Venous Thrombosis in Behcet’s Disease

Behcet’s Disease (BD) is manifested by a triad of relapsing hypopyon uveitis, aphthous stomatitis and genital ulcers. The disease initially described by a Turkish dermatologist Hulusi Behcet in 1937. The etiology and pathogenesis of Behcet’s disease have not been fully clarified yet. However, it is now recognized as a multisystemic, immunoinflammatory disorder involving vessels of all sizes. The disease is most prevalent in the Mediterranean countries, Middle East, and Japan but has a worldwide distribution (Durmazlar et al., 2009; Kartal Durmazlar et al., 2008a).


Introduction
Behcet's Disease (BD) is manifested by a triad of relapsing hypopyon uveitis, aphthous stomatitis and genital ulcers.The disease initially described by a Turkish dermatologist Hulusi Behcet in 1937.The etiology and pathogenesis of Behçet's disease have not been fully clarified yet.However, it is now recognized as a multisystemic, immunoinflammatory disorder involving vessels of all sizes.The disease is most prevalent in the Mediterranean countries, Middle East, and Japan but has a worldwide distribution (Durmazlar et al., 2009;Kartal Durmazlar et al., 2008a).

History and diagnosis
The disease, currently known all over the world as "Behçet disease", "Behçet syndrome", "Behçet's triad", "Morbus Behçet" or "Tri-symptom Behçet" was first recognized by Dr. Hulusi Behçet (1889-1948) with a patient in 1924 (Tuzun, 2006;Ustun, 2002;Kartal Durmazlar & Kandi, 2011).This patient, who had been examined because of eye disturbances, recurrent oral and genital ulcers both in Istanbul and Vienna for 40 years, was given several diagnoses.Some doctors thought of tuberculosis or syphilis while some other doctors said a microorganism which was not present in Europe might have caused the disease.Hulusi Behçet, who continued to examine the patient after his loss of vision, thought that the causative agent was a virus.In the next several years he met two more patients with similar to that was seen in the previous patient.Hulusi Behçet thought the symptoms of these three patients were the symptoms of a new disease and reported his ideas on this topic firstly in 1936, in the Journal of Skin and Venereal Diseases (Tuzun, 2006;Ustun, 2002;Kartal Durmazlar & Kandi, 2011;Saylan, 1997).Later, in 1937 he wrote clear examples of symptomatic triad, which are still used as criterias worlwide for diagnosis of Behçet's disease, in Dermatologische Wochenschrift.In the same year at the meeting of the Society of Paris Dermatology he declared that several factors may cause the etiology of the disease, which still can be an acceptable statement.Later he diagnosed further patients and published in German as " Tri-Symptomenkomplex" in 1939, and in English as "Triple symptom complex" in 1940(Tuzun, 2006;Ustun, 2002;Kartal Durmazlar & Kandi, 2011;Saylan, 1997;Evereklioglu, 2006).In subsequent years, this unique disorder drew the attention, and the term "Behçet syndrome" was first used by Jensen in 1941(Jensen, 1941).The term "Behçet disease" was first used by Fiegenbaum andKornblueth in 1946 (Kartal Durmazlar &Kandi, 2011;Figenbaum, 1946;Dilsen, 1996;Alpsoy, 2009).On 13 September 1947, international dermatologic societies came together in Zurich and named the disease as "Morbus Behçet", which honored the first describer of "triple symptom complex" after Zurich Medical Faculty Professor Mischner's proposal.In fact, several authors before Hulusi Behçet described one or several individual findings of this disorder.Among these physicians, for example, Hippocrates in the fifth century BC reported some individual symptoms attributed to an originally endemic and epidemic disease.But, due to sporadic appereance of the disease in the course of time, the disease became less significant and was forgotten.There were also other physicians who described one or several individual findings of this disorder, for example, Janin (1772), Reis (1906), Blüthe (1908), Gilbert (1920, 1921, 1923), Planner and Remenowsky (1922), Weve (1923), Shigeta (1924), Adamantiades (1930), Dascalopoulos (1932), Whitwell (1934), Nishimura (1936), Blobner (1937) reported several individual findings of this disorder.However, all these papers ascribed the findings either to another disease, such as tuberculosis, syphilis, sepsis or allergy, or to a coincidence and none of them indicated a new or a single syndrome with "classical triad" (Kartal Durmazlar & Kandi, 2011;Alpsoy 2009;Evereklioglu, 2006Evereklioglu, , 2007aEvereklioglu, , 2007bEvereklioglu, , 2007c;;Freigenbaum, 1956).The disease is sometimes named as Adamantiades-Behcet's disease, however, Behcet's disease should be preferred as suggested by International Associations and Societies of "Behcet" (Mendes et al., 2009).Several diagnostic criteria have been developed during the years, all have in common the 3 major features of oral ulceration, genital ulceration and eye lesion (16).Today, International Study Group criteria for the diagnosis of Behcet's disease is used worldwide (Table 1) (International Study Group diagnostic criteria, 1990.).

Recurrent oral ulceration
Minor aphthous, major aphthous, or herpetiform ulceration observed by physician or patient recurring at least three times in one 12-month period

Vascular involvement in Behcet's disease
Vasculo-Behcet Disease (VBD), which involves the arterial and venous system, is found in 15-38% of patients with BD.Three major manifestations of VBD have been identified: venous occlusion, arterial occlusion and aneurysm formation, with a clear preponderance of the venous lesions compared to arterial involvement.The coexistence of arterial and venous involvement is not frequent and is one of the major causes of morbidity and mortality.Venous involvement, including superficial thromboflebitis and deep venous thrombosis, is a characteristic manifestation.Thrombosis of superficial and deep vein is more frequent than arterial aneurism and thrombotic occlusions (Kartal Durmazlar et al., 2008a, 2009;Houman et al., 2001;Aksoy et al., 2010).Venous thrombosis appeared to be the major vascular involvement reported in 7 to 33% of cases with BD with a male predominance, and representing 85 to 93% of VBD (Houman et al., 2001).Deep vein thrombosis is seen in about one-fifth of Turkish patients with BD (Gul et al., 1999).Lower extremities is the most frequent site of thromboses but thromboses of other venous sites such as superior and inferior vena cava, coronary, portal, renal and pulmonary veins have been identified (Houman et al., 2001;La Regina et al., 2010).Leg ulcers in BD, which may be caused by vasculitis or deep vein thrombosis, have a chronic recurrent course and are refractory to treatment (Jung et al., 2008;Kartal Durmazlar et al, 2008b;Akgul & Kartal Durmazlar, 2008).

Pathogenesis of Behcet's disease and thrombosis
The main pathology in BD is an inflammatory process of small arteries and veins and thrombosis as a result of vasculitis of the vaso vasorum (Evereklioglu et al., 2002).
Histopathological studies revealed cellular infiltrations consisting of lymphocytes, plasmocytes, monocytes and PMN in varying degrees, depending on the stage of lesion in BD.Since cytokines are involved in the regulation of functions of lymphocytes and phagocytes, they are playing important role in the pathogenesis of the disease (Durmazlar et al, 2009).Chemotactic and phagocytic activity of neutrophils in patients with BD has been reported to be high (19).Increased spontaneous secretion of Tumor necrotizing factor (TNFα), Interleukin-6 (IL-6) and Interleukin-8 (IL-8 ) i n m o n o c y t e c u l t u r e s o b t a i n e d f r o m B D patients have been reported (Mege et al., 1993).IL-8 secretion after incubation of human dermal microvascular endothelial cells with serum of BD patients indicates that chemotaxis is an initial process of inflammation.IL-8 upregulates neutrophil chemotaxis as mRNA expression have been reported to be more prominent in patients with active BD than in patients with inactive disease (Evereklioglu, 2005).IL-8, a major chemokine known as neutrofil activating factor, attract and activate leukocytes has been assumed to represent such a notable link between immune system activation and endothelial alterations in BD (Durmazlar et al., 2009;Evereklioglu, 2005;Tursen, 2009).It has been suggested that Th1 type cytokines and chemokines including IL-17, largely produced by activated CD4 + and CD8 + T cells, are involved in the recruitment of neutrophils to the site of inflammation.Activated neutrophils in BD patients produce significant quantities of IL-12 and IL-18 (Pay et al., 2007).
The pathogenesis of thrombotic events in BD is not fully understood.The primary abnormalities of the coagulation, anticoagulation, or fibrinolytic systems have not been confirmed yet in BD.The main factor responsible for the increased frequency of thrombosis in BD is thought to be endothelial dysfunction caused by vascular inflammation (Evereklioglu, 2005).There is accumulating evidence for inflammation markers as a result of thrombosis.Deep vein thrombosis significantly associates with the male gender and a positive pathergy test (Houman et al., 2001).A number of studies have explored the pathogenesis of thrombophilia in Behçet's disease.Neither deficiency in protein C, in protein S, in factor V Leiden and in antithrombin III nor resistance to activated protein C and anticardiolipin antibody levels seem to be correlated with vascular thrombosis in Behçet's disease (Houman et al., 2001;Espinosa et al., 2002;Hirohata & Kikuchi, 2003).In BD, there is an occlusive inflammatory thrombus formation, strictly adherent to inflamed vessel wall, which is typically not complicated with thromboembolism (Lakhanpal et al., 1985;Kobayashi et al., 2000;Matsumoto et al., 1991).There are increased thrombin generation, fibrinolysis, and thrombomodulin in Behçet's disease, but these abnormalities are not related to thrombosis (Espinosa et al., 2002).These results therefore suggest that thrombophilia in Behçet's disease may be related more to inflammation than to clotting disorder (Hirohata & Kikuchi, 2003).Studies have disclosed the occurrence of antiendothelial cell antibodies, increased E-selectin and myeloperoxydase expression in Behçet's disease (Houman et al., 2001;Espinosa et al., 2002;Hirohata & Kikuchi, 2003).As neutrophils from active Behçet's disease release increased amounts of myeloperoxydase, it is probable that neutrophil activation as well as the expression of antiendothelial cell antibodies may play an important role in the development of endothelial inflammatory damages, leading to thrombophilia (Houman et al., 2001;Espinosa et al., 2002;Hirohata & Kikuchi, 2003).Figure 1 summarizes the immunopathogenesis of Behcet's disease (Pay et al., 2007).Homocysteine (Hcy) is an intermediary sulphydryl-containing aminoacid formed during the conversion of methionine to cysteine.Its sulphydryl group can cause direct endothelial cytotoxicity, inhibition of glutathione peroxidase and nitric oxide, interference with clotting factor, and LDL oxidation (Kartal Durmazlar et al., 2008a, 2009).The association between Hcy levels and endothelial dysfunction and its correlation to the degree of endothelial damage have been shown in patients with BD.Hcy is thought to induce proinflammatory cytokines.Suggested mechanisms of Hcy in promoting such a clotting cascade are the inactivation of protein C, activation of coagulation factor V, and inhibition of thrombomodulin (Kartal Durmazlar et al., 2008a, 2009).The increase in Hcy concentration in patients at risk for vascular disease is expressed as odds ratio and for venous thrombosis, this odds ratio is approximately 1.6.In a study, a change of 1 µmol/l in Hcy concentration was found to correspond to a risk ratio of 1.01 (Willems et al., 2006).A study reported that 5 µmol/l increase of Hcy was associated with a 60% and 27% increased risk of venous thrombosis in retrospective and prospective studies, respectively (Omar et al., 2007).The association between Hcy levels and endothelial dysfunction and its correlation to the degree of endothelial damage has been shown in patients with BD (Ozdemir et al., 2004).Hcy generates superoxide and hydrogen peroxide, both of which have been linked to endothelial damage (Er et al., 2002).Hcy-induced vascular problems are thought to be multifactorial, including direct Hcy damage to the endothelium, enhanced lipid peroxidation and increased platelet aggregation by the effects on the coagulation system (Er et al., 2002;Sarican et al., 2007).Hcy has been shown in vivo and in vitro to promote inflammatory process such as the adhesion of neutrophils to endothelial cells as well as the release of the inflammatory cytokine IL-8 and monocyte chemoattractant protein-1 (MPC-1) (Koga et al., 2002).Hcy was shown to enhance the cytokine-stimulated expression of endothelial cell adhesion molecules and monocyte and T-cell adhesion to endothelial cells (Koga et al., 2002).Hcy was shown to promote TNF-α mediated induction of vascular cell adhesion molecule-1 (VCAM-1) in endothelial cells (Silverman et al., 2002).Some studies have shown hyperhomocysteinemia as a correctable risk factor for thrombosis in BD (Kartal Durmazlar et al., 2008a, 2009;Omar et al., 2007;Ozdemir et al., 2004;Er et al., 2002;Sarican et al., 2007).In a recent work, thrombogenesis in BD is discussed through the concept of Virchow's triad of venous thrombosis (La Regina et al., 2010).Based on this concept; abnormal blood flow, abnormal vessel wall, abnormal blood constituents are presented in Table 3.

Blood flow abnormalities
Enhanced

Medical management of Behcet's disease
The choice of treatment is generally based on the clinical presentation and the site affected.
Although the treatment has become much more effective in recent years, BD still associates with severe morbidity and considerable mortality.Therefore, the main aim of the treatment should be the prevention of irreversible organ damage, especially, during the early, active phase of the disease.Male sex and a younger age of onset have been reported to be associated with severe disease, which in case may require aggressive treatment (Alpsoy & Akman, 2009).Recently, a group of experts developed recommendations for the management of BD by combining the current evidence from controlled trials (Hatemi et al., 2008).CNS: Central nervous system; IFN: Interferon; TNF: Tumour necrosis factor.* There is no firm evidence to guide the management of major vessel disease in BD ** There is no evidence-based treatment that can be recommended for the management of gastrointestinal involvement of BD *** There are no controlled data to guide the management of CNS involvement in BD Table 4. EULAR recommendations for treatment of Behcet's disease (Hatemi et al., 2008) www.intechopen.com

Conclusion
The pathogenesis of thrombotic events in BD is not fully understood.The primary abnormalities of the coagulation, anticoagulation, or fibrinolytic systems have not been confirmed yet in BD.In this review current knowledge of venous thrombosis in BD are summarized.There is no agreement on the treatment of thrombosis in BD.However, in general immunosuppressive agents such as corticosteroids, azathioprine, cyclophosphamide or cyclosporine are recommended for the treatment of venous thrombosis in BD.There is no enough evidence of benefit with anticoagulants or fibrinolytic agents in the management of thrombosis of BD (La Regina et al., 2010).Further studies are needed to clarify the safety and effectiveness of antithrombotic therapy in BD.However, owing to the complications of established thrombus, it would be reasonable to target different steps of the coagulation cascade for the prophylaxis and treatment of thrombosis in BD.
*Findings applicable only in the absence of other clinical explanationsAorta and pulmonary artery aneurysms, infarct and hemorrhage, pleural effusion, pulmonary thromboembolism, tracheobronchial ulcerations, pneumonitis, mediastinitis, paranchymal fibrosis, arteriobronchial fistula, cor pulmonale, hilar and mediastinal lymphadenopathy, and lobular perfusion defects.Symptoms: hemoptysis, cough, dyspnea, and pleuritic chest painGIS involvementUlcerative lesions especially terminal ileum, cecum, occasionally in esophagus and stomach.Symptoms: anorexia, dysphagia, dyspepsia, vomiting, flatulence, vague abdominal discomfort, distention and pain, bloating, and diarrhea.Perforation can occur and malabsorbtion is common Vascular involvement Superficial and deep obliterative thrombophlebitis in lower extremity, varices, embolization, infarction, bleeding ulcers.Veins are affected more frequently than arteries.Large vessel thromboses in superior and inferior vena cava with a caput medusa, deep femoral and subclavian veins can occur.Occasionally, aorta, carotid, and popliteal aneurysms, radial artery occlusion, and thromboses of the hepatic (Budd-Chiari syndrome), mesenteric, pulmonary, iliac and renal veins with intracranial hypertension, mesenteric artery aneurysm CNS _ central nervous system; GIS _ gastrointestinal system.
The European League against Rheumatism (EULAR) recommendations are summarized in Table4.