AT-III Levels Research Articles

The state of development of coagulation alternatives for cardiopulmonary bypass

U'ufractionatcd heparin (UFH) is currently the most common anticoagulant used for cardiopulmonary bypass (CPB). Heparin was first used clinically in the 1930s and is widely prescribed due to rapid action and ready reversibility. The pharmacodynamics and pharmacokinetics of UFH are well studied and almost all research related to CPB utilizes UFH as the primary anticoagulant. Until recently, there have been no viable alternatives to heparin for anticoagulation during CPB. In recent years, a number of issues have emerged related to the use of UFH, particularly involving the immunological reaction of heparininduced thrombocytopenia (HIT). A search began for alternate anticoagulants with more favorable biological profiles and for different techniques that could minimize immunological reactions to heparin, particularly in cardiac surgery patients. Adverse effects of UFH during cardiopulmonary bypass may include significant inflammatory and hemostatic derangements as well as sensitization to future immunological reactions. Indeed, the problems seen with heparin in HIT may well be the tip of the iceberg with more subtle and often unrecognized immunologic and inflammatory changes occurring in most patients receiving heparin, particularly for CPB. I The ideal anticoagulant for CPB should meet several criteria: predictable onset and action, doserelated effect, easy and reliable monitoring with rapid point-of-care testing in the operating room, easy reversibility, minimal or no antigenic properties, minimal hemodynamic effects, and minimal effect on normal hemostasis. 2 Heparin is currently the gold for anticoagulation during cardiopulmonary bypass and is monitored by the activated clotting time (ACT), with well-established parameters for safe anticoagulation. However, heparin is unable to inhibit thrombin bound in an existing clot or bound to fibrin in the CPB circuit. Heparin's mechanism of action is dependent on anti-thrombin III (AT-lID, which can be problematic in AT-III deficient or depleted patients. Heparin decreases the concentration of AT-III either from chronic administration or acutely during CPB. The levels of AT-III seen during CPB are most often in the 40-60% of normal range but significant numbers of patients encounter levels of 20-30%. Levels below 40% are those that are seen during shock and diffuse intravascular coagulation. The implications of such low AT-Ill levels (2040%) during CPB is still under investigation. Finally, heparin is bound by plasma proteins and has a wide range of effect, so each patient's response to the drug must be monitored closely. Accurate ACT monitoring is affected by hemodilution, hypothermia and the use of aprotinin. Problems with heparin itself, heparin-induced thrombocytopenia, and monitoring of heparin effect lead to the development of new agents that could more effectively inhibit thrombin and reduce the risk of HIT) Alternate techniques that reduce or avoid the use of heparin include extreme hemodilution and heparin-bonded cardiopulmonary bypass circuits. Currently available pharmacological alternatives to heparin include: low molecular weight heparins (enoxaparin), heparinoids (danaparoid), ancrod, and the direct thrombin inhibitors recombinant hirudin (lepirudin), bivalirudin and argatroban. Also, standard doses of unfractionated heparin may be used in conjunction with the platelet anesthesia agents including prostaglandins (iloprost and prostacyclin) and the glycoprotein IIa-Illb inhil~itor tirofiban. Each alternative anticoagulant has attendant difficulties with its use related to availability, dosing and monitoring, antigenic cross-reactivity, excessive bleeding and thrombotic complications. Although alternative anticoagulant strategies are

Pathogenetic factors underlying juvenile deep vein thrombosis (DVT) in Indians.

The role of hereditary antithrombotic protein defects in juvenile deep vein thrombosis (DVT) was evaluated. Fifty six young patients (age <45 yr) with doppler-proven DVT were investigated for the presence of resistance to activated protein C (APC-R), lupus anticoagulant (LA), anticardiolipin antibodies and deficiencies of protein C, protein S, ATIII activities. Fifty nine normal healthy individuals served as controls. APC-R was observed to be the commonest defect underlying the Indian DVT as seen in 39.2% of patients followed by elevated ACA (5.3%), PAI (2.8%), presence of LA (2.8%) and reduced ATIII levels (2.8%). None of the subjects had protein C or S deficiency. APC-R was associated with ATIII deficiency in one case, and elevated ACA in two cases. In two subjects, APC-R was associated with elevated PAI levels. Patients with more than one prothrombotic factor had a higher prevalence of pulmonary thromboembolism, suggesting that the thrombogenic potential of APC-R is enhanced by the presence of coexisting hereditary or acquired prothrombotic defect.

Degree of Hypercoagulability and Hyperfibrinolysis is Related to Organ Failure and Prognosis after Burn Trauma

Severely burned patients often present a hypercoagulability situation. However, its magnitude, time course, and relationship with organ failure and outcome remains to be established. Forty-three patients were studied on the first and seventh day after burn for hypercoagulability and fibrinolysis parameters. A hypercoagulability and hyperfibrinolysis state was found the first day after burn demonstrated by high levels of activated factor VII (VIIa, p<0.01), thrombin-antithrombin III complex (TAT, p<0.01), tissue plasminogen activator (t-PA, p<0.001) and D dimer (DD, p<0.01) and low levels of antithrombin III (ATIII, p<0.01), protein C (PC, p<0.01), plasminogen (PG, p<0.001) and alpha2 antiplasmin (AP, p<0.001). A paradoxical coexisting hypofibrinolysis was found as suggested by a low global fibrinolytic activity in the euglobulin plasma fraction fibrin plate assay (FA, p<0.01) and high levels of tissue plasminogen activator inhibitor type 1 (PAI-1, p<0.01). On day 7, a less marked hypercoagulability situation was found, with low ATIII ( p<0.01) and PC ( p<0.01), persisting the hypofibrinolytic situation observed on the first day. Non-survivors (NS) showed higher levels of VIIa ( p<0.01), TAT ( p<0.05) and t-PA ( p<0.05), and lower levels of ATIII ( p<0.05), PC ( p<0.05) and AP ( p<0.001) than survivors (S) on the first day. Also, there was a positive correlation of Marshall organ failure score with ATIII, (r 2=0.49, p<0.001), PC, (r 2=0.14, p<0.045) and PG levels, (r 2=0.41, p<0.0003). Severely burned patients show a state of transient disseminated intravascular coagulation, related to the development of organ failure and outcome.

Coagulation and fibrinolytic systems in the ill preterm newborn.

The activation pattern of the clotting and fibrinolytic systems in 63 preterm infants (GA 31, 6 +/- 2.3 weeks) was studied. The infants were divided into four groups: (i) IRDS, (ii) asphyxia at birth, (iii) sepsis, and (iv) mild infection. A control group was composed of preterm infants without any apparent disease (GA 32 +/- 1.8 weeks). During IRDS we found a systemic activation of both coagulation and fibrinolysis at birth which was represented by lower levels of ATIII (27.7 +/- 8.8%) and significantly greater levels of TAT (37.9 +/- 31.9 ng/ml), D-dimers (1242.7 +/- 206.9 ng/ml), tPA Ag (10.9 +/- 5.3 ng/ml) and PAI Ag (59.9 +/- 16.7 ng/ml) than in the control group. In the asphyxiated newborns there were no significant differences from the controls. During their seventh day of life, a significant reduction of all the analysed parameters (TAT, D-dimers, tPA, PAI) and a significant increase in ATIII were seen in the newborns with IRDS, while no significant modification was observed in the newborns with asphyxia at birth. When the newborns with sepsis were compared with those with mild infection, their TAT and PAI values proved to be significantly higher for the first tests (21.7 +/- 18.8 vs 9.2 +/- 6.9 microg/l and 53.6 +/- 14.4 vs 37.7 +/- 10.2 ng/ml respectively). During the second tests, 7 days later, only TAT (16.7 +/- 14.7 vs 6.3 +/- 4 microg/l) levels remained high while D-dimers (1094.2 +/- 400.6 vs 646 +/- 200ng/ml) and tPA (11.3 +/- 8 vs 4.9 +/- 2 ng/ml) were significantly higher in the septic group of newborns than those with mild infection. These data indicate that there is an activation of the clotting and fibrinolytic systems both in the initial phase of IRDS as well as during sepsis.

Maternal and cord blood hemostasis at delivery.

Today we known that the coagulation system of the neonate differs in many ways from that of the adult system. We see a general reduction of the coagulation factors II-XIII (except VIII), the fibrinogen and of the coagulation inhibitors ATIII, protein C and heparin cofactor II at the same time. In addition the newborns show different levels of the coagulation factors for premature and full-term infants. This situation necessitates the generation of not one, but several, reference ranges for the various components of the hemostatic system. While the above-mentioned factors of the coagulation and fibrinolytic system of the newborn are well studied, our knowledge of others is still lagging behind that of the adult. That applies to the vWF and PAI and even more to D-Dimer. Our aim was to collect some data for vWF, PAI and D-Dimer to complete the understanding of the physiology of the hemostatic system in the newborn. Therefore we used the blood samples from 59 newborns and their mothers to obtain a number of different components of the coagulation and fibrinolytic system. Besides some rheological parameters (erythrocyte aggregation, plasma viscosity) we measured the aPTT, PT and the plasma levels of ATIII, fibrinogen and protein C (PC). But we paid special attention to the plasma levels of von Willebrand factor (vWF), plasma activator inhibitor (PAI) and D-Dimer. The blood samples were collected from the umbilical cord and the cubital vein of the mother immediately after delivery, anti-coagulated, centrifuged and stored until measurement at -70 degrees C. ATIII, aPTT, PT and fibrinogen were measured by the clotting technique test on the Chromotimer (Behring, Marburg, Germany). D-Dimer, vWF and protein C were determined with a commercially available ELISA obtained from Boehringer Mannheim (Mannheim, Germany). PAI activity was measured by a two-stage amiolytic method (Behring, Marburg). Besides the known differences of the neonatal hemostatic components to their mothers, such as a prolonged aPTT (52.19 s +/- 13.4 newborn, 35.26 s +/- 4.2 mother), reduced PT (64.34 s +/- 20.15 vs. 91.03 s +/- 1.25), ATIII (83.36% +/- 24.42 vs. 92.58% +/- 11.43) and fibrinogen (156.05 mg/dl +/- 91.68 vs. 344 mg/dl +/- 55.25), we found some peculiarities. The newborns show a clear reduction in the vWF (97.79 ng/ml +/- 36.33 vs. 183.43 ng/ml +/- 16.03) as well as the PAI (0.846 U/ml +/- 1.44 vs. 7.652 U/ml +/- 0.764). D-Dimer levels in the umbilical cord samples (1514.02 ng/ml +/- 953.56) are clearly prolonged in contrast to the maternal levels (740.2 ng/ml +/- 139.68). We were also able to find a difference of these factors related to gestational age. Premature infants showed a clearly higher level of PAI (2.2 U/ml +/- 2.86 vs. 0.69 +/- 1.13; p = 0.0136) compared with full-term infants, as well as significantly lower levels of ATIII (48.8% +/- 23.19 vs. 86.62 +/- 22.04; p = 0.0006) and protein C (25.33% +/- 9.37 vs. 35.73 +/- 7.53; p = 0.0027). D-Dimer, vWF, fibrinogen and the rheological parameters are similar. This seems to show an increased tendency for bleeding with the premature infant. Newborns show a balance of the coagulation system solely on a lower level. This is due to the general reduction of the coagulation factors with a reduction of the coagulation inhibitors at the same time. The physiologically low level of the vitamin K dependent and other coagulation factors and ATIII leads to a prolonged aPTT and reduced PT of the newborn. As well as these differences, known from literature, we found the following specialities: lower vWF and PAI and higher D-Dimer levels of the newborn compared with their mothers.

MONITORING THROMBIN GENERATION WITH PROTHROMBIN FRAGMENT 1.2 ASSAY DURING CARDIOPULMONARY BYPASS SURGERY

Despite high plasma levels of heparin during cardiopulmonary bypass surgery, activation of the coagulation system has been reported. We hypothesize that the coagulation system activity most appropriately could be assessed by molecular markers of thrombin generation. The aim of the present study was to describe the changes in thrombin generation during CPB, using prothrombin fragment F1+2 (F1.2) as an indicator and evaluate different blood sampling regimens for interpretation of the F1.2 measurements. Twenty patients, operated under extracorporeal circulation with coronary artery bypass grafting (CABG), comprised the study material. The heparin levels were maintained above 2.5 IU /ml throughout the bypass procedure and the functional AT-III level was kept above 0.5 U/ml. Despite of this anticipated inactivation of the coagulation system, the concentrations of F1.2 and FpA increased throughout CPB, particularly after release of the aortic crossclamp. F1.2 and FpA correlated significantly (R=0.69). No statistically significant correlation was found between F1.2 formation rate and age, bodyweight, baseline ACT, ACT after 200 IU heparin/kg, average heparin concentration during CPB or average AT-III level during CPB. CONCLUSIONS: Thrombin formation seems to be a continuous process during CPB despite adequate heparinization. The pattern of thrombin generation can be assessed most appropriately in terms of F1.2 generation rate. Extraordinary high levels of F1.2 were seen after release of the aortic crossclamp, indicating that the periods before and after aortic crossclamping should be evaluated separately.

Supplemental Use of Antithrombin Ill Concentrate in the Pediatric Patient

Decreased AT-III levels during cardiopulmonary bypass (CPB) have been observed in pediatric patients and are attributable to hemodilution. Prebypass administration of AT-III to the pediatric patient has been shown to prevent decreases in serum AT-III levels and elevated fibrinopeptide A (FPA) levels before and after bypass. We compared the clinical outcome of patients receiving supplemental AT-III injectate to control patients. Patients with preoperative AT-III levels less than 80% received AT-III injectate prior to heparinization. A retrospective analysis of 149 patients (31 study patients vs. 118 controls) revealed that a greater percentage of patients receiving AT-III were cyanotic (p=0.001) and underwent more complex cardiac repairs (p=0.001). Compared to patients not receiving AT-III, surgeries were performed at lower temperatures (p=0.040) with longer CPB times (p=0.031) and circulatory arrest times (p=0.047). Baseline AT-III levels were significantly lower in the treated group (p&lt;0.0001) but were significantly higher during CPB (p=0.0001). Total postoperative blood loss, blood product administration, rate of reoperation, total time in ICU and mortality proved not to be significantly different between the groups after adjusting for above covariates (p=NS). It appears that maintenance of higher AT-III levels did not affect the clinically measurable outcome variables associated with hemostasis.

Augmented Procoagulant Activity in Cancer Patients, Treated with Recombinant Interferon-γ in Addition to Recombinant Tumor Necrosis Factor-α and Melphalan

Several investigators have reported that interferon-gamma (IFN gamma) can alter tumor necrosis factor alpha induced effects in vitro. We assessed in vivo effects of recombinant interferon-gamma (rIFN gamma) on recombinant tumor necrosis factor-alpha (rTNF alpha) induced activation of systemic blood coagulation in a non-randomized study in 20 consecutive cancer patients. Eight patients were treated with rIFN gamma prior to and during hyperthermic isolated limb perfusion with rTNF alpha and melphalan (IFN gamma group). They were compared with twelve patients who did not additionally receive rIFN gamma (non-IFN gamma group). Before start of perfusion, higher levels of TNF alpha, F1+2 and TAT levels were found in the IFN gamma group. Fibrinogen and ATIII levels tended to be lower in this group. High TNF alpha levels, due to leakage during perfusion, were associated with activation of coagulation in all patients, that became obvious after the end of perfusion, when heparin treatment had been antagonized. Activation, measured by increased F1+2 and TAT levels, was significantly stronger in the IFN gamma group. Monocytic TF remained low, possibly due to shedding of TF positive vesicles and/or sequestration of TF positive activated monocytes against the vessel wall. In both groups F1+2 and TAT levels declined 24 h after the perfusion, whereas monocytic TF increased to levels that were higher in the IFN gamma group. In conclusion, our data confirm a strong activation of coagulation induced by rTNF alpha in cancer patients. They suggest that rIFN gamma may lead to a slight activation of coagulation and augments TNF alpha induced procoagulant activity. These effects may be due to rIFN gamma induced sustained monocytic TF activity.

Recombinant hirudin (HBW 023): biological data of ten patients with severe venous thrombo-embolism.

This study reports on the biological data of ten patients with acute venous thrombo-embolism. They were treated for 5 days with continuous intravenous infusion of a fixed dose (0.05 mg/kg/hr) of a recombinant hirudin (r-H HBW 023 Behringwerke, Germany). The plasma level of r-H (HBW 023), assessed by an anti-factor IIa amidolytic activity, was stable after Day 2 and showed considerable individual variations. It correlated with APTT ratio, suggesting that this test is a reliable tool to monitor therapy. In contrast, thrombin time was constantly over 120 sec (control 15 sec) and consequently was not a useful parameter. Prothrombin time showed a slight, but significant, prolongation, which was correlated with the increase of APTT ratio. There was no bleeding time prolongation, platelet count, or ATIII level decrease. Levels of thrombin-antithrombin III complexes, and D-dimers, which were high in all patients on admission, decreased during the course of the treatment but remained abnormal on Day 5, showing an ongoing hemostasis and fibrinolysis activation: this is consistent with the delayed, but only slightly decreased thrombin generation evidenced by thrombin generation test performed on Day 3. These results suggest that thrombin inhibition by rH-hirudin at this dosage is only partial, which allows the generation of traces of thrombin needed for the feed-back thrombin production generated by factor V and VIII activation.

Disseminated intravascular coagulation in liver cirrhosis

We measured thrombin-antithrombin III complex (TAT), soluble fibrin (SF) and D-dimer levels in 51 patients with liver cirrhosis to determine whether these tests provide new evidence for the presence of disseminated intravascular coagulation (DIC) in liver cirrhosis. TAT levels (median, range) were increased in the patient group (4.2 μg/l, 1.8–60.0) compared to the reference group (2.0 μg/l, range 1.5–7.6 μg/l). SF levels (0 nmol/l, range 0–80 nmol/l) were also increased in the patients as compared to the controls (0 nmol/l, 0), but there was no correlation between TAT and SF levels ( r = 0.23, p < 0.98). TAT levels did not correlate with AT-III levels ( r = −0.36, p < 0.49), but there was an inverse correlation between SF and AT-III ( r = 0.60, p < 0.001). If AT-III levels were above 0.30 U/ml, SF levels remained low, whereas SF levels were increased in patients with AT-III levels below 0.30 U/ml. These findings suggest that if sufficient AT-III is present, thrombin formation is adequately controlled, whereas at low levels of AT-III, thrombin escapes inactivation by AT-III and may act upon fibrinogen, leading to the formation of SF and a low-grade DIC. SF levels correlated well with D-dimer levels ( r = 0.55, p < 0.001), which is consistent with DIC and secondary fibrinolysis. In conclusion: (1) thrombin formation is increased in liver cirrhosis, as indicated by increased TAT levels in 21 of 51 patients; (2) the plasma concentration of AT-III appears to be of major importance for the development of DIC. The present study provides evidence for DIC in severe liver cirrhosis when AT-III levels are less than 0.30 U/ml.

Diagnostic efficacy of the D-Dimer assay in disseminated intravascular coagulation (DIC)

The D-Dimer (D-D) assay for measuring cross-linked fibrin degradation products is now available for the clinical laboratory. We combined this assay with other tests to assess patients with diagnosed or suspected DIC. Also, a small group of patients (20) with deep venous thrombosis (DVT) were studied. The D-D test, antithrombin-III assay, FDP titer, fibrinopeptide-A level, protamine sulfate test, fibrinogen, prothrombin time, and activated partial thromboplastin time were used. The D-D test was abnormal in 93.7%, the AT-III level was abnormal in 87.5%, the fibrinopeptide-A level was abnormal in 89.5%, and the FDP titer was elevated in 83.7% of patients with DIC. When assessing patients found not to have confirmed DIC the D-D assay was abnormal in 20%, the AT-III level was abnormal in 6%, and the fibrinopeptide-A level was elevated in 13%. We conclude the D-Dimer assay to be a useful molecular marker of hemostasis in diagnosing DIC and this test will often discriminate between those patients with or without DIC, especially when used with the AT-III and fibrinopeptide-A assays. Of the battery of tests used in this study, the most useful, in descending order of efficacy, appear to be the D-dimer assay (93.7% abnormal), the fibrinopeptide-A titer (89.5% abnormal), the AT-III level (87.5% abnormal), and the FDP titer (83.7% abnormal).

The Administration of Antithrombin III in the Management of Severe Preeclampsia

In severe preeclampsia/eclampsia a disseminated intravascular coagulation (DIC)-like syndrome is a prominent feature. Low levels of antithrombin III (AT-III; heparin cofactor) have been described in this syndrome. The objective of this pilot study is to determine whether the low levels of AT-III can be increased to normal by the intravenous administration of purified, concentrated, human AT-III. All patients entered into the study manifested thrombocytopenia, hemolytic anemia, coagulopathy, evidence of liver disease, and/or a bleeding diathesis. Each patient received a dose of AT-III equivalent to the amount in 3,000 ml of plasma. The levels of AT-III as measured by a functional assay were significantly increased (1.5–2x) following the initial 3,000 unit bolus of AT-III and prior to any other blood replacement therapy. The response of individual patients is proportional to the initial level of AT-III. In the control group there was no difference between the predelivery levels of AT-III and those obtained ...

Complement activation and the production of inflammatory mediators during the treatment of severe sepsis in humans.

Sepsis or septic shock is frequently associated with activation of the complement system, coagulation and fibrinolytic changes and the release of several cytokines. In this study we analyzed the relation of complement activation to the inflammatory mediators, hemodynamic and biochemical parameters and severity of illness and outcome in 20 consecutive patients with clinically defined sepsis. Levels of C3a and C3d were elevated in 90% of the patients (median levels 0.19 mg/l and 8.6 mg/l respectively) in comparison to 14% and 42%, respectively of 7 patients with non-septic shock. Levels of C4 were decreased in only 1 of the 20 septic patients. Levels of TNF and IL-6 were elevated in 94% and 100% of the patients, Levels of TNF and IL-6 were elevated in 94% and 100% of the patients, respectively (median levels 122 ng/l and 1300 U/ml) and were clearly interrelated (r = 0.67, p less than 0.01). C3a levels correlated with the APACHE II score (r = 0.57, p less than 0.05) and high C3a levels were associated with fatal outcome (p less than 0.05). C3a was also correlated inversely with mean arterial pressure (r = 0.50, p less than 0.01). Levels of complement C3a and C3d significantly correlated with levels of plasminogen activator inhibitor-1 (PAI) and correlated inversely with AT-III levels. We found no correlation between these complement products and leukocyte counts or lactate levels, nor was there a correlation between C3a or C3d and the cytokines TNF and IL-6. Levels of C3a and C3d did not decrease significantly during the first 24 h of treatment, in contrast to a clear decrease in IL-6 levels in all patients and a decrease in TNF in the surviving patients. TNF levels remained stable or increased in the non-survivors. We conclude that both the complement system and the cytokine system are involved in the pathogenesis of septic shock and may be involved in the development of some of the fatal complications like hypotension and disseminated intravascular coagulation.

ATIII and pulmonary embolism in the post prostatectomy

The variation in ATIII activity in the post prostatectomy period is examined by the Authors and is correlated with pulmonary embolism. Type of anaesthesia, blood transfusion and modality of blood transfusion (autotransfusion V/S homologous transfusion) were the parameters considered. In the post surgery period, the ATIII level decreases and afterwards slowly recovers. ATIII variations were similar in both auto transfused and non-transfused patients. The ATIII level decreased more in transfused patients than in those auto or not transfused. Other factors lowering the ATIII level were suprapubic prostatectomy and loco-regional anaesthesia; TURP or general anaesthesia were less influential. In the patients with pulmonary embolism ATIII activity decreased to below 70%. The Authors correlate these data with the risk of embolism.

Effects of dietary palm oil on serum lipid peroxidation, antithrombin III, plasma cyclic AMP, and platelet aggregation.

Intravascular thrombus formation in association with lipid depositions in the arterial wall is thought to be involved in the process of atheroma formation. We have previously shown the beneficial effect of palm oil on the serum lipid profile resulting in a lowering of serum triacylglycerol and an elevation of the HDL/LDL ratio. The present study investigates the effect of dietary palm oil on the biochemical parameters associated with clotting and platelet aggregation in young rats (70 g body wt) fed a palm oil diet over a period of 10 weeks. Palm oil-fed rats showed significantly lower levels of fibrinogen and serum lipid peroxide and elevated AtIII levels resulting in a prolongation of clotting time. Reduced platelet aggregation and ATP release associated with a prolongation of bleeding time were also found. These findings, together with our earlier findings on the effect of palm oil on the serum lipid profile, suggest that dietary palm oil may be antithrombotic as well as beneficial in preventing the deposition of lipids on the vessel wall and may, therefore, be protective against the development of atherosclerosis.

The Relationship between Clinical Signs and Hypercoagulable State in Toxemia of Pregnancy

The hypercoagulable state in patients with toxemia of pregnancy was investigated in comparison with normal pregnant women using new coagulation parameters, mainly thrombin-antithrombin III (TAT) complexes, alpha 2-antiplasmin-plasmin complexes (PIP), and D-dimer FDP. When the patients were categorized by the classification of the WHO Study Group (1985), significant increases of TAT complexes and alpha 2-PIP complexes with decreases of the ATIII level were observed in the groups with preeclampsia and severe gestational hypertensive disease as compared to normal pregnant women. A significant increase of D-dimer FDP was observed in a group with severe gestational hypertensive disease. Additionally, the relationship between clinical signs and the hypercoagulable state in the patients was analyzed using canonical correlation analysis as a multivariate analysis. The clinical signs and coagulation parameters had a significantly high correlation of lambda 1 = 0.7219, p less than 0.01. The results showed that clinical signs were associated with simultaneous coagulation abnormalities. The indices obtained from the results of canonical correlation analysis, which were called the clinical index and the coagulation index, should be useful in evaluating the efficacy of anticoagulation therapy.

Preoperative Plasmapheresis in Patients Undergoing Cardiac Surgery Procedures

Donor plasmapheresis that is carried out weeks before the operation has proven to be of benefit in elective orthopedic patients with regard to reducing homologous blood consumption and preserving coagulation. In this study acute preoperatively performed plasmapheresis (APP) was investigated in cardiac surgery patients. Forty-five patients scheduled for elective aortocoronary bypass surgery were randomly divided into three groups of 15 patients each: 1) removal of platelet-poor plasma (PPP), 2) removal of platelet-rich plasma (PRP), and 3) no plasmapheresis (control group). Plasma volume removed was 10 ml/kg in all APP patients, and plasma was replaced by the same amount of low-molecular weight hydroxyethylstarch solution (6% HES 200/0.5). Various laboratory data were investigated before, during, and after extracorporeal circulation (ECC). Blood loss in control patients was more pronounced than in the two APP groups; two of the control patients needed packed red cells. APP itself did not affect coagulation variables, free hemoglobin, or polymorphonuclear (PMN) elastase. At the end of the operation, 5 h after ECC, and at the first postoperative day the number of platelets was significantly lower in the control group; PRP patients showed the highest values. Fibrinogen and AT-III levels were less compromised in APP patients than in the control group. Global coagulation parameters did not differ between the groups within the whole investigation period. PMN elastase increased significantly during ECC in all groups with the greatest increase in the control group (722%) and the smallest increase in PRP patients (280%), possibly due to the removal of cellular elements in this group.(ABSTRACT TRUNCATED AT 250 WORDS)

The comparison of the pharmacokinetics of a low molecular weight heparin in the newborn and adult pig

Standard heparin (SH) is frequently used in the sick neonate to prevent catheter related thrombosis. SH can cause significant bleeding complications in the adult and its use in the neonate is linked to an increased incidence of intraventricular hemorrhage. Recently available low molecular weight heparins (LMWH) offer potential advantages over SH in the adult by exhibiting a longer half life and decreased bleeding side effects compared to SH. Whether LMWHs would offer similar therapeutic advantages to the sick neonate is unknown. Using the porcine model of neonatal hemostasis we measured the pharmacokinetics of a LMWH (Choay 222) in the pig (ATIII level: 100%), in the piglet (ATIII level:50% of adult) and in the piglet given exogenous ATIII. All pigs were bolused with 125I-LMWH (5, 25 or 100 anti-factor Xa units/kg) and blood samples collected for the measurement of 125I-radioactivity, and anti-factor Xa activity. The half life of LMWH, measured as either 125I-radioactivity or as anti-factor Xa activity, was not dose dependent and was similar in pigs and piglets; however, the volume of distribution was greater in the piglet resulting in an increased total clearance compared to the pig. As well, the supplementation of the piglet with exogenous ATIII did not influence the pharmacokinetics of LMWH. The half life of the LMWH in both pigs and piglets was approximately twice as long as previously reported values for SH in the same animal model. Thus the longer half life of LMWH in the piglet, and the similarity of the half life in piglets and pigs suggest that LMWH may have a therapeutic advantage in the newborn over SH.

Antithrombin III/Low-Dose Heparin in the Prevention of Deep-Vein Thrombosis After Total Knee Arthroplasty

This preliminary report outlines the rationale for a new approach to deep-vein thrombosis (DVT) prophylaxis in total knee arthroplasty (TKA) patients and describes preliminary hematologic and venographic findings. A protocol was employed to (1) document a series of hematologic events surrounding cemented TKA and the alterations of these events by the study drugs and (2) compare the safety and efficacy of a regimen of antithrombin III/low-dose heparin (ATIII/LDH) to that of low-molecular-weight dextran (LMWD) in the prevention of DVT after TKA. Using a dosage regimen of 3000 units of ATIII as a loading dose followed postoperatively by 2000 units daily combined with 5000 units of LDH twice daily, a prospective randomized study of patients treated by cemented TKA was performed. The ATIII/LDH regimen was compared with LMWD (10 ml/kg x 12 hours loading dose followed by 7 ml/kg x 24 hours maintenance dose). The rate of DVT after TKA in 42 patients was 25% (5/20) for the ATIII/LDH group versus 82% (18/22) for the LMWD group (p less than 0.001). Bleeding complications were minimal and comparable for each group. Hematologic studies demonstrated that quantitative and functional ATIII levels decreased after TKA and that preoperative loading with ATIII prevented levels from falling below 100%. Studies of clot formation (fibrinopeptide A) and plasmin activity (fibrinopeptides B beta 15-42 and 1-42) in 34 patients suggest some reduction in procoagulant activity in patients in the ATIII/LDH group. These findings indicate that the combination of ATIII and LDH may offer superior protection from DVT than does LMWD.

Replacement Therapy in Antithrombin III Deficiency

NTITHROMBIN III (ATIll) has two impor­ tant roles in hemostasis; it is the predomi­ nant circulating inhibitor of clotting factors acti­ vated during blood coagulation, and the major heparin cofactor in plasma. 1 Its key modulatory function is clearly illustrated by the long-recog­ nized causal relationship between inherited an­ tithrombin deficiency and familial venous thromboembolism. 2 There are, of course, other hemostatic control mechanisms. Indeed, recent investigations have begun to show the complex network of free and surface-bound inhibitory proteins (ATIII and thrombomodulin), glycosaminoglycans (heparan and dermatan sulphates), heparin cofactors (ATIII and HCII) , and negative feedback mechanisms (protein Ca and protein Sa)' which, together with the adsorption of thrombin to fibrin, normally en­ sures that coagulation factors activated by throm­ bogenic stimuli are neutralized, and the extent and duration of thrombin generation remains limited. 1.3-5 Inherited ATIII deficiency is relatively uncom­ mon, but moderate to severe, or transient or sus­ tained, acquired reduction in ATIII level or activ­ ity commonly follows major surgery, occurs during treatment with certain drugs (heparin, es­ trogen-containing oral contraceptives, and L-as­ paraginase), and is a feature of many disease pro­ cesses (notably disseminated intravascular coagulation (DIC), but also acute or chronic liver failure, severe pre-eclampsia, and the nephrotic syndrome). These observations are of more than passing in­ terest, given that ATIll concentrates prepared by conventional plasma fractionation methods are now widely available for replacement therapy, and that recombinant technology could provide ex­ tremely pure ATIII for clinical use in the not very distant future. Hence, it becomes important in a practical sense to question the pathogenetic signif­ icance of ATIll deficiency in various clinical set­ tings' and to ask when and if replacement therapy is warranted. This review will therefore examine the evidence that quantitative or qualitative ATIII deficiency may (l) predispose to thromboembolism, (2) ex­ acerbate or perpetuate thromboembolic processes,