heparitin-sulfate and Multiple-Organ-Failure

For patients with heparin-induced thrombocytopenia (HIT), reexposure to heparin is generally not recommended. However, these patients are likely to require anticoagulation therapy at some point in the future. During acute HIT, when thrombocytopenia and anti-heparin-platelet factor 4 antibodies (or HIT antibodies) are present, therapy with heparin must be avoided. In patients with subacute HIT, when platelets have recovered but HIT antibodies are still present, therapy with heparin should be avoided. In patients with a remote history of HIT, when HIT antibodies have cleared, heparin reexposure may be safe, although recurrent HIT has been described in some patients. For all of these patients, the use of alternate anticoagulant agents, including direct thrombin inhibitors and anti-Xa agents, is preferable. There is an increasing amount of data supporting the use of these alternative agents in a wide variety of clinical circumstances, including thromboprophylaxis and treatment of acute thrombosis. Except for a few clinical situations, it is generally possible to avoid heparin reexposure in patients with a history of HIT.

Topics: Angina, Unstable; Antibodies; Anticoagulants; Chondroitin Sulfates; Dermatan Sulfate; Drug Combinations; Female; Fondaparinux; Heparin; Heparitin Sulfate; Hirudins; Humans; Male; Multiple Organ Failure; Platelet Factor 4; Polysaccharides; Pregnancy; Preoperative Care; Recombinant Proteins; Thrombin; Thrombocytopenia; Venous Thrombosis

Glycosaminoglycans (GAGs) are negatively charged polysaccharides present, e.g., on the luminal face of the blood vessels as heparan sulphate (HS) and hyaluronic acid (HA), in the interstitium as HA, and in neutrofils and plasma as chondroitin sulphate (CS) and HA. Total plasma levels of GAG are increased in human septic shock, but the origin and pathophysiological implications are unclear. In order to determine the source of circulating GAG in sepsis, we compared plasma levels of HS, HA, CS and keratan sulphate (KS) in patients with septic shock and controls.. HS and KS were measured with enzyme-linked immunosorbent assay, and HA and CS disaccharides with liquid chromatography tandem mass spectrometry in plasma obtained from patients admitted to intensive care fulfilling criteria for septic shock as well as from matched control patients scheduled for neurosurgery.. Median levels of HS and HA were fourfold increased in septic shock and were higher in patients that did not survive 90 days (threefold and fivefold for HS and HA, respectively). Median CS levels were unaltered, while KS levels were slightly decreased in sepsis patients. HS and HA levels correlated with levels of interleukin-6 and interleukin-10. Except for HA, GAG levels did not correlate to liver or kidney sequential organ function score.. Median plasma level of HS and HA is increased in septic shock patients, are higher in patients that do not survive, and correlates with inflammatory activation and failing circulation. The increased levels could be due to vascular damage.

Topics: Adult; Aged; Aged, 80 and over; C-Reactive Protein; Chondroitin Sulfates; Disaccharides; Enzyme-Linked Immunosorbent Assay; Female; Glycosaminoglycans; Heparitin Sulfate; Humans; Hyaluronic Acid; Indicators and Reagents; Interleukin-10; Interleukin-6; Keratan Sulfate; Male; Middle Aged; Multiple Organ Failure; Peroxidase; Sepsis; Shock, Septic; Survival

Anticoagulant therapy attracts much attention for the treatment of severe sepsis since recent studies have revealed that some anticoagulants have the ability to regulate the inflammatory response. The purpose of this study was to examine whether danaparoid sodium (DA) is effective for the treatment of organ dysfunction in sepsis.. Sixty-four Wistar rats were intravenously injected with 5.0 mg/kg of lipopolysaccharide (LPS) and then divided into two groups: the DA group and the control group (n = 32 each). The DA group was injected intravenously with 400 U/kg of DA immediately after LPS injection, whereas the control group received saline. Blood samples were drawn at 1, 6, 12, and 24 hours after LPS injection, and organ damage markers and coagulation markers were measured. In the other series, 10 rats treated with LPS were divided into DA and control groups (n = 5 each). Blood samples were collected at 1, 3, and 6 hours after LPS injection and served for the cytokine measurements.. The elevation of the organ damage markers, such as alanine aminotransferase and lactate dehydrogenase, was significantly suppressed in the DA group. Coagulation markers, such as AT activity and fibrinogen levels, were maintained better in the DA group at 6 hours. The elevation of proinflammatory cytokines such as tumor necrosis factor-alpha, interleukin (IL)-1, and IL-6 was significantly suppressed in the DA group. On the other hand, there was no significant difference in anti-inflammatory cytokines such as IL-4 and IL-10.. DA preserves the organ dysfunction in LPS-challenged rats. Although the mechanism is not fully elucidated, not only the improvement of coagulation disorder but also the regulation of circulating levels of proinflammatory cytokines may play a role in the mechanism.

Topics: Animals; Chondroitin Sulfates; Cytokines; Dermatan Sulfate; Endotoxemia; Heparitin Sulfate; Inflammation Mediators; Lipopolysaccharides; Multiple Organ Failure; Rats; Rats, Wistar

This study investigated the potential benefits of combination therapy using antithrombin (AT) with danaparoid sodium (DA) compared with the use of AT with unfractionated heparin (UFH) in the treatment of sepsis.. Rats infused with lipopolysaccharide were treated with either DA alone, AT alone, AT plus DA, AT plus UFH, or human serum albumin as controls. AT (125 U/kg) was injected into the AT group immediately after lipopolysaccharide infusion. The AT/DA and AT/UFH groups received the same dose of AT in conjunction with either DA (400 U/kg) or UFH (400 U/kg). The status of the mesenteric microcirculation was examined by intra-vital microscopy and the laboratory indices of coagulation, inflammation, and organ dysfunction were measured.. The coagulation markers were improved following the administration of DA or UFH. The decreases in the WBC counts were significantly suppressed in the AT/DA group. The elevation of IL-6 decreased in the AT, DA, and AT/DA groups (all p<0.01) but not in the AT/UFH group. The prostaglandin I2 levels were significantly elevated only in the AT/DA group (p<0.05). The WBC adhesion was significantly suppressed in the DA, AT/UFH, and AT/DA groups (p<0.05), and the RBC velocity was best maintained in the AT/DA group with no associated increase in capillary hemorrhage. The elevation of ALT and BUN significantly improved only in the AT/DA group. ONCLUSION: Organ dysfunction can thus be alleviated by even moderate doses of AT replacement when co-administered with DA.

Topics: 6-Ketoprostaglandin F1 alpha; Alanine Transaminase; Animals; Anticoagulants; Antithrombins; Blood Urea Nitrogen; Chondroitin Sulfates; Dermatan Sulfate; Drug Therapy, Combination; Fibrinolytic Agents; Heparin; Heparitin Sulfate; Interleukin-6; Leukocyte Count; Lipopolysaccharides; Multiple Organ Failure; Platelet Count; Rats; Rats, Wistar

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

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

Multiple system organ failure (MOF) remains a major source of morbidity and mortality in trauma patients. Despite restoration of central hemodynamics, intestinal hypoperfusion can persist. Mucosal ischemia and barrier breakdown are factors in the genesis of MOF. Heparan sulfate is a gycosaminoglycan similar to heparin, but with minimal anticoagulant properties. As an adjunct to resuscitation, it improves immunologic function and restores mucosal oxygenation and function. We hypothesized that resuscitation with heparan following hemorrhage wound prevents intestinal hypoperfusion.. In vivo videomicroscopy was used to study small intestine microcirculation in rats. Animals were hemorrhaged to 50% of baseline mean arterial pressure (MAP) and maintained there. Resuscitation was initiated when the return of 10% shed blood was required to keep MAP at 50%. Animals received either heparan (7 mg/kg/1 ml saline) or saline (1 ml) followed by the remaining shed blood and an equal volume of saline. MAP, cardiac output (CO), A1 arteriole diameters, and flow were determined.. Resuscitation of the saline control group resulted in normal MAP with elevation of CO to 25-40% above baseline. The heparan group had return of MAP but only a moderate increase in CO (7-15%). Saline resuscitation led to progressive deterioration in A1 diameters and flow. The addition of heparan prevented delayed A1 constriction and significantly improved perfusion.. Heparan prior to resuscitation improved intestinal perfusion, despite a relative reduction in CO. Improvement in nutrient blood flow may protect the mucosal barrier, reducing the incidence of MOF, and suggests that heparan may be useful in resuscitation of trauma patients.

Topics: Animals; Hemodynamics; Heparitin Sulfate; Intestines; Male; Microcirculation; Multiple Organ Failure; Rats; Rats, Sprague-Dawley; Resuscitation; Shock, Hemorrhagic; Video Recording

Topics: Chondroitin Sulfates; Critical Illness; Dermatan Sulfate; Extracorporeal Circulation; Female; Glycosaminoglycans; Hemofiltration; Heparinoids; Heparitin Sulfate; Humans; Male; Middle Aged; Multiple Organ Failure; Renal Dialysis; Thrombocytopenia