heparitin-sulfate and Shock--Septic

To review the experimental and clinical evidence that antithrombin has multiple mechanisms for both its anticoagulant and anti-inflammatory properties. The interaction between antithrombin and specific polysulfated, acidic oligosaccharide moieties found on heparin and related proteoglycan molecules within the circulation and on endothelial surfaces will also be examined.. Review of the literature relating to antithrombin published during the past 25 yrs.. Antithrombin is the most abundant endogenous anticoagulant circulating in human plasma. This serine protease inhibitor participates in the regulation of clotting in both physiologic and pathologic states. Reduced antithrombin activity in the early phases of sepsis contributes to a procoagulant state with excess activation of the innate immune response. Antithrombin binds to specific pentasaccharides expressed on heparin, glycosaminoglycans, and related proteoglycans within the circulation and along endothelial surfaces. The functions of neutrophils, monocytes, and endothelial cells are altered as a result of their interaction with antithrombin. These effects are mediated by the enzyme inhibitory action of antithrombin and its ability to function as a ligand for antithrombin receptors on cell surfaces. In addition, antithrombin exerts anti-inflammatory properties by both prostacyclin-dependent and prostacyclin-independent actions; heparin interferes with these anti-inflammatory properties. The role of antithrombin in sepsis, its therapeutic utility in severe sepsis, and its combination with heparin remain the subject of considerable debate. The results of a recent phase 3 clinical trials with high-dose antithrombin in sepsis suggested a beneficial effect in patients who did not concomitantly receive heparin, thereby generating new challenges in the understanding of interactions between antithrombin and heparin or heparin-like proteoglycans.. Antithrombin has complex interactions with host coagulopathic and systemic inflammatory responses under physiologic conditions and in sepsis. The impact of these interactions in critically ill patients and the therapeutic implications of administration of antithrombin, and various doses and types of heparin in such patients, need further clarification.

Topics: Anticoagulants; Antithrombins; Clinical Trials as Topic; Drug Synergism; Epoprostenol; Heparin; Heparitin Sulfate; Humans; Shock, Septic

The heart is one of the most frequently affected organs in sepsis. Recent studies focused on lipopolysaccharide-induced mitochondrial dysfunction; however myocardial dysfunction is not restricted to gram-negative bacterial sepsis. The purpose of this study was to investigate circulating heparan sulfate (HS) as an endogenous danger associated molecule causing cardiac mitochondrial dysfunction in sepsis. We used an in vitro model with native sera (SsP) and sera eliminated from HS (HS-free), both of septic shock patients, to stimulate murine cardiomyocytes. As determined by extracellular flux analyzing, SsP increased basal mitochondrial respiration, but reduced maximum mitochondrial respiration, compared with unstimulated cells (P < 0.0001 and P < 0.0001, respectively). Cells stimulated with HS-free serum revealed unaltered basal and maximum mitochondrial respiration, compared with unstimulated cells (P = 0.1174 and P = 0.8992, respectively). Cellular ATP-level were decreased in SsP-stimulated cells but unaltered in cells stimulated with HS-free serum compared with unstimulated cells (P < 0.0001 and P = 0.1593, respectively). Live-cell imaging revealed an increased production of mitochondrial reactive oxygen species in cells stimulated with SsP compared with cells stimulated with HS-free serum (P < 0.0001). Expression of peroxisome proliferator-activated receptors (PPARα and PPARγ) and their co-activators PGC-1α, which regulate mitochondrial function, were studied using PCR. Cells stimulated with SsP showed downregulated PPARs and PGC-1α mRNA-levels compared with HS-free serum (P = 0.0082, P = 0.0128, and P = 0.0185, respectively). Blocking Toll-like receptor 4 revealed an inhibition of HS-dependent downregulation of PPARs and PGC-1α (all P < 0.0001). In conclusion, circulating HS in serum of septic shock patients cause cardiac mitochondrial dysfunction, suggesting that HS may be targets of therapeutics in septic cardiomyopathy.

Topics: Adenosine Triphosphate; Aged; Animals; Down-Regulation; Enzyme-Linked Immunosorbent Assay; Female; Heparitin Sulfate; Humans; Male; Mice; Middle Aged; Mitochondria; Myocytes, Cardiac; Oxygen Consumption; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; PPAR alpha; PPAR gamma; Reactive Oxygen Species; Sepsis; Shock, Septic; Transcription Factors

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

Early clinical signs of heparin induced thrombocytopenia (HIT) are nonspecific and include a sudden drop in the number of platelets as well as formation of arterial and venous thromboses. Regional citrate anticoagulation (RCA) is increasingly used as a very effective modality to prevent filter clotting during renal replacement therapy (RRT). We report the first case where repeated premature filter clotting despite RCA indicated a manifestation of HIT.. A 71-year old woman admitted to the ICU for a compartment syndrome of the leg developed septic shock with acute kidney injury requiring continuous veno-venous hemodialysis (CVVHD). Because of unexpected and repeated premature filter clotting during CVVHD using RCA, HIT was suspected.. The diagnosis of HIT was confirmed by the presence of IgG antibodies against heparin and platelet factor (PF) 4 complexes and six points in the 4T score. Discontinuation of heparin administration and initiation of systemic anticoagulation with danaparoid sodium resulted in the normalization of platelet count and hemofilter lifetime.. RCA does not seem to be sufficient to prevent hemofilter clotting during HIT. Thus, in case of repeated premature filter clotting despite RCA, one should suspect HIT and prompt diagnostic workup as well as a switch to alternative anticoagulation.

Topics: Acute Kidney Injury; Aged; Anticoagulants; Chondroitin Sulfates; Citrates; Dermatan Sulfate; Equipment Failure; Female; Heparin; Heparitin Sulfate; Humans; Immunoglobulin G; Platelet Factor 4; Renal Dialysis; Shock, Septic; Thrombocytopenia; Thrombosis