the balance between coagulation and anticoagulation systems. These haemostatic changes can increase the risk of bleeding in cirrhotic patients.
Hepatocellular carcinoma (HCC) is a major health problem worldwide. It is the fifth most common cancer in the world, and the third most common cause of cancer-related death, the prognosis is very poor. The goal of early diagnosis and management is a reduction in its incidence and mortality.
In Egypt studies showed a steady increase of HCC from (1993) onwards. Relative frequency between cirrhotics was recorded to be between 2.5% and 2.9%. It reached a peak in 1997(3.8%). Age ranged from 18 to 82 years with a median of 56 years. Male to female ratio was 2.8:1. HCC is strongly associated with HCV infection, in Egypt it was found that HCV antibodies were detected in 76% of HCC patients. Although there is no available confirming data, death rates from HCC in Egypt appear to be increasing over the last decades.
Serum tumor markers could be valuable supplementaries to ultrasonography and computer tomography in the diagnosis of HCC. Using the appropriate single or combination of tumor markers may improve the effectiveness in screening HCC patients. HCC usually occurs as a progression of a preexisting chronic liver disease, most commonly following viral hepatitis or alcohol abuse. Therefore, for an early diagnosis, a close follow up of predisposed patients with effective regular screening is desirable.
Summary
Current practice is screening for HCC by ultrasonography and serum AFP.
AFP is considered as the reference biological marker; however the lack of increase of AFP in some cases justifies the search for new markers allowing earlier and broader detection.
In this thesis we studied the fibrinolytic activity in cases of HCC post viral hepatitis trying to reveal its impact on haemostatic states of such patients and to evaluate the clinical usefulness of them as tumor markers in patients with primary liver cancer. This was done by studing the plasma levels of AFP, t-PA antigen, PAI-1 antigen and fibrinogen antigen in HCC and cirrhotic patients.
The study was conducted on 75 persons: 20 patients with liver cirrhosis (group I), 45 patients of hepatocellular carcinoma (group II) and 10 normal persons as control (group III).This was done by studying the plasma levels of t-PA antigen, PAI-1 antigen ,fibrinogen antigen and serum AFP in HCC and cirrhotic patients.
Plasma level of t-PA antigen in cirrhotic patients was significantly and markedly increased than plasma levels of t-PA antigen in control group while plasma levels of PAI-1 antigen were slightly and insignificantly increased in cirrhotic patients than plasma levels of PAI-1 in normal persons.
Fibrinogen is one of the coagulation factors that are synthesized in the liver and megakrocytes produce some fibrinogen as well. Qualitative and quantitative abnormalities of fibrinogen occur in liver cirrhosis. Fibrinogen antigen plasma level is decreased in cirrhotic patients than normal control persons but it is not a significant decrease. Quantitative and qualitative abnormalities of fibrinogen and increased levels of t-PA not balanced with an equivalent increase in PAI-1 leads to increased fibrinolysis in cirrhosis.
In cirrhotic liver nearly a balance is present in the haemostatic system. The relative equilibrium which is present between the changes in the activators and the changes in the inhibitors can not cause or initiate a major bleeding like variceal bleeding however but it may play a role in aggravating it and facilitating its recurrences and may have a role in increase bleeding from mucosal membranes like mouth, gums and nose (epistaxis).
Summary
Under stress as during infection, during surgery, severe ascites or during bleeding the balance in the fibrinolytic system may become lost resulting in increased bleeding tendency. So, early and proper treatment of infections, urgent and suitable treatment for bleeding and good presurgical preparation of the cirrhotic patients must be fulfilled.
In HCC hypofibrinolysis is prominent due to marked increase of plasma level of PAI-1 without the same increase in t-PA level, and this may be responsible for the increased incidence of thrombosis in HCC patients like portal or mesenteric vein thrombosis. In HCC patients plasma level of PAI-1 antigen was significantly increased than that in cirrhotic patients and that in normal control persons. In patients with tumor size >5cm plasma level of PAI-1 was significantly higher than that in <5 cm tumor sized patients. Plasma level of t-PA antigen was significantly increased in HCC patients than that in normal control persons, but it was not significantly increased than that of the cirrhotic patients. t-PA was significantly increased in patients with tumor size >5cm than those with tumor size <5 cm.
Fibrinogen level was significantly elevated in HCC patients than cirrhotic and normal control persons. It was significantly increased in patients with tumor size >5cm than those with tumor size <5 cm. AFP was significantly elevated in HCC patients than cirrhotic and normal control persons. It was significantly increased in patients with tumor size >5cm than those with tumor size <5 cm.
Therefore, plasma levelof PAI-1, fibrinogen, t-PA and serum AFP increase with increase the size of the tumor, so they can be used for follow up the progression, invasiveness and prognosis of HCC , in estimating the response of patients to treatment and HCC recurrence after surgical removal or liver transplantation.
The clinical value of t-PA, PAI-1and fibrinogen in primary liver cancer as tumor markers was not fulfilled yet, therefore, using the ROC curve; sensitivity and specificity were evaluated for these markers. Our aim was to determine the reliability of t-PA, PAI-1and fibrinogen in detection of primary liver cancer as compared to or combined with the established tumor marker AFP.
Summary
• Plasma level of AFP was significantly elevated in HCC group as compared to cirrhotic group. Specificity of AFP was 80% and sensitivity was 66.7 %.
• Plasma levels of PAI-1 were significantly elevated in HCC group as compared to cirrhotic group. Specificity of PAI-1 was 80% and sensitivity was 57.8%.
• Plasma levels of t-PA were not significantly elevated in HCC group as compared to cirrhotic group. So, t-PA will not be a dependable marker for differentiating cirrhotic patients with HCC from cirrhotic patients without HCC.
• Plasma levels of fibrinogen were significantly elevated in HCC group as compared to cirrhotic group. Specificity of fibrinogen was 70% and sensitivity was 64.4%.
In association between PAI-1 and AFP for detection of HCC. Sensitivity raised to 80%, while increased specificity to 90% was obtained when simultaneous elevations of both markers are used.
In association between AFP and fibrinogen for detection of HCC sensitivity raised 75.5% and specificity raised to 80%. When the combination of AFP, PAI-1 and fibrinogen was used for detection of HCC sensitivity was raised to 80% and specificity raised to 100%.
Although PIVKA II and AFP L3 have high rates of sensitivity and specificity for detection of HCC in many studies, our results give competitor results as in combination of AFP and PAI-1, and superior rate in combination of AFP, PAI-1 and fibrinogen.
The cost of use AFP, PAI-1and fibrinogen is significantly lower than that of AFP- L3 and PIVKA-II, So, our study tumor markers are not only have a competitor sensitivity and specificity but they also have a competitor cost effectivness.
Recommendations
We recommend that:
• PAI-1, AFP and fibrinogen can be used as markers for detection of HCC with a good sensitivity and specificity ratio especially when combined with each others and they have a competitor cost effectivnes.
• Plasma PAI-1antigen, t-PA, fibrinogen and serum AFP are increased with the increase the size of HCC, so they can be used in follow up of HCC progression, its response to treatment and its relapse after medical or surgical removal or recurrence after liver transplantation.
• t-PA can not be used as a tumor marker for HCC as its plasma level is not significantly different between liver cirrhosis and HCC patients.
• Further studies on large number of patients at different centers in different countries needed for more accurate detection of the best cut off values of PAI-1 and fibrinogen with the highest sensitivity and specificity suitable for early detection and follow up of HCC.
• In cirrhotic patients there is increased hyperfibrinolysis, so, early and proper treatment of infections, urgent and suitable treatment for bleeding and good presurgical preparation of the cirrhotic patients must be fulfilled to avoid major bleeding.
•In HCC patients there is hypofibrinolytic state which plays a role in increased incidence of thrombosis in HCC patients. So, further studies for the suitable precautions and treatment of this prothrombotic condition is recommended.
Hersch SL, Kunelis T, Francis RB Jr. The pathogenesis of accelerated fibrinolysis in liver cirrhosis: a critical role for tissue plasminogen activator inhibitor. Blood 1987; 69: 1315-1319
Fibrinogen can be considered at present as confident markers for the morphological diagnosis of HCC( Calea, 1988)
Anticancer Res. 2008 Jan-Feb;28(1A):223-8. Links
PAI-1, t-PA and circulating hTERT DNA as related to virus infection in liver carcinogenesis.
Divella R, Lacalamita R, Tommasi S, Coviello M, Daniele A, Garrisi VM, Abbate I, Simone G, Gadaleta C, Paradiso A, Quaranta M.
Coagulation assays as diagnostic markers of hepatocellular carcinoma.
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Thrombophilic changes are common in HCC patients and they might contribute to the observed thrombotic complications in this malignancy. Decreased hepatic synthesis of AT, protein C and protein S have been demonstrated in cancer patients, and correlate with serum albumin levels. Another mechanism of haemostasis impairment is the over-production of functionally intact factors of coagulation and fibrinolysis in HCC .
PAI-1 and fibrinogen 78 80
Association between PAI-1 and Fibrinogen for HCC detection:
When the combination of PAI-1 and fibrinogen was used to calculate the sensitivity for detection of primary liver cancer, 35.5% of HCC patients showed elevation of both markers, 78% of patients showed elevation of at least one marker.
The specificity of the combination of PAI-1 and fibrinogen, one or both markers was normal in 80% of the control group, there was two cases had elevation of the two markers above the cut-off values (20%false positive cases).
PAI-1, t-PA, Fibrinogen and alpha fetoprotein in GroupI:
GroupI consists of 6 patients of Child A, 8 patients of Child B and 6 patients of Child C
PAI-1, t-PA, fibrinogen and AFP were assessed in each Child subgroup and we noticed
that
AFP ng/ml
Mean ±SD
Fibrinogen mg/dl
Mean ± SD
PAI-1ng/ml
Mean ± SD
t-PA ng/ml
Mean ± SD
Variable
9 ± 3 ± 85249 25.4 ± 11.2 11.3 ± 2.1 Child A
16 ± 7 229± 112 27.6 ± 9.8 17.6± 4.2 Child B
14 ± 5 162± 46 34.3 ± 13.7 21.1± 6.1 Child C
The slight increase in fibrinolysis in liver cirrhosis due to increased plasma level of t-PA antigen, without a similar increase in PAI-1 antigen can cause only mild mucosal bleeding but is not responsible for major bleeding as variceal bleeding..
In HCC hypofibrinolysis is prominent due to marked increase of plasma level of PAI-1 without the same increase in t-PA level , and this may be responsible for the increased incidence of thrombosis in HCC patients like portal or mesenteric vein thrombosis. Plasma PAI-1antigen, t-PA, fibrinogen and AFP are increased with the increase the size of HCC, its progression and invasiveness, so they can be used in follow up of HCC progression , its response to treatment, its relapse after medical or surgical removal or recurrence after liver transplantation.
t-PA can not used as a tumor marker for HCC as it has not a significant difference between liver cirrhosis and HCC patients. PAI-1, AFP and fibrinogen have a significant difference between liver cirrhosis and HCC patients and give a reasonable ratio of sensitivity and specificity as shown by the ROC curve, so they can be used as markers for HCC especially with combining AFP with PAI-1 or fibrinogen or with both of them which rise the sensitivity and specificity of them to diagnose HCC to a good ratio competitor to other established serum markers of HCC with more cost effectivness
Further studies on large number of patients and at different centers in different countries needed for more accurate detection of the best cut off values of PAI-1 and fibrinogen with the highest sensitivity and specificity suitable for early detection and follow up of HCC.