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Thomas L Ortel

Publications and source records attributed to Thomas L Ortel.

44 records · Page 3Linked to original sources
PubMed2002

Two classes of germline genes both derived from the V(H)1 family direct the formation of human antibodies that recognize distinct antigenic sites in the C2 domain of factor VIII.

Most plasmas from patients with inhibitors contain antibodies that are reactive with the C2 domain of factor VIII. Previously, we have shown that the variable heavy chain (V(H)) regions of antibodies to the C2 domain are encoded by the closely related germline gene segments DP-10, DP-14, and DP-88, which all belong to the V(H)1 gene family. Here, we report on the isolation and characterization of additional anti-C2 antibodies that are derived from V(H) gene segments DP-88 and DP-5. Competition experiments using murine monoclonal antibodies CLB-CAg 117 and ESH4 demonstrated that antibodies derived from DP-5 and DP-88 bound to different sites within the C2 domain. Epitope mapping studies using a series of factor VIII/factor V hybrids revealed that residues 2223 to 2332 of factor VIII are required for binding of the DP-10-, DP-14-, and DP-88-encoded antibodies. In contrast, binding of the DP-5-encoded antibodies required residues in both the amino- and carboxy-terminus of the C2 domain. Inspection of the reactivity of the antibodies with a series of human/porcine hybrids yielded similar data. Binding of antibodies derived from germline gene segments DP-10, DP-14, and DP-88 was unaffected by replacement of residues 2181 to 2243 of human factor VIII for the porcine sequence, whereas binding of the DP-5-encoded antibodies was abrogated by this replacement. Together these data indicate that antibodies assembled from V(H) gene segments DP-5 and the closely related germline gene segments DP-10, DP-14, and DP-88 target 2 distinct antigenic sites in the C2 domain of factor VIII.

Amino Acid Sequence↗
PubMed2002

Frequency of anti-heparin-platelet factor 4 antibodies in hemodialysis patients and correlation with recurrent vascular access thrombosis.

Heparin-induced thrombocytopenia (HIT), characterized by the formation of antibodies to a complex of platelet factor 4 (PF4) and heparin, is a well-recognized risk factor for thromboembolic complications. The frequency of antibody development varies among patient populations. Hemodialysis patients have repeated heparin exposure and should be at risk of developing HIT. This might, contribute to the development of vascular access thrombosis. We prospectively evaluated 88 hemodialysis patients for the presence of anti-PF4/heparin antibodies. Eighteen patients (20%) had a prior history of 1 or more prior access thrombosis. One patient (1.14%), without a history of graft thrombosis, tested positive for anti-PF4/heparin antibodies. In our study, the presence of anti-PF4/heparin antibodies was rare and was not increased in patients with a history of vascular access thrombosis.

Antibodies↗
PubMed2002

Issues in the utilization of low molecular weight heparins.

Low molecular weight heparins (LMWHs) are parenteral anticoagulants that are widely used for the prevention and treatment of thromboembolic disease. These agents possess several advantages compared to standard heparin, including a more predictable anticoagulant response, better bioavailability allowing for subcutaneous therapy, and a longer half-life. Laboratory monitoring of the LMWHs uses an anti-factor Xa assay, but monitoring is generally not necessary for most patients. However, certain patient populations do benefit from an individualized approach to therapy and, in some cases, therapeutic monitoring, because of an increased bleeding risk and/or relative contraindications to anticoagulant therapy. For example, since LMWHs are cleared by the kidney, they must be used with caution in renal insufficiency. LMWHs are safe and effective during pregnancy but may not be the optimal antithrombotic agent in pregnant women with prosthetic valves. In addition, management around the time of delivery can be difficult because of the bleeding risk, particularly associated with epidural anesthesia. Therapeutic monitoring also may be useful for the morbidly obese, in children, and for patients with malignancy.

Anticoagulants↗
PubMed2002

Antiphospholipid antibodies after surgical exposure to topical bovine thrombin.

Exposure to topical bovine thrombin during surgery frequently results in the development of antibodies to multiple protein and carbohydrate antigens. We investigated the frequency of increased levels of antibodies to cardiolipin and beta(2)-glycoprotein I (beta(2)-GPI) in two groups of patients, one exposed to bovine thrombin during cardiovascular surgery (n = 151) and a "control" group undergoing cardiovascular surgery but without exposure to bovine thrombin (n = 11). Anticardiolipin antibody levels were increased before surgery in 10 of the 151 patients exposed to topical thrombin (6.6%). Four to 8 weeks after surgery, 84 patients (55.6%) had increased anticardiolipin antibody levels (P <.0001). In the control group, an increased anticardiolipin antibody level was present in a single patient before and after surgery (9%). Increased levels of antibodies to bovine and human beta(2)-GPI were also observed after surgery in the patients exposed to topical thrombin (37.7% and 38.2%, respectively). Increased anticardiolipin levels correlated with higher levels of antibody to bovine, but not human, beta(2)-GPI. In addition, increased levels of anticardiolipin antibody were associated with higher levels of antibodies to bovine factor V and prothrombin, as well as human factor V. Antibody binding on an enzyme-linked immunosorbent assay conducted to detect anticardiolipin antibody was dependent on the presence of anionic phospholipid, indicating that binding was not linked to the fetal bovine serum in the blocking buffer alone. Seven of 8 patients with delayed thromboembolic complications had increased anticardiolipin IgG antibody levels after surgery, but this association was not statistically significant. Nevertheless, our findings support the recommendation that the clinical safety of these commonly used hemostatic agents should be reassessed.

Administration, Topical↗
PubMed2002

Coagulation and inflammation in acute lung injury.

The acute respiratory distress syndrome (ARDS) is a severe lung injury in patients with sepsis and other acute inflammatory insults, which is characterized by fibrin deposition in the pulmonary parenchyma, vasculature, and airspaces. Recent evidence suggests that progressive ARDS is closely linked to activation of inflammation and coagulation. Coagulation becomes activated by circulating endotoxin or bacteria, and a procoagulant state develops in the vascular and the alveolar compartments of the lung. This state is Tissue Factor (TF)-dependent and associated with increased elaboration of inflammatory cytokines. A similar procoagulant state is found in bronchoalveolar lavage of patients with ARDS, suggesting that extravascular coagulation contributes to lung inflammation. TF and other coagulation proteins, including Factor Xa, thrombin, and fibrin, also contribute to the pathogenesis of acute lung injury through multi-level interactions with inflammatory effectors, in which these proteins coordinately act as regulators of tissue injury responses. Each coagulation protein has direct and independent effects on inflammatory events that influences lung injury through changes in cytokine elaboration, inflammatory cell migration and activation, surfactant function, and repair mechanisms. New interventional strategies directed at procoagulant activity highlight the importance of the coagulation system to acute lung injury and suggest that blockade of initiation of coagulation may have therapeutic benefit in patients with ARDS.

Animals↗
PubMed2002

Anti-beta(2)-glycoprotein I antibody-mediated inhibition of activated protein C requires binding of beta(2)-glycoprotein I to phospholipids.

To clarify the role(s) of anti-beta(2) GPI antibodies on thrombosis in anti-phospholipid antibody syndromes (APS), the effect of IgG from three patients on activated protein C (APC) was investigated using phospholipid vesicles and purified proteins. Two of the total IgG inhibited APC activity in the presence of beta(2)GPI, whereas the third IgG did not. In addition, one IgG inhibited APC activity without beta(2)GPI. Anti-beta(2)GPI IgG from the two inhibitory IgG preparations inhibited APC activity only in the presence of beta(2)GPI. Inhibition was suppressed partially by excess APC and almost completely by excess phospholipid vesicles. Cleaved beta(2)GPI, a non-phospholipid-binding form, did not support inhibitory activity, even though the anti-beta(2)GPI IgG bound to the cleaved molecule. This study confirms that anti-beta(2)GPI antibodies from APS patients inhibit APC activity, and demonstrates the requirement of phospholipid binding of beta(2)GPI for expression of the inhibitory activity of these antibodies.

Antiphospholipid Syndrome↗
PubMedDate not supplied

Alternative methods of anticoagulation for dialysis-dependent patients with heparin-induced thrombocytopenia.

Dialysis patients who are continually exposed to heparin are at risk for heparin-induced thrombocytopenia (HIT). Heparin-induced antibodies have been reported to occur in 0-12% of hemodialysis (HD) patients. The diagnosis or suspicion of HIT in this patient population requires careful confirmation of the diagnosis and substitution of heparin with an alternate anticoagulant for dialysis. Alternate agents such as the direct thrombin inhibitors (hirudin and argatroban) are available, but careful dosing and monitoring of the anticoagulant effect are required. Despite careful dosing, hemorrhagic complications have occurred with these agents. Unfortunately there are limited options for treatment of hemorrhagic complications and no specific antidotes are available for the direct thrombin inhibitors. In this report the currently available alternatives to heparin for dialysis, including dosing and monitoring recommendations, are reviewed.

Anticoagulants↗