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Harold R Roberts

Publications and source records attributed to Harold R Roberts.

12 recordsLinked to original sources
PubMed2004

Monitoring coagulation and the clinical effects of recombinant factor VIIa.

Accurately monitoring hemostasis in patients with coagulation disorders is vital in order to allow physicians to optimize anticoagulant therapy and deliver effective patient management. Traditional assays, based on the measurement of the time to first evidence of clot formation, fail to describe the kinetics of clot production that ultimately define the quality of the final clot. This review describes the technologies that have been developed to accurately describe and monitor the kinetics of clot formation. Using clinical examples, the utility of these technologies is assessed and conclusions drawn about the most useful diagnostic measures for monitoring hemostasis.

Blood Coagulation↗
PubMed2004

Safety profile of recombinant factor VIIa.

Recombinant factor VIIa (rFVIIa; NovoSeven(R), Novo Nordisk, Bagsvaerd, Denmark) has been used for many years in the successful management of bleeding episodes in patients with hemophilia and inhibitors. More recently, rFVIIa has also shown considerable success as a hemostatic agent in trauma and surgery patients without pre-existing coagulopathy. Despite extensive and varied usage of rFVIIa, the incidence of serious adverse events associated with its use is less than 1%; however, there remain concerns regarding the agent's potential to induce thrombosis. This paper will review the safety profile of rFVIIa by examining existing clinical evidence, and will demonstrate that the isolated thrombotic events reported following rFVIIa treatment are due primarily to an improvement in the coagulation mechanism rather than rFVIIa treatment per se. The demonstrated safety of rFVIIa is probably due to its localization to injured areas of the vascular tree by binding to tissue factor (TF) and activated platelets at the bleeding site, thus avoiding systemic activation of coagulation. Finally, those situations in which rFVIIa therapy may not be safe, such as disseminated intravascular coagulation (DIC) and sepsis, will also be discussed.

Blood Coagulation↗
PubMed2004

Current concepts of hemostasis: implications for therapy.

The revised model of coagulation has implications for therapy of both hemorrhagic and thrombotic disorders. Of particular interest to anesthesiologists is the management of clotting abnormalities before, during, and after surgery. Most hereditary and acquired coagulation factor deficiencies can be managed by specific replacement therapy using clotting factor concentrates. Specific guidelines have also been developed for perioperative management of patients using anticoagulant agents that inhibit platelet or coagulation factor functions. Finally, recombinant factor VIIa has been used off-label as a hemostatic agent in some surgical situations associated with excessive bleeding that is not responsive to conventional therapy.

Animals↗
PubMed2002

Elevated prothrombin results in clots with an altered fiber structure: a possible mechanism of the increased thrombotic risk.

Individuals with elevated prothrombin levels are at increased risk of venous thrombosis. To understand the mechanism behind this observation, we studied the effect of prothrombin concentration on thrombin generation and fibrin clot structure. The pattern of thrombin generation was directly related to the prothrombin level at all concentrations tested. From 0% to 300% of normal plasma levels of prothrombin, increasing the prothrombin concentration increased the initial rate, peak, and total amount of thrombin generated. Importantly, fibrin clot structure was also affected by the prothrombin concentration. Fibrin clots made from prothrombin concentrations less than 10% of plasma levels were weak and poorly formed. Fibrin clots made at 10% to 100% of plasma levels of prothrombin had similar fiber structures (mass-to-length ratio; mu). However, the fiber mass-to-length ratio decreased with increasing prothrombin levels more than 100% of plasma levels, in a dose-dependent manner. These results suggest that increased levels of prothrombin alter thrombin generation and clot structure. Specifically, elevated prothrombin levels produce clots with reduced fibrin mass-to-length ratios compared with normal clots. We hypothesize that this alteration in fibrin clot structure is an important determinant of the risk of thrombosis.

Blood Coagulation↗
PubMed2002

Platelets and thrombin generation.

This review examines the evidence that platelets play a major role in localizing and controlling the burst of thrombin generation leading to fibrin clot formation. From the first functional description of platelets, it has been recognized that platelets supply factors that support the activation of prothrombin. Studies have demonstrated that on activation, the amount of one specific lipid, phosphatidylserine, is significantly increased on the outer leaflet of platelet membranes. When it was found that phosphatidylserine containing lipid extracts could be substituted for platelets in clotting assays, this suggested the possibility that changes in platelet lipid composition were necessary and sufficient to account for platelet surface thrombin generation. Because a growing body of data suggest that platelet-binding proteins provide much of the specificity for platelet thrombin generation, we review in this report data suggesting that changes in lipid composition are necessary but not sufficient to account for platelet surface regulation of thrombin generation. Also, we review data suggesting that platelets from different individuals differ in their capacity to generate thrombin, whereas platelets from a single subject support thrombin generation in a reproducible manner. Individual differences in platelet thrombin generation might be accounted for by differences in platelet-binding proteins.

Animals↗
PubMed2002

Activated protein C cleaves factor Va more efficiently on endothelium than on platelet surfaces.

The protein C/protein S system is known to regulate thrombin generation in vivo by cleaving factors Va and VIIIa. We have examined the activity of activated protein C in several tissue factor-initiated models of coagulation. We used 4 models: monocytes as the tissue factor source with platelets as the thrombin-generating surface; endothelial cells as the tissue factor source with platelets as the thrombin-generating surface; endothelial cells as both the tissue factor source and the thrombin-generating surface; and relipidated tissue factor with lipid vesicles providing the surface for thrombin generation. With the lipid surface, activated protein C dose-dependently reduced thrombin generation. Similarly, when endothelial cells provided the only surface for thrombin generation, activated protein C dose-dependently decreased thrombin generation significantly. By contrast, whenever platelets were present, activated protein C only minimally affected the amount of thrombin generated. When endothelial cells were the tissue factor source with platelets providing the surface for thrombin generation, activated protein C did increase the time until the burst of thrombin generation but had minimal effects on the total amount of thrombin generated. Activated protein C had essentially no effect on thrombin generation when monocytes were the tissue factor source with platelets providing the surface for thrombin generation. From the studies reported here, we conclude that in vivo, despite the important role of the protein C system in regulating thrombosis, activated protein C does not serve as a primary regulator of platelet-dependent thrombin generation.

Blood Coagulation↗
PubMed2002

Circulating and binding characteristics of wild-type factor IX and certain Gla domain mutants in vivo.

Residue K5 in factor IX gamma-carboxyglutamic acid (Gla) domain participates in binding endothelial cells/collagen IV. We injected recombinant factor IX containing mutations at residue 5 (K5A, K5R) into factor IX-deficient mice and compared their behavior with that of wild-type factor IX. The plasma concentration of factor IX that binds to endothelial cells/collagen IV (recombinant wild type and K5R) was consistently lower than that of the one that does not bind (K5A). Mice treated with wild type or K5R had 79% of the injected factor IX in the liver after 2 minutes, whereas 17% remained in circulation. In mice injected with K5A, 59% of the injected factor IX was found in liver and 31% was found in plasma. When we blocked the liver circulation before factor IX injection, 74% of K5A and 64% of K5R remained in the blood. When we treated the mouse with EDTA after injecting exogenous factor IX, the blood levels of factor IX that bind to endothelial cells/collagen IV increased, presumably because of release from endothelial cell/collagen IV binding sites. In contrast, the levels of the mutants that do not bind were unaffected by EDTA. In immunohistochemical studies, factor IX appears on the endothelial surfaces of mouse arteries after factor IX injection and of human arteries from surgical specimens. Thus, we have demonstrated that factor IX binds in vivo to endothelial cell-collagen IV surfaces. Our results suggest that factor IX Gla-domain mediated binding to endothelial cells/collagen IV plays a role in controlling factor IX concentration in the blood.

Animals↗
PubMed2002

Overview of anticoagulant drugs for the future.

More efficacious, safer, and easier to use anticoagulants are under development. Multiple agents have been shown to be effective in ex vivo or animal thrombosis models and several have progressed to clinical studies. Investigators have not yet determined if pharmaceuticals that inhibit coagulation factor activity earlier in the cascade (for example, inhibitors of tissue factor/factor VIIa, factor IXa, or Xa) are superior to those that block the cascade at a later point. Orally bioavailable drugs for the long-term treatment of thrombotic disorders, particularly those that do not require monitoring, are needed and are under development. Local delivery of anticoagulants or genes modulating anticoagulant control at sites of increased thrombogenicity, such as in diseased arteries, is a promising treatment modality that may decrease systemic bleeding problems. Much about the initiating pathophysiologic events leading to venous thrombotic disease needs to be elucidated before such local therapy can be tested in the venous vasculature. While awaiting better anticoagulants to become routinely available, we need to improve patient management with existing drugs by instituting anticoagulation clinics, promoting patient self-monitoring, and improving efforts to educate patients and health care providers about the use of anticoagulant drugs.

Anticoagulants↗
PubMed2002

Recombinant activated factor VII: its mechanism of action and role in the control of hemorrhage.

PURPOSE: Recombinant activated factor VII (rFVIIa) has proven both safe and efficacious in the treatment of bleeding episodes in patients with hemophilia A or B who have developed inhibitors. More recently, a growing number of reports suggests that rFVIIa may also have indications for the treatment of bleeding in patients with other hemostatic disorders, including qualitative and quantitative platelet defects, factor deficiencies other than hemophilia, and in otherwise healthy patients with uncontrollable hemorrhage following surgery or trauma. We have attempted to reconcile the various proposed mechanisms of action of rFVIIa with its apparent efficacy in such diverse clinical settings. SOURCE: A review of the literature was performed to determine those clinical scenarios in which rFVIIa appears to have been effective in controlling associated hemorrhage. PRINCIPAL FINDINGS: Findings from our group and others have demonstrated that rFVIIa is able to directly activate factor X and increase thrombin production on the surface of activated platelets in the absence of factor VIII or IX, as well as to improve thrombin generation in thrombocytopenia, and to yield a fibrin dot more resistant to fibrinolysis in vitro. CONCLUSIONS: Through these primary mechanisms, we believe that rFVIIa may be able to compensate for a variety of defects in hemostasis and merits further investigation as a general therapeutic for uncontrollable hemorrhage.

Blood Coagulation↗