Pharmacokinetic optimisation of the treatment of deep vein thrombosis

The current treatment for deep vein thrombosis is a 5- to 10-day course of heparin followed by 3 to 6 months of oral anticoagulants. Both heparin and oral anticoagulants present a high inter- and intra-individual variability and require individualisation and monitoring of their dosage. The pharmacokinetic properties of heparin have been difficult to assess through the radiolabelling procedures typically used for many other drugs. This is partially a result of the heterogeneous nature of heparin. Thus, the pharmacokinetics of heparin are expressed in terms of its pharmacodynamic activity. Improved coagulation test methodology coupled with the incorporation of patient factors such as bodyweight, height, baseline coagulation status, pretreatment heparin sensitivity and heparin concentrations, can be used to improve the accuracy of heparin dosage determination. Computer-based systems are now available to assist clinicians in quantitating dosage requirements, estimating bleeding risks, and storing patient dose-response relationships for future therapy monitoring. Low molecular weight heparin products might improve our ability to control anticoagulant therapy because drug concentration, as well as the effect on the clotting system, will be more predictable in patients receiving these products. In addition, low molecular weight heparins produce a more consistent, predictable anticoagulant response, and clinicians have a new pharmacological tool which may readily lend itself to patient-controlled, home-based anticoagulant pharmacotherapy. Where pharmacokinetics and pharmacodynamics could contribute to the optimisation of warfarin treatment is in the initiation of treatment, the estimation of the dosage required, the methods for drug monitoring, the assessment of unusual responses and the avoidance of drug interactions. Traditional pharmaco kinetic methods have limited applicability to the optimisation of warfarin therapy because there is no direct relationship between drug concentration and therapeutic effect. However, a variety of simple or sophisticated computer-assisted methods have been developed to help clinicians in individualising and monitoring warfarin treatment. New therapeutic approaches, such as direct thrombin inhibitors and thrombolytic agents, could overcome some limitations of the standard heparin plus oral anticoagulation therapy.     

Purpura fulminans in the newborn. Report of two cases successfully treated with heparin and antithrombin III

Purpura fulminans is a rare form of disseminated intravascular coagulation characterized by rapidly progressive purpuric lesions, hypotension and, in some cases, fever. In neonates, purpura fulminans usually develops following deficiency of anticoagulant protein C or S, although acquired forms have been described. The management of disseminated intravascular coagulation is still controversial, with some studies finding a positive effect of anticoagulants and others showing no effect or even a detrimental one. Therefore, at present, management is limited to the treatment of underlying disease and replacement of clotting factors. Personal experience is reported on the efficacy of heparin in combination with antithrombin III in the treatment of purpura fulminans in two preterm neonates who did not have inherited deficiency of protein C or S and developed the disease possibly following prolonged labor (36 hours) in the first case, and maternal neoplasia, in the second. Both neonates presented with widespread cyanotic areas rapidly evolving in purpuric lesions and hemorrhagic bullae. Laboratory tests (prolonged prothrombin and partial thromboplastin time, fibrinogen and antithrombin III concentrations below normal ranges, d-dimer highly positive) were consistent with disseminated intravascular coagulation. In both cases anticoagulant treatment with heparin (50 UI/kg in bolus followed by 15 UI/kg/h) and antithrombin III was associated with resolution of disseminated intravascular coagulation and prompt amelioration of the purpuric lesions, without apparent side effects.     

Vasoflux, a new anticoagulant with a novel mechanism of action

BACKGROUND: Heparin and direct thrombin inhibitors, such as hirudin, have limitations in the treatment of acute coronary syndromes. Heparin does not inactivate fibrin-bound thrombin, whereas hirudin fails to block thrombin generation. In contrast, Vasoflux is a novel anticoagulant that inactivates fibrin-bound thrombin and attenuates factor Xa generation. METHODS AND RESULTS: Vasoflux is prepared by depolymerization of heparin, restricting molecular size to between 3000 and 8000 Da, and reducing antithrombin affinity by periodate oxidation. Vasoflux catalyzes fibrin-bound thrombin inactivation by heparin cofactor II (HCII) and inhibits factor IXa activation of factor X independently of antithrombin and HCII. Compared with other anticoagulants in a thrombogenic extracorporeal circuit, Vasoflux maintains filter patency at concentrations that produce an activated clotting time (ACT) of 220 seconds. In contrast, to maintain filter patency, heparin, low-molecular-weight heparin (LMWH), and hirudin require concentrations that produced an ACT of 720, 415, and >1500 seconds, respectively, whereas dermatan sulfate was ineffective at concentrations that produced an ACT of 360 seconds. CONCLUSIONS: Vasoflux is more effective than heparin and LMWH because it inactivates fibrin-bound thrombin and is superior to hirudin and dermatan sulfate because it also blocks factor Xa generation.     

Severe glomerulonephritis complicated by coagulopathy: treatment with anticoaguland and immunosuppresive drugs

Serial determinations, using plasma fibrinogen gel chromatography as well as standard methodology, demonstrated that six children with severe glomerulonephritis, characterized on renal biopsy by glomerular necrosis and crescent formation, had persistent evidence of intravascular coagulation. Based on these observations, therapy with anticoagulants and azathicoagulants and azathioprine was instituted for one year; treatment with anticoagulants was continued for a second year. Anticoagulant therapy was initiated with heparin, followed by oral anticoagulation with phenindione and dipyridamole. In contrast to our earlier experience with similar patients, each of the present patients improved. Urinalyses returned to normal and glomerular filtration rates to near normal values in all patients at the end of the treatment period and have remained so for up to 3.9 years since treatment has been completed. Post-treatment biopsies showed remarkable improvement, with virtually no glomerulosclerosis even in patients who had had a high incidence of glomerular crescents before treatment. It is suggested that the therapeutic regimen favorably influenced the natural history of disease and that plasma fibrinogen chromatographic findings may be helpful in selecting patients likely to benefit from the use of anticoagulant therapy.     

PHLECO: a multicenter study of the fate of 1647 hospital patients treated conservatively without fibrinolysis and surgery

The PHLECO Study (phlebothrombosis conservative therapy) is a multicenter investigation of patients with deep vein thrombosis receiving conservative nonfibrinolytic hospital treatment. A second study (part II: PHLEFI, phlebothrombosis fibrinolytic treatment) to be published later deals with the outcome of fibrinolytic therapy. In both studies the incidence of life-threatening sequelae, such as pulmonary embolism, is of major interest. The 49 medical departments participating in the study mailed the relevant data to the Duisburg Coordination Center for further data analysis and the following information was gained: (a) In descending order of frequency, the clinical conditions of thrombosis were: immobility, postoperative status, malignancy, hormone treatment, posttraumatic conditions, and pregnancy. (b) In descending order of frequency, the sites of thrombosis were: femoral vein, calf vein, iliac vein, popliteal vein, and subclavian vein. Left-sided thrombosis predominated in the iliac and subclavian vein groups. (c) In descending order of frequency, the treatment regimens employed were: intravenous heparin+oral anticoagulants, intravenous heparin+subcutaneous heparin, intravenous heparin alone, subcutaneous heparin alone, intravenous heparin+subcutaneous heparin+oral anticoagulants, subcutaneous heparin+oral anticoagulants, intravenous heparin+platelet aggregation inhibitors. (d) The average hospital stay was 23.7 +/- 15.6 days. No correlation existed between duration of hospital stay and particular types of therapy. (e) The incidence of nonfatal pulmonary embolism was 16.1% while that of fatal pulmonary embolism was 2.33%. (f) Women outnumbered men in the group with fatal pulmonary embolism, and the death rate among older patients was higher than that among younger patients. (g) Patients with fatal pulmonary embolism had a shorter history of thrombosis than patients in the unselected cohort (patients with and without pulmonary embolism).(ABSTRACT TRUNCATED AT 250 WORDS)     

Anticoagulant therapy with recombinant hirudin in patients with thrombopenia induced by heparin

OBJECTIVES: Heparin-induced thrombocytopenia is an uncommon and severe complication of heparin therapy. Both venous and arterial thromboembolic events can occur, requiring withdrawal of the heparin therapy. When anticoagulant therapy is mandatory, recombinant hirudin can be used. METHODS: We used recombinant hirudin (HBW 023) in 6 patients with heparin induced thrombocytopenia. In case of venous thromboembolism, an initial intravenous bolus (0.07 mg/kg) was followed by continuous infusion (0.05 mg/kg/h); for arterial thromboembolism the initial bolus was 0.7 mg/kg and infusion rate 0.15 mg/kg/h. When possible oral anticoagulants were started and hirudin withdrawn when the INR ratio reached 3. RESULTS: The clinical course was uneventful in all 6 patients. There was no recurrent thromboembolism. Cephalin-activated coagulation time (patient/control) varied between 1.8 and 3.5 (median 2.4) during hirudin administration. Platelet count rose to the nadir (median 70 x 10(9)/l, range 15-90) reaching over 100 x 10(9)/l in all patients between the third and sixth day (median 5 days) after stopping heparin. CONCLUSION: Intravenous administration of hirudin provides effective immediate anticoagulation in patients with heparin-induced thrombocytopenia, thus allowing conversion to oral anticoagulants without risking recurrent thromboembolism.     

Monitoring anticoagulant treatment with the KEM-O-MAT 2HP autoanalyzer

Synthetic chromogenic substrates were adapted to KEM-O-MAT 2HP for an automated monitoring of anticoagulant treatments, determination of factor X (S 2337) in oral anticoagulation, anti-Xa (Hepachrom) and anti-lla (S 2238) activities of heparin in prophylactic and curative heparin therapies. In all cases, these methods revealed high sensitivity, reproducibility, and a good correlation of their results with those of classical clotting assays. The present cost of synthetic substrates seriously limits the potential value of chromogenic assays for routine controls. However, the development of automated amidolytic techniques should provide an easier standardization in the laboratory control of anticoagulant treatments.     

r-Hirudin inhibits platelet-dependent thrombosis during cardiopulmonary bypass in baboons

BACKGROUND: Systemic anticoagulation is required during cardiopulmonary bypass (CPB) to inhibit the activation of platelets, the coagulation system and ultimately thrombus formation. Unfractionated heparin is most commonly used, but it is neither entirely safe nor completely effective. The use of protamine sulphate to reverse the anticoagulant effect further complicates the use of heparin. The clinical need for a heparin substitute is therefore obvious. We evaluated the efficacy of r-Hirudin, a potent and specific inhibitor of thrombin, as anticoagulant in a baboon model of cardiopulmonary bypass. METHODS: Ten baboons, divided into two groups of five each, were used. The one group received 0.7 mg/kg r-Hirudin as a bolus before CPB was started, followed by a constant infusion of 1.4 mg/kg/hr for the 90 min of CPB. The other group received a bolus of 2.5 mg/kg heparin before the start of CPB, followed by maintenance dosages to maintain the activated clotting time (ACT) >400 sec. RESULTS: Adequate anticoagulation was obtained with both anticoagulants. Haemodilution due to priming the extracorporeal system with Ringer's lactate and appropriately anticoagulated donor blood, was equivalent in both groups. During CPB with heparin, but not with hirudin, there was a significant increase in the number of circulating platelet aggregates, thrombin-antithrombin (TAT) complexes and 111In-labelled platelet accumulation in the oxygenator. After the initial decrease in platelet count due to haemodilution, it further decreased significantly during CPB with heparin but remained relatively constant when r-Hirudin was used. CONCLUSIONS: Our results strongly suggest that r-Hirudin is superior to heparin especially with respect to its inhibitory effect on platelet dependent thrombogenesis caused by the biomembranes of the oxygenator.     

Increased platelet responsiveness following coronary stenting. Heparin as a possible aetiological factor in stent thrombosis

AIMS: Platelet activation may be a determinant of thrombotic and restenotic complications following intracoronary stenting. In order to measure the effect of stenting on platelet activation antigen expression we used whole blood flow cytometry in 18 patients undergoing Palmaz-Schatz stenting (treated with full anticoagulation) and compared these with a group of 18 patients undergoing elective angioplasty. The effects of low molecular weight heparin and unfractionated heparin on platelet behaviour were also studied, both in vitro and in vivo to determine the contribution of prolonged heparin therapy to platelet activation following stenting. METHODS AND RESULTS: Fibrinogen binding to activated GPIIb-IIIa, and surface expression of P-selectin, GPIb and GPIIb-IIIa antigens were measured in unstimulated peripheral blood samples (rest) and on stimulation with adenosine diphosphate (0.1-10 micromol x 1(-1)) and thrombin (0.02-0.16 U x ml(-1)). No changes were seen in resting samples following angioplasty or stenting. Agonist responsiveness was unaltered after angioplasty, but in stented patients antigen expression in response to thrombin was significantly reduced (P< or =0.04), whilst the adenosine diphosphate response was significantly increased (P=0.01). Similar effects were observed in patients with unstable angina treated with either low molecular weight heparin or unfractionated heparin in vivo. In vitro, both unfractionated and low molecular weight heparin inhibited thrombin-induced platelet activation, but stimulation of adenosine diphosphate responses was more marked with unfractionated than low molecular weight heparin. CONCLUSIONS: There was a significant increase in platelet responsiveness to adenosine diphosphate following intracoronary stenting in patients treated with conventional anticoagulants. This was probably a consequence of treatment with heparin. Activation of platelets by heparin may explain the increased rate of stent thrombosis in patients treated with anticoagulant therapy. Low molecular weight heparins stimulate platelets less than unfractionated heparin.     

Heparin-induced thrombocytopenia and thrombosis

Although heparin is widely used as the injectable anticoagulant of choice, it has several potential shortcomings. These include heparin resistance, excessive bleeding, allergic reactions, and, with longterm use, occasional osteoporosis or alopecia. Perhaps the most notorious complication is heparin-induced thrombocytopenia and thrombosis (HITT); although unusual, it often results in major morbidity or death. Until recently, reliable diagnostic tests and anticoagulation alternatives have not been widely available. After a review of the pharmacology of heparin and related drugs, advances in the prevention, diagnosis, and treatment of this problem are discussed.     

Non-anticoagulant heparin increases endothelial nitric oxide synthase activity: role of inhibitory guanine nucleotide proteins

Heparin, which is widely used clinically, has recently been shown to have specific properties affecting the vascular endothelium. We hypothesized that heparin stimulates endothelial nitric oxide synthase (eNOS) activity by a mechanism independent of its anticoagulant properties and dependent on an inhibitory guanine nucleotide regulatory protein (Gi). We determined the effect of both heparin and N-acetyl heparin (Non-Hep), a heparin derivative without anticoagulant properties, on eNOS activity in cultured bovine aortic endothelial cells and on endothelium-dependent relaxation in isolated vascular rings. The eNOS activity was determined by measuring both citrulline and nitric oxide (NO) metabolite formation. Heparin and Non-Hep dose-dependently increased basal eNOS activity (ED50 1.0 microgram/ml or 0.15 U/ml), an effect that was significantly inhibited by pertussis toxin (100 ng/ml), a Gi-protein inhibitor. Agonist-stimulated (acetylcholine, 10 microM) eNOS activity was potentiated following pre-treatment with both heparin and Non-Hep and reversed by pertussis toxin. Heparin and Non-Hep induced a dose-dependent relaxation in preconstricted thoracic aortic rings, an effect that was significantly inhibited by pertussis toxin, endothelial inactivation (following treatment with sodium deoxycholate) and NG-nitro-L-arginine-methyl ester (L-NAME). We conclude that heparin and non-anticoagulant heparin induce endothelium-dependent relaxation following activation of eNOS by a mechanism involving a Gi-protein. Administration of heparin derivatives without anticoagulant properties may have therapeutic implications for the preservation of eNOS in conditions characterized by endothelial dysfunction.     

Medical treatment of heart failure at a tertiary hospital of S?o Paulo]

The clinical hemostatic effect of tranexamic acid mouthwash after oral surgery was evaluated in 47 patients receiving oral anticoagulant therapy. Surgery was performed after the anticoagulant medication was reduced in 15 patients (control group) and with no change in anticoagulant therapy in 32 patients (test group). The only statistical difference between the two treatment groups at baseline was the level of anticoagulation, which was significantly higher in the test group. There was no significant difference between the two treatment groups in the incidence of bleeding after oral surgery. The results indicated that a combination of local antifibrinolytic therapy and a local hemostatic agent is effective in preventing postoperative bleeding after oral surgery in patients treated with anticoagulants.     

Self-blame and peer victimization in middle school: an attributional analysis

Intravenous heparin followed by warfarin has been the classical anticoagulant therapy of acute venous thromboembolism for the past 30 years. In recent years a number of low-molecular-weight heparins have become available for clinical trials. These agents have a number of advantages over unfractionated heparin and are now being used internationally for the prevention and treatment of venous thromboembolism. Low-molecular-weight heparin will undoubtedly replace intravenous unfractionated heparin not only in the treatment of venous thromboembolism but in other conditions where heparin therapy is indicated. Whether or not the low-molecular-weight heparins can decrease or eliminate some of the complications of unfractionated heparin will depend on the outcome of future clinical trials.     

Enhanced expression of bcl-2 inhibits apoptosis in cultured human keratinocytes

Intravenous heparin followed by oral warfarin sodium is effective for preventing recurrent thromboembolism in patients who have pulmonary embolism or proximal vein thrombosis. The effectiveness of intravenous heparin depends on obtaining an adequate anticoagulant response early during therapy. A validated heparin protocol should be used to ensure that an adequate anticoagulant response is obtained as soon as possible. Low molecular weight heparin has the practical advantage that it does not require monitoring and dose finding. If thrombolytic therapy is indicated, it is safer for many patients to base management on the noninvasive diagnosis rather than performing pulmonary angiography. In patients suspected to have pulmonary embolism who have nondiagnostic lung scan and adequate cardiorespiratory reserve, serial noninvasive leg testing is a practical approach that avoids pulmonary angiography, identifies patients who have proximal vein thrombosis requiring treatment, and avoids the risks of anticoagulant treatment in the majority of patients.     

Laboratory assessment of antithrombotic therapy: what tests and if so why?

A critical review is given of the tests available for the assessment of the action of anticoagulants, such as heparins, oral anticoagulants and direct thrombin inhibitors, in patients under antithrombotic therapy. The principle of action and the performance of the thromboplastin time (PT), the activated partial thromboplastin time (aPTT), the whole blood clotting time, the thrombin time, the ecarin clotting time and the endogenous thrombin potential (ETP) is discussed, as well as the evidence behind the accepted therapeutic ranges. The two most common tests, PT and aPTT, respond in an essentially different way to clinically effective anticoagulation with heparin and with oral anticoagulants. This means that they covariate with, but do not themselves represent the essential parameter influenced by anticoagulation. The experimental basis for the widely accepted two times prolongation of the aPTT as an indicator for adequate anticoagulation is shown to be meagre in the case of unfractionated heparin and lacking for the other anticoagulants. Common sources for error in the interpretation of anti-factor Xa- and anti-thrombin activity of heparins are indicated. Extensive experience with new tests like the ecarin clotting time and the ETP is still lacking. On the basis of preliminary data and in view of the importance of the enzymatic action of thrombin in the pathogenesis of thrombosis, the ETP is considered a possible candidate for a common parameter to assess different types of anticoagulants.     

Anticoagulants for venous thrombosis

The anticoagulant agents heparin and warfarin were introduced before the era of randomised clinical trials. As a result, the indications, dosages and monitoring techniques of these drugs have undergone re-evaluation in multiple clinical trials in the past years. Low molecular weight heparin has been developed, which has led to new approaches in anticoagulant management. Current levels of laboratory, pharmacology and clinical knowledge in the treatment of venous thromboembolism are discussed.     

Cardiopulmonary bypass with danaparoid sodium and ancrod in heparin-induced thrombocytopenia

Heparin is the standard anticoagulant for patients undergoing cardiopulmonary bypass. There are some patients for whom heparin is unsuitable and ancrod (a defibrinogenating enzyme) has been used as an alternative. We present a patient with heparin-induced thrombocytopenia in whom treatment ancrod was ineffective. The addition of danaparoid sodium (a heparinoid) allowed safe cardiopulmonary bypass. We discuss the reasons for this and suggest that the combination of ancrod and danaparoid sodium is a logical one in such cases.     

Evaluation of a modified APTT-based method for determination of APC resistance in plasma from patients on heparin or oral anticoagulant therapy

An APTT-based kit method (Coatest APC Resistance), modified by predilution 1+4 of sample plasma in a plasma diluent containing a heparin antagonist (V-DEF plasma), has been evaluated on plasmas from patients treated with unfractionated (n = 110) or either of three different low molecular heparins (n=44), or with oral anticoagulants (n=147). Irrespective of treatment, no difference was observed in the APC response as compared to untreated individuals (n=62), and a complete discrimination was obtained between individuals with a normal factor V genotype and those carrying the FV:Q506 mutation. Furthermore, in contrast to the original, APTT-based kit method, where anticoagulant therapy results in a prolongation of the APTT, the modified kit provided APTT values within the normal range for orally anticoagulated (INR< or =6) and for all heparin treated (< or =1 IU/mL) patients except for one with a suspected presence of phospholipid antibodies. Due to the predilution in V-DEF plasma, contamination with platelets up to 1.5 x 10(4)/microL had a negligible effect on analysis of frozen plasmas regarding their classification as normal or abnormal. Analyses of fresh plasmas show no influence at platelet counts up to 6x10(4)/microL. Consequently, negligible differences in APC ratios were obtained between fresh and frozen plasmas. In conclusion, the modified kit method is applicable to plasmas from anticoagulated patients as well as from untreated individuals, allowing a safe assignment regarding the presence or absence of the FV:Q506 genotype.     

Cholesterol crystal embolism during treatment with low-molecular-weight heparin

BACKGROUND: Cholesterol crystal embolism is often an iatrogenic complication in ulcerated atherosclerosis of the aorta. CASE REPORTS: Two cases of multi-organ embolism of cholesterol crystals were histologically proven in patients treated with low-molecular-weight heparin. Both patients had acute renal failure, hypertension with acute pulmonary edema, skin necrosis and ischemia of the digestive tract. Outcome was favorable after discontinuing anticoagulants, symptomatic treatment, definitive hemodialysis and low-dose corticosteroids. DISCUSSION: These two cases are the first reported in the literature of cholesterol crystal embolism occurring during prophylactic treatment with low-molecular-weight heparin. They demonstrate that there is a risk of severe cholesterol embolism in high-risk patients after administration of low-molecular-weight heparin as for non-fractionated heparin, fibrinolytics, arteriography and cardiovascular surgery. Low-molecular-weight heparin thus should not be used in patients with a diagnosis of cholesterol crystal embolism.     

Effect of gamma radiation on the molecular weight and the anticoagulant activity of heparin

4 g% aqueous solutions of heparin were irradiated with the gamma radiation doses of 4.6 x 10(5) or 9.2 x 10(5) rads. The irradiated and also the non-irradiated heparin samples were fractionated using a Sephadex G-200 column. With radiation, the peak of the molecular weight distribution curves shifted toward the lower molecular weight. Also, the number average molecular weight decreased by 8.2 and 11.5% with the doses of 4.6 x 10(5) and 9.2 x 10(5) rads, respectively. The anticoagulant activity depended on the molecular weight of the heparin fractions. For the heparin fractions with molecular weights below 7,900, the anticoagulant activity decreased with radiation. Thus, for a heparin fraction with a molecular weight of 6,200, the anticoagulant activity decreased from 211 to 198 IU/mg after 4 h of irradiation.