Antithrombin III Levels Research Articles

SERUM ALBUMIN LEVELS ANTICIPATE ANTITHROMBIN III ACTIVITIES BEFORE AND AFTER ANTITHROMBIN III AGENT IN CRITICAL PATIENTS WITH DISSEMINATED INTRAVASCULAR COAGULATION

Elevated thrombin-antithrombin complex (TAT) or decreased serum albumin levels suggest heightened vascular permeability in disseminated intravascular coagulation (DIC). In such a situation, plasma antithrombin III (AT-III) may decrease because of the leakage. We thus examined whether AT-III activity before and after administration of an AT-III agent changed depending on plasma TAT and/or serum albumin levels in 20 consecutive patients with DIC. We also analyzed the pharmacokinetics for AT-III using a two-compartment model. Serum albumin levels before AT-III administration correlated with preadministered and postadministered AT-III activity, but TAT levels did not. Regardless of TAT levels, AT-III trough activity on the third day increased significantly. In patients with albumin levels of 2.5 g/dL or less, AT-III trough levels on the third day were significantly lower than those with higher levels of albumin. The half-life of the distribution phase for AT-III agent in the patients was shortened to less than one third the value reported in congenital AT-III deficiency, suggesting increased vascular permeability in the acute state patients here. The distribution volume of the agent increased remarkably compared with the previous control. We report here for the first time that in critical patients with DIC, plasma AT-III levels before and after AT-III administration could be predicted by preadministered serum albumin levels, but not by TAT. These findings could be explained by the pharmacokinetic profile, increased vascular permeability and distribution volume, observed in critical patients.

Antithrombin-III as an early prognostic factor in children with acute lung injury

Purpose : To evaluate the potential prognostic value of the antithrombin-III (AT-III) level in the children with acute lung injury (ALI), we analyzed several early predictive factors of death including AT-III level at the onset of ALI and compared the relative risk of them for mortality. Methods : Over a 18-month period, a total of 198 children were admitted to our pediatric intensive care unit and 21 mechanically ventilated patients met ALI criteria, as defined by American-European consensus conference, i.e., bilateral pulmonary infiltrates and PaO2/FiO2 lower than 300 without left atrial hypertension. Demographic variables, hemodynamic and respiratory parameters, underlying diseases, as well as Pediatric Risk of Mortality-III (PRISM-III) scores and Lung Injury Score (LIS) at admission were collected. AT-III levels were measured within 3 hours after admission. These variables were compared between survivors and non-survivors and entered into a multiple logistic regression analysis to evaluate their independent prognostic roles. Results : The overall mortality rate was 38.1% (8/21). Non-survivors showed lower age, lower lung compliance, higher PEEP, higher oxygenation index (OI), lower arterial pH, lower PaO2/FiO2, higher PRISM-III score and LIS, and lower AT-III level. PRISM-III score, LIS, OI and decreased AT-III level (less than 70%) were independently associated with a risk of death and the odds ratio of decreased AT-III level for mortality is 2.75 (95% confidence interval; 1.28-4.12) Conclusion : These results suggest that the decreased level of AT-III is an important prognostic factor in children with ALI and the replacement of AT-III may be considered as an early therapeutic trial.

Clinical Measures of Heparin’s Effect and Thrombin Inhibitor Levels in Pediatric Patients with Congenital Heart Disease

In this investigation, we examined the relationship among three thrombin inhibitors, antithrombin III (ATIII), heparin cofactor II (HCII), and alpha-2-macroglobulin (alpha2M), and several clinical tests of heparin's effect in pediatric patients with congenital heart disease undergoing cardiopulmonary bypass. One hundred eighteen children were stratified into six age groups: <1 mo, 1-3 mo, 3-6 mo, 6-12 mo, 12-24 mo, and >10 yr. Baseline ATIII, HCII, and alpha2M values were measured. Baseline celite- and kaolin-activated clotting times (ACT) were also measured and repeated 3 min after a standard heparin dose of 400 U/kg. Differences in ACT values before and after heparin administration and a heparin dose-response relationship were calculated for each patient. Kaolin-activated ACT tests showed less variation after heparin administration than celite-activated tests. In contrast to what has been demonstrated in adults, ATIII showed no positive correlation with the clinical tests of heparin's effect nor did the other thrombin inhibitors. Additionally, patients <1 mo old had unexpectedly low levels of alpha2M accompanying their expected low levels of ATIII and HCII. Our findings raise concerns about the ability of heparin to adequately anticoagulate these neonates during cardiopulmonary bypass and, consequently, challenge the accuracy of ACT prolongation to truly reflect the extent of their anticoagulation.

Differences in inflammatory and thrombotic markers between unstable angina and acute myocardial infarction

Background Unstable coronary syndromes are characterised by increased inflammatory process and endothelial activation. However, the underlying mechanisms of the acute coronary syndromes are still obscure. We evaluated the differences of inflammatory and thrombotic markers, at the acute phase of unstable angina (UA) and acute myocardial infarction (AMI). Methods The population of the study consisted of 216 subjects: 136 patients with UA, 57 patients with AMI and 23 healthy controls. Blood samples were taken by their admission to the hospital. Inflammatory and thrombotic markers were measured by ELISA. Results Patients with UA had significantly higher levels of interleukin-6 (IL-6), soluble vascular cells adhesion molecule (sVCAM-1) and von Willebrand factor (vWF) ( p < 0.05 vs controls), and lower levels of antithrombin III (ATIII) ( p < 0.01 vs controls) and protein C (PrtC) ( p < 0.05 vs controls). Similarly, patients with AMI had higher levels of IL-6, sVCAM-1, vWF and tissue plasminogen activator (tPA) ( p < 0.01 vs controls) and lower levels of ATIII ( p < 0.01 vs controls) and prtC ( p < 005 vs controls). Patients with AMI had significantly higher levels of vWF, tPA and sVCAM-1 compared to UA patients ( p < 0.05). Conclusions Patients with unstable coronary syndromes had increased levels of IL-6, sVCAM-1 and vWF as well as decreased levels of ATIII and PrtC by their admission. However, patients with AMI had higher levels of all the endothelium-derived inflammatory (e.g. sVCAM-1) of thrombotic/fibrinolytic (e.g. tPA and vWF) markers, compared to those with UA. These findings imply that patients with myocardial infarction show further increase of endothelium-derived inflammatory and thrombotic markers compared to patients with unstable angina, in response to a similar proinflammatory stimuli.

Hematological changes and related gene mutation of post-severe acute respiratory syndrome patients with osteonecrosis

To investigate the hematological changes and related gene mutation of post-severe acute respiratory syndrome (SARS) patients with osteonecrosis so as to find the sensitive molecular symbols for early screening of the high risk populations. Fast peripheral venous blood samples were collected from 61 post-SARS patients with osteonecrosis, 25 males and 36 females, aged 30.4 (20 - 60), and 52 sex and age-matched healthy persons as controls. ELISA was used to detect the coagulation and fibrinolysis indicators: activated partial thromboplastin time (APTT), protein C (PC), antithrombin III (AT-III), plasminogen activator inhibitor (PAI), activated protein C resistance (APC-R), plasminogen (PLG), von Willebrand factor (VWF), D-dimer (D-D), and fibrinogen (Fib). Real-time PCR was used to detect the mutation of factor V G1601A (FV Leiden) and prothrombin G20210A. The levels of PC, AT-III, and PLG of the osteonecrosis group were 85% +/- 34%, 84 +/- 29%, and 69 +/- 23%, significantly lower than that of the control group (109% +/- 20%, 104% +/- 14%, and 94% +/- 15% respectively, all P < 0.01). PAI of the osteonecrosis group was 16 U/ml +/- 14 U/ml, significantly higher than that of the control group (8.0 U/ml +/- 4.3 U/ml, P < 0.01). The percentage of patients with abnormal indicators was 99.5% (54/61) in the osteonecrosis group, significantly higher than that of the control group (36.5%, 19/52, P < 0.01). The percentage of patients with 3 or more abnormal indicators was 72.1% (44/61) in the osteonecrosis group, significantly higher than that of the control group (17.3%, 9/52, P < 0.01). No mutations of F V Leiden and prothrombin G20210A was found in both groups. Trends of hypercoagulation and hypofibrinolysis exist in the post-SARS patients with osteonecrosis. APTT, PC, AT-III, and PLG can be used as sensitive indicator for screening high risk populations of osteonecrosis.

The Association between Fibrinogen, von Willebrand Factor, Antithrombin III, and D-dimer Levels and Survival Outcome by 36 Months from Ovarian Cancer

Thirty-five patients diagnosed to have ovarian cancer (early FIGO stage I/II n = 11, advanced FIGO stage III/IV, n = 24) were evaluated for hemostatic parameters relating to survival outcome by 36 months of disease. Systemic plasminogen activators and inhibitors were evaluated and we found no significant association with survival outcome and eventually only fibrinogen, von Willebrand Factor (vWF), antithrombin III (ATIII), and D-dimer levels were determined for their association with disease outcome by 12 months, 24 months, and 36 months. Twenty-four patients succumbed to the disease by 36 months (early n = 2, advanced n = 22). The 11 surviving patients (advanced n = 3, including one deceased at 52 months) is still living past 36 months and 82 months at the time of analysis. Elevated fibrinogen, vWF, and D-dimer together with reduced ATIII levels were found to be associated with poor survival outcome by 12 months of disease. Moreover, elevated vWF and D-dimer with reduced ATIII levels was strongly implicated with poor survival outcome by 36 months from ovarian cancer. The overall survival rate at 36 months from ovarian cancer was 31.4%. It is therefore suggested that fibrinogen, vWF, ATIII, and D-dimer levels be used together as prognostic markers for disease outcome especially in patients with advanced ovarian cancer within 36 months of disease. An expanded study is required to confirm these findings.

Applicability of Disseminated Intravascular Coagulation Parameters in the Assessment of the Severity of Acute Pancreatitis

To evaluate the clinical applicability of the determination of disseminated intravascular coagulation (DIC) parameters in acute pancreatitis. The subjects for this study were 139 consecutive patients with acute pancreatitis. DIC parameters were assessed at the initial observation of these patients. The levels of the DIC parameters at admission were significantly associated with the severity and the prognosis of acute pancreatitis. Antithrombin III (AT-III), fibrin/fibrinogen degradation products-E, platelet count, D-dimer, and thrombin-AT-III complex at admission showed better area under the receiver operating characteristics curve values compared with C-reactive protein. An AT-III value of 69% at admission was the best cut-off value to predict fatal outcome (sensitivity, 81%; specificity, 86%). The aggravated coagulation parameters predict a fatal outcome in patients with acute pancreatitis. AT-III level (<69%) was the most accurate marker for poor outcome of acute pancreatitis at admission.

Vena cava superior syndrome developing in a dialysis patient with antithrombin III deficiency following temporary catheterization

Despite being widely reported in patients with neoplasms, vena cava superior (VCS) syndrome linked to thrombosis is a major catheter complication that can be encountered during the use of the hemodialysis catheter. Antithrombin III (AT-III), responsible for a large part of thrombin inactivation capacity in plasma, is the most powerful inhibitor of the thrombosis process. This report describes a case of VCS syndrome developing two weeks following the extraction of a right-sided subclavian catheter in a patient transferred from peritoneal dialysis to hemodialysis for one week due to leakage. The patient presented complaining of swelling and pain in the right arm. At Doppler examination, total thrombosis was observed in the subclavian and internal jugular vein. At advanced examinations due to lack of response to heparin and clinical worsening, VCS and AT-III deficiency were determined. Following thrombolytic therapy with streptokinase, AT-III levels were raised by the administration of plasma, and clinical and radiological stabilization was established by continuing heparin and continuous oral anticoagulant therapy.

A Randomized Trial of Heparin Plus Anti-Thrombin III (ATIII) vs. Heparin Alone To Prevent VOD after HSCT.

Background: Hepatic veno-occlusive disease (VOD) is a devastating regimen-related toxicity after hematopoietic stem cell transplantation (HSCT). There is no safe and proven therapy for established VOD, and focus has been on its prevention. Previous studies have shown that ATIII level is markedly decreased in patients with VOD. We conducted a prospective, randomized trial to compare heparin plus ATIII versus heparin alone in HSCT recipients.Methods: A clinical diagnosis of hepatic VOD was defined as satisfying two of the following criteria: bilirubin > 2.0 mg/dl, unexplained weight gain of > 2% from baseline, and hepatomegaly. The levels of PAI-1, TFG-β and TNF-α were measured at weekly basis for correlative analysis. Patients were randomized to receive or not receive prophylactic ATIII 1000U twice daily from day 1 until day +14 post-HSCT plus heparin 5U/kg/hr from day 1 until day +21 or discharge after HSCT.Results: Thirty patients were enrolled for the study. Fourteen patients received heparin + ATIII and 16 patients received heparin alone for VOD prophylaxis during HSCT. There were 9 AML, 6 NHL, 4 ALL, 3 CML, 2 ABL, 2 MM, 1 MDS, 1 HD, 1 AA and 1 SLL patient. Of the 30 patients enrolled, 13 patients received sibling allogeneic HSCT, 13 autologous, 3 unrelated allogeneic and 1 cord blood HSCT. VOD occurred in 4 patients (25%) in the heparin alone group and none in the heparin + ATIII group (0%, P = 0.044). The incidence of bleeding complication was higher in the heparin alone group (4/16, 25%) than the heparin + ATIII group (1/14, 7%) without statistical significance (P = 0.190). The mean baseline level of PAI-1 was slightly higher in the heparin + ATIII group (30.9 ± 31.0 ng/ml) when compared to the heparin group (18.9 ± 13.0 ng/ml, P = 0.062). The PAI-1 level decreased markedly in the heparin + ATIII group (23.0 ±10.1 ng/ml) by the third week following VOD prophylaxis therapy (heparin group; PAI level 40.3 ± 40 ng/ml, P = 0.010). The mean baseline levels of TGF-β and TNF-α did not differ significantly between the two groups. There was no VOD-related death.Conclusions: Although it was a preliminary analysis, the combination of ATIII and heparin for VOD prophylaxis in HSCT recipients seems to be more effective than heparin alone without increasing the hemorrhagic complication.

Regional citrate versus systemic heparin anticoagulation for continuous renal replacement in critically ill patients

We determined the effect of regional citrate versus systemic heparin anticoagulation for continuous renal replacement therapy in critically ill subjects suffering from acute renal failure who were not at high risk for hemorrhagic complications. Between April 1999 and June 2002, 30 critically ill subjects requiring continuous renal replacement therapy and using 79 hemofilters were randomly assigned to receive regional citrate or systemic heparin anticoagulation. The median hemofilter survival time was 124.5 hours (95% CI 95.3 to 157.4) in the citrate group, which was significantly longer than the 38.3 hours (95% CI 24.8 to 61.9) in the heparin group (P < 0.001). Increasing illness severity score, male gender, and decreasing antithrombin-III levels were independent predictors of an increased relative hazard of hemofilter failure. After adjustment for illness severity, antithrombin-III levels increased significantly more over the period of study in the citrate as compared to the heparin group (P= 0.038). Moreover, after adjustment for antithrombin-III levels and illness severity score, the relative risk of hemorrhage with citrate anticoagulation was significantly lower than that with heparin (relative risk of 0.14; 95% CI 0.02 to 0.96, P= 0.05). Compared with systemic heparin anticoagulation, regional citrate anticoagulation significantly increases hemofilter survival time, and significantly decreases bleeding risk in critically ill patients suffering from acute renal failure and requiring continuous renal replacement therapy.

Effects of early administration of atorvastatin treatment on thrombotic process in normocholesterolemic patients with unstable angina

Background Although statin-treatment during the acute phase of unstable coronary syndromes improve the outcome their effects on thrombosis/fibrinolysis system in normocholesterolemic patients admitted with unstable angina remain obscure. We assessed the effects of short-term atorvastatin treatment on thrombotic/fibrinolysis markers in normocholesterolemic in patients with unstable angina. Methods Forty-five patients with unstable angina were allocated into two groups to receive atorvastatin 10 mg/day ( n = 24) or no statin ( n = 21) for 6 weeks. Circulating levels of von Willebrand Factor (vWF), factor V (fV), protein C (prC), tissue plasminogen activator (tPA) and antithrombin III (ATIII) were measured by enzyme linked immunosorbent assay, by the patients admission and at the 1st and 6th week of the study. Results After 1 week of treatment, a significant increase of ATIII ( p < 0.05), fV ( p < 0.01) and vWF ( p < 0.05) was found in the control group, but not in atorvastatin-treated group. Similarly, at 6 weeks after admission, plasma levels of ATIII were still significantly higher than at baseline in controls ( p < 0.05), but not in atorvastatin-treated group. Plasma levels of PrtC were significantly increased in both controls ( p < 0.01) and atorvastatin-treated patients ( p < 0.05) at 1 week, while remained unaffected in atorvastatin-treated group at 6th week. There was no significant difference in the variations of plasma levels of tPA, PrtS and fVII between the two groups at 1 and 6 weeks after admission. Conclusions In normocholesterolemic patients admitted with unstable angina the early administration of atorvastatin, significantly affects von Willebrand factor levels and the expression of liver-derived components of both thrombosis and fibrinolysis system.

Anticoagulation during extracorporeal circulation under conditions of an ongoing systemic inflammatory response syndrome: effects of heparin

Open-heart surgery with cardiopulmonary bypass (CPB) causes changes in haemostasis. Artificial surfaces are bioincompatible and, thus, may initiate a reaction similar to an acute inflammation. In some patients, this 'postperfusion syndrome' (PPS), which includes changes in haemostasis, is the beginning of a systemic inflammatory response syndrome (SIRS). However, it is not clear whether the changes in coagulation represent a consequence or a main cause of the inflammatory reaction. Thus, the aim of our study was to investigate the cascade of coagulation and the effects of heparin under special circumstances of an ongoing SIRS. In a prospective evaluation using standardized operative procedures with CPB, we compared Group A (control group with normal postoperative course, n =20) with Group B (patients with postoperative SIRS, n =12). At six time points beginning before and ending two days after surgery, we measured platelet counts, leucocyte counts and plasma levels of fibrinogen, factor XII and antithrombin III (ATIII), in addition to standard coagulation tests (PTT, TT and ACT). Furthermore, we determined parameters of inflammation, such as C-reactive protein, PCT, IL-6, IL-8, IL-10 and TNF-alpha. In Group B (SIRS), we found a reduced anticoagulation during CPB with significantly lower values for PTT (60+/-7 versus 160+/-11 s), ACT (270+/-33 versus 532+/-44 s) TT (40+/-3 versus 150+/-15 s) compared to the control Group A. Simultaneously, we found a significant increase of factor XII in the SIRS group (191+/-16 versus 10+/-2%). There were no significant differences concerning the preoperative ATIII levels and the intraoperative dosage of heparin; the intraoperative decrease of fibrinogen, ATIII and platelets was comparable in both groups. Furthermore, we could see that significant changes of inflammatory parameters in the SIRS group (increasing levels of TNF-alpha, Il-6, IL-8 and IL-10) occurred at least 30 min after the observed reduction of anticoagulatory effect. With our results, it could be demonstrated that the development of inflammatory complications after CPB is correlated to a significantly reduced intraoperative effect of heparin. As this reduction of anticoagulation significantly preceded the changes of inflammatory parameters in SIRS patients, we think that a hypercoagulatory state, especially in cases of ongoing inflammation, is an additional trigger of SIRS.

A Novel Chemically Induced Fischer F344 Rat Model for Thrombotic Sequelae of Hemolytic Anemias.

In hemolytic diseases like sickle cell disease (SCD) and thalassemia, the mechanisms of thrombosis are poorly understood. Appropriate animal models would help increase our understanding of the pathophysiology of thrombosis, and in the development of specific disease modifying agents. We recently demonstrated that gavage exposure to a toxin, 2-butoxyethanol (2-BE), in Fischer F344 rats leads to the development of a unique chemically induced rat model of hemolytic anemia and microvascular thrombi. Using in vitro red blood cell (RBC) flow analysis of aggregability, adherence and deformability, we demonstrated that microthrombi formation in rats exposed to 2-BE was predominantly due to enhanced RBC adherence, possibly secondary to the recruitment of cellular adhesion molecules at the endothelial cell (EC)-RBC interface (Arch Toxicol. 2003,77(8):465–69). To validate our previous findings, and to further elucidate the mechanisms of thrombosis, we exposed Fischer F344 rats to 250mg/kg of 2-BE for up to 4 days. The exposure and laboratory outcome analysis was performed on 8 groups (5 animals/group) of rats, 4 control (treated with vehicle carrier) and 4 treatment groups. One control and one treatment group were terminated each day, after the 1st, 2nd, 3rd, and 4th daily dose. Blood collection for laboratory testing was performed on each day prior to euthanasia. Multiple rat tissue sites were evaluated for histopathologic evidence of thrombosis and infarction. In addition, ocular expression of vascular cell adhesion molecule-1 (VCAM-1), endothelial intercellular adhesion molecule-1 (ICAM-1), and P-selectin was determined using immunohistochemical testing. Consistent with our previous findings, all 2-BE exposed rats developed acute hemolysis as evidenced by anisopoikilocytosis, fragmented RBCs, an increased reticulocyte count, and a > 50% drop in hemoglobin (Hgb) after the first dose. The mean pre- and post-2-BE exposure Hgb was 15.0 gm/dl (range: 14.7–15.3 gm/dl) and 5.4 gm/dl (range: 3.5–10.3 gm/dl) respectively (p < 0.01; Mann-Whitney). In addition, gross and histopathologic evidence of microvascular thrombosis in multiple organs including brain, lungs, and bone were identified by day 4, in the rats treated with 2-BE. In contrast, serial platelet counts, prothrombin times, activated plasma thromboplastin times, fibrinogen, antithrombin-III levels, and D-dimers, were unchanged between the treated and control rats. Tissue expression of VCAM-1 correlated strongly with the presence and extent of thrombosis, but no change in the expression of ICAM-1 and P-selectin was seen. Hence, from our studies, it is suggested that the RBC/EC interaction appears to be a more potent catalyst for thrombosis seen in hemolytic disorders, in contrast to abnormalities involving platelets or coagulation factors. This is consistent with the observations of increased RBC/EC interaction, and increased VCAM-1 expression observed in human studies during acute sickle cell crises, and provides an explanation for the relative failure of anticoagulant/antiplatelet strategies during acute thrombotic episodes in SCD. Thus, with further characterization, our chemically induced rat model may serve as an ideal model to characterize thrombotic sequelae of SCD and thalassemia. Future studies using our model may also lead to the development of unique therapeutic strategies in SCD, aimed at decreasing the RBC/EC interaction (e.g. targeting VCAM-1), and ultimately thrombosis.

Anti-thrombin III in the management of hematopoietic stem-cell transplantation-associated toxicity.

To describe the evidence assessing the use of anti-thrombin III (AT-III) in the management of toxicity associated with hematopoietic stem-cell transplantation (HSCT)-conditioning regimens. Clinical literature was accessed through conference proceedings, EMBASE, the Cochrane database, and MEDLINE (1966-December 2003). Case reports, small case series, case-control and cohort studies, and randomized controlled trials of AT-III in HSCT were evaluated. Publications examining AT-III use in the non-HSCT setting were also explored. Key search terms included AT-III, transplantation, and veno-occlusive disease (VOD). Severe VOD and ensuing multiple organ dysfunction is associated with high mortality in HSCT. A low AT-III level has been shown to correlate with the development of organ dysfunction. Phase II trials, case series, and one small, randomized, placebo-controlled study suggest a benefit when AT-III therapy is instituted early in the course of VOD/multiple organ dysfunction syndrome. In all of these reports, AT-III use was devoid of adverse events. Although further studies are needed to ascertain the optimal target level, method, and duration of administration, AT-III is still a viable alternative for the treatment of severe VOD and ensuing multiple organ dysfunction.

High prevalence of thrombophilia among young patients with myocardial infarction and few conventional risk factors

Background: Thrombophilia refers to series of acquired and inherited conditions that confer a tendency to thrombus formation. The exact relationship between thrombophilia and MI is not well established. Objectives: To determine the prevalence of thrombophilia in young patients with their first MI and few conventional risk factors. Methods: We evaluated the baseline characteristics and the thrombophilia profile, including anti-cardiolipin antibodies, activated protein C resistance (APCR) with the factor V Leiden mutation, prothrombin G20210A mutation, protein C, protein S, and antithrombin-III levels, among 85 consecutive patients (<50 year old) who were admitted to CCU with their first MI. Patients were divided into two groups: group A—patients with ≤1 risk factor and group B—patients with ≥2 risk factors. Results: 92% were male and 55% with anterior wall MI. Overall, the risk factor profile was: smoking in 60%, hyperlipidemia in 42%, positive family history in 29%, hypertension in 18%, diabetes mellitus in 13%, and obesity in 8%. Forty-seven percent of patients had ≤1 risk factor ( n=40, group A) and 53% had ≥2 risk factors ( n=45, group B). The prevalence of the prothrombin mutation was 15% in group A compared to 7% in group B ( p=0.12). APCR secondary to a heterozygous genotype of factor V Leiden mutation was found in 20% in group A compared to 2% in group B ( p<0.01). Anti-cardiolipin antibodies were found in 16% in group A compared to 22% in group B ( p=ns). Finally, we have found that the likelihood of identifying at least one thrombophilia marker was 50% in group A compared to 29% in group B ( p=0.046). Conclusions: The likelihood to detect at least one thrombophilia marker in young patients with MI and few conventional risk factors is significantly high. Thrombophilia may contribute to the development of MI in this specific group of young patients.

Influence of modest endotoxemia on postoperative antithrombin deficiency and circulating secretory immunoglobulin a levels.

To evaluate the influence of modest endotoxemia on postoperative antithrombin deficiency and cholestasis. It has not been determined whether endotoxin translocation in small amounts is a physiological phenomenon or whether it is a potential health hazard. Blood endotoxin, antithrombin III (ATIII), secretory immunoglobulin A (sIgA), which was selected as a marker of cholestasis, C-reactive protein (CRP), and alpha-1-antitrypsin (AAT) concentrations were measured from the 20 patients undergoing curative gastrectomy for gastric cancer preoperatively and postoperatively. Portal and systemic blood samples were taken for the analysis of endotoxin and interleukin-6 (IL-6) concentrations during surgery in these patients. Although plasma endotoxin levels showed a significant increase during surgery, we did not find a correlation with ATIII, sIgA, CRP, and IL-6 levels. Systemic blood endotoxin levels during surgery correlated with a postoperative rise of serum AAT levels. Plasma ATIII levels transiently decreased on the first and third postoperative day, and sIgA levels were shown to increase on the seventh postoperative day. There was a weak relationship between the extent of postoperative endotoxemia and a reduction in ATIII concentrations. The influence of modest endotoxemia on postoperative antithrombin deficiency and cholestasis was limited, and increased translocational endotoxemia during abdominal surgery may be a physiological phenomenon to trigger off an acute-phase protein response.

Correlation of thrombophilia and hypofibrinolysis with pulmonary embolism following total hip arthroplasty: an analysis of genetic factors.

The increased thromboembolic risk associated with total hip arthroplasty is multifactorial. We assessed whether the prevalence of abnormalities shown by newer genetic screening tests for thrombophilia and hypofibrinolysis was higher in patients in whom pulmonary embolism had developed after total hip arthroplasty than it was in matched control patients. Fourteen patients with documented pulmonary embolism after total hip arthroplasty and fourteen matched control patients who had undergone total hip arthroplasty without any clinical indication of thromboembolism were evaluated for risks of thrombophilia and hypofibrinolysis. Functional tests of hemostasis included evaluations of prothrombin time; activated partial thromboplastin time; levels of fibrinogen, serum homocysteine, protein C and S, and antithrombin III; activated protein-C resistance; and dilute Russell viper venom time. Molecular genetic testing was performed for factor-V Leiden, prothrombin promoter G20210A, methylenetetrahydrofolate reductase C677T, plasminogen activator inhibitor-1 4G/4G, and platelet glycoprotein IIb/IIIa A1/A2 or A2/A2 mutations. The total number of genetic thrombophilic abnormalities identified was higher in the pulmonary embolism group (twenty-four abnormalities) than in the control group (fifteen abnormalities). Only patients with pulmonary embolism were found to have heterozygosity or homozygosity for the prothrombin G20210A mutation (four of fourteen patients; p = 0.05 compared with the control group) and a decreased antithrombin-III level (three of thirteen patients; p = 0.10 compared with the control group). Patients with pulmonary embolism were much more likely than control patients to have at least one thrombophilic abnormality: seven of fourteen patients with pulmonary embolism had a low antithrombin-III level or the prothrombin G20210A gene mutation compared with none of the fourteen in the control group (Fisher exact test, p < 0.01). The presence of the prothrombin G20210A gene mutation was significantly correlated with pulmonary embolism (r = 0.41, p = 0.03), as was the presence of least one abnormality (a low antithrombin-III level or the presence of the prothrombin G20210A gene mutation) (r = 0.58, p = 0.001). Genetic thrombophilia and hypofibrinolysis were more frequent in patients who had had pulmonary embolism after total hip arthroplasty than in those who had not. The presence of multiple genetic thrombophilic polymorphisms, particularly prothrombin G20210A and antithrombin III, rather than any single genetic prothrombotic abnormality, appears to signal an increased thromboembolic risk in patients undergoing total hip arthroplasty. Future refinements and availability of these tests will likely allow preoperative identification of patients with an increased genetic predisposition for thromboembolism.

Transfusion for coagulopathy after heart surgery: efficacy of laboratory studies.

Limited information exists regarding transfusions specifically for coagulopathy following cardiac surgery and the value of pre- and postoperative coagulation tests. Procedures (86% coronary bypass, 7.5% valve, and 6.5% combined valve and bypass) on 478 patients were reviewed; 101 patients (21%) were transfused for postoperative coagulopathy. Compared to those not transfused, patients with coagulopathy were significantly older and smaller, and they had more combined valve procedures, emergency operations, and preoperative heparin treatment as well as longer crossclamp and bypass times. Three preoperative tests showed significant differences in the coagulopathy group: activated clotting time, partial thromboplastin time, and antithrombin-III level. Four postoperative tests showed significant differences between the groups: prothrombin time, partial thromboplastin time, fibrinogen level, and fibrin split products at 10 dilutions. Patient characteristics and pre- and postoperative testing can identify patients at high risk of transfusion specifically related to coagulopathy.

Keeping the Circuit Open: Lessons from the Lab

Background: Hemofiltration circuits generally require anticoagulation to prevent the membrane from clotting. Understanding the mechanisms involved in premature clotting of the filtration circuit is useful to optimize anticoagulation and maintain filter patency. Aims: To discuss research performed at our institution which throws light on the causes of premature clotting of the hemofilter, and to highlight our approach to anticoagulation. Discussion: Premature clotting of the circuit is related to low baseline levels of antithrombin III (AT-III), heparin co-factor II and tissue factor pathway inhibitor. Clotting is preceded by a precipitous rise in thrombin-antithrombin complexes, suggesting thrombin generation. Our standard anticoagulant is unfractionated heparin, where the primary mode of action is potentiation of endogenous AT-III. However, AT-III levels are diminished in sepsis and other causes of systemic inflammation. To supplement or prevent consumption of AT-III we use fresh frozen plasma or aprotinin (as cheaper alternatives to AT-III) in situations where filter life span is limited and mechanical obstruction has been excluded. Anticoagulation can be managed in heparin-induced thrombocytopenic patients with danaparoid, prostaglandins and/or predilution.

Coagulative System Activation and Fibrinolytic System Inhibition Activities Arise From Tumoral Draining Vein in Colon Carcinoma

Hypercoagulability and activation/inhibition of the fibrinolytic system have been observed in abdominal cancer surgery. Because surgery itself and also neoplastic diseases are associated with these situations, a method for separating the origin of these two processes was designed. Eighteen patients with colon cancer who underwent a surgical procedure were studied: Immediately before surgery blood was taken from a peripheral vein. During the surgical procedure, before the exclusion of tumoral tissue from general circulation and at the same time of a second peripheral vein blood sample, a blood sample was taken from the main tumoral draining vein. Platelet-poor plasma samples were aliquoted and stored at −72 °C, ready for analytical procedures. Results: A moderate activation of the fibrinolytic system during surgery was observed, expressed by elevation of tissue plasminogen activator (t-PA) ( P<.05) and D-dimer (DD) ( P<.05) levels, without changes in fibrinogen (FG), plasminogen (PG) or antiplasmin (AP) levels. There were no modifications in antithrombin III (AT-III) and protein C (PC) levels. In the tumoral draining vein samples, there was a high elevation of levels of thrombin–antithrombin III complexes (TAT) ( P<.001) and PAI-1 ( P<.01), compared with the second sample peripheral vein. There was no difference between peripheral and tumoral vein sample levels of AT-III, PC, FG, DD, PG and AP. Conclusions: The tumour itself is the origin of hypercoagulability (TAT) and fibrinolytic system inhibition (PAI-1); the surgical procedure elicits an evident though moderate activation of the fibrinolytic system (t-PA and DD elevation).