Biomedical subjects

Jacob H Rand

Publications and source records attributed to Jacob H Rand.

13 recordsLinked to original sources

PubMed2006

Correlation between antiphospholipid antibodies that recognize domain I of beta2-glycoprotein I and a reduction in the anticoagulant activity of annexin A5.

The paradoxical correlation between thrombosis and the lupus anticoagulant (LAC) effect is an enigmatic feature of the antiphospholipid (aPL) syndrome. The Dutch authors previously reported that thrombosis-related anti-beta2-glycoprotein I (beta2GPI) antibodies recognize domain I and cause LAC. The American authors reported that aPLs disrupt an anticoagulant annexin A5 (AnxA5) crystal shield. We investigated whether antidomain I antibodies correlate with disruption of AnxA5-anticoagulant activity. We studied a well-characterized group of 33 patients including subgroups with beta2GPI-dependent LAC that recognize domain I (n=11), with beta2GPI-independent LAC (n=12), and lacking LAC (n=10). The effects on AnxA5-anticoagulant activity were determined with an AnxA5 resistance assay that measures coagulation times with and without AnxA5. Patients with beta2GPI-dependent LAC (group A, all with thrombosis) had significantly lower AnxA5-anticoagulant ratios than those with beta2GPI-independent LAC (group B, thrombosis n=4; 157.8% versus 235.6%, P<.001) and those without LAC (group C, thrombosis n=2; 157.8% versus 232.5%, P<.001). There was no difference in the ratios between groups B and C (P=.92). Plasmas with beta2GPI-dependent LAC that recognize domain I displayed significantly increased AnxA5 resistance, suggesting that specifically anti-beta2GPI antibodies compete with AnxA5 for anionic phospholipids. These results are consistent with a model in which aPL antibodies may promote thrombosis by interfering with the anticoagulant activity of AnxA5.

Adult↗

PubMed2006

Analysis of circulating annexin A5 parameters during pregnancy: absence of differences between women with recurrent spontaneous pregnancy losses and controls.

OBJECTIVE: We investigated whether levels of annexin A5 (AnxA5), AnxA5 anticoagulant activity and binding, and anti-AnxA5 antibodies might be altered in women with previous histories of recurrent spontaneous pregnancy losses (RSPL) when tested during pregnancy. STUDY DESIGN: Ninety pregnant women with histories of 3 or more RSPL (cases) and 150 women without adverse pregnancy histories (controls) were assayed for these AnxA5 parameters. RESULTS: There were no significant differences between cases and controls in AnxA5 levels (median, 23.1 ng/mL [range, 2.1-201.1 ng/mL] vs 19.7 ng/mL [2.1-151.5 ng/mL]; P = .20), AnxA5 anticoagulant activity (183% [101%-236%] vs 168% [128%-256%]; P = .39) and binding (6.0 ng/aliquot PL [2.1-19.5 ng/aliquot PL) vs 6.1 ng/aliquot PL [1.6-16.8 ng/aliquot PL]; P = .72), and anti-AnxA5 antibody levels. CONCLUSIONS: AnxA5 parameters do not distinguish between cases and controls when tested during pregnancy. The pregnant state itself appears to be associated with altered levels of AnxA5 parameters.

Abortion, Habitual↗

PubMed2006

Annexin A5 levels in midtrimester amniotic fluid: association with intrauterine growth restriction.

OBJECTIVE: The purpose of this study was to determine whether amniotic fluid levels of annexin A5 (AF-AnxA5) may be associated with intrauterine growth restriction (IUGR). STUDY DESIGN: Amniotic fluid was obtained in a cohort of pregnant patients (n = 172) undergoing amniocentesis at 15 to 24 weeks' gestation and annexin A5 (AnxA5) levels were determined with enzyme-linked immunosorbent assay (ELISA). Patients who developed IUGR were compared with the remainder of the cohort. RESULTS: AF-AnxA5 levels significantly increased through gestation (P = .003). The mean level of AF-AnxA5 in IUGR patients (n = 15) was significantly higher (P = .028) than in the remainder of the cohort (n = 130). Elevated AF-AnxA5 > 20 ng/mL was associated with a relative risk of 3.5 for the development of IUGR (P = .023). CONCLUSION: AnxA5 is present in amniotic fluid and increases through gestation from 15 to 24 weeks. Elevated AF-AnxA5 levels were present in patients who developed IUGR. AF-AnxA5 may be a useful marker for identifying pregnancy abnormalities.

Adult↗

PubMed2006

Reduction of circulating annexin A5 levels and resistance to annexin A5 anticoagulant activity in women with recurrent spontaneous pregnancy losses.

OBJECTIVE: We investigated whether levels of annexin A5, evidence for resistance to annexin A5 activity, and levels anti-annexin A5 antibodies might be altered in women with a history of recurrent spontaneous pregnancy losses. STUDY DESIGN: These annexin A5 parameters were assayed in 70 nonpregnant women with a history of > or = 3 recurrent spontaneous pregnancy losses (cases) and 50 women without adverse pregnancy history (control subjects). RESULTS: Cases had significantly lower plasma annexin A5 levels than control subjects (median, 4.7 ng/mL [range, 0.3-40.4 ng/mL] vs 6.7 ng/mL [range, 0.7-56.0]; P = .01), significantly reduced anticoagulant ratios (188% [range, 119%-279%] vs 238% [range, 159%-286%]; P < .0001), and reduced binding of annexin A5 to phospholipid (6.3 ng/aliquot phospholipid [range, 1.5-16.4 ng/aliquot phospholipid] vs 9.7 ng/aliquot phospholipid (range, 3.5-17.0 ng/aliquot phospholipid]; P = .0002). There were no significant differences in anti-annexin A5 antibody levels. CONCLUSION: Reduction of annexin A5 and interference with its anticoagulant and binding activities are associated significantly with a history of recurrent spontaneous pregnancy losses. These data support the concept of a significant role for annexin A5 in the maintenance of pregnancy.

Abortion, Habitual↗

PubMed2006

An evaluation of thrombophilia screening in an urban tertiary care medical center: A "real world" experience.

To evaluate the utilization of thrombophilia screening at a large urban academic tertiary care center, we retrospectively examined the indications, appropriateness, and results of 200 consecutive thrombophilia panels. Of the panels, 103 (51.5%) were ordered for venous thromboembolism; 124 (62.0%) were ordered during acute thrombotic episodes, and at least 40 (20.0%) had abnormal protein C and S results, of which 25 (63%) were attributable to anticoagulation and the remainder to pregnancy. Of the 200 panels, 46 (23.0%) had a significant abnormality; the most common abnormal result was a lupus anticoagulant, occurring in 23 cases (11.3%). Thrombophilia screening seems to be overutilized in our population, especially considering that the majority of tests are ordered during suboptimal conditions, eg, acute thrombosis, pregnancy, or anticoagulation. At present, outside the research setting, thrombophilia panels should be reserved for special circumstances, targeted to factors for which there would be a specific clinical impact, and performed in the absence of confounding clinical variables.

Adolescent↗

PubMed2006

ADAMTS13-binding IgG are present in patients with thrombotic thrombocytopenic purpura.

Functional assays are commonly used to measure the antibodies of ADAMTS13 found in patients of thrombotic thrombocytopenic purpura (TTP). In this study we used an enzyme-linked immunoassay to analyze the ADAMTS13-binding IgG levels in six groups of individuals: normal, random hospitalized patients, acute TTP, TTP after receiving plasma therapy, TTP in remission, and other types of thrombotic microangiopathy (TMA). The results showed that ADAMTS13-binding IgG levels were elevated in 100% of the acute TTP group, 75% of the TTP group after receiving plasma therapy, and 40% of the remission group. Overall, the ADAMTS13-binding IgG levels correlated with the inhibitory activity levels againstADAMTS13 (r = -0.69, P < 0.0001). The assay also detected elevated IgG binding levels in 5% - 15% of the normal, random, and other TMA control groups. Addition of purified ADAMTS13 protein to the plasma samples suppressed the IgG binding in each of the acute TTP patients, but in none of the non-TTP groups. Serial measurement in a patient that had two exacerbations of TTP within the first three weeks revealed that the ADAMTS13 activity levels remained <0.1 U/ml during this period, and the ADAMTS13-binding IgG remained elevated, suggesting that ADAMTS13 analysis may provide valuable insight to the disease status during the course of therapy. Analysis of ADAMTS13-binding IgG is helpful for the diagnosis and management of TTP.

ADAM Proteins↗

PubMed2004

Detection of antibody-mediated reduction of annexin A5 anticoagulant activity in plasmas of patients with the antiphospholipid syndrome.

Annexin A5 (A5) forms 2-dimensional crystals over phospholipid bilayers, blocking their availability for coagulation reactions. Recently, human antiphospholipid (aPL) monoclonal antibodies (mAbs) have been demonstrated by atomic force microscopy (AFM) to disrupt this crystallization and accelerate coagulation. We therefore performed a study with small, well-defined groups of patients to investigate whether these effects on A5 binding and activity are also detectable in plasmas from patients with the aPL syndrome. A5 binding to phospholipid was significantly reduced by plasmas of patients with the aPL syndrome and thromboembolism compared with healthy controls (mean +/- SD, 26.7 +/- 4.3 ng/well [n = 25] vs 30.5 +/- 3.1 ng/well [n = 20], P < .01) and the non-aPL thromboembolism group (29.9 +/- 3.2 ng/well [n = 15], P < .05). A5 anticoagulant activity was reduced by plasmas of patients with aPL syndrome and thromboembolism compared with aPL antibodies without thrombosis (182 +/- 31% [n = 25] vs 210 +/- 35% [n = 26], P < .01), non-aPL thromboembolism (229 +/- 16% [n = 15], P < .001), and healthy controls (231 +/- 14% [n = 30], P < .001). In conclusion, in accordance with recent AFM data with monoclonal human aPL antibodies, plasmas from patients with aPL antibodies with thromboembolism reduce both A5 binding to phospholipid and A5 anticoagulant activity. This "annexin A5 resistance" identifies a novel mechanism for thrombosis in the aPL syndrome.

Annexin A5↗

PubMed2004

Antibody-mediated interference with annexins in the antiphospholipid syndrome.

Targeting of the annexin A5 anticoagulant shield may be a significant mechanism for thrombosis and pregnancy losses in APS. This may occur via high affinity antibodies that recognize phospholipid-binding proteins that are capable of interfering with the assembly of the annexin A5 shield on phospholipid surfaces or via direct recognition of annexin A5 by autoantibodies. In addition, antibodies against other members of the annexin family of proteins may also have pathogenic roles in APS. It is anticipated that further research will elucidate the biologic functions of these proteins and their roles in the aPL disease processes.

Annexin A5↗

PubMed2003

Human monoclonal antiphospholipid antibodies disrupt the annexin A5 anticoagulant crystal shield on phospholipid bilayers: evidence from atomic force microscopy and functional assay.

The antiphospholipid (aPL) syndrome is an autoimmune condition that is marked by recurrent pregnancy losses and/or systemic vascular thrombosis in patients who have antibodies against phospholipid/co-factor complexes. The mechanism(s) for pregnancy losses and thrombosis in this condition is (are) not known. Annexin A5 is a potent anticoagulant protein, expressed by placental trophoblasts and endothelial cells, that crystallizes over anionic phospholipids, shielding them from availability for coagulation reactions. We previously presented data supporting the hypothesis that aPL antibody-mediated disruption of the anticoagulant annexin A5 shield could be a thrombogenic mechanism in the aPL syndrome. However, this has remained a subject of controversy. We therefore used atomic force microscopy, a method previously used to study the crystallization of annexin A5, to image the effects of monoclonal human aPL antibodies on the crystal structure of the protein over phospholipid bilayers. In the presence of the aPL monoclonal antibodies (mAbs) and beta(2)-GPI, the major aPL co-factor, structures presumed to be aPL mAb-antigen complexes were associated with varying degrees of disruption to the annexin A5 crystallization pattern over the bilayer. In addition, measurements of prothrombinase activity on the phospholipid bilayers showed that the aPL mAbs reduced the anti-coagulant effect of annexin A5 and promoted thrombin generation. These data provide morphological evidence that support the hypothesis that aPL antibodies can disrupt annexin A5 binding to phospholipid membranes and permit increased generation of thrombin. The aPL antibody-mediated disruption of the annexin A5 anticoagulant shield may be an important prothrombotic mechanism in the aPL syndrome.

Annexin A5↗

PubMed2003

Platelet-endothelial interactions: sepsis, HIT, and antiphospholipid syndrome.

Acquired abnormalities in platelets, endothelium, and their interaction occur in sepsis, immune heparin-induced thrombocytopenia (HIT), and the antiphospholipid syndrome. Although of distinct pathogeneses, these three disorders have several clinical features in common, including thrombocytopenia and the potential for life- and limb-threatening thrombotic events, ranging from microvascular (sepsis > antiphospholipid > HIT) to macrovascular (HIT > antiphospholipid > sepsis) thrombosis, both venous and arterial. In Section I, Dr. William Aird reviews basic aspects of endothelial-platelet interactions as a springboard to considering the common problem of thrombocytopenia (and its mechanism) in sepsis. The relationship between thrombocytopenia and other aspects of the host response in sepsis, including activation of coagulation/inflammation pathways and the development of organ dysfunction, is discussed. Practical issues of platelet count triggers and targeted use of activated protein C concentrates are reviewed. In Section II, Dr. Theodore Warkentin describes HIT as a clinicopathologic syndrome, i.e., the diagnosis should be based on the concurrence of an appropriate clinical picture together with detection of platelet-activating and/or platelet factor 4-dependent antibodies (usually in high levels). HIT is a profound prothrombotic state (odds ratio for thrombosis, 20-40), and the risk for thrombosis persists for a time even when heparin is stopped. Thus, pharmacologic control of thrombin (or its generation), and postponing oral anticoagulation pending substantial resolution of thrombocytopenia, is appropriate. Indeed, coumarin-associated protein C depletion during uncontrolled thrombin generation of HIT can explain limb loss (coumarin-associated venous limb gangrene) or skin necrosis syndromes in some patients. In Section III, Dr. Jacob Rand presents the most recent concepts on the mechanisms of thrombosis in the antiphospholipid syndrome, and focuses on the role of beta(2)-glycoprotein I as a major antigenic target in this condition. Diagnosis of the syndrome is often complicated because the clinical laboratory tests to identify this condition have been empirically derived. Dr. Rand addresses the practical aspects of current testing for the syndrome and current recommendations for treating patients with thrombosis and with spontaneous pregnancy losses.

Antiphospholipid Syndrome↗

PubMed2003

Controversies in differentiating thrombotic thrombocytopenic purpura and hemolytic uremic syndrome.

The diagnoses of thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) often remain questionable, forcing the clinician to make the difficult decision of initiating therapy based on symptomatology and clinical judgment and, sometimes, instinct. An increased awareness of characteristic symptoms and early diagnoses of TTP and HUS are of utmost importance, given the excellent results obtained with prompt plasma exchange therapy. Tremendous progress has been made in understanding TTP and HUS since TTP was first described more than 75 years ago at Mount Sinai. However, several questions are still not definitively answered. In this article, we will review background on both entities, and then describe the controversy in differentiating between them.

Diagnosis, Differential↗

PubMed2002

Molecular pathogenesis of the antiphospholipid syndrome.

The antiphospholipid (aPL) syndrome is an acquired autoimmune disorder of unknown etiology in which patients present with thrombosis together with laboratory evidence for antibodies in blood that recognize anionic phospholipid-protein complexes. The main antigenic target for the aPL antibodies has been identified to be beta(2) glycoprotein I (beta(2)GPI), a phospholipid-binding protein. The high affinity of aPL antibody-beta(2)GPI complex for phospholipid membranes seems to be a critical step in the mechanism of this disease. This review focuses on some of the major mechanisms that have been proposed to explain this disorder.

Animals↗

PubMed2001

The antiphospholipid syndrome.

The antiphospholipid (aPL) antibody syndrome is an autoimmune condition in which vascular thrombosis and/or recurrent pregnancy losses occur in patients with laboratory evidence for antibodies that bind to phospholipids. There have been significant advances in the recognition of the role of phospholipid-binding cofactors, primarily beta2GPI, as the true immunologic targets of the antibodies. Recent evidence suggests that the antibodies disrupt phospholipid-dependent anticoagulant mechanisms and/or that aPL antibodies induce the expression of procoagulant and proadhesive molecules on endothelial cells. Current diagnosis is based on clinical findings and empirically derived tests, such as assays for antibodies that bind to phospholipids or putative cofactors and coagulation assays that detect inhibition of phospholipid-dependent coagulation reactions. Current treatment relies primarily on anticoagulant therapy. Research advances are expected to bring mechanistically based diagnostic tests and improved therapy that target the roots of the disease process.

Abortion, Habitual↗