Biomedical subjects

C W Francis

Publications and source records attributed to C W Francis.

At least 19 recordsLinked to original sources

PubMed2005

Direct thrombin inhibitors for treatment of heparin induced thrombocytopenia, deep vein thrombosis and atrial fibrillation.

Thrombin is a central enzyme in hemostasis, exerting potent procoagulant effects and activating platelets. Recently, several small molecule direct thrombin inhibitors (DTI's) with important clinical applications have been developed. Both lepirudin and argatroban are effective in treatment of heparin-induced thrombocytopenia resulting in rapid normalization of platelet counts and a reduction in thrombotic events. Because of differences in clearance mechanisms, argatroban is preferable in patients with renal insufficiency and lepirudin if there is hepatic impairment. DTI's have also been evaluated in treatment of venous thromboembolism. Small studies with recombinant hirudin have shown promise. Ximelagatran is a new DTI in late-stage clinical trials with advantages for treatment of venous thromboembolism including oral administration and fixed dosing, making it convenient for long-term treatment. A Phase III trial demonstrated that ximelagatran was superior to placebo for preventing recurrent thrombosis in patients who had undergone six months of standard anticoagulant therapy for venous thromboembolism. Another large trial compared ximelagatran to standard treatment with enoxaparin and warfarin for treatment of symptomatic deep vein thrombosis in a Phase III trial of 2,528 patients. The results showed that ximelagatran administered twice daily was as effective as standard treatment in preventing recurrence with no increase in bleeding complications. Ximelagatran has also been evaluated in two Phase III trials in patients with atrial fibrillation. The primary analysis of both showed that ximelagatran was non-inferior to warfarin for preventing stroke and other embolic events with no increase in bleeding complications. Unexpectedly, elevated serum transaminase levels were observed in 5-10% of patients receiving ximelagatran for over 1 month, and routine monitoring may be necessary. The introduction of DTIs represents an important advance in treatment of heparin-induced thrombocytopenia. The oral direct thrombin inhibitor, ximelagatran, shows promise in providing simplified, effective therapy for venous thromboembolism and atrial fibrillation.

Animals↗

PubMed2004

Low-intensity ultrasound increases endothelial cell nitric oxide synthase activity and nitric oxide synthesis.

Low-intensity ultrasound (US) increases tissue perfusion in ischemic muscle through a nitric oxide (NO)-dependent mechanism. We have developed a model to expose endothelial cells to well-characterized acoustic fields in vitro and investigate the physical and biological mechanisms involved. Human umbilical vein endothelial cells (HUVEC) or bovine aortic endothelial cells (BAEC) were grown in tissue culture plates suspended in a temperature-controlled water bath and exposed to US. Exposure to 27 kHz continuous wave US at 0.25 W cm(-2) for 10 min increased HUVEC media NO by 102 +/- 19% (P < 0.05) and BAEC by 117 +/- 23% (P < 0.01). Endothelial cell NO synthase activity increased by 27 +/- 24% in HUVEC and by 32 +/- 16% in BAEC (P < 0.05 for each). The cell response was rapid with a significant increase in NO synthesis by 10 s and a maximum increase after exposure for 1 min. By 30 min post-exposure NO synthesis declined to baseline, indicating that the response was transient. Unexpectedly, pulsing at a 10% duty cycle resulted in a 46% increase in NO synthesis over the response seen with continuous wave US, resulting in an increase of 147 +/- 18%. Cells responded to very low intensity US, with a significant increase at 0.075 W cm(-2) (P < 0.01) and a maximum response at 0.125 W cm(-2). US caused minor reversible changes in cell morphology but did not alter proliferative capacity, indicating absence of injury. We conclude that exposure of endothelial cells to low-intensity, low-frequency US increases NO synthase activity and NO production, which could be used to induce vasodilatation experimentally or therapeutically.

Animals↗

PubMed2004

Effects of lipids and lipid-lowering therapy on hemostatic factors in patients with myocardial infarction.

BACKGROUND: The risk of cardiovascular disease (CVD) is associated with specific hemostatic markers and lipid profiles, and evidence indicates that there are associations between lipid profiles and the levels of certain hemostatic factors. The disturbances in hemostasis and the risk of CVD can be ameliorated by lipid-lowering therapy. OBJECTIVE: We investigated the associations of lipid profiles with factor (F)VIIa, von Willebrand factor (VWF), D-dimer and plasminogen activator inhibitor-1 (PAI-1), and examined whether lipid-lowering statin therapy would affect the levels of these hemostatic markers. PATIENTS AND METHODS: This cross-sectional study analyzed 1045 postmyocardial infarction patients. RESULTS: In multivariate regression analyses (without adjusting for clinical covariates) HDL-cholesterol (HDL-C) and HDL size were independent and significant predictors of FVIIa; HDL size was a predictor of VWF; HDL size, HDL-C and LDL size were predictors of D-dimer; and triglyceride and HDL size were predictors of PAI-1. After adjusting for clinical covariates, HDL-C, lipoprotein (Lp)(a), apolipoprotein B (apoB) and warfarin were independent and significant predictors of FVIIa; HDL size, age, diabetes mellitus, insulin, race and warfarin were predictors of VWF; HDL-C, HDL size, LDL size, age, warfarin, hypertension and gender were predictors of D-dimer; and triglyceride, HDL size, body mass index, insulin and hypertension were predictors of PAI-1. Patients on statin therapy had significantly lower levels of D-dimer than those who were not on this therapy. CONCLUSION: There are significant associations of lipid profiles with hemostatic factors, the directions of which suggest novel pathways by which dyslipidemia may contribute to coronary heart disease.

Adult↗

PubMed2004

Fibrinogen binding potentiates FGF-2 but not VEGF induced expression of u-PA, u-PAR, and PAI-1 in endothelial cells.

Endothelial cell responses at sites of injury occur in a fibrin matrix and are regulated by growth factors including those of the FGF and VEGF families. The pericellular proteolytic balance is important in these responses, and FGF-2 and VEGF up-regulate endothelial cell u-PA, u-PAR and PAI-1. Because both VEGF and FGF-2 bind to fibrinogen, we have examined the capacity of fibrinogen to modulate the up-regulation of these proteins by FGF-2 and VEGF. Confluent cultures of endothelial cells were exposed to FGF-2, VEGF, and fibrinogen or to combinations of growth factors with fibrinogen. Changes in mRNA levels of u-PA, u-PAR and PAI-1 were measured by Northern blot. FGF-2 increased u-PA, u-PAR, and PAI-1 mRNA, but there was a significantly greater induction when fibrinogen was added to FGF-2 at all concentrations. The potentiation by fibrinogen was particularly evident at an FGF-2 concentration of 0.1 ng mL(-1), which resulted in non-significant change in transcript levels by itself, but significantly increased up to 2.6-fold with fibrinogen. VEGF also increased endothelial cell expression of u-PA, u-PAR and PAI-1, but this effect was not potentiated by fibrinogen. Addition of LM609, a monoclonal antibody to alphaVbeta3, significantly inhibited induction of u-PA mRNA and activity by fibrinogen-bound FGF-2 compared to FGF-2. A monoclonal antibody to FGFR1 also inhibited u-PA mRNA expression induced by fibrinogen-bound FGF-2. We conclude that fibrinogen increases the capacity of FGF-2, but not of VEGF, to up-regulate u-PA, u-PAR, and PAI-1 in endothelial cells and that fibrinogen-bound FGF-2 requires alphaVbeta3 binding to up-regulate endothelial cell u-PA.

Base Sequence↗

PubMed2003

Protein S declines during winter respiratory infections.

There is an increase in cardiovascular and cerebrovascular morbidity and mortality in the older adult population during the winter that could be related to prothrombotic changes caused by seasonal effects or acute respiratory tract infections. Therefore, a prospective cohort study was conducted to assess the effect of acute winter respiratory infection on hemostatic parameters including complement 4b-binding protein (C4-BP), functional protein S, total protein S, free protein S, and the inflammatory marker, interleukin-6 (IL-6), in younger and older adults. The changes in the levels of hemostatic and inflammatory markers during winter respiratory infections in the younger and older adults were compared with matched, non-infected controls. In younger and older adults (combined), total protein S increased from 83% [95% confidence interval (CI); 77-88] to 98% (95% CI; 91-106, P < 0.001) while free protein S decreased from 100% (95% CI; 95-105) to 70% (95% CI; 66-75, P < 0.001). There were no significant changes in C4-BP (P = 0.622), functional protein S (P = 0.061) or IL-6 (P = 0.651) from baseline. In a multivariate analysis, only total protein S and free protein S showed significant association with seasonal change after adjusting for the effect of infection. The estimated effect of season on total protein S was 15 +/- 4%, P < 0.001 and on free protein S was -27 +/- 3%, P < 0.001. After adjusting for seasonal effect, only functional protein S showed a significant association with infection, with the estimated effect of -17 +/- 5%, P < 0.001. The results in the younger and older adults were similar to those in the combined groups. Seasonal and infection-related changes in hemostatic parameters including an increase in fibrinogen and a decrease in free protein S, observed in this study, may contribute to thrombotic risk and excess vascular disease morbidity and mortality in older populations in the winter season.

Age Factors↗

PubMed2003

Plasmic degradation modulates activity of fibrinogen-bound fibroblast growth factor-2.

Fibroblast growth factor-2 (FGF-2) binds to fibrin(ogen) with high affinity, and fibrinogen potentiates FGF-2-stimulated proliferation of endothelial cells. Because plasmin degrades fibrin(ogen) physiologically and could liberate growth factor from fibrin deposits or alter its activity, we have now investigated the effect of plasmic degradation on the activity of fibrin(ogen)-bound FGF-2. Fibrinogen with bound FGF-2 was incubated with plasmin, the products characterized by SDS-PAGE, and the proliferative activity determined by (3)H-thymidine incorporation into endothelial cells. Before plasmin exposure, proliferation was increased 3.7 +/- 0.6-fold with fibrinogen-bound FGF-2 compared with medium alone (P < 0.005). Plasmic degradation resulted in progressive decrease in the proliferative capacity, with the 60-min digest showing predominantly fragment D1 and E and (3)H-thymidine uptake of only 1.2 +/- 0.2-fold, significantly less than the activity of an equal concentration of free FGF-2 (P < 0.02). However, further degradation increased activity, and proliferation with a 90-min digest increased to 2.6 +/- 0.5-fold, significantly greater than the 60-min digest (P < 0.02). Plasmic degradation in the presence of 10 mm calcium chloride prevented degradation of D1 to D2 and D3, and the activity did not increase with extended degradation. Immunoprecipitation of the digests with antifibrinogen antibody showed 70 +/- 8% of fibrinogen-bound FGF-2 in the presence of calcium but only 15 +/- 4% in its absence, indicating that cleavage of D1 to D2 and D3 is critical in binding. Fragment D1 and D2, but not D3, bound to a column containing immobilized FGF-2, indicating that a binding site is lost upon degradation to D3. The results demonstrate that plasmic degradation of fibrinogen modulates the activity and binding of FGF-2 that involves a site near the carboxyl terminus of the gamma chain.

Binding Sites↗

PubMed2003

FGF-2 but not FGF-1 binds fibrin and supports prolonged endothelial cell growth.

Endothelial cell viability and growth are dependent on both polypeptide growth factors, and integrin-mediated matrix interactions. We have now examined the ability of fibrin-binding and non-binding growth factors to support long-term endothelial cell growth in the presence or absence of the soluble form. Endothelial cells were cultured on a fibrin surface, with or without FGF-1 or FGF-2, and proliferation was determined by (3)H-thymidine incorporation. Cells cultured on fibrin with no growth factor showed minimal proliferation up to 96 h. In contrast, when FGF-2 was incorporated into fibrin, proliferation was increased 6.5 +/- 0.6-fold, equal to growth on a fibrin surface with FGF-2 continually present in the medium. Thymidine incorporation was similar when cells were cultured on a fibrin surface that had been incubated with FGF-2 and then the growth factor removed (8.6 +/- 0.5-fold). In contrast to results with FGF-2, a surface of fibrin exposed to FGF-1 supported minimal growth, whereas growth was comparable to either FGF-1 or FGF-2 present in the medium. Comparable results were observed when proliferation was quantitated by cell counting at times up to 48 h. Binding studies demonstrated no high-affinity interaction of FGF-1 with fibrinogen or fibrin. We conclude that FGF-2 bound to fibrin supports prolonged endothelial cell growth as well as soluble FGF-2, whereas FGF-1 does not bind to fibrin and can support endothelial cell growth only if continually present in soluble form. Fibrin may serve as a matrix reservoir for FGF-2 to support cell growth at sites of injury or thrombosis.

Cell Division↗

PubMed2003

Comparison of ximelagatran, an oral direct thrombin inhibitor, with enoxaparin for the prevention of venous thromboembolism following total hip replacement. A randomized, double-blind study.

BACKGROUND: Prophylaxis is recommended following total joint replacement because of the high risk of venous thromboembolism (VTE). Postoperative low-molecular-weight heparin (LMWH) reduces the incidence of venographically detected deep vein thrombosis (DVT) to about 10-15% in total hip replacement (THR) patients. Ximelagatran is a novel, oral direct thrombin inhibitor that selectively and competitively inhibits both free and clot-bound thrombin. We compared the efficacy and safety of ximelagatran with those of enoxaparin for the prevention of VTE in patients undergoing THR. METHODS: This was a prospective, randomized, multicenter, double-blind study conducted principally in the USA and Canada. Patients received fixed-dose oral ximelagatran 24 mg bid or subcutaneous enoxaparin 30 mg bid and matched placebo for 7-12 days; both regimens were initiated the morning after surgery. The incidence of VTE (by postoperative day 12) included thrombosis determined by mandatory venography of the leg on which surgery was performed and symptomatic, objectively proven DVT or pulmonary embolism (PE). VTE and bleeding events were interpreted by an independent central adjudication committee for primary analysis. RESULTS: Of the 1838 patients randomized, 1557 had either adequate venography or symptomatic, proven VTE (efficacy population). Overall rate of venography acceptable for evaluation was 85.4%. Overall rates of total VTE were 7.9% (62 of 782 patients) in the ximelagatran group and 4.6% (36 of 775 patients) in the enoxaparin group, with an absolute difference of 3.3% and a 95% confidence interval for the difference of 0.9% to 5.7%. Proximal DVT and/or PE occurred in 3.6% (28 of 782 patients) in the ximelagatran group and 1.2% (nine of 774 patients) in the enoxaparin group. Major bleeding events were observed in 0.8% (seven of 906) of the ximelagatran-treated patients and in 0.9% (eight of 910) of the enoxaparin-treated patients (P > 0.95). Non-inferiority of ximelagatran 24 mg bid based on a prespecified margin of 5% was not met, resulting in superiority of the enoxaparin regimen. CONCLUSIONS: Both ximelagatran and enoxaparin decreased the overall rate of VTE compared with that reported historically. However, in this study, enoxaparin 30 mg bid was more effective than ximelagatran 24 mg bid for prevention of VTE in THR. Oral ximelagatran was used without coagulation monitoring, was well tolerated, and had bleeding rates comparable to those of enoxaparin. Further refinement by testing a higher dose of ximelagatran in the patients undergoing THR is warranted.

Administration, Oral↗

PubMed2002

Neuropathologic findings in a Guillain-Barré patient with strokes after IVIg therapy.

Strokes have been rarely associated with immunoglobulin G (IVIg) therapy. A 70-year-old woman with stable polycythemia vera developed Guillain-Barré syndrome and received IVIg, 8 days following which she became comatose due to bilaterally symmetric cerebral infarcts. Autopsy showed intravascular aggregates of fibrin-IgG but also platelets and a necrotizing microangiopathy in the infarcts.

Aged↗

PubMed2001

Comparison of the oral direct thrombin inhibitor ximelagatran with enoxaparin as prophylaxis against venous thromboembolism after total knee replacement: a phase 2 dose-finding study.

BACKGROUND: Up to one third of patients who undergo total knee replacement develop deep vein thrombosis after surgery despite receiving low-molecular-weight heparin prophylaxis. Ximelagatran is a novel direct inhibitor of free and clot-bound thrombin. METHODS: We performed a randomized, parallel, dose-finding study of 600 adults undergoing elective total knee replacement at 68 North American hospitals to determine the optimum dose of ximelagatran to use as prophylaxis against venous thromboembolism after total knee replacement. Patients received either ximelagatran twice daily by mouth in blinded fixed doses of 8, 12, 18, or 24 mg or open-label enoxaparin sodium, 30 mg, subcutaneously twice daily, starting 12 to 24 hours after surgery and continuing for 6 to 12 days. We measured the 6- to 12-day cumulative incidence of symptomatic or venographic deep vein thrombosis, symptomatic pulmonary embolism, and bleeding. RESULTS: A total of 594 patients received at least 1 dose of the study drug; 443 patients were evaluable for efficacy. Rates of overall venous thromboembolism (and proximal deep vein thrombosis or pulmonary embolism) for the 8-, 12-, 18-, and 24-mg doses of ximelagatran were 27% (6.6%), 19.8% (2.0%), 28.7% (5.8%), and 15.8% (3.2%), respectively. Rates of overall venous thromboembolism (22.7%) and proximal deep vein thrombosis or pulmonary embolism (3.1%) for enoxaparin did not differ significantly compared with 24-mg ximelagatran (overall difference, -6.9%; 95% confidence interval, -18.0% to 4.2%; P=.3). There was no major bleeding with administration of 24 mg of ximelagatran twice daily. CONCLUSION: Fixed-dose, unmonitored ximelagatran, 24 mg twice daily, given after surgery appears to be safe and effective oral prophylaxis against venous thromboembolism after total knee replacement.

Administration, Oral↗

PubMed2001

Timing of initial administration of low-molecular-weight heparin prophylaxis against deep vein thrombosis in patients following elective hip arthroplasty: a systematic review.

BACKGROUND: Perioperative and postoperative venous thrombosis are common in patients undergoing elective hip surgery. Prophylactic regimens include subcutaneous low-molecular-weight heparin 12 hours or more before or after surgery and oral anticoagulants. Recent clinical trials suggest that low-molecular-weight heparin initiated in closer proximity to surgery is more effective than the present clinical practice. We performed a systematic review of the literature to assess the efficacy and safety of low-molecular-weight heparin administered at different times in relation to surgery vs oral anticoagulant prophylaxis. METHODS: Reviewers (A.F.M. and S.M.M.) identified studies by searching MEDLINE, reviewing references from retrieved articles, scanning abstracts from conference proceedings, and contacting investigators and pharmaceutical companies. Randomized trials comparing low-molecular-weight heparin administered at different times relative to surgery with oral anticoagulants in patients undergoing elective hip arthroplasty, evaluated using contrast phlebography, were selected. Two reviewers (A.F.M. and S.M.M.) extracted data independently. RESULTS: The literature review identified 4 randomized trials meeting predefined inclusion criteria. The results indicate that low-molecular-weight heparin initiated in close proximity to surgery resulted in absolute risk reductions of 11% to 13% for deep vein thrombosis, corresponding to relative risk reductions of 43% to 55% compared with oral anticoagulants. Low-molecular-weight heparin initiated 12 hours before surgery or 12 to 24 hours postoperatively was not more effective than oral anticoagulants. Low-molecular-weight heparin initiated postoperatively in close proximity to surgery at half the usual dose was not associated with a clinically or statistically significant increase in major bleeding rates (P =.16). CONCLUSIONS: The timing of initiating low-molecular-weight heparin significantly influences antithrombotic effectiveness. The practice of delayed initiation of low-molecular-weight heparin prophylaxis results in suboptimal antithrombotic effectiveness without a substantive safety advantage.

Administration, Oral↗

PubMed2001

Response of C-reactive protein and serum amyloid A to influenza A infection in older adults.

Influenza epidemics are associated with significant morbidity and mortality in the elderly, with a substantial proportion of deaths due to cardiovascular events. Elevations of acute-phase proteins have been associated with an increased risk of atherosclerotic events. Therefore, serum amyloid A (SAA) and C-reactive protein (CRP) were measured during influenza illness and 4 weeks later in 7 young persons, 15 elderly outpatients, and 36 hospitalized adults. Striking elevations were seen in mean acute SAA and CRP levels in all groups, but hospitalized patients had the highest levels (SAA, 503 vs. 310 microg/mL [P=.006]; CRP, 120 vs. 34 microg/mL [P<.001]). The presence of dyspnea, wheezing, and fever was also associated with high CRP levels. Influenza infection is associated with significant elevations of SAA and CRP levels in elderly patients, especially those who require hospitalization. It is possible that direct effects of CRP may exacerbate preexisting atherosclerotic lesions and may help explain cardiovascular events associated with acute influenza.

Acute Disease↗

PubMed2001

Posttransfusion purpura secondary to an alloantibody reactive with HPA-5a (Br(b)).

BACKGROUND: Posttransfusion purpura (PTP) is characterized by severe thrombocytopenia following blood transfusion that results from alloimmunization to platelet-specific alloantigens. Most cases involve antibodies against HPA-1a in homozygous HPA-1b persons. CASE REPORT: A patient developed PTP after cardiopulmonary bypass associated with a platelet-specific antibody with strong reactivity against HPA-5a (Br(b)). Geno-typing confirmed that the patient was homozygous for HPA-5b. CONCLUSION: This is the first well-documented occurrence of PTP associated with isolated allosensitization to HPA-5a or Br(b). The case highlights the importance of maintaining a high level of suspicion for PTP in the appropriate clinical setting, even in an atypical patient.

Aged↗

PubMed2001

Ultrasound-enhanced thrombolysis.

Problems with current thrombolytic therapy include slow and incomplete thrombolysis and frequent bleeding complications. Increasing evidence from in vitro, animal, and initial patient studies indicates that application of ultrasound as an adjunct to thrombolytic therapy offers unique potential to improve effectiveness and decrease bleeding complications. Numerous studies in vitro demonstrate that low intensity ultrasound increases enzymatic fibrinolysis through mechanisms that include improving drug transport, reversibly altering fibrin structure, and increasing tPA binding to fibrin. These observations have been confirmed in animal models that demonstrated that ultrasound delivered transcutaneously or with an endovascular catheter accelerates thrombolysis in models of venous, arterial, and small vessel thrombosis. Ultrasound delivered at higher intensities using either an endovascular vibrating wire or transcutaneously in conjunction with stabilized microbubbles can cause mechanical fragmentation of thrombus without administration of plasminogen activator. Recent studies indicate that ultrasound at lower frequencies in the range of 20-40 kHz has a greater effect on thrombolysis with improved tissue penetration and less heating. These studies form the basis for clinical trials investigating the potential of ultrasound as an adjunct to improve thrombolytic therapy.

Animals↗

PubMed2001

Fibrin degradation products, fibrin monomer and soluble fibrin in disseminated intravascular coagulation.

Disseminated intravascular coagulation (DIC) is characterized by activation of hemostasis and fibrinolysis resulting in the formation of thrombin and plasmin, and the characteristic effects of these enzymes on plasma fibrinogen can be useful in diagnosis. Thrombin cleaves fibrinopeptides from fibrinogen, forming fibrin monomer that rapidly polymerizes to form a clot. Small amounts can circulate in plasma as "soluble fibrin," which may have a complex composition and include fibrinogen and a variable amount of cross-linking. Plasmic degradation of cross-linked fibrin forms a heterogeneous group of degradation products reactive in assays for D-dimer, and their levels provide a measure of the amount of fibrin formation and lysis. Caution should be exercised in comparing quantitative results using different assays because of problems with standardization and variable reactivity with different molecular forms. Marked elevations of fibrin(ogen) degradation products are a constant finding in experimental animal models of DIC. In human models of DIC resulting from endotoxin infusion, D-dimer is elevated early and high levels persist, reflecting lysis of microvascular fibrin deposits. Elevated levels of D-dimer and soluble fibrin are very sensitive for the diagnosis of DIC, and a normal level has a high negative predictive value. Serial monitoring of soluble fibrin or D-dimer assays may be of value in evaluating the response to therapy and possibly in identifying at-risk patients.

Animals↗

PubMed2001

Ultrasound and thrombolysis.

Thrombolytic therapy and mechanical interventions are frequently used in the treatment of both arterial and venous thrombotic disease. Limitations to these approaches include failure to achieve reperfusion and complications including bleeding and vessel wall damage. Increasing evidence indicates that the use of ultrasound offers potential therapeutic advantages. This review considers two distinct approaches which include the use of high intensity ultrasound to mechanically fragment clots and also the use of low intensity ultrasound to augment enzymatic fibrinolysis. High intensity ultrasound can be delivered via catheter or transcutaneously to disrupt clots in vitro or in animal models into small fragments. Initial clinical studies demonstrate potential clinical value in peripheral and coronary arterial thrombosis and occluded saphenous vein bypass grafts treated with the catheter approach. Studies in vitro indicate that low intensity ultrasound accelerates enzymatic thrombolysis through non-thermal mechanisms involving improvement in drug transport. The effect is larger at low frequencies, which also offer better tissue penetration and less heating. The ability to accelerate thrombolysis has been confirmed in animal models demonstrating markedly increased reperfusion and minimal toxicity. The use of ultrasound to mechanically disrupt occlusive thrombi or to accelerate enzymatic thrombolysis offers a new approach to treating occlusive thrombotic disease.

Animals↗

PubMed2001

Prothrombotic changes in hemostatic parameters and C-reactive protein in the elderly with winter acute respiratory tract infections.

Mortality rates attributable to cerebrovascular and ischemic heart disease increase among older adults during the winter. Prothrombotic changes in the hemostatic system related to seasonal factors, such as ambient temperature changes, and winter acute respiratory tract infections, may contribute to this excess seasonal mortality. A prospective nested case-control study was conducted to assess the impact of winter acute respiratory tract infections on fibrinogen, factor VII, factor VIIa, D-dimer, prothrombin fragment 1.2, PAI-1, soluble P-selectin and C-reactive protein (CRP) in older adults. The change in laboratory parameters from baseline (fall) to the time of infection in both middle-aged and elderly individuals was compared with matched non-infected controls. In older adult participants with winter acute respiratory tract infections, significant increases occurred in fibrinogen and C-reactive protein, but not in any other markers. The mean fibrinogen increased 1.52 g/L (38%) and the mean CRP increased 37 mg/L (370%) over baseline (both p <0.001). In a multivariate analysis, both infection and season were associated with the increase in fibrinogen, but only infection was associated with the CRP increase. Old age magnified the increase in CRP but not in fibrinogen. Winter acute respiratory tract infections induce an exaggerated inflammatory response in older adults. The associated increase in fibrinogen, an independent risk factor for ischemic heart disease, may be partly responsible for the excess winter vascular mortality.

Acute Disease↗

PubMed2000

Vascular endothelial growth factor binds to fibrinogen and fibrin and stimulates endothelial cell proliferation.

Vascular development and response to injury are regulated by several cytokines and growth factors including the members of the fibroblast growth factor and vascular endothelial cell growth factor (VEGF) families. Fibrinogen and fibrin are also important in these processes and affect many endothelial cell properties. Possible specific interactions between VEGF and fibrinogen that could play a role in coordinating vascular responses to injury are investigated. Binding studies using the 165 amino acid form of VEGF immobilized on Sepharose beads and soluble iodine 125 ((125)I)-labeled fibrinogen demonstrated saturable and specific binding. Scatchard analysis indicated 2 classes of binding sites with dissociation constants (K(d)s) of 5.9 and 462 nmol/L. The maximum molar binding ratio of VEGF:fibrinogen was 3.8:1. Further studies characterized binding to fibrin using (125)I-labeled VEGF- and Sepharose-immobilized fibrin monomer. These also demonstrated specific and saturable binding with 2 classes of sites having K(d)s of 0.13 and 97 nmol/L and a molar binding ratio of 3.6:1. Binding to polymerized fibrin demonstrated one binding site with a K(d) of 9.3 nmol/L. Binding of VEGF to fibrin(ogen) was independent of FGF-2, indicating that there are distinct binding sites for each angiogenic peptide. VEGF bound to soluble fibrinogen in medium and to surface immobilized fibrinogen or fibrin retained its capacity to support endothelial cell proliferation. VEGF binds specifically and saturably to fibrinogen and fibrin with high affinity, and this may affect the localization and activity of VEGF at sites of tissue injury. (Blood. 2000;96:3772-3778)

Binding Sites↗