Papers by Frederick Ofosu
Thrombosis and Haemostasis, 1987
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Thrombosis and Haemostasis, 1987
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Blood, Nov 1, 1988
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Analytical Biochemistry, Dec 1, 1977
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Thrombosis and Haemostasis, 1990
SummaryIt has been suggested that protamine sulfate is a poor antidote for the bleeding side-effe... more SummaryIt has been suggested that protamine sulfate is a poor antidote for the bleeding side-effeets of low molecular weight heparins (LMWHs) in vivo, since protamine sulfate does not completely neutralize the anti-factor Xa activity of LMWHs in vitro or ex vivo. Therefore, we performed experiments to compare directly the abilities of protamine sulfate to neutralize the anticoagulant activities of the LMWH, enoxaparine, and unfractionated heparin ex vivo, with its ability to neutralize the bleeding side-effeets of both compounds in vivo. Bleeding was measured as the amount of blood lost from 5 cuts made in rabbits ears before and after treatment with enoxaparine or unfractionated heparin ± protamine sulfate. Plasma anti-factor Xa and anti-thrombin activities ex vivo, were measured chromogenically. Doses of 400 and 1,500 anti-factor Xa U/kg of heparin and enoxaparine, respectively, were required to enhance blood loss to the same extent. Protamine sulfate completely neutralized blood loss induced by both compounds, but did not neutralize the anti-factor Xa nor antithrombin activities ex vivo. We conclude that protamine sulfate is an effective antidote for the bleeding side-effeets of enoxaparine and unfractionated heparin, despite its inability to completely neutralize their anticoagulant activities.
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Blood Coagulation & Fibrinolysis, Aug 1, 1992
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Journal of Laboratory and Clinical Medicine, May 1, 1991
Three recent studies have reported that fibrin in solution significantly inhibits the ability of ... more Three recent studies have reported that fibrin in solution significantly inhibits the ability of heparin to catalyze the inhibition of thrombin by antithrombin III. In addition, heparin inhibits the release of fibrinopeptide A by clot-bound thrombin less effectively than it inhibits the release of fibrinopeptide A by thrombin in solution. We have also reported that dermatan sulfate, which catalyzes thrombin inhibition by heparin cofactor II, inhibits thrombus growth in rabbits more effectively than heparin. Because the results of these studies suggest that fibrin inhibits the reactivity of thrombin with antithrombin III-heparin but not with heparin cofactor II-dermatan sulfate, we compared the relative catalytic effects of heparin and dermatan sulfate on thrombin inhibition in plasma, both in the presence and absence of fibrin. We quantitated the rates of thrombin inhibition by antithrombin III and heparin cofactor II by specific enzyme-linked immunosorbent assays. When it was generated, fibrin was kept in solution by adding 2 mmol/L Gly-Pro-Arg-Pro to plasma. Fibrinogen-fibrin reduced the reactivity of thrombin with plasma antithrombin III, both in the presence of and in the absence of heparin. In contrast, the catalytic action of dermatan sulfate on thrombin inhibition by plasma heparin cofactor II was unimpaired by fibrinogen-fibrin. Based on the ability of dermatan sulfate to inhibit thrombus growth in rabbits, failure of fibrinogen-fibrin to moderate the catalytic action of dermatan sulfate may account for its greater antithrombotic effectiveness relative to that of heparin.
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XIth International Congress on Thrombosis and Haemostasis, 1987
We have previously proposed that the steps in coagulation most sensitive to inhibition by heparin... more We have previously proposed that the steps in coagulation most sensitive to inhibition by heparin are the thrombin-dependent activation of factor V and factor VIII. This observation was based on the demonstration that therapeutic concentrations of heparin or 1μM of the thrombin specific inhibitor, phe-pro-arg CH2Cl (PPACK) completely inhibited the activation of prothrombin when contact-activated plasma (CAP) was recalcified for up to 1 min. Under similar conditions, heparin and PPACK only partially inhibited the activation of factor X. Moreover, the addition of thrombin (lOnM) to CAP 1 min before that of heparin or PPACK reversed their inhibitory effects. We now provide further support for our hypothesis by showing that when the activity of thrombin is suppressed by heparin or PPACK, efficient activation of radiolabelled prothrombin occurs only when the factor Xa then present activates factor V and factor VIII. We compared the effects of HEP of PPACK on the following four systems fo...
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Biochemical Journal, 1987
Heparin catalyses the inhibition of two key enzymes of blood coagulation, namely Factor Xa and th... more Heparin catalyses the inhibition of two key enzymes of blood coagulation, namely Factor Xa and thrombin, by enhancing the antiproteinase activities of plasma antithrombin III and heparin cofactor II. In addition, heparin can directly inhibit the activation of Factor X and prothrombin. The contributions of each of these effects to the anticoagulant activity of heparin have not been delineated. We therefore performed experiments to assess how each of these effects of heparin contributes to its anticoagulant activity by comparing the effects of heparin, pentosan polysulphate and D-Phe-Pro-Arg-CH2Cl on the intrinsic pathway of coagulation. Unlike heparin, pentosan polysulphate catalyses only the inhibition of thrombin by plasma. D-Phe-Pro-Arg-CH2Cl is rapid enough an inhibitor of thrombin so that when added to plasma no complexes of thrombin with its inhibitors are formed, whether or not the plasma also contains heparin. Heparin (0.66 microgram/ml) and pentosan polysulphate (6.6 microgr...
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Biochemical Journal, 1987
Heparan sulphate and dermatan sulphate have both antithrombotic and anticoagulant properties. The... more Heparan sulphate and dermatan sulphate have both antithrombotic and anticoagulant properties. These are, however, significantly weaker than those of a comparable amount of standard pig mucosal heparin. Antithrombotic and anticoagulant effects of glycosaminoglycans depend on their ability to catalyse the inhibition of thrombin and/or to inhibit the activation of prothrombin. Since heparan sulphate and dermatan sulphate are less sulphated than unfractionated heparin, we investigated whether the decreased sulphation contributes to the lower antithrombotic and anticoagulant activities compared with standard heparin. To do this, we compared the anticoagulant activities of heparan sulphate and dermatan sulphate with those of their derivatives resulphated in vitro. The ratio of sulphate to carboxylate in these resulphated heparan sulphate and dermatan sulphate derivatives was approximately twice that of the parent compounds and similar to that of standard heparin. Anticoagulant effects wer...
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VIIIth International Congress on Thrombosis and Haemostasis, 1981
It has been known for many years that the effects of heparin are antagonized by platelets. This e... more It has been known for many years that the effects of heparin are antagonized by platelets. This effect has generally been attributed to the release of platelet factor 4 (PF4). Heparin has recently been shown to disrupt the interactions of vitamin K-dependent clotting factors with phospholipid. This is due in part to the binding of heparin to phospholipid. The present investigations therefore explored the possible effects of phospholipid (cephalin) and degranulated platelets on the interaction of thrombin or factor Xa with antithrombin-III in the presence of heparin. These interactions were determined by the measurement of the second order rate constants for the inactivation of purified factor Xa or thrombin by purified antithrombin-III. The rates of inactivation of thrombin or factor Xa by antithrombin-III increased with increasing concentrations of heparin. Cephalin reduced the magnitude of the heparin effect on factor Xa but had no additional effect on thrombin inactivation. Relat...
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Canadian Journal of Biochemistry, 1971
Two fragments, P1 and P2, which were obtained by digestion of haptoglobin by plasmin remained ass... more Two fragments, P1 and P2, which were obtained by digestion of haptoglobin by plasmin remained associated in neutral and alkaline buffers, although the electrophoretic and ultracentrifugal behavior of the complex was significantly different from that of native haptoglobin. The P1–P2 complex bound hemoglobin yielding a product indistinguishable at neutral pH from the normal haptoglobin–hemoglobin complex. P2 had no hemoglobin-binding property. There appears to be a weak interaction between Hb and P1 as shown by lowered electrophoretic mobility of P1 in presence of hemoglobin. However, no evidence for a stable complex between P1 and hemoglobin was obtained.
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British Journal of Haematology, 1990
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Antimicrobial Agents and Chemotherapy, 1986
The reported high incidence of vitamin-K-reversible hypoprothrombinemia associated with the new b... more The reported high incidence of vitamin-K-reversible hypoprothrombinemia associated with the new beta-lactamase-stable cephalosporins prompted us to evaluate the effect on hemostasis of three cephalosporins (cefamandole, ceftriaxone, and ceftazidime) in 30 patients with serious infections. Cefamandole and ceftriaxone, both containing a sulfhydryl group, induced a significant and similar prolongation of prothrombin time and decrease in factor VII activity. Ceftazidime, in contrast, had no effect on these two parameters.
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Pathophysiology of Haemostasis and Thrombosis, 1991
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Immunobiology of HLA, 1989
It has been postulated that antiidiotypic antibodies play an important role in maintaining tolera... more It has been postulated that antiidiotypic antibodies play an important role in maintaining tolerance in vivo, thereby enhancing allograft survival in renal transplant recipients (1–3). These antibodies have been shown to be present in recipients following blood transfusions and in recipients of long-term functioning renal allografts (4,5). It has been possible to transform human B lymphocytes with Epstein-Barr Virus (EBV) to obtain stable lymphoblastoid cell lines that will produce monoclonal antibodies of the desired specificity (6). Using this technique of lymphoblastoid transformation with EBV, we have established a B cell line from a recipient of a long-term functioning renal allograft. This B cell line secreted antiidiotypic antibodies, which specifically inhibited (a) the lymphocytotoxic activity of the kidney donor alloantigen-specific anti-HLA reference sera, and (b) proliferative responses in MLC of recipient’s lymphocytes and of third-party cells sharing HLA-B,DR antigens with the recipient, against stimulator cells bearing HLA-B/DR antigens present in the kidney donor.
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Blood, 1991
Antithrombin III (ATIII) deficiency has been implicated in adults as a predisposing factor to thr... more Antithrombin III (ATIII) deficiency has been implicated in adults as a predisposing factor to thrombosis; however, thromboembolic complications are rare in children with the same deficiency. We hypothesized that because of the elevated levels of plasma alpha-2- macroglobulin (alpha 2M) throughout childhood, plasmas of ATIII- deficient children inhibit thrombin more efficiently than those of ATIII-deficient adults. In total, 14 ATIII-deficient adults (ages 25 to 46 years), 13 ATIII-deficient children (ages 2 to 13 years), 9 normal children (ages 3 to 15 years), and 16 normal adults were studied. We measured thrombin inhibition in these plasmas, as well as the contributions of ATIII, alpha 2M, and heparin cofactor II (HCII) as thrombin inhibitors in each plasma. 125I-alpha-thrombin, 25 nmol/L, was added to each plasma (defibrinated with Arvin at 37 degrees C), and 90 seconds later the free thrombin and thrombin-inhibitor complexes were quantitated after sodium dodecyl sulfate-polyacry...
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Blood, 1980
Affinity chromatography of human cryosupernatants on anti-human factor VIII-Sepharose yielded a p... more Affinity chromatography of human cryosupernatants on anti-human factor VIII-Sepharose yielded a plasma devoid of detectable factor VIIIC, VIIIR:Ag, and VIIIR:WF activities. This plasma was indistinguishable from severe congenital hemophilic plasma when used as substrate in factor VIII coagulant assays.
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Thrombosis and Haemostasis, 1986
SummaryStandard heparin and a LMWH, CY222 do not cross the placenta nor alter fetal coagulation w... more SummaryStandard heparin and a LMWH, CY222 do not cross the placenta nor alter fetal coagulation when injected into the pregnant ewe. We found that another LMWH, Pharmuka-10169 (PK-10169) alters fetal coagulation without crossing the placenta in the pregnant sheep. To characterize this anticoagulant we measured the in vitro and in vivo effects of 125I-PK-10169 in maternal and fetal plasmas following administration of PK-10169 to the mother or fetus. The fetal anticoagulant activity was not neutralizable by protamine sulphate and was attributable to the inhibition of thrombin but not factor Xa. In vitro, the fetal anticoagulant activity had properties similar to dermatan sulphate : both catalyzed the inhibition of thrombin but not factor Xa by sheep plasma; and neither was neutralizable by protamine sulphate. These effects were due to the enhanced neutralization of thrombin by heparin cofactor II. We conclude that PK-10169 does not cross the placenta, but does induce the release of an...
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Papers by Frederick Ofosu