**3. 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).

## **4. 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).

voiding dysfunction

tumor cerebri.

CNS \_ central nervous system; GIS \_ gastrointestinal system.

**3. Vascular involvement in Behcet's disease** 

**4. Pathogenesis of Behcet's disease and thrombosis** 

bipolar disorder, and chorea

Table 2. Additional Systemic Features of Behcet Disease (From Evereklioglu, 2005).

Inflammation of the testis, typically epididymitis with painful swelling or uncommonly orchiepididymitis, urethritis, cystitis,

5–10% of patients are affected. Focal or multifocal parenchymal , peripheral or CNS involvement with both motor and sensory manifestations, migraine-like headache (most frequent initial sign),

hemiparesis, behavioral changes, stiff neck, pyramidal and extrapyramidal signs, cerebellar ataxia, cerebral vein thrombosis, isolated cerebral sinus thrombosis, cranial nerve palsies, peripheral

neuropathy, seizures, benign intracranial hypertension, lifethreatening brainstem and spinal cord lesions, aseptic meningitis, chronic meningoencephalitis, multiple sclerosis-like illness, organic confusional syndrome, acute myelitis, aneurysms, stroke, and pseudo-

cognitive deficits, memory disturbances, impairment in

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

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).

Character disorders, aggressiveness, anxiety, depression, dementia,

acquisition/information storage, personality change, attention deficit,

Genitourinary involvement

involvement

Psychosomatic

Durmazlar, 2008).

status

CNS

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) in monocyte cultures obtained from BD 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

Venous Thrombosis in Behcet's Disease 49

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,

Enhanced erythrocyte aggregation, increased fibrinogen, high blood

Turbulent blood flow at sites of venous varices and arterial aneurysms

Endothelial factors such as vWF, t-PA, thrombomodulin, NO, VEGF,

Procoagulant factors such as factor V Leiden and prothrombin

hyperhomocystenemia, factors VIII, IX, lipoprotein a

Anticoagulant factors (protein C, S, Z, antithrombin) vWF: von Willebrand factor, t-PA: tissue plasminogen activator, NO: nitric oxide, VEGF: vascular endothelial growth factor, PAI-1: the type-1 inhibitor of plasminogen activators, t-PA: tissue

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). The European League against Rheumatism (EULAR) recommendations are

Table 3. Thrombogenesis in Behcet's Disease according to Virchow's triad of venous

Factors of fibrinolysis such as PAI-1, t-PA

abnormal vessel wall, abnormal blood constituents are presented in Table 3.

Impaired microcirculation

Endothelial dysfunction

Arterial and venous occlusion

Aneurysms and pseudoaneurysms

viscosity

Perivasculitis

endothelin-1

mutations,

thrombosis (From La Regina et al., 2010).

**5. Medical management of Behcet's disease** 

Venous varices

Blood flow abnormalities

Abnormal vessel wall

Abnormal blood constituents

plasminogen activator

summarized in Table 4.

APC: Antigen presenting cell, MICA: MHC class I related gene, eNOS: Endothial NO synthetase, ICAM-1: intracellular adhesion molecule-1

Fig. 1. Immunopathogenesis of Behcet's disease (From Pay et al., 2007).

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

VIRAL / BACTERIAL ANTIGENS (HSV – 1, Sangius, Mycobacteries)

AUTOANTIGENS (HSP60, HSP70, αβ-crystallin, Retinal S, α-enolase)

HLA – B51 TNF MICA

APC

KIR MEFV

IL – 1 IL – 18

ICAM-1: intracellular adhesion molecule-1

SUPERANTIGENS (Staphillococcus)

T Cell Neutrophill

INFLAMMATION THROMBOSIS TISSUE DAMAGE

ENDOTHELIAL DYSFUNCTION COAGULATION & FIBRINOLYTIC SYSTEM ABNORMALITIES (ICAM-1, eNOS, Factor V)

APC: Antigen presenting cell, MICA: MHC class I related gene, eNOS: Endothial NO synthetase,

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

Fig. 1. Immunopathogenesis of Behcet's disease (From Pay et al., 2007).

IL18 – IL12 IL8 – IL17 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.


vWF: von Willebrand factor, t-PA: tissue plasminogen activator, NO: nitric oxide, VEGF: vascular endothelial growth factor, PAI-1: the type-1 inhibitor of plasminogen activators, t-PA: tissue plasminogen activator

Table 3. Thrombogenesis in Behcet's Disease according to Virchow's triad of venous thrombosis (From La Regina et al., 2010).

### **5. 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). The European League against Rheumatism (EULAR) recommendations are summarized in Table 4.

Venous Thrombosis in Behcet's Disease 51

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

Akgul, A. & Kartal Durmazlar, SP. (2008). Medical treatment of venöz ulcers. *Turkiye* 

Aksoy, Y.; Ercan, A.; Dalmizrak, O.; Canpinar, H.; Kartal Durmazlar, SP. & Bayazit, M.

Alpsoy, E. & Akman, A., (2009). Behçet's disease: an algorithmic approach to its treatment.

Dilsen, N. (1996). History and development of Behçet's disease. *Revue du Rhumatisme English* 

Durmazlar, SP.; Bahar Ulkar, G.; Eskioglu, F.; Tatlican, S.; Mert, A. & Akgul, A. (2009).

Er, H.; Evereklioglu, C.; Cumurcu, T.; Türköz, Y.; Ozerol, E.; Sahin, K. & Doganay, S. (2002).

thrombomodulin. *The American Journal of Medicine,* Vol*.*112, pp. 37-43 Evereklioglu, C.; Er, H.; Turkoz, Y. & Cekmen, M. (2002). Serum levels of TNF-alpha, sIL-2R,

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cascade for the prophylaxis and treatment of thrombosis in BD.

**6. Conclusion** 

**7. References** 


CNS: Central nervous system; IFN: Interferon; TNF: Tumour necrosis factor.

Table 4. EULAR recommendations for treatment of Behcet's disease (Hatemi et al., 2008)

<sup>\*</sup> There is no firm evidence to guide the management of major vessel disease in BD

<sup>\*\*</sup> There is no evidence-based treatment that can be recommended for the management of gastrointestinal involvement of BD

<sup>\*\*\*</sup> There are no controlled data to guide the management of CNS involvement in BD

#### **6. Conclusion**

50 Venous Thrombosis – Principles and Practice

local and systemic corticosteroids

corticosteroids or IFN-a alone or with

Thrombosis of the vena cava and Budd–Chiari

 Pulmonary and peripheral arterial aneurysms: Cyclophosphamide and corticosteroids; surgery Anticoagulants, antiplatelet and antifibrinolytic

syndrome: Cyclophosphamide

concomitant pulmonary aneurysms)

 Dural sinus thrombosis: Corticosteroids Cyclosporine should be avoided in case of

 Isolated lesions: Topical measures such as corticosteroids preparations, lidocaine gel, chlorhexidine, sucralfate suspension

Erythema nodosum: Colchicines

antagonists or thalidomide; surgery

 If refractory eye involvement (retinal vasculitis or macular involvement): Cyclosporine A or infliximab in combination with azathioprine and

azathioprine, cyclophosphamide or cyclosporine A

agents are not recommended ( there are no controlled data on, or evidence of benefit from uncontrolled experience with anticoagulants, antiplatelet or antifibrinolytic agents in the management of deep vein thrombosis pulmonary embolism is rare and there is the risk of major bleeding in case there are

azathioprine, cyclophosphamide, methotrexate,

neurological involvement due to neurotoxicity, unless necessary for intraocular inflammation.

Acne-like lesions: Topical measures as used in acne

 Resistant cases: Azathioprine, IFNa and TNFa antagonists may be considered in resistant cases.

Eye disease Affecting the posterior segment: Azathioprine and

corticosteroids

Major vessel disease\* Acute deep vein thrombosis: Corticosteroids,

Gastrointestinal involvement\*\* Sulfasalazine, corticosteroids, azathioprine, TNF-a

Mucocutaneous involvement (oral, genital and skin lesions)

gastrointestinal involvement of BD

Articular involvement Colchicine; IFN-a, azathioprine, TNF-a antagonists in resistant cases CNS involvement\*\*\* Parenchymal disease: Corticosteroids, IFN-a,

vulgaris

Table 4. EULAR recommendations for treatment of Behcet's disease (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

\*\*\* There are no controlled data to guide the management of CNS involvement in BD

TNF-a antagonists

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.

#### **7. References**


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**3** 

Ertugrul Okuyan

*Turkey* 

**Antiphospholipd Syndrome** 

*Bagcilar Education and Research Hospital Istanbul* 

Antiphospholipid syndrome(APLS) is a prothrombotic state characterized by recurrent venous thrombotic events including deep venous thrombosis, as well as pulmonary embolism, arterial thrombosis, recurrent fatal loss due to placental thrombosis and the presence of circulating antiphospholipid antibodies(APA) (Roubey RAS, 2001). As both thrombosis and pregnancy morbidity have a large number of other origins, the diagnosis of APLS relies on the quality and reliability of the laboratory investigations, on the persistent positivity of the APA assays, and sometimes on the lack of any other cause. Although a broad spectrum of APA exists, the universally accepted diagnostic APA tests are lupus anticoagulant(LA) functional coagulation assay; anticardiolipin antibody(ACA) enzymelinked immunosorbent assay(ELISA); and anti-β2-glycoprotein I antibody(aβ2GPI) ELISA. Antiphospholipid antibodies were first described in 1906 in patients with syphilis. These complement-fixing antibodies reacting with extracts from bovine hearts(mitochondrial phospholipid cardiolipin) formed the basis for the serologic syphilis test(Venereal Disease Research Laboratory-VDRL assay). Mass population screening for syphilis demonstrated that patients with systemic lupus erythematosus(SLE) without clinical syphilis had persistently false-positive VDRL tests(Haserick J,et al 1952, Baker WF, et al 2008). As falsepositive VDRL tests in patients with SLE were also found to be associated with prolonged in

The lupus anticoagulant is an antibody that prolongs phospholipid dependent coagulation tests in vitro. It was given this name in 1972 because clear proof of its site of action was lacking, and because the anticoagulant had been recognized in patients with systemic lupus erythematosus(Donald I Feinstein 2009 ). It is a misnomer because the lupus anticoagulant is more frequently encountered in patients without lupus and is associated with thrombosis rather than with bleeding. Immunoglobulins reacting with other hemostatic factors, such as von Willebrand factor (VWF), factor VIII, factor IX, and factor XI, inhibitors of thrombin and fibrin polymerization, and factor XIII have also been described in patients with SLE(Donald

Patients with the lupus anticoagulant who do not have established SLE fall into several different categories: (1) patients with "lupus-like"chronic autoimmune disorders but without findings that fit the criteria for the diagnosis of SLE; (2) patients with other chronic systemic autoimmune disorders; (3) patients presenting with a venous or arterial thrombotic

vitro coagulation, the term 'lupus anticoagulant' was introduced.

I Feinstein 2009), but they are rare compared with the lupus anticoagulant.

**1. Introducton** 

**and Venous Thrombosis** 

Willems, HP.; den Heijer, M.; Gerrits, WB.; Schurgers, LJ.; Havekes, M.; Blom, HJ. & Bos, GM. (2006). Oral anticoagulant treatment with coumarin derivatives does not influence plasma homocysteine concentration. *European Journal of Internal Medicine,* Vol.17, pp. 120-124.
