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Annexin V (ANXV) is a protein with a high affinity for negatively charged phospholipids and shows in vitro a potent anticoagulant activity. It has been suggested that it has a significant role in the prevention of arteriovenous thromboses or fetal loss, or both.1 Increased levels of antibodies against ANXV (aANXV) have been reported in patients with different systemic autoimmune disorders2–4 as well as in women with recurrent fetal loss and pre-eclampsia.5 The presence of aANXV in patients with thromboembolic cerebrovascular disease (CVD), however, has not yet been described. We report on two patients with CVD who had evidently raised levels of IgG aANXV, whereas all the other tested antiphospholipid antibodies (aPL) were negative.
We examined 37 young patients with no evident systemic autoimmune disease (23 women, 14 men; mean age at CVD 32 years (range 18–40)) 11 months to six years after CVD: seven with transient ischaemic attack (TIA), 25 with ischaemic cerebrovascular insult, and five with venous sinus thrombosis. Diagnoses based on the history and clinical manifestations were objectively verified by computed tomography (CT), magnetic resonance imaging (MRI), and/or angiography at the time of the onset of symptoms. After prospective clinical re-examination, two blood samples were obtained from each patient eight weeks apart.
Serum samples were analysed by enzyme linked immunosorbent assay (ELISA) for the presence of aANXV,5 anticardiolipin,6 anti-β2-glycoprotein,7 and anti-prothrombin antibodies.8 Antinuclear antibodies (ANA) were determined by indirect immunofluorescence.
A 36 year old woman with a history of fetal loss in 1982 became pregnant for the second time in 1998. At the 36th gestation week a caesarean section was performed owing to placental abruption. A few days after the delivery, she became somnolent with mild right sided hemiparesis. CT and an MRI scan confirmed superior sagittal sinus thrombosis and therefore treatment with warfarin was started. Three years later, her condition was stable with mild occasional headaches and mild right sided pyramidal symptomatology. Laboratory examinations showed positive ANA (up to 1/320) and persistently raised levels of IgG aANXV, while all the other tested aPL were negative. No clinical manifestations of a systemic autoimmune disease could be found. Except for a short period of smoking, no other thrombotic risk factors were identified.
A 24 year old woman had a TIA in 1996, two months after starting hormonal contraceptives. She experienced paraesthesia over both arms and legs and gait ataxia was found. MRI, echocardiography, and sonography of the neck vessels were normal, suggesting TIA in the vertebrobasilar region. In 2000 she became pregnant for the first time. Generalised oedema and hypertension appeared in the fifth and eighth month, respectively. A healthy child was born one month pre-term. In 2001 she was in good health except for rather frequent headaches. Clinical and special neurological examinations were completely normal. Among the tested aPL only IgG aANXV were found to be positive. Contraceptives were the only risk factor for CVD.
ANXV is one of the possible cofactors for aPL. Rand et al reported that aPL can disrupt the protective shield of ANXV on procoagulant surfaces,9 leaving sufficient space for the formation of coagulation complexes. aANXV were shown to induce the apoptosis of endothelial cells, creating a procoagulant environment10 with increased risk for thrombosis.
Two of 37 young patients after CVD had significantly raised IgG aANXV only. Besides some CVD risk factors (smoking, delivery and bleeding, oral contraceptives) both patients had pregnancy complications, which might be associated with aANXV.5 Our results did not show a statistically significant association between aANXV and CVD. Nevertheless it is possible that aANXV represented an additional risk factor, and together with other factors might have led to thrombosis. A study of larger groups of patients will enable firm conclusions to be drawn about the clinical significance of aANXV in CVD.