chondroitin-sulfates and Hemorrhage

Antithrombotic drugs have some side effects, such as risk of serious bleeding. Development of antithrombotic drugs that inhibit components of the intrinsic coagulation pathway and have a low risk of causing bleeding has recently been a focus of research. Fucosylated glycosaminoglycan (FG), also named as fucosylated chondroitin sulfate (FCS), has potent anticoagulant activity and inhibits intrinsic factor tenase (FXase) complex. Low-molecular-weight FG (LFG) and its oligosaccharides show characteristics of anticoagulant and antithrombotic activities with negligible side effects, such as activation of human FXII, induction of platelet aggregation, and especially, the risk of serious bleeding. They are potential new anticoagulant drugs and have been extensively studied in recent years. This review presents recent findings regarding the preparation, structural analysis, pharmacological activity, and structure-activity relationships of LFG and its derived oligosaccharides, so as to provide a reference for the development of new anticoagulants with low side effects.

Topics: Animals; Anticoagulants; Blood Coagulation; Chondroitin Sulfates; Hemorrhage; Humans; Molecular Structure; Oligosaccharides; Sea Cucumbers; Structure-Activity Relationship

In the context of inpatient and increasingly ambulatory thrombosis prophylaxis, heparins have been recognised as standard therapy for decades. In addition to the therapeutic benefit, therapy with heparins also entails the risk of undesirable side effects, such as bleeding and thrombocytopenia. Heparin-induced thrombocytopenia (HIT II) is deemed a serious side effect.. In the following work, HIT II is subjected to a medico-economic consideration (treatment, pharmaceuticals, subsequent costs due to possible complications) and, with regard to a possible HIT II prophylaxis, aspects of increasingly respected patient safety are also considered.. In the context of a literature search the active ingredients argatroban and danaparoid, which are approved for HIT II treatment, were evaluated.. HIT II - especially in combination with thromboembolic complications - represents a medical-economic burden for the hospital. Although this is only an orientation guide, it shows that HIT II syndrome is not adequately cost-covered by the G‑DRG system. An early thrombosis prophylaxis with argatroban/danaparoid for HIT II risk patients should therefore be taken into account for medical-related as well as patient safety-relevant aspects. According to experience, the pharmaceutical supply for these medically needed products (anticoagulants) should be ensured for reasons of patient safety.. The risk of an immunological response to heparin therapy is known. Within the context of increased patient safety, thrombosis prophylaxis should be issued with a risk-adjusted prophylaxis.

Topics: Arginine; Chondroitin Sulfates; Costs and Cost Analysis; Dermatan Sulfate; Germany; Hemorrhage; Heparin; Heparitin Sulfate; Hospitalization; Humans; Pipecolic Acids; Risk Factors; Sulfonamides; Thrombocytopenia; Thrombosis; Treatment Outcome

Type II heparin-induced thrombocytopenia is currently managed by withdrawing heparin and replacing it with danaparoid sodium. Argatroban, a direct thrombin inhibitor anticoagulant (like lepirudin), is now authorised for this indication in France, following authorisation in several other countries since the early 2000s. Argatroban has not been compared with danaparoid in clinical trials. About 700 patients treated with argatroban in 2 trials were compared to historical controls managed by simple withdrawal of heparin and, in some cases, switching to an oral anticoagulant. Argatroban had no apparent advantages in terms of death or the need for amputation. Argatroban did not appear to increase the risk of bleeding in these trials, but evidence provided by historical comparisons is weak. The adverse effect profile includes hepatic disorders (notably fulminant hepatitis). The risk of pharmacokinetic interactions appears to below. In practice, given the absence of a proven therapeutic advantage, it is better to continue to use danaparoid for first-line treatment, reserving argatroban for the rare situations in which danaparoid is inappropriate.

Topics: Anticoagulants; Antithrombins; Arginine; Chondroitin Sulfates; Dermatan Sulfate; Drug Interactions; Drug Substitution; Hemorrhage; Heparin; Heparitin Sulfate; Humans; Patient Selection; Pipecolic Acids; Risk Assessment; Risk Factors; Sulfonamides; Thrombocytopenia; Treatment Outcome; Venous Thrombosis

Physical medicine and rehabilitation aim to evaluate, diagnose and treat disability in haemophiliac patients, while preventing injury or deterioration. They also aim to maintain the greatest degree of functional capacity and independence in patients with haemophilia, or to return them to that state. Rehabilitation, together with clotting factor replacement therapy, has revolutionized the management of these patients in developed countries and reduced their morbidity/mortality rates. A knowledge of the musculoskeletal signs and symptoms of haemophilia is essential for providing a treatment which is suitable and customized. Physical medicine and rehabilitation techniques, which are based on physical means, are intended to reduce the impact which these injuries and their consequences or sequelae can have on the quality of life of patients with haemophilia. Under ideal haemostatic control conditions (primary prophylaxis), people with haemophilia could achieve good physical condition which will allow them to enjoy both physical activity and a daily life without limitations. Currently, children undergoing primary prophylaxis are quite close to this ideal situation. For these physical activities to be carried out, the safest possible situations must be sought.

Topics: Bone Cysts; Cartilage Diseases; Cartilage, Articular; Chondroitin Sulfates; Combined Modality Therapy; Electric Stimulation Therapy; Exercise Therapy; Factor IX; Factor VIII; Glucosamine; Hemarthrosis; Hemophilia A; Hemorrhage; Humans; Hyaluronic Acid; Hypertrophy; Motor Activity; Musculoskeletal Diseases; Physical and Rehabilitation Medicine; Synovectomy; Synovial Membrane; Synovitis; Transcutaneous Electric Nerve Stimulation

The recent health care changes and approval of a generic low-molecular-weight heparin (LMWH) by the US Food and Drug Administration (FDA) merit a review of the facts regarding the new and generic anticoagulants. Fatal hypotension from anaphylactoid type reactions following heparin administration was responsible for more than 149 deaths all over the world. Researchers detected a heparin-like semisynthetic contaminant, over-sulfated chondroitin sulfate (OSCS), that appeared to be intentional. Low-molecular-weight heparins are produced using unfractionated heparin and OSCS has been found in various batches of LMWHs. Some newer anticoagulants are claiming to be free from the need to monitor for therapeutic effect and bleeding risk. Therefore, monitoring assays are not being developed and there is no antidote to reverse bleeding. In addition, there are concerns about reproducibility, product variation, and quality. In conclusion, although the generic LMWHs and newer anticoagulants may appear to be effective for qualified indications, their safety remains to be a concern.

Topics: Anaphylaxis; Animals; Anticoagulants; Chondroitin Sulfates; Drug Contamination; Drug-Related Side Effects and Adverse Reactions; Drugs, Generic; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Hypotension; Monitoring, Physiologic; United States; United States Food and Drug Administration

Danaparoid case reports of 91 pregnancies in 83 patients with a history of thrombophilia and/or intra-uterine growth retardation have been analysed. All had intolerance to the heparins including HIT and acute or past thromboses or a history of repeated pregnancy loss (RPL). Danaparoid was started in the first, second and third trimesters in 60.2%, 19.3% and 20.5% pregnancies respectively at a dosing intensity of 1000 to 7500 U/day. Subcutaneous and/or intravenous administration was continued for a median 105 days (range 1-252) during pregnancy and 7 days (range 2 to 56) post-partum. The live birth rate was 90.4% (75/81) and danaparoid was restarted after 37 deliveries. Maternal adverse events in 46.2% of the pregnancies included 2 post cesarean deaths (a failed post-operative resuscitation and a major bleed in a patient refusing transfusion), 3 non-fatal major bleeds (associated with cesarean section and faulty placental implantation), 3 thrombo-embolic events unresponsive to danaparoid dose increase and 10 recurrent rashes. Seven early miscarriages, 1 therapeutic termination and 1 neonatal death occurred. In 13 reports a maternal, but no fetal, adverse event was attributed to danaparoid. Anti-Xa activity levels in maternal plasma were between 0.1 and 1.2 U/mL, absent from 6 fetal cord blood samples and 0 - 0.07 U/mL in the 5 maternal breast milk samples tested.. The successful birth rate and adverse event profile indicates that danaparoid can be an effective and safe alternative anti-thrombotic in pregnancies complicated by HIT or intolerance or resistance to (LMW)heparins.

Topics: Abortion, Spontaneous; Chondroitin Sulfates; Dermatan Sulfate; Exanthema; Female; Hemorrhage; Heparin; Heparin, Low-Molecular-Weight; Heparitin Sulfate; Humans; Infant, Newborn; Infusions, Intravenous; Injections, Subcutaneous; Pregnancy; Research; Thrombosis; Treatment Outcome

One hundred and twenty-two case reports of treatment outcomes of danaparoid use for intermittent haemodialysis (HD) in severely ill patients with heparin intolerance (including 97 HIT patients) have been analysed. HD sessions of 4 - 6 hours were successfully conducted daily to 3 times/week for periods of up to 4 years (median 7 sessions/patient (range 1 - >650). In these patients danaparoid use was relatively safe (4 unprovoked non-fatal major bleeds) and efficacious in protecting the circuit (95% no clotting problem) or patient (6 thromboses: 4 fatal or leading to danaparoid discontinuation). HIT diagnosis was improved if recurrent platelet count reduction with each HD and circuit/AV graft clotting were included. Alternative reasons for and very low nadirs of the platelet count undermined the usefulness of the 4 T pre-test HIT predictability scores, but a positive functional serological test confirmed HIT in most patients. Deaths (15.6%) and thrombosis only occurred in HIT cases. Possible reasons are discussed. Replacing the standard intermittent pre-HD dose regimen with the therapeutic infusion regimen to provide continuous daily systemic antithrombotic protection, should further improve efficacy.. Danaparoid appears to be a useful alternative antithrombotic for patients with heparin intolerance and renal failure requiring haemodialysis.

Topics: Chondroitin Sulfates; Dermatan Sulfate; Female; Hemorrhage; Heparin; Heparitin Sulfate; Humans; Platelet Count; Pregnancy; Recurrence; Renal Dialysis; Thrombosis; Treatment Outcome

Numerous acquired hemostatic abnormalities have been identified in renal insufficiency. Hemodialysis procedures add to these disturbances as they repetitively imply turbulent blood flow, high shear stress, and contact of blood to artificial surfaces. This nonphysiological environment leads to activation of platelets, leukocytes, and the coagulation cascade, resulting in fouling of the membrane and ultimately in clotting of fibers and the whole hemodialyzer. Anticoagulation in hemodialysis is targeted to prevent this activation of coagulation during the procedure. Most agents inhibit the plasmatic coagulation cascade. Still commonly used is unfractionated heparin, followed by low-molecular-weight heparin preparations with distinct advantages. Immune-mediated heparin-induced thrombocytopenia constitutes a potentially life-threatening complication of heparin therapy requiring immediate switch to nonheparin alternative anticoagulants. Danaparoid, lepirudin, and argatroban are currently being used for alternative anticoagulation, all of which possess both advantages and limitations. In the past, empirical strategies reducing or avoiding heparin were applied for patients at bleeding risk, whereas nowadays regional citrate anticoagulation is increasingly used to prevent bleeding by allowing procedures without any systemic anticoagulation. Avoidance of clotting within the whole hemodialyzer circuit is not granted. Specific knowledge of the mechanisms of coagulation, the targets of the anticoagulants in use, and their respective characteristics constitutes the basis for individualized anticoagulation aimed at achieving full patency of the circuit throughout the procedure. Patency of the circuit is an important prerequisite for optimal hemodialysis quality.

Topics: Anticoagulants; Arginine; Blood Coagulation; Chondroitin Sulfates; Dermatan Sulfate; Equipment Failure; Hemorrhage; Heparin; Heparitin Sulfate; Hirudins; Humans; Pipecolic Acids; Recombinant Proteins; Renal Dialysis; Renal Insufficiency, Chronic; Sulfonamides

Heparin-induced thrombocytopenia (HIT) is a potentially devastating immune mediated adverse drug reaction caused by the emergence of antibodies that activate platelets in the presence of heparin. Despite thrombocytopenia, bleeding is rare; rather, HIT is strongly associated with thromboembolic complications involving both the arterial and venous systems. A number of laboratory tests are available to confirm the diagnosis; however, when HIT is clinically suspected, treatment should not be withheld pending the result. Fortunately, therapeutic strategies have been refined, and new and effective therapeutic agents are available. Treatment options are focused on inhibiting thrombin formation or direct thrombin inhibition. Warfarin should not be used until the platelet count has recovered.

Topics: Anticoagulants; Arginine; Cardiovascular Surgical Procedures; Chondroitin Sulfates; Dermatan Sulfate; Fibrinolytic Agents; Hemorrhage; Heparin; Heparitin Sulfate; Hirudins; Humans; Pipecolic Acids; Recombinant Proteins; Renal Dialysis; Sulfonamides; Thrombocytopenia; Warfarin

Pregnant patients with acute venous thrombosis or a history of thrombosis may need alternative anticoagulation, when heparin intolerance occurs. Only limited data on the use of the heparinoid danaparoid are available in literature. We reviewed the use of danaparoid in 51 pregnancies of 49 patients identified in literature between 1981 and 2004. All patients had developed heparin intolerance (32 due to heparin-induced thrombocytopenia, 19 mainly due to heparin-induced skin rashes) and had a current and/or past history of thromboembolic complications. The initial danaparoid dose regimens ranged from 1000 to 7500 U/day administered s.c. or i.v.. The median duration of danaparoid use was 10 weeks. Danaparoid was used until delivery of a healthy infant in 37 pregnancies. In the remaining 14 pregnancies it was stopped earlier, because anticoagulant treatment was no longer required (3/14) or an adverse event led to a treatment discontinuation (11/14). Four maternal bleeding events were recorded during pregnancy, delivery or postpartum, two of them were fatal due to placental problems. Three fetal deaths were recorded, all associated with maternal complications antedating danaparoid use. Danaparoid cross-reactivity was suspected in 4 HIT patients and 5 non-HIT patients with skin reactions and was confirmed serologically in one of the two HIT patients tested. In none of five fetal cord blood- and three maternal breast milksamples anti-Xa activity transfer was observed. In conclusion danaparoid can be used as an alternative antithrombotic agent in pregnant women with high thrombotic risk and intolerance to heparins.

Topics: Adult; Chondroitin Sulfates; Cross Reactions; Dermatan Sulfate; Drug Evaluation; Drug Hypersensitivity; Exanthema; Female; Hemorrhage; Heparin; Heparitin Sulfate; Humans; MEDLINE; Pregnancy; Pregnancy Complications, Cardiovascular; Pregnancy Outcome; Retrospective Studies; Thrombocytopenia; Thrombosis

Despite the progress made in the development of cardiopulmonary bypass (CPB) equipment, systemic anticoagulation with unfractionated heparin and post-bypass neutralization with protamine are still used in most perfusion procedures. However, there are a number of situations where unfractionated heparin, protamine or both cannot be used for various reasons. Intolerance of protamine can be addressed with extracorporeal heparin removal devices, perfusion with (no) low systemic heparinization and, to some degree, by perfusion with alternative anticoagulants. Various alternative anticoagulation regimens have been used in cases of intolerance to unfractionated heparin, including extreme hemodilution, low molecular weight heparins, danaparoid, ancrod, r-hirudin, abciximab, tirofiban, argatroban and others. In the presence of heparin-induced thrombocytopenia (HIT) and thrombosis, the use of r-hirudin appears to be an acceptable solution which has been well studied. The main issue with r-hirudin is the difficulty in monitoring its activity during CPB, despite the fact that ecarin coagulation time assessment is now available. A more recent approach is based on selective blockage of platelet aggregation by means of monoclonal antibodies directed to GPIIb/IIIa receptors (abciximab) or the use of a GPIIb/IIIa inhibitor (tirofiban). An 80% blockage of the GPIIb/IIIa receptors and suppression of platelet aggregation to less than 20% allows the giving of unfractionated heparin and running CPB in a standard fashion despite HIT and thrombosis. Likewise, at the end of the procedure, unfractionated heparin is neutralized with protamine as usual and donor platelets are transfused if necessary. GPIIb/IIIa inhibitors are frequently used in interventional cardiology and, therefore, are available in most hospitals.

Topics: Abciximab; Ancrod; Antibodies, Monoclonal; Anticoagulants; Arginine; Cardiopulmonary Bypass; Chondroitin Sulfates; Cross Reactions; Dermatan Sulfate; Drug Combinations; Drug Hypersensitivity; Factor Xa Inhibitors; Hemodilution; Hemorrhage; Heparin; Heparin, Low-Molecular-Weight; Heparitin Sulfate; Hirudin Therapy; Humans; Immunoglobulin Fab Fragments; Perfusion; Pipecolic Acids; Platelet Aggregation Inhibitors; Protamines; Sulfonamides; Thrombocytopenia; Thrombophilia; Thrombosis; Tirofiban; Tyrosine

New platelet antagonists act on the activation by ADP (clopidogrel, ATP analogue) or on the mechanism of aggregation itself, by binding to the IIb/IIIa glycoprotein complex. The new anticoagulants are as follows: saccharide structures such as danaparoïd and the pentasaccharide of antithrombin binding, and direct thrombin inhibitors, such as recombinating hirudines (desirudine, lepirudine), bivalirudine, melagatran.... Other molecular targets are possible, both at platelet and blood clotting levels but, for the moment, the dilemma remains and reinforcement of antithrombotic activity goes hand in hand with a greater decrease in the defensive mechanisms against bleeding. In general, there is no antidote and the products are often associated, which increases the risk of haemorrhage. The research and development in this field are handicapped by the lack of biological tools for pertinent, homogenous, reproducible evaluation of the effects on haemostasis. The present tendency is to do without biological monitoring for adapting dosage in favour of optimisation of the impact in a given situation, perhaps, above all, with respect to the preceding problem.

Topics: Anticoagulants; Blood Coagulation; Chondroitin Sulfates; Dermatan Sulfate; Drug Combinations; Fibrinolytic Agents; Hemorrhage; Heparitin Sulfate; Hirudin Therapy; Humans; Platelet Aggregation; Risk Factors; Thromboembolism

Heparin-induced thrombocytopenia (HIT) may be complicated by severe thrombotic complications and death. Currently no specific laboratory test is available to make the diagnosis. When HIT is clinically suspected, heparin should be discontinued immediately. While no specific therapy for HIT exists, there is increasing evidence that acute antithrombin therapy may significantly reduce morbidity and mortality. Among several agents, the direct antithrombins, such as r-hirudin and argatroban, look the most promising for acute treatment.

Topics: Ancrod; Arginine; Chondroitin Sulfates; Dermatan Sulfate; Drug Combinations; Fibrinolytic Agents; Forecasting; Gangrene; Hemorrhage; Heparin; Heparitin Sulfate; Hirudin Therapy; Hirudins; Humans; Pipecolic Acids; Platelet Aggregation; Protein C; Recombinant Proteins; Sulfonamides; Thrombin; Thrombocytopenia; Warfarin

On the basis of the results of the 11 studies reviewed, thromboprophylaxis with unfractionated heparin, low molecular weight (LMW) heparin or a heparinoid (danaparoid sodium; Org 10172) in patients undergoing total hip replacement did not show any important clinical differences with respect to the tolerability profiles of the different compounds. However, as a result of the great variability in the presentation and evaluation of blood losses and bleeding complications in these studies, it is mandatory to perform a direct comparison of the different compounds in question in a double-blind, prospective clinical study.

Topics: Chondroitin Sulfates; Dermatan Sulfate; Fibrinolytic Agents; Hemorrhage; Heparin; Heparinoids; Heparitin Sulfate; Hip Prosthesis; Humans; Molecular Weight; Postoperative Complications; Thrombocytopenia; Thrombosis; Wound Infection

Orgaran is a mixture of glycosaminoglycans extracted from animal mucosa. It consists of heparan, dermatan and chondroitin sulfate; a small proportion of heparan sulfate (4%) has high affinity for antithrombin III (AT III). Orgaran is devoid of heparin or heparin fragments. Orgaran catalyses the inactivation of factor Xa and thrombin. Compared to heparin and most low-molecular-weight heparins, Orgaran has a much higher anti-Xa/anti-IIa ratio. The inactivation of factor Xa is mediated by AT III and that of thrombin by both AT III and heparin cofactor II. Compared to heparin, which is a strong inhibitor of thrombin generation, Orgaran has only moderate inhibitory effects on thrombin generation. Orgaran shows minimal or no effects on platelet function in vitro or in vivo. It inhibits the formation of various types of thrombi (clot-like and mixed thrombi) with approximately the same potency as heparin. Both the high- and low-affinity fraction for AT III contribute to the antithrombotic activity. In contrast to heparin, Orgaran does not inhibit platelet deposition in experimental mixed thrombi unless very high doses of the heparinoid are used. Orgaran is more efficacious than heparin in preventing the extension of established venous thrombosis. Orgaran promotes less bleeding-enhancing activity than heparin in various experimental models. In addition, compared to heparin, it has only minimal effects on platelet degranulation during hemostatic plug formation.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Carbohydrate Sequence; Chondroitin Sulfates; Dermatan Sulfate; Factor Xa Inhibitors; Fibrinolytic Agents; Glycosaminoglycans; Hemorrhage; Heparinoids; Heparitin Sulfate; Molecular Sequence Data; Platelet Aggregation; Rabbits; Rats; Thrombin; Thrombolytic Therapy; Thrombosis

This report presents data from pilot studies of Org 10172 in the management of patients with acute ischemic stroke. The studies have established a potentially optimal dosage and treatment regimen and have provided information for the development of a large randomized trial. The trial of Org 10172 in acute stroke treatment is now underway in the United States.

Topics: Brain Ischemia; Chondroitin Sulfates; Dermatan Sulfate; Drug Evaluation; Factor Xa Inhibitors; Fibrinolytic Agents; Glycosaminoglycans; Hemorrhage; Heparinoids; Heparitin Sulfate; Humans; Incidence; Pilot Projects; Prothrombin; Thrombolytic Therapy; Treatment Outcome; United States

Topics: Animals; Anticoagulants; Blood Coagulation; Cerebrovascular Disorders; Chondroitin Sulfates; Dermatan Sulfate; Drug Evaluation, Preclinical; Fibrinolytic Agents; Glycosaminoglycans; Hemorrhage; Heparin; Heparitin Sulfate; Humans; Incidence; Mammals; Molecular Weight; Platelet Aggregation; Postoperative Complications; Rabbits; Renal Dialysis; Thrombocytopenia; Thrombophlebitis; Thrombosis

Heparin-induced thrombocytopenia (HIT) is a hypercoagulable syndrome strongly associated with thrombosis that is usually treated with drugs that inhibit factor Xa (danaparoid) or thrombin (lepirudin). In the present study the outcome of HIT-patients treated with danaparoid or lepirudin was compared using the single or combined endpoints of new thromboembolic complications (new TECs), amputations and/or death, and major bleeding. HIT-patients treated with lepirudin were enrolled in two prospective trials and patients, who were identified in the same two laboratories during the same time period, who were not enrolled into these studies but treated with danaparoid, were assessed retrospectively according to a standardized questionnaire. 126 danaparoid (60.3% female) and 175 lepirudin treated patients (58.3% female) fulfilled the same inclusion and exclusion criteria. In a time-to-event-analysis the cumulative risk of combined endpoint was higher in HIT-patients without thromboembolic complication at baseline treated with danaparoid (usually in prophylactic dose 750 anti-factor Xa units b.i.d. or t.i.d.s.c.) as compared to lepirudin (aPTT adjusted) (P = 0.020). Whereas HIT-patients with TEC at baseline who were usually treated with therapeutic dose had a similar outcome in both treatment groups (P = 0.913). Major bleeding occurred in 2.5% (95% CI 0.5-7.0%) of danaparoid treated patients as compared to 10.4% (95% CI 6.3-15.9%) of lepirudin treated patients until day 42 (P = 0.009). This indicates that the efficacies of therapeutic doses of danaparoid or lepirudin in preventing death, amputation or new TEC in HIT-patients do not differ largely, but the risk of bleeding seems to be higher in lepirudin treated patients. The prophylactic dose of danaparoid approved in the European Union for HIT without TEC at baseline seems suboptimal. A prospective comparative trial is required to verify these preliminary conclusions.

Topics: Age Factors; Aged; Amputation, Surgical; Anticoagulants; Chondroitin Sulfates; Dermatan Sulfate; Drug Combinations; Drug Evaluation; Female; Hemorrhage; Heparin; Heparitin Sulfate; Hirudins; Humans; Incidence; Male; Middle Aged; Recombinant Proteins; Retrospective Studies; Surveys and Questionnaires; Thrombocytopenia; Thromboembolism; Treatment Outcome

Identification of risk factors for bleeding and prospective evaluation of two bleeding risk scores in the treatment of acute venous thromboembolism.. Secondary analysis of a prospective, randomized, assessorblind, multicenter clinical trial.. One university and 2 regional teaching hospitals.. 188 patients treated with heparin or danaparoid for acute venous thromboembolism.. The presenting clinical features, the doses of the drugs, and the anticoagulant responses were analyzed using univariate and multivariate logistic regression analysis in order to evaluate prognostic factors for bleeding. In addition, the recently developed Utrecht bleeding risk score and Landefeld bleeding risk index were evaluated prospectively.. Major bleeding occurred in 4 patients (2.1%) and minor bleeding in 101 patients (53.7%). For all (major and minor combined) bleeding, body surface area < or = 2 m2 (odds ratio 2.3, 95% CI 1.2-4.4; p = 0.01), and malignancy (odds ratio 2.4, 95% CI 1.1-4.9; p = 0.02) were confirmed to be independent risk factors. An increased treatment-related risk of bleeding was observed in patients treated with high doses of heparin, independent of the concomitant activated partial thromboplastin time ratios. Both bleeding risk scores had low diagnostic value for bleeding in this sample of mainly minor bleeders.. A small body surface area and malignancy were associated with a higher frequency of bleeding. The bleeding risk scores merely offer the clinician a general estimation of the risk of bleeding. In patients with a small body surface area or in patients with malignancy, it may be of interest to study whether limited dose reduction of the anticoagulant drug may cause less bleeding without affecting efficacy.

Topics: Acenocoumarol; Acute Disease; Adult; Aged; Body Surface Area; Chondroitin Sulfates; Comorbidity; Dermatan Sulfate; Drug Combinations; Female; Fibrinolytic Agents; Hemorrhage; Heparin; Heparitin Sulfate; Humans; Male; Middle Aged; Neoplasms; Odds Ratio; Prospective Studies; Risk Factors; Single-Blind Method; Thromboembolism; Thrombolytic Therapy

To compare the efficacy and safety of two subcutaneous doses of danaparoid with that of continuous intravenous administration of unfractionated heparin in the treatment of venous thromboembolism.. An open-label, randomized, multicenter clinical trial.. One university hospital and two university-affiliated hospitals.. 209 patients suspected to have venous thromboembolism. Of these, 188 had a confirmed diagnosis (by ventilation-perfusion lung scan and ultrasonography or contrast venography of the leg) and received study medication.. Patients were randomly assigned to either low-dose danaparoid (intravenous loading dose of 1250 U followed by 1250 U administered subcutaneously twice daily [n = 65]); high-dose danaparoid (intravenous loading dose of 2000 U followed by 2000 U administered subcutaneously twice daily [n = 63]); or unfractionated heparin (intravenous loading dose of 2500 U followed by dose-adjusted continuous infusion [n = 60]). Treatment lasted at least 5 days and was continued until anticoagulation (achieved with acenocoumarol) was adequate.. Efficacy determined clinically and by repeated imaging tests on treatment days 5 to 8; safety determined by daily assessment for bleeding.. Two lung scans were done in each of 179 patients; ultrasonography or venography of the leg was done twice in each of 173 patients; and both repeated leg and lung tests were done in 166 patients. A significant reduction in recurrence or extension of venous thromboembolism was seen in patients receiving high-dose danaparoid (8 of 63 [13%]) compared with patients receiving intravenous unfractionated heparin (17 of 60 [28%]; relative risk, 0.45 [95% CI, 0.21 to 0.96]). Four of 61 patients receiving high-dose danaparoid (7%) and 14 of 58 patients receiving unfractionated heparin (24%) had recurrence of pulmonary embolism (relative risk, 0.27 [CI, 0.09 to 0.78]); 3 of 58 patients receiving high-dose danaparoid (5%) and 6 of 54 patients receiving unfractionated heparin (11%) had recurrence of deep venous thrombosis (relative risk, 0.47 [CI, 0.12 to 1.77]). Occurrence of major and minor bleeding was similar in the three groups; major bleeding occurred in 1 patient receiving low-dose danaparoid, 1 patient receiving high-dose danaparoid, and 2 patients receiving heparin.. Our results suggest that high-dose danaparoid is safer and more effective than unfractionated heparin for the treatment of venous thromboembolism.

Topics: Adult; Aged; Aged, 80 and over; Chondroitin Sulfates; Dermatan Sulfate; Drug Administration Schedule; Drug Combinations; Female; Hemorrhage; Heparin; Heparinoids; Heparitin Sulfate; Humans; Infusions, Intravenous; Injections, Subcutaneous; Male; Middle Aged; Pulmonary Embolism; Thromboembolism; Treatment Outcome

This double-blind, randomised, multicentre trial in 513 patients having elective surgery for intra-abdominal or intrathoracic malignancy compared the efficacy and safety of venous thrombosis (VT) prophylaxis using 750 anti-factor Xa units of Orgaran (a mixture of low molecular weight heparinoids) given subcutaneously (sc) twice-daily with that of twice-daily injections of 5,000 units standard heparin. The main study endpoints were the development of postoperative VT detected by 125I-fibrinogen leg scanning, and the onset of clinically significant venous thromboembolism or bleeding. "Intent to treat" analysis showed a statistically non-significant trend towards less VT during Orgaran prophylaxis (10.4%) than after heparin (14.9%) and there was no difference in bleeding complications between the two study groups. Results remained similar if only patients who completed the intended course of therapy ("compliant patients") were analysed. Other trials have shown that Orgaran prevents VT after hip surgery and stroke. We now show it is also safe and effective in patients having major surgery for cancer.

Topics: Aged; Anticoagulants; Chondroitin Sulfates; Dermatan Sulfate; Double-Blind Method; Elective Surgical Procedures; Female; Gastrointestinal Neoplasms; Glycosaminoglycans; Hematologic Tests; Hemorrhage; Heparinoids; Heparitin Sulfate; Humans; Lung Neoplasms; Male; Middle Aged; Postoperative Complications; Pulmonary Embolism; Thrombophlebitis

Two studies evaluating the effect of Orgaran prophylaxis on the incidence of postoperative thrombosis in hip fracture surgery are reported. In one Scandinavian study, dextran was used in the comparative group, and in the US study, warfarin was used. In both, Orgaran was significantly more effective in reducing the frequency of deep vein thrombosis without producing an increase in bleeding complications or other side effects.

Topics: Aged; Aged, 80 and over; Chondroitin Sulfates; Dermatan Sulfate; Dextrans; Female; Glycosaminoglycans; Hemorrhage; Heparinoids; Heparitin Sulfate; Hip Fractures; Humans; Incidence; Male; Postoperative Complications; Pulmonary Embolism; Scandinavian and Nordic Countries; Single-Blind Method; Thrombophlebitis; United States; Warfarin

This report presents data from pilot studies of Org 10172 in the management of patients with acute ischemic stroke. The studies have established a potentially optimal dosage and treatment regimen and have provided information for the development of a large randomized trial. The trial of Org 10172 in acute stroke treatment is now underway in the United States.

Topics: Brain Ischemia; Chondroitin Sulfates; Dermatan Sulfate; Drug Evaluation; Factor Xa Inhibitors; Fibrinolytic Agents; Glycosaminoglycans; Hemorrhage; Heparinoids; Heparitin Sulfate; Humans; Incidence; Pilot Projects; Prothrombin; Thrombolytic Therapy; Treatment Outcome; United States

To compare the relative safety and efficacy of a low-molecular-weight heparinoid (ORG 10172) with unfractionated heparin in the prevention of deep vein thrombosis in patients with acute ischemic stroke.. Double-blind randomized trial.. Seven Canadian university-affiliated hospitals.. Eighty-seven patients with acute ischemic stroke resulting in lower-limb paresis.. Patients received either low-molecular-weight heparinoid, 750 anti-factor Xa units twice daily, or unfractionated heparin, 5000 units subcutaneously twice daily. Treatment was continued for 14 days or until hospital discharge if sooner.. Deep vein thrombosis was diagnosed using 125I-labeled fibrinogen leg scanning and impedance plethysmography. Venography was indicated if either test was positive. Overt hemorrhage, major or minor, was assessed clinically.. Venous thrombosis occurred in four patients (9%) given low-molecular-weight heparinoid and in 13 patients (31%) given heparin (relative risk reduction, 71%; 95% CI, 16% to 93%. The corresponding rates for proximal vein thrombosis were 4% and 12%, respectively (relative risk reduction, 63%; P greater than 0.2). The incidence of hemorrhage was 2% in both groups.. Low-molecular-weight heparinoid, given in a fixed dose of 750 anti-factor Xa units subcutaneously twice daily, is more effective than subcutaneous low-dose heparin for the prevention of deep vein thrombosis in patients with acute ischemic stroke.

Topics: Acute Disease; Adult; Aged; Aged, 80 and over; Antithrombin III; Brain Ischemia; Chondroitin Sulfates; Dermatan Sulfate; Double-Blind Method; Female; Fibrinolytic Agents; Follow-Up Studies; Glycosaminoglycans; Hemorrhage; Heparin; Heparitin Sulfate; Humans; Male; Middle Aged; Thrombophlebitis

A prospective, randomized, assessor-blind trial has been undertaken to compare the thromboprophylactic effect and safety of the heparinoid Org 10172 (a mixture of low molecular-weight sulfated glycosaminoglycuronides) and dextran 70 in patients operated on for hip fracture. Prestudy biostatistical calculations led to the need for 260 patients. Three hundred eight patients were randomized and 19 were excluded after randomization, the majority because of postponed surgery. Analyses were made on the 289 patients on an intention-to-treat basis, as well as on the 247 patients given correct prophylaxis. Diagnosis of deep vein thrombosis was based on bilateral ascending phlebography on postoperative days 10 through 12. The frequency of deep vein thrombosis on an intention-to-treat basis was 10% in the Org 10172 group and 30% in the dextran 70 group and, on the basis of correct prophylaxis, 12% and 31%, respectively, both differences being significant (p less than 0.001). Two-month mortality rates were equal in the groups. Three fatal pulmonary emboli were seen in the dextran group. Significantly more patients in the dextran group received postoperative transfusions; no other differences in various hemorrhagic parameters were seen. Thus it can be concluded that Org 10172 has a significantly better thromboprophylactic effect than does dextran in patients with hip fractures without significant side effects.

Topics: Aged; Aged, 80 and over; Chondroitin Sulfates; Dermatan Sulfate; Dextrans; Female; Fibrinolytic Agents; Glycosaminoglycans; Hemorrhage; Heparitin Sulfate; Hip Fractures; Humans; Male; Single-Blind Method; Thrombophlebitis

We have measured the effects of Org 10172 (a mixture of naturally occurring glycosaminoglycans derived from hog intestinal mucosa) on blood loss after transurethral prostatectomy (TURP), using doses which are likely to prevent postoperative venous thrombosis (VT). 48 patients entered a double-blind randomised pilot study: 18 were given subcutaneous (sc) injections of a placebo and 30 received sc Org 10172 (750 anti-Xa units/day, 500 units twice daily (bid), or 750 units bid, starting just before TURP and continued until discharge; 10 patients per group). No Org 10172 regimen increased peroperative blood loss but all caused a similar trend towards increased urinary bleeding after surgery. Since there was no apparent dose effect gradient, it was decided to pool the data from all three dosing blocks: this analysis showed that Org 10172 increased geometric mean blood loss during the first 2 days after surgery from 10.4 gm hemoglobin (Hgb; range = 3.2-71) to 20.5 gm Hgb (range = 1.9-147) (p = .005), an effect which retained its significance after allowing for two other major determinants of postoperative bleeding, the weight of prostate resected and the length of surgery, and also when pooling was restricted to the twice daily Org 10172 injection groups and their corresponding controls. Bleeding was not severe, but our results indicate a need for caution when considering the use of Org 10172 in this setting.

Topics: Aged; Chondroitin Sulfates; Dermatan Sulfate; Double-Blind Method; Glycosaminoglycans; Hematuria; Hemorrhage; Heparinoids; Heparitin Sulfate; Humans; Male; Middle Aged; Prostatectomy; Randomized Controlled Trials as Topic; Thrombophlebitis; Urologic Diseases

The potential antithrombotic effect of a new low molecular weight heparinoid, Org 10172, was examined in a randomized, double-blind, placebo-controlled, dose-ranging pilot study of the prevention of deep venous thrombosis (DVT) in 45 high-risk patients having major thoracic or abdominal surgery for cancer. Org 10172 was given in doses of 500, 750 or 1000 U bd subcutaneously. DVT occurred in 9 of 14 patients given placebo and in 4 of 11 patients given 500 U bd but in none of the 20 patients given 750 or 1000 U bd. Operative blood loss and post-operative bleeding were not significantly different between the groups but one patient given 1000 U bd had major post-operative bleeding. Average mid-interval and trough plasma anti-Xa levels reached 0.26 and 0.20 U/ml respectively following the highest dose. It is concluded that Org 10172 is a potentially useful antithrombotic agent and that the effective and safe dose appears to be between 500 and 1000 U bd for prevention of DVT in high-risk patients.

Topics: Aged; Aged, 80 and over; Chondroitin Sulfates; Dermatan Sulfate; Factor X; Factor Xa; Female; Glycosaminoglycans; Hemorrhage; Heparitin Sulfate; Humans; Injections, Subcutaneous; Male; Middle Aged; Neoplasms; Pilot Projects; Research Design; Thoracic Surgery; Thrombophlebitis

The prophylactic effect of a semisynthetic heparin analogue (SSHA) on deep vein thrombosis was investigated in a prospective double-blind multicentre trial. 440 major general surgical and gynaecological patients were randomized to one of three treatment groups: 50 mg SSHA, 37.5 mg SSHA and 5000 units sodium heparin subcutaneously 12-hourly. Deep venous thrombosis (DVT) was diagnosed with the fibrinogen uptake test and verified with phlebography. Bleeding complications and other side-effects were carefully monitored. There were no significant differences between the three treatment groups of patients in age, sex, type of operation or risk factors. A DVT was diagnosed in 16 patients (12 per cent) in the SSHA 50 mg group, in 21 patients (15 per cent) in the SSHA 37.5 mg group and 21 patients (14 per cent) in the heparin-treated group. No significant differences were found in the number of patients who bled unexpectedly in the postoperative period, required transfusion or developed wound haematomas. Blood loss at operation was similar in all three groups. Three pulmonary emboli were diagnosed by pulmonary scintigraphy, one in each group.

Topics: Adult; Aged; Anticoagulants; Chondroitin; Chondroitin Sulfates; Double-Blind Method; Female; Hemorrhage; Heparin; Humans; Intraoperative Complications; Male; Middle Aged; Postoperative Complications; Prospective Studies; Random Allocation; Risk; Surgical Procedures, Operative; Thrombophlebitis

Fucosylated chondroitin sulfate (FCS) polysaccharide isolated from sea cucumber has potent anticoagulant activity. Based on its resistance to the enzymes present in vertebrates, it may serve as an anticoagulant and shows antithrombotic effects when delivered through gastro-resistant (GR) tablets. However, due to the multiple plasma targets of FCS polysaccharide in the coagulation pathway, bleeding can occur after its oral administration. In the current study, we used FCS oligomers, in particular a mixture of oligosaccharides having 6 to 18 saccharide units, as the active ingredient in GR microcapsules for oral anticoagulation. In a Caco-2 model, the FCS oligomers showed higher absorption than native FCS polysaccharides. Oral administration of FCS oligomer-GR microcapsules provided a dose-dependent, prolonged anticoagulant effect with a selective inhibition of the intrinsic coagulation pathway when compared with

Topics: Administration, Oral; Animals; Caco-2 Cells; Capsules; Chondroitin Sulfates; Drug Liberation; Fibrinolytic Agents; Hemorrhage; Humans; Intestinal Absorption; Male; Rats, Sprague-Dawley; Venous Thrombosis

Danaparoid sodium and synthetic protease inhibitors (SPIs) have been approved for the treatment of disseminated intravascular coagulation (DIC) in Japan.. To compare the clinical results of the treatment of DIC with danaparoid or SPIs.. We retrospectively examined 188 patients with hematological malignancy-related DIC.. DIC resolution rate in the danaparoid group was higher than that in the SPIs group (61.5 vs. 42.6%; p = 0.031) on day 7. Multivariate analysis identified the response to chemotherapy as independent predictive factor for DIC resolution on day 7 (odds ratio, OR, 2.28; 95% confidence interval, CI, 1.21-4.31; p = 0.011). While there was no significant difference in the DIC resolution rate on day 14 (75.0 vs. 62.4%; p = 0.117), in a subgroup analysis of patients who did not show an improvement in the underlying disease, the danaparoid group showed a significantly better DIC resolution rate (OR 3.89; 95% CI 1.15-13.2; p = 0.030). There was no difference in the rate of cumulative mortality from bleeding within 28 days between the 2 groups (6.6 vs. 3.3%; p = 0.278).. Danaparoid may be associated with more frequent resolution of DIC in patients with refractory underlying disease.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Blood Component Transfusion; Chondroitin Sulfates; Dermatan Sulfate; Disseminated Intravascular Coagulation; Female; Fibrin Fibrinogen Degradation Products; Fibrinogen; Hematologic Neoplasms; Hemorrhage; Heparitin Sulfate; Humans; Male; Middle Aged; Plasma; Protease Inhibitors; Prothrombin Time; Retrospective Studies; Treatment Outcome

Extracellular histones induce lethal thrombosis by promoting platelet aggregation, neutrophil migration, and cell injuries. Heparin, which has negative charges, can bind to extracellular histones; however, heparin strongly inhibits the activation of coagulation. Since chondroitin sulfate (CS) shows less effect on the coagulation system than heparin does, CS has the potential to become an effective drug for lethal thrombosis with high risk of bleeding. To elucidate the therapeutic mechanisms of CS in lethal thrombosis, we investigated the interaction between CS and extracellular histones. Mouse vascular endothelial cells were incubated with histones in the presence of heparin or CS, and the expression of caspase-3/7 was measured. The interactions between histones and heparin or CS were measured by surface plasmon resonance analysis. Vascular permeability, platelet counts, liver and renal functions, and coagulation times were evaluated in an in vivo assay. The apoptosis induced by histones was inhibited by treatment with heparin or CS. Heparin and CS showed strong binding to histones and inhibited vascular hyperpermeability. The platelet counts as well as liver and renal functions were not decreased by the treatment with heparin or CS. Moreover, CS showed less effect on the coagulation system than heparin did. These results suggested that CS can be a novel agent for lethal thrombosis with the risk for hemorrhage. Since vascular endothelial cell injuries occur at an early stage of lethal thrombosis, administration of CS might be a useful approach.

Topics: Animals; Anticoagulants; Blood Coagulation; Capillary Permeability; Chondroitin Sulfates; Disease Models, Animal; Endothelial Cells; Hemorrhage; Heparin; Histones; Humans; Male; Mice; Mice, Inbred DBA; Platelet Aggregation; Platelet Function Tests; Surface Plasmon Resonance; Thrombosis; Treatment Outcome

Life-threatening heparin-induced thrombocytopenia (HIT) is treated with the alternative nonheparin anticoagulants argatroban, lepirudin, or danaparoid. Frequently, the pentasaccharide fondaparinux is used off-label.. The authors sought to investigate the safety and efficacy of the different anticoagulants for treating HIT.. In a national, multicenter registry study, hospitalized patients who were diagnosed with HIT, an at least intermediate clinical HIT-risk (4Ts score ≥4 points), and received treatment with ≥1 dose of the aforementioned anticoagulants were included. Main outcome measures were the incidences of HIT-specific complications (thromboembolic venous/arterial events, amputations, recurrent/persistent thrombocytopenia, skin lesions) and bleedings.. Of 195 patients, 46 (23.6%), 4 (2.1%), 61 (31.3%), and 84 (43.1%) had been treated first-line with argatroban, lepirudin, danaparoid, and fondaparinux, respectively. The composite endpoint of HIT-specific complications (thromboembolic events, amputation, skin necrosis) occurred in 11.7% of patients treated with approved alternative anticoagulation and in 0.0% of fondaparinux-treated patients. The all-cause in-hospital mortality rates were 14.4% during approved alternative anticoagulation and 0.0% during fondaparinux treatment. Bleeding complications occurred in alternatively anticoagulated patients and in fondaparinux-treated patients in 6.3% and 4.8%, respectively. Post hoc analysis of clinical and laboratory features confirmed "true" HIT in at least 74 of 195 (38.0%) patients; 35 of 74 (47.3%) were treated with fondaparinux.. Fondaparinux is effective and safe in suspected acute HIT; no HIT-specific complications occurred in the fondaparinux-treated patients, even among those with a high clinical HIT probability. Further data from randomized controlled trials are urgently needed because lepirudin was recalled from the market; danaparoid access has been limited and is not approved in the United States; and argatroban is contraindicated in patients with impaired liver function, and activated partial thromboplastin time confounding may interfere with monitoring. (Retrospective Registry of Patients With Acute Heparin-induced Thrombocytopenia Type II; NCT01304238).

Topics: Anticoagulants; Arginine; Chondroitin Sulfates; Dermatan Sulfate; Factor Xa Inhibitors; Female; Fondaparinux; Hemorrhage; Heparin; Heparitin Sulfate; Hirudins; Hospital Mortality; Hospitalization; Humans; Male; Necrosis; Off-Label Use; Partial Thromboplastin Time; Patient Safety; Pipecolic Acids; Polysaccharides; Recombinant Proteins; Registries; Retrospective Studies; Sulfonamides; Thrombocytopenia; Thromboembolism; Treatment Outcome

Fucosylated chondroitin sulfate (FucCS) is a potent anticoagulant polysaccharide extracted from sea cucumber. Its anticoagulant activity is attributed to the presence of unique branches of sulfated fucose. Although this glycosaminoglycan exerts an antithrombotic effect following oral administration, high doses are necessary to achieve the maximum effect. The diminished activity of FucCS following oral administration is likely due to its degradation in the gastrointestinal tract and its limited ability to cross the intestinal cell membranes. The latter aspect is particularly difficult to overcome. However, gastro-resistant tablet formulation may help limit the degradation of FucCS in the gastrointestinal tract. In the present work, we found that the oral administration of FucCS as gastro-resistant tablets produces a more potent and prolonged anticoagulant effect compared with its administration as an aqueous solution, with no significant changes in the bleeding tendency or arterial blood pressure. Experiments using animal models of arterial thrombosis initiated by endothelial injury demonstrated that FucCS delivered as gastro-protective tablets produced a potent antithrombotic effect, whereas its aqueous solution was ineffective. However, there was no significant difference between the effects of FucCS delivered as gastro-resistant tablets or as aqueous solution in a venous thrombosis model, likely due to the high dose of thromboplastin used. New oral anticoagulants tested in these experimental models for comparison showed significantly increased bleeding tendencies. Our study provides a framework for developing effective oral anticoagulants based on sulfated polysaccharides from marine organisms. The present results suggest that FucCS is a promising oral anticoagulant.

Topics: Administration, Oral; Animals; Anticoagulants; Blood Coagulation; Carotid Artery Diseases; Chondroitin Sulfates; Disease Models, Animal; Drug Compounding; Female; Hemorrhage; Male; Rats, Wistar; Tablets, Enteric-Coated; Thrombosis; Time Factors; Venous Thrombosis

The sulphated polysaccharide from the widespread Tridax procumbens plant was studied for the anticoagulant, antiherpetic and antibacterial activity. The anticoagulant activity was determined by the activated partial thromboplastin time assay. The sulphated polysaccharide from T. procumbens represented potent anticoagulant reaching the efficacy to heparin and chondroitin sulphate. Moreover, the sulphated polysaccharide extracted from T. procumbens was found non-toxic on Vero cell lines up to the concentration of 200 μg/ml. Sulphated polysaccharide exhibited detectable antiviral effect towards HSV-1 with IC(50) value 100-150 μg/ml. Furthermore, sulphated polysaccharide from T. procumbens was highly inhibitory against the bacterial strains Vibrio alginolyticus and Vibrio harveyi isolated from oil sardine.

Topics: Animals; Anti-Bacterial Agents; Anticoagulants; Antiviral Agents; Asteraceae; Chemistry, Pharmaceutical; Chlorocebus aethiops; Chondroitin Sulfates; Hemorrhage; Heparin; Herpes Simplex; Herpesvirus 1, Human; Inhibitory Concentration 50; Partial Thromboplastin Time; Phytotherapy; Plant Extracts; Plants, Medicinal; Polysaccharides; Vero Cells; Vibrio alginolyticus; Vibrio Infections

Sulfated polysaccharides from marine invertebrates have well-defined structures and constitute a reliable class of molecules for structure-activity relationship studies. We tested the effects of two of these polysaccharides, namely a sulfated fucan and a fucosylated chondroitin sulfate, on coagulation, thrombosis and bleeding. The compounds share similar 2,4-disulfated fucose units, which are required for high anticoagulant activity in this class of polymer. These residues occur either as branches in fucosylated chondroitin sulfate or as components of the linear chain in the sulfated fucan. These polysaccharides possess anticoagulant activity but differ significantly in their mechanisms of action. The fucosylated chondroitin sulfate inhibits thrombin by heparin cofactor II, whereas sulfated fucan inhibits thrombin by both antithrombin and heparin cofactor II. In addition, these polysaccharides also have serpin-independent anticoagulant activities. Fucosylated chondroitin sulfate, but not sulfated fucan, activates factor XII. As a result of the complex anticoagulant mechanism, the invertebrate polysaccharides differ in their effects on experimental thrombosis. For instance, the sulfated fucan inhibits venous thrombosis at lower doses than fucosylated chondroitin sulfate. In contrast, fucosylated chondroitin sulfate is significantly more potent than sulfated fucan in arterial thrombosis. Finally, fucosylated chondroitin sulfate increases bleeding, while sulfated fucan has only a discrete effect. In conclusion, the location of 2,4-disulfated fucose units in the polysaccharide chains dictates the effects on coagulation, thrombosis and bleeding.

Topics: Animals; Anticoagulants; Blood Coagulation; Carbohydrate Conformation; Carbohydrate Sequence; Carotid Artery Thrombosis; Chondroitin Sulfates; Drug Evaluation, Preclinical; Enzyme Activation; Factor XII; Female; Fibrinolytic Agents; Fucose; Hemorrhage; Male; Molecular Sequence Data; Molecular Structure; Polysaccharides; Rats; Rats, Wistar; Sea Cucumbers; Structure-Activity Relationship; Thrombosis; Venous Thrombosis

Immune-mediated heparin-induced thrombocytopenia (HIT) is an uncommon but serious complication of therapy with heparins. It affects all ages and requires replacement of the causative anticoagulant. However, information on alternative antithrombotic use in children with HIT is limited. This paper reviews 27 published and 7 unpublished case reports of children aged 2 weeks to 17 years treated with danaparoid. Thirty-three suffered from HIT or suspected HIT, and 1 child without HIT had a high bleeding risk. All children had severe underlying problems increasing their thrombotic and/or bleeding risk. HIT diagnosis was confirmed serologically or clinically in 26 cases (78.8%). Danaparoid regimens were similar to those used in adults, but in general, younger children needed higher daily doses of danaparoid to achieve the same target plasma anti-Xa levels than teenagers or adults. Of those with a known outcome 28/33 children (84.8%) survived, 7 having suffered from a serious adverse event. Five deaths occurred including 1 thrombotic and 2 major bleeds. Three of the in total 4 major bleeding events occurred in children undergoing surgery with cardiopulmonary bypass. We conclude that despite the reported adverse events danaparoid can be used as an alternative antithrombotic for children who are intolerant of the heparins, except in cases requiring cardiopulmonary bypass surgery.

Topics: Adolescent; Adult; Child; Child, Preschool; Chondroitin Sulfates; Dermatan Sulfate; Drug Evaluation; Fibrinolytic Agents; Hemorrhage; Heparin; Heparitin Sulfate; Humans; Infant; Infant, Newborn; Male; Purpura, Thrombocytopenic, Idiopathic; Risk Factors; Thrombosis

Heparin-induced thrombocytopenia (HIT) is the most common form of drug-induced immune-mediated thrombocytopenia. HIT may be aggravated by life-threatening arterial and venous thrombosis and, to a lesser extent, hemorrhagic complications. We investigated the incidence of thromboembolic and hemorrhagic complications in critically ill patients with the multiple organ dysfunction syndrome and HIT.. Case-control study.. A 33-bed general intensive care unit in a university-affiliated teaching hospital.. Twenty consecutive patients with laboratory-proven HIT compared with 20 contemporary, consecutive patients without HIT.. Unfractionated heparin or low-molecular-weight heparin were replaced by danaparoid sodium in patients with HIT.. Heparin-induced thrombocytopenia was proven by a positive platelet aggregation test. The HIT group consisted of 14 males and 6 females aged 65.2+/-10.8 years (mean +/- standard deviation) with APACHE II scores of 26.7+/-5.4. Thrombocytopenia less than 100 x 10(9)/l developed within 6.4+/-7.0 days. In 12 patients thrombocytopenia resolved after discontinuation of unfractionated heparin in 8.8+/-6.4 days. Arterial and venous thromboembolic complications occurred more frequently in HIT patients than in non-HIT patients (10/20 (50%) versus 0/20 (0%); chi-square p<0.001). Hemorrhagic complications also occurred more frequently in HIT patients than in non-HIT patients (17/20 (85%) versus 7/20 (35%); chi-square p=0.001).. In critically ill patients with HIT, the incidence of thromboembolic complications and hemorrhagic complications was remarkably high.

Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; Case-Control Studies; Chondroitin Sulfates; Critical Illness; Dermatan Sulfate; Drug Combinations; Female; Hemorrhage; Heparin; Heparitin Sulfate; Humans; Incidence; Intensive Care Units; Male; Middle Aged; Multiple Organ Failure; Risk Factors; Thrombocytopenia; Venous Thrombosis

Fucosylated chondroitin sulfate is a glycosaminoglycan from sea cucumber, made up of alternating beta-D-glucuronic acid and N-acetyl-beta-D-galactosamine units, like mammalian chondroitin sulfate. But the beta-D-glucuronic acid residues have branches of sulfated fucose, which confer high anticoagulant and antithrombotic properties on this compound. We have now compared the anticoagulant, bleeding and antithrombotic effects of this fucosylated chondroitin sulfate and its carboxyl-reduced derivative. Both compounds have similar anticoagulant action, mostly due to acceleration of thrombin inhibition in the presence of heparin cofactor II. The native glycosaminoglycan shows a correlation among anticoagulant, bleeding and antithrombotic effects. Inhibition of thrombosis in an arterio-venous shunt occurs at low doses, which are almost ineffective in modifying the anticoagulant activity of plasma. In a venous experimental model, on the contrary, antithrombotic activity requires high doses and occurs concomitantly with an increase in the anticoagulant activity of plasma. The action of fucosylated chondroitin sulfate on thrombosis is apparently unrelated to its effect on platelet aggregation. The carboxyl-reduced derivative of fucosylated chondroitin sulfate prevented thrombosis in the arterio-venous shunt, but not in the venous experimental model. This derivative did not increase bleeding, in spite of its potent anticoagulant activity. Therefore, our results reveal a dissociation of the anticoagulant, bleeding and antithrombotic effects of the glycosaminoglycan. Furthermore, we demonstrate that a polysaccharide may be a potent inhibitor of one type of thrombotic episode, but inactive on another. We propose that the different effects of fucosylated chondroitin sulfate and its carboxyl-reduced derivative on venous thrombosis may be related to adherence of the glycosaminoglycan to the vessel wall.

Topics: Acetylgalactosamine; Animals; Anticoagulants; Blood Coagulation; Carotid Arteries; Chondroitin Sulfates; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Fucose; Glucuronic Acid; Hemorrhage; Heparin; Heparin Cofactor II; Male; Rats; Rats, Wistar; Sea Cucumbers; Venous Thrombosis

Paclitaxel can inhibit vascular smooth muscle proliferation in vitro, and early studies suggest that paclitaxel may be useful in preventing restenosis. Early and late intimal growth and local vascular pathological changes associated with paclitaxel delivered via stents have not been fully explored.. Localized drug delivery was accomplished with balloon-expandable stainless steel stents coated with a cross-linked biodegradable polymer, chondroitin sulfate and gelatin (CSG), containing various doses of paclitaxel. CSG-coated stents with paclitaxel (42.0, 20.2, 8.6, or 1.5 microgram of paclitaxel per stent), CSG-coated stents without paclitaxel, and uncoated stents (without paclitaxel or CSG) were deployed in the iliac arteries of New Zealand White rabbits, which were killed 28 days after implant. Mean neointimal thickness at stent strut sites was reduced 49% (P<0.0003) and 36% (P<0.007) with stents containing 42.0 and 20.2 microgram of paclitaxel per stent, respectively, versus CSG-coated stents without paclitaxel. However, histological findings suggested incomplete healing in the higher-dose (42.0 and 20.2 microgram) paclitaxel-containing stents consisting of persistent intimal fibrin deposition, intraintimal hemorrhage, and increased intimal and adventitial inflammation. Stents coated with CSG alone (without paclitaxel) had similar neointimal growth as uncoated stents. In a separate group of rabbits killed at 90 days, neointimal growth was no longer suppressed by CSG-coated stents containing 42.0 or 21.0 microgram of paclitaxel. CSG coating appears to be a promising medium for localized drug delivery. Paclitaxel polymer-coated stents reduce neointima formation but are associated with evidence of incomplete healing at 28 days. However, neointimal suppression was not maintained at 90 days.

Topics: Angiogenesis Inhibitors; Animals; Cell Division; Chondroitin Sulfates; Dose-Response Relationship, Drug; Drug Delivery Systems; Fibrin; Gelatin; Hemorrhage; Iliac Artery; Inflammation; Male; Paclitaxel; Polymers; Rabbits; Stents; Time Factors; Tunica Intima

The purpose of this study was to evaluate the efficacy and safety of danaparoid in the treatment of critically ill patients with acute renal failure and suspected heparin-induced thrombocytopenia (HIT) needing renal replacement therapy (RRT). We conducted a retrospective analysis of 13 consecutive intensive care patients with acute renal failure and suspected HIT who were treated with danaparoid for at least 3 days during RRT. In eight patients, continuous venovenous hemofiltration was performed. The mean infusion rate of danaparoid was 140 +/- 86 U/hour. Filter exchange was necessary every 37.5 hours. In five patients, continuous venovenous hemodialysis was used. A bolus injection of 750 U danaparoid was followed by a mean infusion rate of 138 +/- 122 U/hour. Filters were exchanged every 24 hours. In 7 of 13 patients, even a low mean infusion rate of 88 +/- 35 U/hour was efficient. Mean anti-Xa (aXa) levels were approximately 0.4 +/- 0.2 aXa U/mL. Persistent thrombocytopenia despite discontinuation of heparin treatment was observed in 9 of 13 patients, owing to disseminated intravascular coagulation (DIC). HIT was confirmed by an increase in platelet count and positive heparin-induced antibodies in 2 of 13 patients. No thromboembolic complications occurred, but major bleeding was observed in 6 of 13 patients, which could be explained by consumption of coagulation factors and platelets due to DIC in 5 of 6 patients. Nine of 13 patients died of multiorgan failure or sepsis, or both. In none of these patients was the fatal outcome related to danaparoid treatment. In critically ill patients with renal impairment and suspected HIT, a bolus injection of 750 U danaparoid followed by a mean infusion rate of 50 to 150 U/hour appears to be a safe and efficient treatment option when alternative anticoagulation is necessary.

Topics: Adult; Aged; Anticoagulants; Chondroitin Sulfates; Contraindications; Critical Care; Dermatan Sulfate; Drug Combinations; Drug Evaluation; Female; Hemorrhage; Heparin; Heparinoids; Heparitin Sulfate; Humans; Male; Middle Aged; Multiple Organ Failure; Renal Replacement Therapy; Retrospective Studies; Thrombosis; Treatment Outcome

Heparin-induced thrombocytopenia (HIT) has become more prevalent in today's cardiac setting and has resulted in the need for alternative anticoagulant therapies. Danaparoid sodium, one alternative to heparin, has been used in six cardiopulmonary bypass procedures in this hospital. This clinical experience has resulted in the progressive refinement of a protocol for the 'safe' clinical use of danaparoid sodium. Although there were six positive outcomes with the use of danaparoid sodium, alternatives must be explored in order to find the optimal anticoagulant for the treatment of HIT.

Topics: Adult; Aged; Anticoagulants; Cardiopulmonary Bypass; Chondroitin Sulfates; Dermatan Sulfate; Drug Combinations; Female; Hemorrhage; Heparin; Heparitin Sulfate; Humans; Male; Middle Aged; Postoperative Complications; Thrombocytopenia

Heparin-induced thrombocytopenia is a rare and serious complication of anticoagulation therapy. There remains a paucity of information pertaining to alternative anticoagulation strategies for use during cardiopulmonary bypass concomitant with heparin-induced thrombocytopenia, especially in children. We report the successful treatment of heparin-induced thrombocytopenia and subsequent hemorrhagic complications postoperatively in a 2-year-old child with Danaparoid (orgaran). Emergent conduit revision with cardiopulmonary bypass was required for a thrombosed systemic-venous to pulmonary-arterial connection (completion modified Fontan procedure). Required doses of Danaparoid were consistently twofold that previously reported for adults.

Topics: Anticoagulants; Cardiopulmonary Bypass; Child, Preschool; Chondroitin Sulfates; Dermatan Sulfate; Drug Combinations; Female; Heart Defects, Congenital; Hemorrhage; Heparin; Heparitin Sulfate; Humans; Thrombocytopenia; Thrombosis

Topics: Acute Kidney Injury; Aged; Anticoagulants; Chondroitin Sulfates; Dermatan Sulfate; Drug Combinations; Hemorrhage; Heparin; Heparitin Sulfate; Humans; Lung Diseases; Male; Phlebography; Renal Dialysis; Thrombocytopenia; Venous Thrombosis

We evaluated the safety and possible efficacy of large doses of the heparinoid ORG 10172 in 57 patients with acute or progressing ischemic stroke. Patients received a loading bolus of the drug followed by a maintenance intravenous infusion for 7 days. The plasma level of ORG 10172 was monitored by the degree of inhibition of coagulation factor Xa. In general, the drug was well tolerated and few hemorrhagic complications occurred. Two patients with large cardioembolic hemispheric strokes had intracranial hemorrhagic complications. Most patients improved during treatment. By 3 months after the stroke, 37 patients (65%) had a favorable outcome (minimal or no residual disability). This study suggests that high-dose intravenous infusions of ORG 10172 can be safely given to patients with acute ischemic stroke.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Brain Ischemia; Cerebrovascular Disorders; Chondroitin Sulfates; Dermatan Sulfate; Fibrinolytic Agents; Glycosaminoglycans; Hemorrhage; Heparitin Sulfate; Humans; Injections, Intravenous; Middle Aged; Pilot Projects

An intravenous infusion of a low molecular weight heparinoid, with a reduced risk of hemorrhage, may be an alternative to heparin in the management of acute ischemic stroke. To evaluate this hypothesis, we studied the safety of the heparinoid, ORG 10172, in a dose-escalation study in 26 patients. The drug was administered as a loading bolus followed by a 7-day infusion in five rates with target anti-factor Xa levels from 0.2 to 1.0 U/ml. The drug was well tolerated; no major bleeding complications or thrombocytopenia occurred. There were no deaths or hemorrhagic transformation of cerebral infarctions. The results indicate that ORG 10172 at doses to achieve a level of 1.0 U/ml or less may be used safely in management of acute cerebral infarction.

Topics: Adult; Aged; Aged, 80 and over; Cerebrovascular Disorders; Chondroitin Sulfates; Dermatan Sulfate; Dose-Response Relationship, Drug; Female; Glycosaminoglycans; Hemorrhage; Heparinoids; Heparitin Sulfate; Humans; Male; Middle Aged; Molecular Weight

Org 10172 shows dose-dependent antithrombotic activity in various experimental thrombosis models. It produces less hemorrhage at an equivalent antithrombotic effect than commercial heparin in various experimental bleeding models. It shows a better benefit (antithrombotic) to risk (bleeding) ratio than SP54 and commercial heparin. The benefit to risk ratio of Org 10172 is better than some LMW heparins and equivalent to other LMW heparins, depending on the method of preparation. The antithrombotic effect of Org 10172 in animal models has a much longer duration than that of commercial heparin and also LMW heparins. Org 10172 predominantly inactivates generated thrombin via the formation of HC II-thrombin complexes, whereas commercial heparin and LMW heparins inactivate generated thrombin via AT III-thrombin complexes.

Topics: Animals; Anticoagulants; Chondroitin Sulfates; Dermatan Sulfate; Drug Evaluation, Preclinical; Fibrinolytic Agents; Glycosaminoglycans; Hemorrhage; Heparin; Heparin, Low-Molecular-Weight; Heparinoids; Heparitin Sulfate; Injections, Intravenous; Injections, Subcutaneous; Rabbits; Rats; Thrombosis

Postoperative hemorrhage remains a serious complication in cardiopulmonary bypass (CPB) surgery. In our study, alternative anticoagulation with a new low molecular weight (LMW) heparinoid (Org 10172) was compared with a standardized heparin regimen. A preliminary dose-finding study indicated the minimal effective heparinoid dose to be 260 anti-Xa U/kg body weight, which was comparable to the standardized heparin regime, as revealed by similar plasma anti-Xa values. The following randomized open pilot study in 12 mongrel dogs undergoing CPB showed the heparinoid to be as effective as heparin, with an additional advantageous decrease in postoperative blood loss in the Org 10172 group. Our randomized blind study in 16 mongrel dogs undergoing CPB was performed to confirm previous results. Both antithrombotic agents were effective in the prevention of clot formation within the extracorporeal circuit. Hematocrit values and erythrocyte and platelet counts showed no significant intergroup differences. Post-CPB leukocyte counts revealed a significantly more rapid increase in the group given heparinoid (P less than 0.05). In the group given heparin, the expected prolongations of both the thrombin time (TT) and activated partial thromboplastin time (APTT) were noted, whereas in the group given heparinoid, only a transient peak prolongation of the TT after dose administration was revealed, and no significant prolongation of the APTT. Mean anti-Xa plasma levels were similar during CPB, showing a rapid decrease in the group given heparin on protamine administration, as did the APTT. Assessment of the operating field indicated an elevated intraoperative blood loss in the group given heparin. Postoperative blood loss measured over a period of 2.5 hours after closure of the thorax was significantly lower in the group given heparinoid than in the heparinized animals (625 +/- 100.0 ml, mean +/- SD, and 806 +/- 178.2 ml, respectively; P less than 0.05). Our observations suggest that the LMW heparinoid Org 10172 has an increased benefit/risk ratio over standard heparin and is effective in CPB in dogs. Additional investigations in humans should verify the possibility of use of this substance as an alternative means of anticoagulation during CPB in patients in whom heparin is relatively contraindicated.

Topics: Animals; Antithrombins; Blood Coagulation Tests; Blood Volume; Cardiopulmonary Bypass; Chondroitin Sulfates; Dermatan Sulfate; Dogs; Drug Evaluation, Preclinical; Fibrinolytic Agents; Glycosaminoglycans; Hematocrit; Hemorrhage; Heparin; Heparitin Sulfate; Leukocyte Count; Molecular Weight; Platelet Count; Postoperative Complications; Random Allocation

Org 10172, a new, natural heparinoid, was used as the sole anticoagulant in twelve patients with acute or acute-on-chronic renal failure, who underwent haemodialysis 55 times. All patients had either intercurrent bleeding or a high risk of severe haemorrhagic complications if given standard heparin therapy. After a single loading dose of 300-600 mg of Org 10172, plasma anti-Xa levels in the range 0.42 - 0.93 U/ml were achieved. All haemodialysis runs were completed without adverse side-effects. There were no haemorrhagic complications and deposition of 125I-fibrinogen on the renal dialysis membrane was successfully inhibited in the 4 patients in whom this was studied. Org 10172 seems to prevent thrombosis during renal haemodialysis. It may have a lower risk/benefit ratio than other anticoagulants, such as heparin, in patients at high risk of haemorrhagic complications undergoing haemodialysis.

Topics: Acute Kidney Injury; Adult; Aged; Blood Platelet Disorders; Chondroitin Sulfates; Dermatan Sulfate; Drug Evaluation; Female; Fibrinolytic Agents; Glycosaminoglycans; Hemorrhage; Heparitin Sulfate; Humans; Kidney Failure, Chronic; Male; Middle Aged; Renal Dialysis; Risk