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PubMedDate not supplied

Negligible hemostatic toxicity of intermediate-dose Erwinase in adult patients with acute lymphoblastic leukemia: preliminary data.

The hemostatic toxicity of low dose L-asparaginase from Erwinia carotovora (Erwinase) has been reported to be negligible in adult patients with acute lymphoblastic leukemia (ALL); conversely, no consistent data have been obtained when Erwinase is administered at intermediate doses. We report preliminary clinical and laboratory hemostatic data from 10 adult patients with ALL treated during induction phase with intermediate doses of Erwinase (20,000 IU/m2s.c. every other day, for a total of six administrations). No thrombotic or hemorrhagic events were registered and the mean values of PT, aPTT, fibrinogen, antithrombin and D-dimer did not change during treatment. Only one patient showed a decrease of antithrombin (48% on day 8) requiring temporary suspension of Erwinase therapy. These data suggest that intermediate doses of Erwinase also have negligible hemostatic toxicity in adult patients with ALL.

Adolescent↗
PubMed1994

Disorders of hemostasis in sepsis.

Sepsis is noted for producing disruptions in hemostasis. The patient-related risk factors, clinical presentation, and management strategies are dependent upon the presiding disorder. Platelet deficiency and dysfunction, hepatic protein disorders, and disseminated intravascular coagulation are the most common clinical problems. Nursing care focuses on prevention, early recognition, and supportive care for the thrombotic or bleeding patient. An overview of the disorders of hemostasis in sepsis and nursing care of these patients are described in this article.

Blood Coagulation Disorders↗
PubMed1997

[Blood rheology in patients with gastric cancer].

Blood rheology was examined in 163 patients with gastric cancer. The 4th stage of the disease was detected in 51 of them. The following changes of blood rheology were found: changes of a blood and plasma viscosity and red blood cells hyperaggregation. These changes lead to hypo- and dysproteinaemia, erythron system disorders, endogenous intoxication, hemostasis disorders which correlated in severity with the disease stage. These patients need correction of rheological disorders.

Blood Coagulation Disorders↗
PubMed2002

Structural and functional characterization of tissue factor pathway inhibitor following degradation by matrix metalloproteinase-8.

Vascular injury results in the activation of coagulation and the release of proteolytic enzymes from neutrophils and connective- tissue cells. High concentrations of these inflammatory proteinases may destroy blood coagulation proteins, contributing to coagulation and bleeding disorders associated with severe inflammation. Matrix metalloproteinase-8 (MMP-8) is released from neutrophils at sites of inflammation and vascular disease. We have investigated the effect of MMP-8 degradation on the anticoagulant function of tissue factor pathway inhibitor (TFPI) as a potential pathological mechanism contributing to coagulation disorders. MMP-8 cleaves TFPI following Ser(174) within the connecting region between the second and third Kunitz domains ( k (cat)/ K (m) approximately 75 M(-1).s(-1)) as well as following Lys(20) within the NH(2)-terminal region. MMP-8 cleavage of TFPI decreases the anticoagulant activity of TFPI in factor Xa initiated clotting assays as well as the ability of TFPI to inhibit factor Xa in amidolytic assays. Yet, MMP-8 cleavage does not alter the ability of TFPI to inhibit trypsin. Since the inhibition of both factor Xa and trypsin is mediated by binding to the second Kunitz domain, these results suggest that regions of TFPI other than the second Kunitz domain may directly interact with factor Xa. (125)I-factor Xa ligand blots of TFPI fragments generated following MMP-8 degradation were used for probing binding interactions between factor Xa and regions of TFPI, other than the second Kunitz domain. In experiments performed under reducing conditions that disrupt the Kunitz domain structure, (125)I-factor Xa binds to the C-terminal fragment of MMP-8-degraded TFPI. This fragment contains portions of TFPI distal to Ser(174), which include the third Kunitz domain and the basic C-terminal region. An altered form of TFPI lacking the third Kunitz domain, but containing the C-terminal region, was used to demonstrate that the C-terminal region directly interacts with factor Xa.

Amino Acid Sequence↗
PubMed1988

The role of protein C in congenital and acquired thrombotic disorders.

Control of the coagulation pathway requires mechanisms that limit and localize the clotting process. The vascular endothelium has been shown to play an active role in preventing blood clot formation in vivo. The endothelial cell surface contains a thrombin-binding protein, thrombomodulin, which, when complexed with thrombin, activates vitamin K-dependent protein C, an endogenous anticoagulant. Protein C and its cofactor, protein S, inhibit the clotting process by inactivating factors Va and VIIIa and, additionally, enhance the lysis of fibrin. It has been demonstrated by the detection of heterozygous and homozygous protein C-deficient patients with severe thrombotic complications that protein C is a major regulatory protein of hemostasis and thrombosis. This endogenous anticoagulant pathway is providing a better understanding of both congenital and acquired thrombotic disorders.

Blood Coagulation↗
PubMed2002

[Action of venoms on blood coagulation: diagnosis of hemorrhagic syndromes].

Venoms from Viperidae, Crotalidae, some Australian Elapidae and few Colubridae are a mixture of enzymes which impact on blood coagulation in several ways. These proteins can be classified as haemorragins which induce disorders of the capillary permeability, disintegrins and related proteins which disturb the clotting time while acting on plate adhesion, and proteases which cleave peptides. Venoms contain molecules directed against several targets of the coagulation system. The same molecule may present different activities. Components of snake venoms are used in diagnostic coagulation tests, fundamental research and as drugs against infectious agents, cancer or haematological disorders. The structural differences between proteins from snake venoms and natural coagulation factors and the target diversity of the venom components explain why it remains illusory to treat bleedings when acting just at symptom level. Conversely, antivenom, whose components are directed against the venom proteins, is the only aetiological therapy effective against snake envenomations.

Animals↗
PubMed2004

Universal changes in biomarkers of coagulation and inflammation occur in patients with severe sepsis, regardless of causative micro-organism [ISRCTN74215569].

INTRODUCTION: PROWESS (Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis) was a phase III, randomized, double blind, placebo controlled, multicenter trial conducted in patients with severe sepsis from 164 medical centers. Here we report data collected at study entry for 1690 patients and over the following 7 days for the 840 patients who received placebo (in addition to usual standard of care). METHODS: Nineteen biomarkers of coagulation activation, anticoagulation, fibrinolysis, endothelial injury, and inflammation were analyzed to determine the relationships between baseline values and their change over time, with 28-day survival, and type of infecting causative micro-organism. RESULTS: Levels of 13 of the 19 biomarkers at baseline correlated with Acute Physiology and Chronic Health Evaluation II scores, and nearly all patients exhibited coagulopathy, endothelial injury, and inflammation at baseline. At study entry, elevated D-dimer, thrombin-antithrombin complexes, IL-6, and prolonged prothrombin time were present in 99.7%, 95.5%, 98.5%, and 93.4% of patients, respectively. Markers of endothelial injury (soluble thrombomodulin) and deficient protein C, protein S, and antithrombin were apparent in 72%, 87.6%, 77.8%, and 81.7%, respectively. Impaired fibrinolysis (elevated plasminogen activator inhibitor-1) was observed in 44% of patients. During the first 7 days, increased prothrombin time (which is readily measurable in most clinical settings) was highly evident among patients who were not alive at 28 days. CONCLUSION: Abnormalities in biomarkers of inflammation and coagulation were related to disease severity and mortality outcome in patients with severe sepsis. Coagulopathy and inflammation were universal host responses to infection in patients with severe sepsis, which were similar across causative micro-organism groups.

APACHE↗
PubMed2003

Use of drotrecorgin alfa--recombinant activated human protein C in treatment of septic shock in the course of therapy for nephrolithiasis.

BACKGROUND: Septic shock is the most dangerous complication of nephrolithiasis management utilizing percutaneous methods. CASE REPORT: The patient, D.M., aged 60 was subjected to scheduled percutaneous nephrolithotomy due to coral calculosis of the pyelocalyceal system. As pyuria was noted intraoperatively, nephrostomy was left after the procedure. Over ten hours after the surgery the patient developed the symptoms of severe septic shock with progressive respiratory distress, renal failure, intravascular coagulation syndrome and impaired consciousness. Nephrectomy was performed, antibiotic treatment and high doses of norepinephrine instituted. Hemodynamic stabilization was obtained, without, however, marked improvement of the patient's condition. Because of persistent coagulation disorders and multiorgan dysfunction, recombinant activated protein C preparation--drotrecorgin alfa (Xigris Eli Lilly) was added to the therapeutic regimen. From the second day of infusion, systematic improvement of the coagulation system parameters was observed, making it possible to reduce the doses of catecholamines, oxygen concentration in the gas mixture used for ventilation, as well as stabilization of the function of the preserved kidney. The patient was weaned off the respirator on the 8th day of treatment and on the 13th day referred to the Urology Department, from which she was soon discharged home. CONCLUSIONS: 1. Surgical resection of the infection source and cause of the septic shock is the prerequisite for successful pharmacological treatment. 2. Administration of rh-APC to a patient meeting the PROWESS criteria may be an effective and safe method of treatment in the complex management of septic shock.

Disseminated Intravascular Coagulation↗
PubMed1999

Inhibition of tissue factor-dependent and -independent coagulation by cell surface expression of novel anticoagulant fusion proteins.

BACKGROUND: Thrombotic vascular occlusion occurs in disorders of diverse etiology, including atherosclerosis, vasculitis, and disseminated intravascular coagulation. The same process results in hyperacute rejection of renal allografts transplanted into sensitized patients and remains a major problem in experimental xenotransplantation. METHODS: We have previously described the design and expression of several genetic constructs encoding novel fusion proteins with anticoagulant properties. They are based on two naturally occurring soluble anticoagulant proteins, human tissue factor pathway inhibitor (hTFPI) and the leech protein hirudin, which act early and late in the clotting cascade, respectively. We report the expression of human hTFPI-CD4 on the surface of immortalized porcine endothelial cells (IPEC), and show that it functions across the species divide as evidenced by the binding of membrane-expressed porcine tissue factor (pTF)-human factor VIIa complexes. RESULTS: Using a human plasma recalcification clotting assay, we distinguished between pTF-dependent and pTF-independent fibrin generation, and we have demonstrated that expression of hTFPI-CD4 on IPEC effectively prevented pTF-dependent clotting. Moreover, we show that when hTFPI-CD4 was co-expressed with the hirudin construct, the procoagulant properties of in vitro cultured, activated IPEC were almost completely abolished. CONCLUSIONS: These results suggest that these novel anticoagulant molecules may prove useful therapeutic agents for gene therapy or for transgenic expression in animals whose organs may be used for cliniCal xenotransplantation.

Animals↗