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REVIEW ARTICLE Table of Contents   
Year : 2003  |  Volume : 9  |  Issue : 2  |  Page : 59-68
The liver and the haemeostatic system

Department of Physiology, King Khalid University Hospital, Riyadh, Saudi Arabia

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Date of Submission02-Feb-2003
Date of Acceptance02-Mar-2003


The liver plays a central role in the control of haemostasis being the site of synthesis of most of the coagulation factors and natural anticoagulants, as well as fibrinolytic factors except the main activators of the fibrinolytic system (t-PA and u-PA). The liver also clears many of the activated clotting and fibrinolytic factors, as well as haemostatic activation complexes (TAT and PAP) and end product of fibrin degradation, FDP. Therefore, liver disease results in a complex and multifactorial pattern of defects in haemostatic function in the form of: (i) decreased synthesis of coagulation factors (ii) Abnormal protein synthesis e.g. dysfibrinogen (iii) Deficiency of natural anticoagulants (iv) Enhanced fibrinolytic activity (v) Quantitative and qualitative platelet defects (vi) Consumptive coagulopathy as in advanced liver disease. These abnormalities of haemostasis, which often occurs in the form of multiple defects, underlie the haemorrhagic diathesis, which often complicates liver disease. In the same manner, measurement of various haemostatic factors can be employed to reflect the degree of liver damage

Keywords: liver disease. haemostasis, coagulation, fibrinolysis, natural anticoagulant, antithrombin III, protein C. protein S and platelets

How to cite this article:
Al Ghumlas AK, AbdelGader AG. The liver and the haemeostatic system. Saudi J Gastroenterol 2003;9:59-68

How to cite this URL:
Al Ghumlas AK, AbdelGader AG. The liver and the haemeostatic system. Saudi J Gastroenterol [serial online] 2003 [cited 2022 Dec 3];9:59-68. Available from:

The liver is the most metabolically active organ, which has multiple functions: (i) metabolic: Carbohydrate, lipid, protein, bilirubin and bile acid metabolism. (ii) Synthetic: plasma proteins, clotting factors, hormone-binding protein and RBC in utero. (iii) Clearance: RBC, activated coagulation factors, fibrinolytic parameters and drugs. (iv) Storage: Vitamin B 12 , folate, Iron and glycogen.

   Physiology of haemostasis Top

Haemostasis encompasses a group of mechanisms that lead to the prevention of bleeding from ruptured blood vessels. These include vasoconstriction, platelets adhesion and aggregation and activation of the coagulation and fibrinolytic systems [1] .

Coagulation system: Activation of the coagulation cascade; either through the extrinsic or intrinsic pathways converges in activation of factor X. Thereafter, it proceeds through a single common pathway leading to the generation of thrombin which in turn, converts the soluble plasma fibrinogen into fibrin (the solid clot) [Figure - 1].

Activation of the coagulation system in vivo can result in excessive formation and deposition of fibrin in the vascular system with serious and often catastrophic consequences. Therefore, such system is kept under check by a variety of factors, which include the vascular endothelium as well as circulating natural anticoagulants.

Natural coagulation inhibitors: Several natural coagulation inhibitors exist to down-regulate every step of the coagulation pathway and these include:

i-Antithrombin III (AT-III) is the major physiologic regulator of all serine protease enzymes which is synthesized mainly by the liver and to a minor extent by endothelial cells. It is the natural inhibitor of thrombin, but also acts at several different stages of the coagulation cascade [2] [Figure - 1].

ii- Protein C (PC) is a vitamin K-dependent glycoprotein which is also synthesized by the liver. [Figure - 2] shows the mechanism of its anticoagulant action. When thrombin is formed as a result of coagulation activation, it will bind to thrombomodulin which is a membrane bound receptor for thrombin and expressed on normal endothelium; in this complexed form thrombin activates PC to form activated protein C (APC). APC exerts its anticoagulant action by inactivating the active forms of factors V and VIII. Also APC inactivates plasminogen activator inhibitor (PAI-1) and causes a reduction in its production by endothelia cells [3]

iii- Protein S (PS) is also a vitamin K-dependent glycoprotein which is produced mainly by hepatocytes [4]. PS acts as a cofactor for inactivating factors V and VIII [5][Figure - 2].

iv-Tissue factor pathway inhibitor (TFPI): TFPI is a recently characterized physiological inhibitor of coagulation which inhibits the tissue factor pathway soon after initiation [6] it is synthesized by endothelial cells.

v-Heparin cofactor II (HCII): HCII specifically inhibits thrombin in the presence of heparin. It is also synthesized by endothelial cells.

The fibrinolytic system is an important protective mechanism against thrombosis. It is considered a counterpart to the coagulation system as it operates constantly to prevent excessive fibrin deposits on the vessel wall.

A summary of the factors involved in fibrinolysis is shown in [Figure - 3]. Plasmin is formed from its inactive precursor plasminogen by the specific plasminogen activators: tissue plasminogen activator (t-PA) and urokinase plasminogen activator (u-PA). The formed plasmin degrades fibrin into soluble fibrin degradation products (FDPs). Free plasmin in the blood is very rapidly inactivated by alpha-2-antiplasmin to form plasmin antiplasmin complex (PAP). The other circulating plasmin inhibitor is alpha-2- macroglobulin. On the other hand, the activators of plasminogen are inhibited by the main fast acting inhibitor, PAI-1 [7] .

Haemostatic functions of the liver

i- Synthesis

The liver plays a central role in the control of coagulation. It is the principal site of synthesis of most of the coagulation factors, inhibitors of coagulation and fibrinolytic factors except von Willebrand factor (vWF) and the two main activators of the fibrinolytic system, t-PA and u­-PA [8],[9] .

Coagulation factors: Fibrinogen, factors II, VII, IX, X and V are produced in the rough endoplasmic reticulum of hepatocytes [10] in precursor form [11] . Synthesis by the liver of factors IX, VII, X and FII depends on the availability of vitamin K [12] . Vitamin K carboxylates the glutamic acid residues of the precursors before secretion, by cleaving the carbon hydrogen bonds on the glutamyl residues, thereby enabling them to bind via Ca ++ bridges to phospholipid and to function as coagulation protein [13]

Coagulation inhibitors: The most important physiological inhibitor of coagulation is ATIII, which is synthesized mainly by the liver. Other natural anticoagulants include PC and its cofactor PS are also produced by the hepatocytes [2]

Fibrinolytic parameters: Plasminogen, which is the inactive precursor of plasmin, is synthesized by the liver. On the other hand, the potent t-PA inhibitor, PAI-1, is synthesized by both the liver and the endothelium. The plasmin inhibitors, which include alpha-2-antiplasmin and alpha-2- macroglobulin, are also synthesized in the liver.

ii- Clearance: Macrophages in the liver clear many of the activated coagulation factors, fibrinolytic factors (t-PA and PAI), haemostatic activation complexes (thrombin anti-thrombin and PAP) and end products of fibrinogen to fibrin conversion (FDPs) [9] .

Haemostatic abnormalities in liver disease

Liver disease results in a complex and multifactorial pattern of defects in haemostatic function.

Effect on coagulation factors: Disordered synthesis of coagulation factors: Hepatocellular disease whether acute or chronic hepatitis, causes impaired production of proteins by the liver leading to deficiencies of the clotting factors. On the other hand, normal or overproduction of coagulation factors usually accompanies biliary tract disease (biliary cirrhosis and obstructive jaundice) reflecting accelerated non­specific protein synthesis [14] . The clotting factors, which are measured by the common screening tests, are in the normal range until their plasma levels are reduced below 30-40% [15]

i- Vitamin K-dependent clotting factors:

Deficiencies of the vitamin K-dependent clotting factors (II, VII, IX and X) are common in both acute and chronic parenchymal hepatic diseases, as a result of failed synthesis [12] . On the other hand, the levels of these factors are normal in mild liver disease, fatty liver, acute ethanol intoxication, early obstructive jaundice and biliary cirrhosis [14] . Usually the deficiency of these four factors occur together [12] ; however, it is more marked for FVII than for the others, because FVII has the shortest half life (5-6 hours) and therefore, it is the first factor to decrease with impairment of hepatocyte synthetic function [16] . Moreover, severe reduction of FVII (<9%) carries poor prognosis in patients with acute hepatic failure [17] . On the other hand, FVII levels less than 34% identified 93% of patients with liver cirrhosis who died within 10 months of follow­up [18] . Thus, FVII is considered an early predictor of survival. Manzano et al. (2000) [19] reported impaired FVII activity in liver cirrhosis despite normal prothrombin activity. Recently, recombinant activated factor VII (rFVIIa) has become available and has offered another treatment option for patient with liver cirrhosis and bleeding. It was shown to be effective and safe since the administration of rFVIIa corrects the abnormality in clotting tests in these patients and allows invasive procedures to be undertaken without risk of bleeding [20] . Similarly, rFVIIa was found to reverse the prolonged prothrombin time (PT) in ten non-bleeding cirrhotic patients and in two patients with fulminant hepatic failure undergoing liver transplantation [21]

In addition to the depressed levels of the vitamin K dependent factors, inactive precursor forms have also been described in patients with liver disease without vitamin K deficiency, suggesting an acquired defect or the synthesis of an abnormal clotting proteins [11]

The best and most sensitive test for detecting a deficiency of vitamin K dependent factors in the absence of deficiency of vitamin K is the prothrombin time (PT) [22] . Vitamin K is present in most vegetables (K1) and is formed in the gut by bacteria (K2). Effective absorption from the gut require bile salts because it is a fat soluble vitamin [23] . Therefore, vitamin K deficiency may result from: (i) failure of production due to elimination of intestinal flora by broad spectrum antibiotics. (ii) Failure of absorption of vitamin K from the gut as a result of obstructive jaundice, or (iii) as a result of administration of anticoagulant drugs (such as warfarin) which inhibit vitamin K action in the liver [12] . Prolongation of the PT may be noted while other biochemical tests of liver function are still normal, indicating that the failure to synthesize these factors is an early sign of liver disease [17] . Also, the presence of dysfunctional clotting factors contributes further to the prolongation of PT [24] . Correction of an abnormal PT after administration of vitamin K suggests that the clotting factors deficiency is due to vitamin K deficiency rather than impaired synthesis per se [23].

ii- Factor V (Proaccelerin):

FV is manufactured by the liver and is not a Vitamin K dependent factor. Low levels have been found in fulminant hepatic failure and a value of less than 20% is associated with poor prognosis [17] . However, FV may be raised in patients with acute infection. Therefore, FV doesn't appear to be a useful marker to distinguish hepatocellular failure from obstructive jaundice [17] . Besides, its level is not a useful indicator of hepatic synthetic function as it is extremely sensitive to digestion by plasmin and to consumption secondary to thrombin activation [14]

iii- Factor VIII.:

FVIII is known to be synthesized in both hepatic and extrahepatic sites [14]. In contrast to other coagulation factors, in liver disease, the concentrations of both FVIII (anti-haemophilic factor) and von Willebrand factor (vWF) are usually elevated. However, the concentrations of both VIII and vWF antigens were found to be much higher than the biological activities of these factors in patients with liver disease; i.e. there is disproportionate increase in the non-functional antigens [11]

The highest concentrations of both FVIII and vWF are found in patients with alcoholic liver disease or cholestasis [13] . Also, raised levels have been described in acute viral hepatitis, alcoholic cirrhosis and non-alcoholic cirrhosis [17]

FVIII assays are of little help clinically for evaluating the coagulation defect in liver disease. The rise in FVIII levels in liver disease, could be due its release from the necrotic hepatocytes [14] as a result of increase rate of synthesis as an acute phase reactant [25] her proposed mechanisms include impaired clearance of FVIII by the damaged liver [17] production of an abnormal hypoactive FVIII in liver disease similar to dysfibrinogenemia [11] . It is also possible that there is decrease inactivation of FVIII as a result of an abnormal PC molecule leading to higher FVIII levels [17]

iv- Coagulation factors of the contact system:

The levels of FXI, FXII, HMWK and prekallikrein (so called contact factors) were shown to be low in hepatic disease. The decrease in the levels of these factors correlate with the diminution of protein production in liver disease [14] . Decreased levels of these factors contribute to the prolongation of activated partial thromboplastin time (APTT) [22][Figure - 4].

v- Factor XIII:

Low levels of FXIII are found in acute and chronic hepatocellular disease, but not in biliary cirrhosis or obstructive jaundice. However, reduction in the circulating levels of this factor rarely plays a significant role in abnormal bleeding in patients with liver disease [14],[17]

vi- Fibrinogen:

Hypofibrinogenaemia of moderate degree is usually found in association with acute or chronic hepatic disease and this suggests poor prognosis [12] . Hypofibrinogenaemia, in general may be due to decrease synthesis of fibrinogen, consumption during disseminating intravascular coagulation (DIC), destruction by abnormal plasma fibrinolytic activity or accelerated catabolism [12] Fibrinogen level may be normal or high in acute and chronic hepatocellular disorders [26],[27],[28],[29] as well as in obstructive jaundice, biliary cirrhosis, hepatoma and metastatic liver tumors [14] . Fibrinogen is an acute phase reactive protein and its level rises in response to infection, obstruction of biliary tract and neoplasms [17] . The fibrinogen levels are depressed only in the late stages of liver cirrhosis and fulminant hepatic failure [28],[29],[30],[31]

Production of an abnormal fibrinogen molecule has also been described in liver disease resulting in acquired dysfibrinogenemia [32],[33] . The action of thrombin on the abnormal fibrinogen results in the formation of defective fibrin monomers and impaired ability to polymerize. Furthermore, the decreased cross linkage of fibrin monomers due to acquired FXIII deficiency contributes further to poor fibrin formation and the production of a friable Clot [25] . Dysfibrinogenemia is commonly found in patients with liver cirrhosis and it is usually a manifestation of severe liver disease [22] . Dysfibrinogenemia can be detected in 50-78% of patients with chronic liver disease; the fibrinogen in patients with dysfibrinogenemia contains excessive numbers of sialic acid residues of the a and (3 chains of fibrinogen [11] .

The contribution and clinical importance of dysfibrinogenaemia in the bleeding diathesis which is associated with severe liver disease is uncertain [12] . But, in an early study of 13 patients suffering from bleeding esophageal varices, abnormal fibrinogen was found in most of those who died but not in those who survived, indicating its prognostic significance [32] . Also the same workers found that in patients with obstructive jaundice, fibrin polymerization was normal, implying that this test may help to differentiate obstructive jaundice from sever parenchymal liver disease.

Thrombin time, which measures the rate of conversion of fibrinogen to fibrin [Figure - 4] is sensitive to decreased levels of fibrinogen, the presence of fibrin degradation products and abnormal fibrinogen molecules (dysfibrinogenemia) [23] . Thus, there is prolongation of thrombin time in patients with low fibrinogen level or dysfibrinogenemia due to abnormal fibrin polymerization. Also, the reptilase time (RT) is a test that uses the snake venom (Bothrops atrox) and measures fibrin formation after the cleavage of only fibrinopeptide A from fibrinogen molecule. RT is prolonged in hypofibrinogenaemia or- dysfibrinogenemia. However, it is more sensitive to qualitative fibrinogen abnormality than thrombin time [17] . Reduction of sialic acid content by neuraminidase returns the fibrin polymerization and thrombin time to normal [13] .

Inhibitors of coagulation

Deficiency of the main inhibitor of thrombin, ATIII occurs in a variety of liver diseases including chronic liver disease (CLD) and fulminant hepatic failure [34],[35],[36],[37],[38] . . The low ATIII levels results fi - om decreased production, increased consumption by thrombin or both [8] . As a result the inhibition of the coagulation cascade is diminished. In acute liver failure, plasma ATIII levels fall to less than 20% of normal values [25] . In liver cirrhosis ATIII is also severely depressed [22] .

PC and PS concentrations were shown to be reduced in chronic, as well as acute liver disease [8],[25],[37],[39]. The low levels of both functional activity and antigen can be attributed to reduced synthesis or increased consumption [11]

HCII is reduced in parallel with ATIII in DIC and fulminant hepatic failure [40] . Low levels of HCII correlated significantly with serum albumin which confirms further the failure of hepatic synthetic function [17]

α 2 -macroglobulin performs around 25% of normal thrombin inactivation. In severe liver disease the plasma concentration of this protein was shown to be reduced. [8] However, Paramo and Rocha reported normal or increased levels in liver cirrhosis which might compensate for the decreased levels for ATIII deficiency [22] . Lastly, the plasma levels of TFPI are decreased in advanced chronic liver disease [41] .

Abnormalities of fibrinolytic activity

The observation of enhanced fibrinolytic activity in liver cirrhosis is supported by the finding of accelerated lysis of incubated clotted blood obtained from patients with cirrhosis. However, this is unusual in acute hepatic disease, liver carcinoma, primary biliary cirrhosis and obstructive jaundice [12] . The mechanisms involved in the changes in fibrinolytic system in liver disease are complex. Enhanced fibrinolysis consequent upon an increase in plasmin activity may be either a primary abnormality of fibrinolysis or a secondary response to excessive thrombin generation as a result of DI C [42] .

Primary activation can be attributed to:­

i) Poor clearance of plasminogen activators (t-PA and u-PA) by the diseased hepatocytes, resulting in an increase in their levels and as a consequence more conversion of plasminogen to plasmin.

ii) Diminished production of inhibitors, particularly α 2 -antiplasmin and PAI-1 [11],[22],[43]

These explanations were supported by the observations that patients with chronic liver disease including cirrhosis and chronic hepatitis exhibited a marked increase in t-PA and PAM antigen and a significant decrease in plasminogen and a2­antiplasmin. Also a positive correlation was found between t-PA antigen and serum bilirubin indicating that this activator can be a marker of sever liver failure. Thus, in patients with advanced liver disease, a marked elevation oft-PA and a reduction of α2-antipasmin contribute to excessive fibrinolysis [22] . Furthermore, others [44] attributed the hyperfibrinolysis in liver cirrhosis to an increase in t-PA concentrations without increased active PAI-1 levels.

Global tests of fibrinolytic activity, such as the euglobulin clot lysis time, plasma clot lysis time and whole blood clot lysis time, are useful screening tests for hyperfibrinolysis. They are all found to be abnormally short in liver cirrhosis. [9],[17]

For many years it has been known that abnormally enhanced fibrinolysis and compromised coagulation system are responsible for some of the haemorrhagic problems in liver disease [14],[28] The fact that patients with congenital α 2 -antiplasmin deficiency and low levels of this protein similar to those seen in cirrhosis, exhibit life-long bleeding [14],[45] , indicates that hyperfibrinolysis is an important risk factor for bleeding. Patients with accelerated fibrinolysis are at increased risk of major soft tissue haemorrhage after trauma [46] and a heightened incidence of mucocutaneous bleeding. Thus, procedures such as liver biopsy and tooth extraction carry increased risk of bleeding in such patients [47] . Furthermore, the risk of bleeding in severe degree of cirrhosis such as Child Class C patients, is higher than in Class B and in those with higher values of FDP and t-PA levels, than those with negative results of FDP and lower values of t-PA [48]

Disseminated intravascular coagulation (DIC)

DIC is an acquired syndrome characterized by a pathologic stimulation of the coagulation cascade that results in intravascular coagulation, consumption of coagulation factors and platelets, ultimately leading to a hemorrhagic state [49] . The definitive event in DIC is generation of thrombin and secondary activation of the fibrinolytic system. Thrombin converts fibrinogen to fibrin, which is precipitated in the microvasculature and activates platelets leading to their consumption. Activation of the fibrinolytic system occurs as a secondary phenomenon resulting in degradation of fibrinogen and fibrin by plasmin producing fibrin degradation products (FDPs) (such as D- dimer) and leading to decreased concentration of fibrinogen. If FDPs are not cleared by the reticuloendothelial system, they will interfere with the cleavage of fibrinogen by thrombin and the polymerization of fibrin monomers and block platelet fibrinogen receptors [14]

In advanced liver disease, there is diminished clearance of activated coagulation factors and their continued presence in the circulation indicates a continuous activation of coagulation system that may culminate in DIC [50] . Also deficiencies of the plasma coagulation inhibitors (ATIII and PC), which are synthesized by the hepatocyte, contribute further to DIC [22] . The initiating factors could be the release of thromboplastic substances from the necrotic hepatocytes [50] . In addition, the presence of circulating endotoxins, which gain access to the circulation from the gut, coupled with failed clearance by the diseased liver, can initiate the activation of the coagulation system, endothelial cell damage, platelet activation and tissue factor production by leukocytes, ultimately leading to DIC [51]

Currently the available data point to low grade DIC occurring in advanced liver disease. The presence of DIC in liver disease is associated with accelerated turnover of fibrinogen as a result of thrombin action. In support of this notion, in advanced hepatic damage, fibrinogen level were found to be markedly reduced [50],[52] and FDPs were elevated [52] . Further evidence of excessive thrombin activity in patients with advanced liver disease, when treated with heparin or ATIII, is marked improvement of fibrinogen survival and circulating levels [50],[52],[53]

Measurement of circulating fibrinopeptide A (FPA), which is cleaved from fibrinogen by thrombin is used as an index of thrombin generation; its plasma levels were reported to be high in liver cirrhosis [54],[27]. The finding that heparin can reduce the levels of FPA to normal in these patients is a further support to the presence of DI C [54] . These findings put together suggest that consumptive coagulopathy is part of the haemostatic disturbances in patients with liver disease and not only a feature of the terminal phase of the disorder.

Platelets defects

Qualitative as well as quantitative abnormalities of platelets were noted in both acute and chronic liver disease [11],[25] . Mild thrombocytopenia is seen in 52% of acute hepatitis with liver failure, 16% of acute hepatitis without liver failure and in 30 to 64% of cirrhotic patients. However, the platelet count is rarely below 30,000 to 40,000/mm 3 and spontaneous bleeding is uncommon [15] This thrombocytopenia results from decreased survival because of splenic sequestration [11] But, it is uncertain whether the platelets are removed as a result of heightened spleen function (hypersplenism) or due to an intrinsic damage of the platelet membrane. [55] Increased platelets destruction by immune mechanisms [14] was also reported in patients with CLD who display a high prevalence of autoantibodies reacting specifically with platelet membrane glycoproteins [55] . Peripheral consumption of platelets by subclinical DIC [22] contributes further to the thrombocytopenia. Thrombocytopenia may also develop when there is impaired ability of the bone marrow to compensate for accelerated platelets removal from the circulation [14] . This can result from folic acid deficiency and bone marrow alcoholic toxicity (22) . In support of this notion a recent study [56] showed a reduced number of reticulated platelets in cirrhotic patients, suggesting impaired platelet production. Serum levels of thrombopoietin (TPO) are reduced in patients with liver cirrhosis and thrombocytopenia [57] , and increased promptly after liver transplantation reaching a peak after the fifth day. Four to six days after the TPO peak, an increase in the number of platelet was observed [58] . Therefore, it was suggested that the decreased hepatic synthesis of TPO plays a role in the thrombocytopenia of cirrhotic patients. [14] .

Platelets function can also be abnormal in liver disease [13] . This abnormality can be attributed to a reduction in the number of large active young platelets, deficient platelet thromboxane A 2 production, increased systemic prostacyclin production and accumulation of FDPs; both hyperfibrinolysis and DIC impair platelet aggregation [22] . Younger et al. demonstrated that the primary functional defect which impairs platelet aggregation in liver cirrhosis is an intrinsic platelet defect [59] . In the absence of deficiency of any coagulation factor, a prolonged bleeding time with a normal platelet count is attributed to abnormalities of platelet functions. Impaired aggregation to adenosine diphosphate, epinephrine, collagen, thrombin and ristocetin have been described in patients with liver disease [15] .

In Saudi Arabia, although there are numerous published reports on various aspects of liver disease, very few haemostatic studies were undertaken on liver disease [60],[61],[62] Al-Mofleh et al., 1989 reported marked derangements of PT, ATIII, and fibrin polymerization mainly in liver cirrhosis when compared with periportal (schistosomal) fibrosis [63] A recent study evaluated the coagulation factors, natural anticoagulants and fibrinolytic factors in both acute and chronic liver disease in Saudi Arabia. This study found significant derangement in synthetic and clearance functions in patients with acute hepatitis, liver cirrhosis and hepatocellular carcinoma as compared to those with chronic hepatitis and hepatitis B carriers. It is noteworthy that this study concluded that the most sensitive markers of hepatocyte malfunction were PS (total and free) and reptilase time as they were abnormal when other biochemical and haemostatic tests were normal [64].

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Correspondence Address:
Abdel Galil Mohammed AbdelGader
Dept of Physiology, King Khalid University Hospital, P. 0. Box 2529, Riyadh 11461
Saudi Arabia
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Source of Support: None, Conflict of Interest: None

PMID: 19861808

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