| 1. |
- Holst, Jan, et al.
(författare)
-
The effect of protamine sulphate on plasma tissue factor pathway inhibitorreleased by intravenous and subcutaneous unfractionated and low molecularweight heparin in man
- 1997
-
Ingår i: Thrombosis Research. - 0049-3848 .- 1879-2472. ; 86:4, s. 343-348
-
Tidskriftsartikel (refereegranskat)abstract
- Heparin, a negatively charged sulphated glycosaminoglycan, is clinically the most important antithrombotic drug. Heparin augments the inhibitory activity of antithrombin (AT) towards thrombin, factor Xa (FXa) and other activated clotting enzymes. Tissue factor pathway inhibitor (TFPI) is an endogenous heparin releasable three domain Kunitz-type coagulation inhibitor which inhibits the crucial tissue factor-factor VIIa (TF-FVIIa) dependent coagulation pathway in the presence of FXa. The importance of the TF-FVIIa pathway and TFPI has recently been reviewed (1). TFPI is located to different vascular pools, the largest being the vascular endothelium from where TFPI can be released dose-dependently to the blood by heparins (2). TFPI is speculated to contribute to the anticoagulant properties of heparins, but to which degree is not yet fully understood. In recent years low molecular weight heparins (LMWH) have proven to be effective and safe both for prophylactic (3) and therapeutic treatment (4) of deep vein thrombosis (DVT). Protamine is the least toxic and clinically most commonly used antidote to heparin. However, in vitro and in vivo LMW heparinized blood is not fully neutralized by protamine, as substantial anti-Xa activity remains following neutralization (5). This post-protamine effect has been shown to be partly TFPI dependent when measured in a dilute TF-dependent assay (6,7). We undertook this in vivo study on healthy volunteers in order to investigate whether TFPI released by UH or LMWH (intravenous (iv) or subcutaneous (sc)) remains in the circulation following neutralization of the heparin activity with protamine sulphate (PS). We measured TFPI by three different methods-chromogenic activity, anticlotting activity and a new antigen assay specific for full-length and three-domain TFPI.
|
|
| 2. |
|
|
| 3. |
- Persson, E, et al.
(författare)
-
Plasma lipolytic activity after subcutaneous administration of heparin and a low molecular weight heparin fragment
- 1987
-
Ingår i: Thrombosis Research. - : Elsevier BV. - 1879-2472 .- 0049-3848. ; 46:5, s. 697-704
-
Tidskriftsartikel (refereegranskat)abstract
- The effect of heparin and a low molecular weight heparin fragment (LMWH, mean molecular weight 4000-6000) on plasma anticoagulation and lipolysis was studied in eight healthy men. The activities of antifactor Xa (antiFXa), lipoprotein lipase (LPL), hepatic lipase (HL) and plasma levels of free fatty acids (FFA) were analysed after the injection of 5000 antiFXa units of heparin or LMWH subcutaneously. In comparison with heparin, the administration of LMWH resulted in a significantly higher antiFXa activity (p less than 0.001) but a lower release of LPL and HL (p less than 0.001), which did not increase plasma FFA. It is concluded that subcutaneous injection of LMWH in men elicits an adequate anticoagulant effect measured as antiFXa activity but has a negligible effect on plasma lipolytic activity.
|
|
| 4. |
|
|
| 5. |
- Deb, S., et al.
(författare)
-
Individual variation in hemostatic alterations caused by tyrosine kinase inhibitors : a way to improve personalized cancer therapy?
- 2016
-
Ingår i: Thrombosis Research. - : Elsevier. - 0049-3848 .- 1879-2472. ; 140:Suppl. 1, s. S196-S197
-
Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: During the last two decades, Bcr-Abl tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of chronic myelogenous leukemia (CML), and are now considered standard treatment for this disease. However, TKIs can induce serious hemostatic side effects including cardiovascular disease and bleeding disorders. Blood platelet aggregation and formation of pro-coagulant platelets are important to allow a well-balanced hemostatic response. Therefore, a detailed understanding of what effect different TKIs exert on platelets and hemostasis could help to understand if there are differences of importance to minimize the risk of bleeding complications in treated patients.AIM: To investigate how TKIs used in CML (imatinib, dasatinib, nilotinib, bosutinib, and ponatinib) affect platelet activation and hemostasis.MATERIALS AND METHODS: We have developed a multi-parameter six color flow cytometry protocol to study different aspects of platelet function upon activation, e.g. formation of aggregatory (PAC-1-positive) and pro-coagulant (phosphatidylserine-exposing) platelets, exocytosis of alpha- and lysosomal granules and mitochondrial membrane potential.This protocol was performed in presence or absence of TKIs in blood from normal donors and in treated patients. Whole blood aggregometry (Multiplate®), thrombin generation in platelet-rich plasma and in vitro thrombus formation by free oscillation rheometry (ReoRox G2) was further evaluated in some situations.RESULTS: At clinically relevant concentrations, dasatinib significantly decreased the formation of procoagulant platelets. Ponatinib induced a slight decrease in formation of procoagulant platelets, whereas bosutinib and nilotinib showed opposite tendencies (n=7). Dasatinib also decreased platelet aggregation (n=4-6) and in vitro thrombus formation (n=3). Thrombin generation was not significantly affected by therapeutic levels of TKIs, whereas higher doses of dasatinib, bosutinib, ponatinib and imatinib significantly changed one or several of the thrombin generation parameters (n=7-8). Interestingly, large differences in response to the drugs were observed among the healthy donors, especially for dasatinib and bosutinib. Major inter-individual variations were also observed in dasatinib-treated patients, see Figure 1.CONCLUSIONS: Different TKIs show varying potency to affect platelet-based hemostasis. In addition, we found large inter-individual variations in how some drugs affected platelet function. Therefore, we suggest that development of a clinically useful protocol for platelet function testing could help to identify patients more susceptible to adverse drug reactions. Such a protocol could potentially help clinicians to gain insight into the risk of side effects, which could help to choose the most suitable drug for each individual patient.
|
|
| 6. |
- Eriksson, Stefan, et al.
(författare)
-
Endothelial cells release casein kinase II like activity capable of phosphorylating fibrinogen in response to thrombin
- 1993
-
Ingår i: Thrombosis Research. - 0049-3848 .- 1879-2472. ; 72:4, s. 315-320
-
Tidskriftsartikel (refereegranskat)abstract
- Rat liver endothelial cells cultivated in the absence of serum and activated with thrombin released up to 10% of the total protein kinase activity into the cell medium using casein or fibrinogen as the phosphate acceptor protein. The activity was partly inhibited by heparin, indicating that it was of the casein kinase II type. The release of kinase started directly after the addition of thrombin (2 NIH U/ml) to the media with two maxima; one after about 10 min and the second after around 30 min. The phosphorylating activity of media from cells incubated for longer times was less dependent on thrombin-induction which probably indicated the start of destruction of the cells. The results reported suggest that phosphorylation of fibrinogen could occur in the blood under acute phase conditions.
|
|
| 7. |
- Ernofsson, Mats, et al.
(författare)
-
Platelet-derived growth factor-BB and monocyte chemotactic protein-1 induce human peripheral blood monocytes to express tissue factor
- 1996
-
Ingår i: Thrombosis Research. - : Elsevier BV. - 0049-3848 .- 1879-2472. ; 83:4, s. 307-320
-
Tidskriftsartikel (refereegranskat)abstract
- Monocytes induced to express tissue factor (TF), the initiator of the clotting cascade, might play an important role in the pathogenesis of atherosclerosis. We have investigated the TF-inducing capacity of two factors thought to be involved in atherogenesis, i.e. the platelet derived growth factor-BB (PDGF-BB) and monocyte chemotactic protein-1 (MCP-1), a member of the chemokine superfamily. PDGF-BB and MCP-1 are potent chemotactic and activating factors for human blood monocytes. alpha-thrombin which is known to induce TF in endothelial cells and that recently has been shown to induce secretion of MCP-1 from endothelial cells and monocytes was also studied. PDGF-BB induced a dose-dependent expression of TF-antigen in monocytes with maximal response at 20-50 ng/mL. At higher concentrations the expression was reduced. No synergistic effect between PDGF-BB and LPS was seen. MCP-1 also induced a dose-dependent TF-expression with maximal response at 50 ng/mL. In contrast to these results thrombin did not. MCP-1 had a slight, but not significant, priming effect on LPS-induced TF expression. These data show that PDGF-BB and MCP-1 are potent inducers of TF in human peripheral blood monocytes. We suggest that this TF-induction might be an important link between hemostasis and inflammation.
|
|
| 8. |
- Henriksson, Anders E., et al.
(författare)
-
Experimental haemorrhage and blood component transfusion in humans : no change in plasma concentration of thrombin-antithrombin complex and plasmin-antiplasmin complex.
- 1996
-
Ingår i: Thrombosis Research. - : Elsevier BV. - 0049-3848 .- 1879-2472. ; 82:5, s. 409-15
-
Tidskriftsartikel (refereegranskat)abstract
- The influence of haemorrhage and blood transfusion on primary haemostasis, coagulation and fibrinolysis was investigated in ten healthy male volunteers. Acute loss of 10% of the blood volume did not give any significant alteration in thrombin- antithrombin III (TAT) complex and plasmin-alpha 2-antiplasmin (PAP) complex levels compared with a control series. The skin bleeding time with the Simplate II device was not altered after the 10% blood loss. Acute loss of 10% of blood volume followed by transfusion of packed red cells or stored plasma did not resulted in any significant change in bleeding time, TAT and PAP complex levels. It could be concluded that a controlled haemorrhage does not give any detectable changes of the platelet dependent primary haemostasis, blood coagulation and fibrinolysis. Transfusion of one unit of packed red cells or stored plasma does not seem to adversely affect the haemostasis.
|
|
| 9. |
- Järemo, Petter, et al.
(författare)
-
Elevated inflammatory parameters are associated with lower platelet density in acute myocardial infarctions with ST-elevation
- 2000
-
Ingår i: Thrombosis Research. - 0049-3848 .- 1879-2472. ; 100:6, s. 471-478
-
Tidskriftsartikel (refereegranskat)abstract
- Objective: Platelets and granulocytes play important roles in coronary disorders. We therefore, investigated platelet and granulocyte alterations in myocardial infarctions (MIs).Patients and study design: A total of 36 individuals having MI with raised ST-segments who were receiving thrombolytic therapy were studied. Sampling was carried out after thrombolysis within 24 h after hospital admission. After 3 to 6 months of recovery, 25 patients were reinvestigated. At the infarction, peak platelet density was determined using a special designed computerised apparatus. In addition, we did counts on platelets, neutrophils and monocytes. Moreover, plasma levels of soluble P-selectin, myeloperoxidase and interleukin 6 were determined to estimate the degree of platelet, neutrophil and monocyte activation, respectively. Peak platelet density was analysed at the MI. All other parameters were determined at the acute event and at recovery.Results: At the MI, compared to the recovery, platelet counts were lower (P<.001). In addition, increased neutrophil counts (P<.001), elevated monocyte counts (P<.001), enhanced myeloperoxidase (P<.001) and interleukin 6 (P<.001) levels were demonstrated. We failed to show elevated soluble P-selectin. Compared to individuals with ST-segment elevations and low platelet density (≤1.058 kg/l), patients having peak platelet densities >1.058 kg/l displayed lower neutrophil counts (P<.01) and decreased interleukin 6 levels (P<.01). Furthermore, we demonstrate that individuals with higher inflammatory response at the MI had higher neutrophil (r=.6; P<.01) and higher monocyte counts (r=.6; P<.001) at recovery.Conclusion: We conclude that MI is associated with an inflammatory response. However, a subgroup of patients having MI with ST-elevations and low peak platelet density was identified. Compared to subjects with higher platelet density, they had more severe inflammatory characteristics. The differences persisted during recovery.
|
|
| 10. |
- Martin, Steven, et al.
(författare)
-
Increased phosphate content of fibrinogen in vivo correlates with alteration in fibrinogen behaviour
- 1992
-
Ingår i: Thrombosis Research. - 0049-3848 .- 1879-2472. ; 68:6, s. 467-473
-
Tidskriftsartikel (refereegranskat)abstract
- Fibrinogen was purified from five patients admitted for hip-replacement surgery the day before (day 0), the day after (day 2) and and one week after the operation (day 8). The behaviour of each patient's three fibrinogens was compared in thrombin gelation assays and plasmin degradation experiments to investigate whether the reported increase in protein-bound phosphate at day 2 and day 8 had any effect on the functional behaviour of fibrinogen as has been demonstrated in vitro. It was found that the thickness of the fibrin fibres produced by thrombin increased markedly at day 2 and declined thereafter. Susceptibility to plasmin appeared to decrease post-operatively by 50% and remained at that level on day 8 despite the phosphate content returning to normal. This has also been shown for fibrinogen phosphorylated in vitro. We conclude, after testing the fibrinogens with and without alkaline phosphatase pretreatment, that our data most resemble the published findings for in vitro phosphorylation of fibrinogen by casein kinase II.
|
|
