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PubMed1993

Complications of dental surgery in persons with HIV disease.

Post tooth extraction infective complications have occasionally been described in HIV-infected persons. However, there is little objective data as to the frequency of this and the need for antibiotic prophylaxis. Similarly the frequency of postextraction bleeding in patients infected with HIV, who may have thrombocytopenia, is unknown. In the present study the frequency of postextraction complications has been investigated in a group of 38 persons at stages 2 to 4 of HIV infection and 26 matched subjects from patients groups commonly at risk of HIV infection but not seropositive. During 40 clinical procedures in HIV-infected patients, 100 (range 1 to 23, median 1) teeth were extracted. Three episodes of delayed postextraction healing were recorded. During 30 procedures in the non-HIV-infected persons, 68 (range 1 to 5, median, 2) teeth were extracted, and two episodes of delayed postextraction healing were recorded. These differences were not significant. Only one HIV-infected patient had an episode of severe postextraction bleeding: this was a hemophiliac who bled despite receiving factor VIII prophylaxis. The bleeding occurred 7 days after the extraction and ceased with tranexamic acid and additional factor VIII. No control subject had severe postextraction hemorrhage. It is concluded that postextraction complications are uncommon in HIV-infected patients and that routine antibiotic prophylaxis is not indicated.

Adult↗
PubMed1993

Dental extractions in patients with bleeding disorders. The use of fibrin glue.

Eighty patients with various bleeding disorders underwent 135 extractions without preventive replacement hematologic therapy. The local hemostatic control involved the use of fibrin glue Beriplast. Secondary bleeding occurred in 9 of 12 patients with severe hemophilia when the concentration of the aprotinin in the fibrin glue was 1,000 KIU/ml. When it was increased to 10,000 KIU/ml and swish and swallow rinses of tranexamic acid before and after the dental extractions were added, only 3 of 25 hemophilia patients suffered from secondary bleeding. Local use of fibrin glue is a safe and cost-effective tool to treat patients with severe bleeding disorders. None of the 43 patients with coagulopathies other than severe hemophilia suffered bleeding after extractions.

Adolescent↗
PubMed1989

Connective tissue breakdown in ovulation.

A meshwork of collagen over the apical region of the follicle must be breached to permit the ovum to escape. We propose that specific collagenase activity is responsible for collagen breakdown in this region. Immature rats are primed with pregnant mare serum gonadotropin (PMSG), followed at 48 h by hCG. At 8 h after hCG, collagenase activity, measured in extracts of ovarian tissue, is elevated about five-fold. Ovulation follows at 10-12 h. Ovaries from PMSG-primed rats are dissected at 48 h, placed in a perfusion apparatus, and perfused with luteinizing hormone and 3-isobutyl-1-methyl xanthine. The ovulations induced by this treatment can be blocked to the extent of 70% with a synthetic collagenase inhibitor. The activation of procollagenase is believed to involve plasminogen activator and plasmin. In support of this, we find that tranexamic acid at 1 mM inhibits ovulation about 70%. The inhibitor must be added within 3-4 h of LH to be effective. A specific plasmin inhibitor, D-Val-Phe-Lys-chloromethyl ketone, is similarly effective.

Animals↗
PubMed1982

Demonstration of 99mTc-labelled plasmin on the surface of ex vivo thrombi.

In an vitro system using the Chandler model for the preparation of in vitro thrombi trace amounts of porcine or human 99mTc-labelled plasmin was found to adsorb to the surface of a preformed thrombus. A radioactive lining of the thrombus could be demonstrated using autoradiography after addition of 99mTc-labelled plasmin in concentrations of 0.04 - 0.07 or 0.4 - 0.7 CTA u/thrombus made from 2 ml whole blood (0.035 - 0.35 microM). The same pattern was found for porcine as for human plasmin. The presence of tranexamic acid in concentrations of 3 to 12 mM did not affect the binding of plasmin indicating that the plasmin binding to fibrin was independent of the lysine binding sites. Furthermore alpha 2-antiplasmin was demonstrated on/in the thrombus also when no plasmin was present indicating a binding of alpha 2-antiplasmin to the thrombus. The plasmin bound to the thrombus was proteolytically inactive. In order to obtain thrombolysis most of the alpha 2-antiplasmin in the surrounding medium had to be neutralized.

Animals↗
PubMed1985

Fibrinolytic action of a new semi-synthetic polysaccharide sulfate, galactan polysulfate (DH 6322), in the rat.

Galactan polysulfate, DH 6322, when added to rat plasma, shortened euglobulin clot lysis time through both increase in the recovery of plasminogen activator activity in euglobulin precipitates and direct acceleration of fibrinolysis. DH 6322 treatment also resulted in accelerating plasma clot lysis induced by urokinase. The effect of DH 6322 was further studied with a purified system composed of bovine fibrinogen and plasminogen. In this system, DH 6322 was found to be a potent stimulator of both fibrinolysis and fibrinogenolysis induced by urokinase. The activation process of plasminogen was not affected by DH 6322 even in the presence of fibrin or fibrinogen. The accelerating effect of DH 6322 on fibrinolysis in the purified system was scarcely affected by addition of plasma antifibrinolytic factors. DH 6322 also stimulated fibrin clot lysis induced by a low concentration of purified plasmin in place of plasminogen and urokinase, and its accelerating effect was not observed in the presence of tranexamic acid. Formation of fibrin clot susceptible to generated plasmin was observed at relatively high concentrations of DH 6322 above 80 micrograms/ml. Additional experiments indicated that DH 6322 increased the amount of plasminogen bound to fibrin. These results suggested that DH 6322 stimulated fibrinolysis through increasing the binding of plasminogen or plasmin to fibrin.

Animals↗
PubMed1988

The influence of the fibrinolytic system on the affinity of fibrinogen for the endothelial-plasma interface.

We use intravital fluorescence microscopy to study the endo-endothelial lining of microcirculatory vessels in vivo and in situ (exposed rat mesentery). In earlier experiments we found that fibrinogen had an affinity for the inner lining of microvessels, particularly venules. This affinity was specific to fibrinogen (and fibronectin); most other plasma proteins (albumin, antithrombin III, gamma-globulin) did not accumulate on the inner surface of microcirculatory blood vessels. We postulated the existence of receptors for fibrinogen and/or fibronectin on the endo-endothelial surface, whose turnover rate differed in arterioles and venules. Blockade of the intravascular coagulation process by heparin did not alter the interaction between fibrinogen and endothelium, but blockade of fibrinolytic activity by tranexamic acid increased the deposition of fibrinogen at the endothelial surface. In the present study we administrated a drug containing the bioflavonoids diosmin and hesperidin, which may activate tissue plasminogen activator. Such pretreatment significantly decreased the accumulation of fibrinogen at the endo-endothelial surface of the venules. We therefore conclude that the endothelial plasma interface is characterized by accumulation of fibrinogen which is not affected by thrombin-mediated activation of the coagulation system. In contrast, interactions between fibrinogen and endothelium are influenced by the fibrinolytic system, both of plasmatic and endothelial origin, thus representing an important aspect of the antithrombotic potential of the endothelium.

Animals↗
PubMed1996

Use of an active center-directed plasmin inhibitor elucidates the multiplicity of plasmin actions.

In our studies, designed to synthesize an active center-directed plasmin (PL) inhibitor, N-(4-aminomethylbenzoyl)-4-(3-picolyloxy)-L-phenylalanine n-hexylamide dihydrochloride (PASI-535) was found. We characterized PASI-535 and analyzed the actions of PL, comparing with those of PASI-535 and tranexamic acid (t-AMCHA). (1) PASI-535 strongly inhibited not only fibrinolysis (IC50: 2.9 x 10(-6) M) but also amidolysis (Ki value: 2.9 x 10(-6) M) and fibrinogenolysis (IC50: 4.5 x 10(-6) M) induced by PL. While t-AMCHA which strongly inhibited fibrinolysis (IC50: 6.0 x 10(-5) M), rarely inhibited amidolysis (Ki value: 4.0 x 10(-2) M) and fibrinogenolysis (IC50: 1.0 x 10(-2) M). (2) PL is able to liberate kinins by degrading kininogen. This kinin-generation by PL was inhibited by 2 x 10(-5) M PASI-535. However, it was little inhibited even by 1 x 10(-3) M t-AMCHA. (3) The inhibitory effect of PASI-535 and t-AMCHA on tumor growth was studied. In sarcoma-180 bearing mice, ascites retention and the increase of tumor cells were markedly suppressed by subcutaneous injection of PASI-535, either 30 mg/kg/day or 50 mg/kg/day, for 5 days, and the inhibitory effect was dose-dependent. Although t-AMCHA also reduced both ascites retention and the increase of tumor cells, it needed approximately 40 times (2 g/kg/day) the amount of PASI-535 to exert these effects. PASI-535 may be a useful tool in analyzing the multiplicity of PL actions. Moreover, PASI-535 can be used as an antifibrinolytic drug which has a mechanism of function different from that of t-AMCHA.

Amino Acid Sequence↗
PubMed1996

Migration of cultured vascular smooth muscle cells into non-crosslinked fibrin gels.

We evaluated the migration of vascular smooth muscle cells into fibrin gels, using an in vitro assay system. Vascular smooth muscle cells from bovine fetal aorta migrated into fibrin gels and showed a characteristic elongated spindle-shaped appearance with long cytoplasmic processes. Varying the concentration of thrombin (0.05-1 NIHU/ml) used to form the fibrin gel had little effect on cell migration although higher concentrations of thrombin inhibited the migration. Migration of the cells into fibrin gels was dependent on RNA and protein synthesis but not on DNA synthesis. The addition of antithrombin III, hirudin, and D-phenylalanyl-L-prolyl-L-arginine chloromethyl ketone after gel formation had no effect, suggesting that residual thrombin in fibrin gels had no influence on subsequent cell migration. Neither the factor XIII-induced crosslinking of fibrin nor the fibrinopeptides released during gel formation were involved in the present migration assay system. Tranexamic acid, an inhibitor of plasminogen activator, or aprotinin, a plasmin inhibitor, also had no significant effect, suggesting that fibrinolysis induced by plasmin was not involved in this system. These findings showed that fibrin gels themselves induce the migration of vascular smooth muscle cells (haptotaxis) without other chemotactic or chemokinetic substances, suggesting an important role for fibrin in the development and progression of such vascular diseases as atherosclerosis, thrombosis and the development of restenosis following balloon angioplasty.

Animals↗
PubMed1986

Quantitative assessment of subcutaneous fibrinolysis in the rat.

A clot lysis model in the rat was described which was responsive to manipulation of the fibrinolytic system. By employing [125I]-labeled fibrinogen in homologous, plasminogen-deficient plasma, clots were prepared in Teflon-perforated cylinders and were implanted subcutaneously. After a brief lag phase, lysis proceeded essentially linearly with 70% of the clot resolved within 12 days. Enhancement of lysis was achieved with a stimulator of fibrinolysis, stanozolol; and inhibition, with the antifibrinolytic, tranexamic acid. Other drugs affecting blood pressure, inflammation, or connective tissue growth had no effect on lysis. Interstitial fluid collected from empty cylinders and fluid obtained from the recovered clots were monitored for plasminogen, alpha 2-antiplasmin, plasminogen activator, and plasminogen activator inhibitor using sensitive and specific assays. All of these fibrinolytic proteins were quantitated relative to their plasma concentrations. The most striking differences between the two fluids and plasma were a threefold higher concentration of the plasminogen activator inhibitor and only traces of free tissue plasminogen activator in the fluids. Nevertheless, significant tissue plasminogen activator was delivered to the clot. It was concluded that lysis occurred via delivery of the fibrinolytic system in interstitial fluid. It is suggested that this model is a technically simple and quantitative screen in vivo for potentially fibrinolytic or antifibrinolytic agents.

Animals↗
PubMed1991

Modifying perioperative blood loss.

Fears about the risks of disease transmission through the transfusion of homologous blood, as well as problems with blood supply and cost have increased the interest in reducing perioperative bleeding. This article discusses the causes of non-surgical perioperative bleeding and attempts to reduce perioperative bleeding with pharmacological agents. There is particular emphasis on the effects of cardiopulmonary bypass on haemostasis as the majority of studies have been conducted in this area. The agents discussed include the use of fibrin sealants, antiplatelet agents such as dipyridamole and prostacyclin analogues, antifibrinolytics and the effects of desmopressin and aprotinin. Currently high dose aprotinin would appear to be the most efficacious method of reducing perioperative bleeding in cardiac surgery, although a full risk benefit analysis is not yet possible. The effectiveness of aprotinin and tranexamic acid in reducing the 'oozing' seen in any surgical patient suggests the contribution of fibrinolysis in causing perioperative bleeding has not been fully evaluated. More research is required in this actively growing area.

Hemorrhage↗
PubMed1996

Hereditary partial deficiency of plasminogen activator inhibitor-1 associated with a lifelong bleeding tendency.

We report a family with a partial deficiency of plasminogen activator inhibitor-1 (PAI-1). The affected family members had had lifelong bleeding episodes, such as rebleeding after tooth extraction and trauma. This bleeding tendency in the propositus was autosomally transmitted from grandfather to son. The characteristic abnormalities of fibrinolysis in the patients were shortened eugloblin lysis time, low PAI activity with low antigen levels of plasminogen activator inhibitor-1 in plasma and serum. Furthermore, plasma 'active PAI' which indicates the quantity of plasminogen activator inhibitor-1 bound with plasminogen activator added was very low in these patients. These parameters were markedly low after the venous occlusion test. Moreover, two of the affected members had a much lower level of platelet PAI-1 than the normal controls. Tranexamic acid (Transamine) was useful to control bleeding in these patients.

Adolescent↗
PubMed2006

Heparin resistance and increased platelet activation in coronary surgery patients treated with enoxaparin preoperatively.

OBJECTIVE: Patients with unstable coronary disease have changes in the hemostatic system. These patients are often treated with low molecular weight heparin. In patients who are accepted for coronary artery bypass grafting, treatment with low molecular weight heparin is frequently continued until surgery. We hypothesized that in coronary artery bypass grafting, the hypercoagulable state seen in unstable patients persists into the intra- and postoperative phase despite preoperative treatment with low molecular weight heparin. The aim of this study was to explore and describe the perioperative hemostatic process in patients with unstable coronary artery disease undergoing coronary artery bypass grafting. METHODS: Thirty-two patients with unstable coronary disease treated preoperatively with enoxaparin, and 32 stable control patients not treated with enoxaparin, were included. All patients were taking low dose aspirin until the day before surgery. Before cardiopulmonary bypass, all patients were given tranexamic acid as a bolus injection. Blood samples for analysis of platelet counts, international normalized ratio, activated partial thromboplastin time, fibrinogen, protein S, protein C, prothrombin fragment 1 + 2, thrombin-antithrombin complex, antithrombin, plasmin-antiplasmin complex, D-dimer, neutrophil-activating peptide 2, platelet-monocyte complexes, and heparin concentrations were drawn preoperatively, after 30 min on cardiopulmonary bypass, and 30 min, 3 h, and 20 h postoperatively. Heparin was given during cardiopulmonary bypass to maintain an activated clotting time above 480 s. RESULTS: Patients in the enoxaparin group needed more heparin to maintain an activated clotting time above 480 s, and had higher heparin concentrations and lower antithrombin values compared with control patients. Neutrophil-activating peptide 2 concentrations were higher in the enoxaparin group. CONCLUSIONS: Patients treated with enoxaparin before coronary artery bypass grafting showed signs of heparin resistance intraoperatively. Enoxaparin-treated patients also had increased perioperative platelet activation. Reasons for the observed difference in platelet activation remain unclear.

Aged↗
PubMed2005

Disseminated intravascular coagulopathy in aortic aneurysms.

Aneurysm-induced disseminated intravascular coagulopathy (DIC) constitutes a rare presentation form of aortic aneurysms. The majority of DIC cases are asymptomatic and this condition is usually diagnosed during the perioperative workup; yet, in a minority of cases, DIC leads to the diagnosis of the vascular abnormality. The management of aneurysm-induced DIC is based both on the treatment of the underlying disorder and on an active scrutiny of the hemodynamic and blood support requirements. Blood replacement therapy should be individualized, guided by the clinical situation of the patient (especially considering the bleeding risk or the presence of hemorrhages), and accompanied by a close monitoring of the coagulation status. Fresh frozen plasma is usually the preferred initial option to replace coagulation factors, but fibrinogen, cryoprecipitates, and platelet concentrates are adequate options in certain contexts. Heparins, both non-fractionated and low-weight molecular types, are the most widely accepted agents for achieving adequate control of the coagulation activation and consumption. Other antithrombotic drugs are under study, including antithrombin III and activated protein C, although only the latter has demonstrated a benefit in terms of survival in a comparative, randomized context. Antifibrinolytic agents such as gabexate mesilate, tranexamic acid, and epsilon-aminocaproic acid (EACA) have been used with conflicting results. These agents may have a role for patients with catastrophic bleeding resistant to other therapeutical options, but their relevance as a first line of treatment is, at present, undefined. An assessment of the multitude of therapeutic approaches available would seem to indicate that there is a lack of standardization in the management of these patients. Multi-center, randomized clinical trials are needed to elucidate the most adequate therapy in this context.

Journal Article↗
PubMed2005

Rehabilitation of a hemophiliac with implants: a medical perspective and case report.

A patient suffering from classical hemophilia had previous surgery for ankylosis of the right temporomandibular joint. This was replaced by a costochondral graft and an overlay of temporalis muscle. A bilateral sagittal split was performed for a micrognathic mandible and a sleep apnea problem. That procedure solved the sleep apnea; however, it resulted in a prognathic mandible and an anterior open bite. The lower anterior teeth were periodontally involved with impaired alveolar support. The restricted opening of the oral cavity of 18 mm between maxillary and mandibular centrals and the potential danger of bleeding complicated the surgical and restorative procedures. The patient was prepared medically on each of 4 occasions with factor VIII replacement concentrate, and oral antifibrinolytic therapy (tranexamic acid). The treatment of choice was the extraction of the remaining lower incisors and their replacement with an implant-supported temporarily cemented retrievable fixed prosthesis. Serial extractions and chairside temporization provided the surgeon with precise guides for implant placement, and enabled the patient to enjoy unimpaired function through periods of healing and osseointegration.

Dental Implantation, Endosseous↗
PubMed2004

Circumcision in hemophilia: a cost-effective method using a novel device.

BACKGROUND/PURPOSE: The authors conducted a prospective clinical study to see whether the need for and the cost of factor substitution after circumcision can be reduced using a novel device for bloodless circumcision in boys with hemophilia. METHODS: Forty-five boys with hemophilia (age range, 1.5 to 25 years; median age, 11; 40 with hemophilia A, 5 with hemophilia B; weight range, 9 to 75 kg; median weight, 30 kg) were circumcised in our department between 1996 and 2001. Severity of the disease was mild in 9 cases, moderate in 11, and severe in 25. After starting systemic prophylaxis including factor substitution and DDAVP (desmopressin acetate) in reduced doses, all patients underwent circumcision under local anesthesia using a modified straight clamp and a battery-operated diathermic knife specially designed for bloodless circumcision. Duration of factor replacement ranged between 7 and 18 days, and the hospitalization period was 2 to 5 days according to severity of the disease. The last 19 patients were given tranexamic acid orally for 7 days after surgery. RESULTS: Transient minimal bleeding was observed in 5 patients and easily responded to factor administration. Moderate edema and hyperemia along the excision line owing to the diathermic effect of the device lasted for 3 to 4 days. Normal cosmetic appearance was regained within 7 to 21 days. Excellent patient and family satisfaction was reported. The average cost of the operation was calculated as 81 dollars, 144 dollars, and 243 dollars per kilogram in mild, moderate, and severe cases, respectively. CONCLUSIONS: Bloodless circumcision with "diathermic knife" is a practical and reliable alternative for boys with hemophilia. Enhancement of local hemostasis using such an alternative device may reduce the need for factor substitution and, accordingly, the cost of circumcision in hemophiliacs, down to 50%.

Adolescent↗
PubMed2004

Safety of deliberate intraoperative and postoperative hypothermia for patients undergoing coronary artery surgery: a randomized trial.

BACKGROUND: Hypothermia in the perioperative period is associated with adverse effects, particularly bleeding. Before termination of cardiopulmonary bypass, rewarming times and perfusion temperatures are often increased to avoid post-cardiopulmonary bypass hypothermia and the presumed complications. This practice may, however, also have adverse effects, particularly cerebral hyperthermia. We present safety outcomes from a trial in which patients undergoing coronary artery surgery were randomly assigned to normothermia or hypothermia for the entire surgical procedure. METHODS: Consenting patients over the age of 60 years presenting for a first, elective coronary artery surgery with cardiopulmonary bypass were randomly assigned to having their nasopharyngeal temperature maintained at either 37 degrees C (group N; 73 patients) or 34 degrees C (group H; 71 patients) throughout the intraoperative period, with no rewarming before arrival in the intensive care unit. All received tranexamic acid. RESULTS: There was no clinically important difference in intraoperative blood product or inotrope use. Temperatures on arrival in the intensive care unit were 36.7 degrees C +/- 0.38 degrees C and 34.3 degrees C +/- 0.38 degrees C in groups N and H, respectively. Blood loss during the first 12 postoperative hours was 596 +/- 356 mL in group N and 666 +/- 405 mL in group H (mean difference +/- 95% confidence interval, 70 +/- 126 mL; P =.28). There was no significant difference in blood product utilization, intubation time, time in the hospital, myocardial infarction, or mortality. The mean time in the intensive care unit was 8.4 hours less in the hypothermic group (P =.02). CONCLUSIONS: Our data support the safety of perioperative mild hypothermia in patients undergoing elective nonreoperative coronary artery surgery with cardiopulmonary bypass. These findings suggest that complete rewarming after hypothermic cardiopulmonary bypass is not necessary in all cases.

Aged↗
PubMed2006

Effects of cardiac surgery on hemostasis.

Cardiac surgery affects both coagulation and platelet function. Revision of surgery due to bleeding has to be performed in 2% to 6% of patients undergoing cardiac surgery and is generally associated with a marked deterioration in prognosis. Factors contributing to acquired hemostatic abnormalities in cardiac surgery include the use of anticoagulants as well as the activation and consumption of coagulation factors and platelets induced by the extracorporeal circulation. Prophylactic use of antifibrinolytic agents such as aprotinin and tranexamic acid has been demonstrated to reduce the blood loss by half. Adequacy of heparin-induced anticoagulation in the perioperative setting is commonly controlled by the activated clotting time. This method also indicates the correct reversal of the heparin effect by protamine. In recent years, thrombelastography has proved to be valuable for diagnosis of coagulopathy associated with cardiac surgery. In addition, the use of thrombelastography-based algorithms has been shown to reduce transfusion requirements. In contrast to point of care methods, laboratory assessment of hemostasis is more time-consuming and, thus, often not as rapidly available as required. At this time, the therapy for perioperative hemostatic abnormalities is based mainly on the administration of blood components (fresh frozen plasma and platelet concentrates). In the future, recombinant activated factor VIIa might prove to be a therapeutic option in patients with otherwise untractable bleeding, but the efficacy of recombinant activated factor VIIa has yet to be defined for this indication.

Blood Coagulation Disorders↗
PubMed2006

Pathophysiology of bleeding in surgery.

Bleeding is a major surgical complication. Although mortality rates of 0.1% are observed for surgical procedures, it may be 5% to 8% for elective vascular surgery, and increase to 20% in the presence of severe bleeding. In major surgery for liver diseases, as well as in cardiac surgery, excessive blood loss is associated with increased mortality, morbidity, and intensive care stay. Approximately 75% to 90% of intraoperative and early postoperative bleeding is due to technical factors. However, in some cases either acquired or congenital coagulopathies may favor, if not directly cause, surgical hemorrhage. Uncontrolled bleeding leads to a combination of hemodilution, hypothermia, consumption of clotting factors, and acidosis, which in turn worsen the clotting process, further exacerbating the problem in a vicious bloody circle. At present, the standard treatment for surgical bleeding is the rapid control of the source of bleeding by either surgical or radiological techniques. Blood-derived products as well as hemostatic agents, such as aprotinin, tranexamic acid, and DDAVP, are widely used to improve hemostatic balance in bleeding patients. Recombinant activated factor VII (rFVIIa) has been reported to be effective for the treatment of surgical or traumatic massive bleeding unresponsive to conventional therapy. Although most reports are anecdotal, and therefore exposed to a "positive" selection bias, the number of cases is impressive, strongly suggesting that in such patients rFVIIa may afford a hemostatic advantage beyond that of conventional replacement therapy.

Blood Coagulation Disorders↗