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- Malm, Karl, et al.
(författare)
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Antithrombotic and anticoagulant effects of wild type and Gla-domain mutated human activated protein C in rats.
- 2007
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Ingår i: Thrombosis Research. - : Elsevier BV. - 1879-2472 .- 0049-3848. ; 120:4, s. 531-539
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Tidskriftsartikel (refereegranskat)abstract
- The antithrombotic and anticoagulant effects of recombinant wild type (WT) and mutated human activated protein C (hAPC) were investigated using a rat model of arterial thrombosis. Recent in vitro studies using human plasma have shown enhanced anticoagulant effects of hAPC by mutagenesis of either loop 148 in the serine protease domain or of the Gla domain. The Gla-domain mutant QGNSEDY-hAPC (=H10Q/S11G/S12N/D23S/Q32E/N33D/H44Y) was found to be particularly active as an anticoagulant. We now combined the two mutations to create the variant QGNSEDY-hAPC:B148 and investigated the in vivo effects of this variant as well as of QGNSEDY-hAPC and WT hAPC using a rat model of arterial thrombosis. In vitro clotting experiments using rat plasma demonstrated WT hAPC to be inefficient, whereas both mutant hAPC variants yielded distinct dose dependent anticoagulant effects. In the arterial injury model, a segment of the left common carotid artery was opened longitudinally. An endarterectomy was performed and the arteriotomy was closed, whereafter the vessel was reperfused and the patency rate determined after 31 min. Three treatment groups each containing 10 rats and a control group of 20 animals were in a blind random fashion given intravenous bolus injections of 0.8 mg/kg WTor mutant hAPC or vehicle only. The ex vivo clotting times of plasma drawn 3 min after the injections, as compared to baseline clotting times, were approximately doubled by QGNSEDY-hAPC and tripled by QGNSEDY-hAPC:B148 infusions, while WT APC had little effect. Compared to the control group, none of the hAPC preparations had significant antithrombotic effect or increased arteriotomy bleeding.
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| 2. |
- Malm, Karl, et al.
(författare)
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Human activated protein C variants in a rat model of arterial thrombosis
- 2008
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Ingår i: Thrombosis Journal. - : Springer Science and Business Media LLC. - 1477-9560. ; 6
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Activated protein C (APC) inhibits coagulation by degrading activated factor V (FVa) and factor VIII (FVIIIa), protein S (PS) functioning as a cofactor to APC.METHODS: By mutagenesis of the vitamin K-dependent Gla domain of APC, we have recently created an APC variant having enhanced anticoagulant activity due to increased affinity for negatively charged phospholipid membranes. In the present study, the potential antithrombotic effects of this APC variant, and of a variant APC that is additionally mutated in the serine protease domain, have been evaluated in a blind randomized study in a rat model of arterial thrombosis. In this model, we have previously found the combination of bovine APC and PS to be highly antithrombotic. Four treatment groups each containing 10 rats were, in a blind random fashion, given intravenous bolus injections of wild-type or mutant variants of APC (0.8 mg/kg) together with human PS (0.6 mg/kg) or human PS (0.6 mg/kg) alone. A control group with 20 animals where given vehicle only.RESULTS: A trend to increased patency rates was noted in a group receiving one of the APC variants, but it did not reach statistical significance.CONCLUSION: In conclusion, administration of human APC variants having enhanced anticoagulant efficacy together with human PS in a rat model of arterial thrombosis did not give an efficient antithrombotic effect. The lack of effect may be due to species-specific differences between the human protein C system and the rat hemostatic system.
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| 3. |
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| 4. |
- Malm, Karl, et al.
(författare)
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Prevention of thrombosis following deep arterial injury in rats by bovine activated protein C requiring co-administration of bovine protein S.
- 2003
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Ingår i: Thrombosis and Haemostasis. - 0340-6245. ; 90:2, s. 227-234
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Tidskriftsartikel (refereegranskat)abstract
- The antithrombotic effect of bovine activated protein C (bAPC) given with or without bovine protein S (bPS) was investigated in a rat model of deep arterial injury. A segment of the left common carotid artery was isolated between vascular clamps and opened longitudinally. An endarterectomy was performed and the arteriotomy was closed with a running suture, whereafter the vessel was reperfused by removing the clamps. The antithrombotic effect (vascular patency rates 31 minutes after reperfusion) and the arteriotomy bleeding were measured. Ten treatment groups each containing 10 rats and a control group of 20 animals were in a blind random fashion given intravenous bolus injections of increasing doses of activated protein C, with or without co-administration of protein S. The groups received either bAPC alone (0.8, 0.4, 0.2 or 0.1 mg/kg), bAPC (0.8, 0.4, 0.2, 0.1 or 0.05 mg/kg) combined with bPS (0.6 mg/kg), or bPS alone (0.6 mg/kg) whereas the control group received vehicle only. Administered alone, bAPC or bPS had no antithrombotic effect, regardless of dosage. In contrast, all groups that were treated with bAPC in combination with bPS demonstrated a significant antithrombotic effect, as compared to controls. Neither bAPC, bPS, nor the combination of bAPC and bPS increased the arteriotomy bleeding significantly compared to controls. In vitro clotting assays using bAPC or bPS alone yielded only minor prolongation of clotting time, where-as bAPC combined with bPS prolonged the clotting time con-siderably, demonstrating the dependence on the APC-cofactor activity of bPS for expression of anticoagulant activity by bAPC. In conclusion, our study shows the in vivo significance of protein S as a cofactor to activated protein C, and that potent antithrombotic effect can be achieved by low doses of bAPC combined with bPS, without producing hemorrhagic side effects.
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| 5. |
- Dahlbäck, Cecilia, et al.
(författare)
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Long-term outcome of lymph vessel transplantation after chronic lymphorrhea
- 2021
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Ingår i: Case Reports in Plastic Surgery and Hand Surgery. - : Informa UK Limited. - 2332-0885. ; 8:1, s. 169-174
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Tidskriftsartikel (refereegranskat)abstract
- A 52-year-old male patient developed a chronic fistula with excessive lymph leakage in the left axilla following removal of an enlarged lymph node with chronic local adipose tissue inflammation due to infection. After multiple surgeries, treatment with lymphatic vessel transplantation was successful. No recurrence occurred over 20 years of follow-up.
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| 6. |
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| 7. |
- Söderström, Torbjörn, et al.
(författare)
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Effect of active site-inactivated factor VIIa on ischaemia/reperfusion injury in a porcine flap model.
- 2004
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Ingår i: Scandinavian Journal of Plastic and Reconstructive Surgery and Hand Surgery. - : Informa UK Limited. - 1651-2073 .- 0284-4311. ; 38:6, s. 326-334
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Tidskriftsartikel (refereegranskat)abstract
- In free flap surgery, restored blood flow following a lengthy ischaemic period may lead to necrosis as a result of ischaemia/reperfusion (IR) injury. This injury comprises both proinflammatory and prothrombotic events, where the tissue factor/factor VIIa complex probably has a key role. Active site-inactivated factor VIIa (FFR-rFVIIa) exerts an antithrombotic effect by binding to tissue factor without initiating coagulation. In this study we have evaluated the potential protective effects of FFR-rFVIIa in IR injury. Bilateral musculocutaneous latissimus dorsi flaps in 16 pigs were made ischaemic for eight hours, then given 1 mg/kg/flap of FFR-rFVIIa or vehicle intra-arterially, and reperfused for 10 hours. The viable:necrotic tissue ratio, and accumulation of radiolabelled leucocytes, fibrinogen, and platelets were measured. There was no effect on tissue survival, but radiolabelled components in viable tissue were increased, though not significantly so. We conclude that FFR-rFVIIa did not prevent IR injury, indicating that tissue factor-mediated coagulation is not an important determinant of IR injury in this setting.
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