Resistance to annexin A5 binding and anticoagulant activity in plasmas from patients with the antiphospholipid syndrome but not with syphilis.
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Annexin A5↗
Biomedical subjects
J H Rand
Publications and source records attributed to J H Rand.
Acquired von Willebrand syndrome 2004: International Registry--diagnosis and management from online to bedside.
The acquired von Willebrand syndrome (AVWS) is a rare bleeding disorder with laboratory findings similar to those for congenital von Willebrand disease. Unlike the congenital form, AVWS usually occurs in individuals with no personal or family history of bleeding. Large studies on AVWS are not available, diagnosis remains difficult and treatment empirical. Acquired von Willebrand syndrome is especially frequent in lympho- or myeloproliferative disorders. It is associated with solid tumours, immunological and cardiovascular disorders as well as other miscellaneous conditions. Diagnosis of AVWS is based on assays measuring ristocetin cofactor activity or collagen binding, which are usually abnormally low, while factor VIII coagulant activity is some-times within the reference range. FVIII/VWF inhibiting activities are found in only a minority of cases. Bleeding episodes in patients with AVWS are mostly of the mucocutaneous type and can be managed with desmopressin, plasma-derived factor VIII/von Willebrand factor (FVIII/VWF) concentrates and intravenous immunoglobulin. Recombinant activated factor VII can be useful in cases unresponsive to standard therapy. In conclusion, the AVWS, although rare, is certainly underestimated in clinical practice: The actual clinical impact of AVWS should be evaluated by prospective studies. The authors are co-ordinating an updated version of the International Registry on AVWS that will allow data to be entered directly online.
Cardiovascular Diseases↗
Non-stroke neurological syndromes associated with antiphospholipid antibodies: evaluation of clinical and experimental studies.
Although many types of neurological disorders and events have been described in association with antiphospholipid antibodies (aPL) and the antiphospholipid syndrome (APS), only ischaemic stroke is reasonably well established and accepted as a diagnostic criterion for the syndrome. We propose to evaluate, classify and rank the association of other neurological manifestations as possible, probable, or definite according to the data available from clinical studies and animal models. By these criteria, none of the neurological disorders or events such as epilepsy, psychiatric disease, dementia, transverse myelitis, multiple sclerosis-like disease, chorea, migraine, Guillian-Barrè syndrome, and sensory-neural hearing loss, can be definitely associated with aPL or APS.
Antibodies, Antiphospholipid↗
Bleeding and thrombotic complications in critically ill patients with cancer.
Alterations in hemostasis are common in patients with cancer admitted to the ICU. Depending on the underlying disease and specific hemostatic abnormality, the patient with cancer may develop bleeding, thrombosis, or both, such as DIC. Bleeding complications usually result from abnormalities in platelets or deficiency of coagulation factors and require specific blood or coagulation factor replacement. Similarly, critically ill patients with cancer are predisposed to thrombotic complications such as DVT, PE, and central vein thrombosis, the last as a result of the widespread use of long-term indwelling catheter devices. Advances in diagnostic imaging and the availability of newer and more potent anticoagulant agents have facilitated the care of these patients greatly. Ultimately, it is hoped that a thorough understanding of the various disturbances in hemostasis, innovative treatment approaches, and implementation of preventive strategies in patients with cancer will lead to decreased morbidity and improved survival rates of critically ill patients with cancer in the ICU.
Anticoagulants↗
Acquired von Willebrand syndrome: an important bleeding complication to be considered in patients with lymphoproliferative and myeloproliferative disorders.
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Female↗
Seasonal distribution of antiphospholipid antibodies.
BACKGROUND AND PURPOSE: The purpose of this study was to determine if there was a seasonal variation in antiphospholipid antibody (aPL) titers and whether this variation differed between stroke cases and control subjects. METHODS: IgG and IgM anticardiolipin and antiphosphatidyl serine antibody titers were obtained on serum samples from 884 stroke patients and 1024 control subjects over a 7-year period. Temporal distributions by month of blood draw were evaluated. RESULTS: Marked seasonal differences in the proportion of positive titers were found for control subjects, but no seasonal variability among patients was noted. In control subjects, positive titers occurred less frequently in the summer months, mirroring the seasonal trends seen in respiratory track infections and rheumatic fever. CONCLUSIONS: Our data suggest some aPL antibodies arise from different origins in patients and control subjects. The seasonality observed in the apparently normal population may be related to antibodies of infectious origin and is consistent with the reported lack of association with thrombosis of infection-related antibodies.
Age Distribution↗
Thrombophilia: what's a practitioner to do?
Management of thrombophilia is an ever-changing field as new disorders are described and additional clinical experience accrues. This paper addresses three common management issues in the care of patients with thrombophilia. The first two topics are updates for common but perplexing hypercoagulable states and the last topic introduces a new option for optimal management of oral anticoagulant therapy. Dr. Jacob Rand updates and organizes the approach to patients with antiphospholipid syndrome. This syndrome is a common acquired thrombophilic state, but the diagnosis and treatment of patients remains a challenge. Dr. Rand outlines his diagnostic and treatment strategies based on the current understanding of this complicated syndrome. Dr. Barbara Konkle addresses the special concerns of managing women with thrombophilia. Hematologists are often asked to advise on the risks of hormonal therapy or pregnancy in a woman with a personal or family history of thrombosis or with an abnormal laboratory finding. Dr. Konkle reviews the available data on the risks of hormonal therapy and pregnancy in women with and without known underlying thrombophilic risk factors. In Section III, Dr. Gail Macik will discuss a new approach to warfarin management. Several instruments are now available for home prothrombin time (PT) monitoring. Self-testing and self management of warfarin are slowly emerging as reliable alternatives to traditional provider-based care and Dr. Macik reviews the instruments available and the results of studies that support this new management option.
Blood Coagulation Tests↗
The annexinopathies: a new category of diseases.
The annexins are a family of highly homologous phospholipid binding proteins, which share a four-domain structure, with one member of the family - annexin VI - having a duplication consisting of eight domains. Thus far, ten annexins have been described in mammals. Although the biological functions of the annexins have not been definitively established, two human diseases involving annexin abnormalities ('annexinopathies') have been identified as of the time of writing. Overexpression of annexin II occurs in the leukocytes of a subset of patients having a hemorrhagic form of acute promyelocytic leukemia. Underexpression of annexin V occurs on placental trophoblasts in the antiphospholipid syndrome and in preeclampsia. Also, an animal model has been described in which annexin VII is underexpressed and is associated with disease, but the relevance of this animal model to human disease is not yet understood. Future research is likely to elucidate additional 'annexinopathies'.
Animals↗
Antiphospholipid antibody-mediated disruption of the annexin-V antithrombotic shield: a thrombogenic mechanism for the antiphospholipid syndrome.
The mechanism(s) for thrombosis and pregnancy losses in the anti-phospholipid antibody syndrome have not yet been established. Annexin-V is an anionic phospholipid-binding protein with potent anticoagulant activity. The protein has been shown to be necessary for the maintenance of placental integrity and may play a thromboregulatory role at the maternal-fetal interface. There, it assembles over the apical surfaces of the placental villi and shields the underlying anionic phospholipids from availability for complexation with coagulation proteins. We have proposed that thrombosis and pregnancy loss in the antiphospholipid syndrome may be due to the disruption of the annexin-V shield by antiphospholipid (and co-factor) antibodies. The data accumulated from tissue immunohistochemistry, trophoblast and endothelial cell culture studies, coagulation studies using non-cellular phospholipids, and competition studies on artificial phospholipid bilayer are consistent with this hypothesis.
Abortion, Habitual↗
The pathogenic role of annexin-V in the antiphospholipid syndrome.
The antiphospholipid antibody syndrome is an autoimmune condition in which venous or arterial thrombosis and recurrent pregnancy losses occur in patients having serologic evidence of antibodies against anionic phospholipid-protein complexes. The pathophysiologic mechanisms of this syndrome have not yet been established. Annexin-V, an anionic phospholipid-binding protein with potent anticoagulant activity, is necessary for maintenance of placental integrity and may play a thromboregulatory role at the vascular-blood interface by forming two-dimensional crystals which shield anionic phospholipids from complexing with coagulation proteins from circulating blood. We propose that thrombosis and pregnancy loss in the antiphospholipid syndrome may be caused by disruption of this Annexin-V shield by antiphospholipid (and cofactor) antibodies, thereby increasing the net quantity of thrombogenic phospholipids exposed to the circulating blood. The data accumulated from tissue immunohistochemistry, trophoblast and endothelial cell culture studies, coagulation studies using noncellular phospholipids, and competition studies on artificial phospholipid bilayer are consistent with the hypothesis that interference with the binding of Annexin-V to anionic phospholipid surfaces is an important mechanism of thrombosis and pregnancy loss in the antiphospholipid syndrome.
Annexin A5↗
Acquired von Willebrand syndrome: data from an international registry.
The acquired von Willebrand syndrome (AvWS) is a rare bleeding disorder with laboratory findings similar to those of congenital von Willebrand disease (vWD). Despite the numerous cases reported in the literature until 1999 (n = 266), large studies on AvWS are not available. Moreover, diagnosis of AvWS has been difficult and treatment empirical. These considerations prompted us to organize an international registry. A questionnaire, devised to collect specific information on AvWS, was sent to all the members of the International Society on Thrombosis and Haemostasis (ISTH), who were invited to respond if they had diagnosed cases with the AvWS cases. 156 members answered the questionnaire and 54 of them sent information on 211 AvWS cases from 50 centers. Data were compared with those already published in the literature and 25 cases already described or not correctly diagnosed were excluded. The 186 AvWS cases that qualified for the registry were associated with lymphoproliferative (48%) and myeloproliferative disorders (15%), neoplasia (5%), immunological (2%), cardiovascular (21%) and miscellaneous disorders (9%). Ristocetin cofactor activity (vWF:RCo) or collagen binding activity (vWF:CBA) were usually low in AvWS (median values 20 U/dL, range 3-150), while factor VIII coagulant activity was sometimes normal (median 25 U/dL, range 3-191). FVIII/vWF inhibiting activities were present in only a minority of cases (16%). Bleeding episodes in AvWS were mostly of mucocutaneous type (68%) and were managed by DDAVP (32%), FVIII/vWF concentrates (37%), intravenous immunoglobulins (33%), plasmapheresis (19%), corticosteroids (19%) and immunosuppressive or chemotherapic agents (35%). Based upon the data of this international registry, it appears that AvWS is especially frequent in lympho- or myeloproliferative and cardiovascular diseases. Therefore, AvWS should be suspected and searched with the appropriate laboratory tests especially when excessive bleeding occurs in patients with these disorders. On the basis of the information provided by this registry guidelines for diagnosis and management of the AvWS are given.
Adolescent↗
Antiphosphatidyl serine antibodies are independently associated with ischemic stroke.
OBJECTIVE: To determine whether elevated titers of antiphosphatidyl serine antibodies (aPS) are associated with an increased risk of ischemic stroke in a general stroke population. BACKGROUND: aPS are members of the family of antiphospholipid antibodies that has been associated with increased stroke risk. Although aPS have been demonstrated to occur in 18% of a group of young patients with cerebrovascular symptoms, their prevalence in the general stroke population is unknown, and no controlled study to assess the strength of their association with ischemic stroke has been undertaken previously. METHODS: A case-control study comparing 267 acute ischemic stroke patients and 653 community controls. Sera were obtained immediately after acute stroke in patients. Titers of IgG aPS >16 IgG phospholipid units or IgM aPS >22 IgM phospholipid units were considered positive. Odds ratios (ORs) were obtained by logistic regression, adjusting for age, gender, race/ethnicity, history of hypertension, diabetes mellitus, cardiovascular disease, and cigarette smoking. RESULTS: The adjusted OR was 5.6 (95% confidence interval [CI] 1.8, 18.0) for IgG aPS and 2.9 (95% CI 1.6, 5.3) for IgM aPS. The adjusted OR for either an elevated IgG or IgM aPS was 3.2 (95% CI 1.8, 5.5). CONCLUSIONS: This study demonstrates that elevated IgG and IgM antiphosphatidyl serine antibodies titers are associated with increased risk of ischemic stroke. The prevalence of these antibodies is lower, but the associated stroke risk is comparable with that of anticardiolipin antibodies.
Aged↗
"Annexinopathies"--a new class of diseases.
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Annexin A2↗
Elevated anticardiolipin antibody titer is a stroke risk factor in a multiethnic population independent of isotype or degree of positivity.
BACKGROUND AND PURPOSE: Previous studies have produced conflicting results regarding the putative association between anticardiolipin antibodies (aCL) and infarction in the general stroke population. These inconsistencies may be a function of sample size and methodological differences among the studies. The purpose of the present study, the largest case-control study of this issue to date, was to assess aCL status as an independent risk factor for ischemic stroke in a multiethnic, urban population. METHODS: We obtained aCL titers in 524 hospitalized acute stroke patients and 1020 community controls enrolled in the Minorities Risk Factors and Stroke Study. The results were interpreted as negative (</=22.9 IgG phospholipid [GPL] or 10.9 IgM phospholipid [MPL] units), low positive (22.9 to 30.0 GPL or 10.9 to 15.0 MPL units), or high positive (>30.0 GPL or 15.0 MPL units). Odds ratios (ORs) were adjusted for age, sex, race/ethnicity, history of diabetes, hypertension, atrial fibrillation, coronary artery disease, and current cigarette smoking. RESULTS: A positive aCL titer was present in 11% (111/1020) of controls and 34% (180/524) of cases. The adjusted OR for any positive aCL titer was 4.0 (95% CI, 3.0 to 5.5). For any positive IgG aCL titer this value was 3.9 (95% CI, 2.8 to 5.5), and for any positive IgM aCL titer it was 3.4 (95% CI, 2.1 to 5.5). There were no significant differences in ORs associated with high- or low-positive IgG or IgM aCL titers. CONCLUSIONS: In the largest study of its kind to date, aCL antibodies were demonstrated to be independent stroke risk factors across the 3 ethnic groups studied, conferring a 4-fold increased risk of ischemic stroke. IgG and for the first time IgM aCL were each shown to be associated with increased stroke risk. The prevalence of these antibodies and the stroke risk associated appear greater than previously reported.
Acute Disease↗
Thrombophilias: diagnosis and treatment of thrombophilia relating to contraception and pregnancy.
The thrombogenicity of oral contraceptives (OCs) has been known since the 1960s. The thrombotic risk remains increased even with the third-generation preparations containing low-dose estrogen and a progesterone. Thromboembolic disorders are a leading cause of maternal morbidity and mortality during pregnancy and puerperium in Western countries. Women with thrombophilic conditions are even more prone to hypercoagulability when using hormone therapy, or during pregnancy and puerperium. At present, it is not recommended that all OC users or pregnant women be routinely screened for thrombophilic abnormalities. The usefulness of testing for these disorders in the presence of multiple thrombotic risk factors should be considered on an individual basis. Anticoagulant treatment may be advised for selected patient populations.
Contraception↗
A possible solution to the paradox of the "lupus anticoagulant": antiphospholipid antibodies accelerate thrombin generation by inhibiting annexin-V.
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Annexin A5↗
Antibody-mediated disruption of the annexin-V antithrombotic shield: a new mechanism for thrombosis in the antiphospholipid syndrome.
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Animals↗
Antiphospholipid antibodies accelerate plasma coagulation by inhibiting annexin-V binding to phospholipids: a "lupus procoagulant" phenomenon.
The antiphospholipid syndrome is a thrombophilic condition marked by antibodies that recognize anionic phospholipid-protein cofactor complexes. We recently reported that exposure to IgG fractions from antiphospholipid patients reduces the level of annexin-V, a phospholipid-binding anticoagulant protein, on cultured trophoblasts and endothelial cells and accelerates coagulation of plasma exposed to these cells. Therefore, we asked whether antiphospholipid antibodies might directly reduce annexin-V binding to noncellular phospholipid substrates. Using ellipsometry, we found that antiphospholipid IgGs reduce the quantity of annexin-V bound to phospholipid bilayers; this reduction is dependent on the presence of beta2-glycoprotein I. Also, exposure to plasmas containing antiphospholipid antibodies reduces annexin-V binding to phosphatidyl serine-coated microtiter plates, frozen thawed washed platelets, activated partial thromboplastin time (aPTT) reagent and prothrombin time reagent and reduces the anticoagulant effect of the protein. These studies show that antiphospholipid antibodies interfere with the binding of annexin-V to anionic phospholipid and with its anticoagulant activity. This acceleration of coagulation, due to reduced binding of annexin V, stands in marked contrast to the "lupus anticoagulant effect" previously described in these patients. These results are the first direct demonstration of the displacement of annexin-V and the consequent acceleration of coagulation on noncellular phospholipid surfaces by antiphospholipid antibodies.
Annexin A5↗