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.     

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.     

Comparative effects of L-NOARG and L-NAME on basal blood flow and ACh-induced vasodilatation in rat diaphragmatic microcirculation

Anticoagulants are widely used in the prevention of thromboembolic disease (particularly during the postoperative period) and in the curative treatment of deep vein thromboses. Two classes of anticoagulants are currently available: heparins (standard heparin, low molecular weight heparin) and coumarin anticoagulants. The choice of anticoagulant must take into account the clinical context (preventive or curative treatment), as well as the pharmacological and pharmacokinetic properties of the anticoagulant. This treatment requires laboratory monitoring adopted to the anticoagulant selected.     

Effect of warfarin on activated partial thromboplastin time in patients receiving heparin

BACKGROUND: The activated partial thromboplastin time (APTT) is used to adjust heparin sodium dosage. However, warfarin sodium is often administered concomitantly with heparin and may also affect the APTT and, therefore, heparin dose. We performed a prospective cohort study to quantify the effect of warfarin on the APTT in patients who are being treated with heparin. METHODS: Serial assays of APTT, international normalized ratio, heparin levels, and functional levels of prothrombin (factor II) and factors VII and X were performed in 24 patients with acute venous thromboembolism who were treated with concomitant continuous intravenous heparin and warfarin. The effects of warfarin, as expressed by international normalized ratio and coagulation factor levels, on APTT were determined. RESULTS: Warfarin markedly affected APTT; for each increase of 1.0 in the international normalized ratio, the APTT increased 16 seconds (95% confidence interval, 10-22 seconds). The effects of warfarin and heparin on APTT were additive. Consequently, warfarin markedly altered the relationship between APTT and heparin levels; of the 29 blood samples with supratherapeutic APTT, 13 had a therapeutic heparin level and 10 had a subtherapeutic heparin level. CONCLUSIONS: In patients receiving concomitant heparin and warfarin therapy, APTT reflects the combined effects of both drugs. Because of the marked effect of warfarin on the APTT, decreasing heparin dose in response to a high APTT frequently results in subtherapeutic heparin levels.     

Genotoxicity of hydrazino-phtalazine antihypertensive drugs assessed by an in vitro micronucleus assay

Oral anticoagulant therapy is effective antithrombotic treatment for several indications. The results of prothrombin time monitoring should be reported as the International Normalized Ratio (INR). An INR of 2 to 3 is the recommended therapeutic range for all indications except for the prevention of systemic embolism in patients with mechanical heart valves and for the long-term treatment of patients with myocardial infarction, for whom an INR range of 2.5 to 3.5 is recommended. Oral anticoagulant therapy with warfarin sodium is the preferred approach for preventing stroke in most patients with atrial fibrillation. The available data suggest that warfarin is more effective than aspirin. Aspirin, 325 mg/d, is indicated for patients in whom warfarin is contraindicated or in patients less than 75 years of age who are at low risk for stroke because risk factors are absent. In patients 75 years of age or more, close monitoring of warfarin treatment is prudent to avoid major bleeding due to poor anticoagulant control. In selected patients, patient-self-monitoring and adjustment of warfarin treatment using a portable prothrombin time monitor may be effective and safe.     

Low-molecular-weight heparins

Low-molecular-weight heparins (LMWH) are a new group of parenteral anticoagulants. They represent a major clinical advance in anticoagulation since the identification of unfractionated heparin (UFH) in 1922 and the introduction of the synthetic coumarin derivative, warfarin, in 1948. Their predictable pharmacokinetics, increased bioavailability, and longer plasma half-life allow for once- or twice-daily dosing and eliminate the need for routine laboratory monitoring. This simplified administration stands to alter the clinical practice of anticoagulation. This review high-lights recent clinical trials and focuses on studies comparing LMWH with the other two major anticoagulants: UFH and coumadin.     

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.     

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.     

Oral delivery of anticoagulant doses of heparin. A randomized, double-blind, controlled study in humans

BACKGROUND: Parenteral heparin is the anticoagulant of choice in hospitalized patients. Continued anticoagulation is achieved by subcutaneous administration of low-molecular-weight heparin or with an orally active anticoagulant such as warfarin. An oral heparin formulation would avoid the inconvenience of subcutaneous injection and the unfavorable drug interactions and adverse events associated with warfarin. A candidate delivery agent, sodium N-[8(-2-hydroxybenzoyl)amino]caprylate (SNAC), was evaluated with escalating oral heparin doses in a randomized, double-blind, controlled clinical study for safety, tolerability, and effects on indexes of anticoagulation. METHODS AND RESULTS: Increases in activated partial thromboplastin time (aPTT), anti-factors IIa and Xa, and tissue factor pathway inhibitor (TFPI) concentrations were detected when normal volunteers were dosed with 10.5 g SNAC/20000 IU heparin by gavage in some subjects. For the entire group, 30000 IU SNAC and heparin elevated TFPI from 74.9+/-7.6 to 254.2+/-12.3 mg/mL (P<0.001) 1 hour after dosing (P<0.001). Similar changes occurred in anti-factor IIa and anti-factor Xa. aPTT rose from 28+/-0.5 to 42.2+/-6.3 seconds 2 hours after dosing (P<0.01). No significant changes in vital signs, physical examination, ECGs, or clinical laboratory values were observed. Neither 30000 IU heparin alone nor 10.5 g SNAC alone altered the hemostatic parameters. Emesis was associated with 10.5 g SNAC. A taste-masked preparation of SNAC 2.25 g was administered orally with heparin 30000 to 150000 IU. Both aPTT and anti-factor Xa increased with escalating doses of heparin. This preparation was well tolerated. Conclusions-Heparin, administered orally in combination with the delivery agent SNAC, produces significant elevations in 4 indexes of anticoagulant effect in healthy human volunteers. These results establish the feasibility of oral delivery of anticoagulant doses of heparin in humans and may have broader implications for the absorption of macromolecules.     

Doxorubicin cardiotoxicity in children: comparison of a consecutive divided daily dose administration schedule with single dose (rapid) infusion administration

Kyphoscoliosis surgery is frequently associated with major blood loss and coagulation disorders. A patient with juvenile rheumatoid arthritis, heart valve prosthesis and respiratory restrictive syndrome, was submitted to surgical correction of kyphoscoliosis. Current drug therapy included digitalis, oral anticoagulant and nonsteroidal anti-inflammatory drugs. After careful preoperative evaluation, oral anticoagulant and nonsteroidal anti-inflammatory drugs were discontinued (five and ten days before surgery, respectively), and intravenous heparin was introduced and maintained until two h before surgery. Bacterial endocarditis prophylaxis was obtained with ampicillin (50 mg.kg-1) and gentamicin (1.5 mg.kg-1). Anaesthetic management followed a general, balanced technique and the use of invasive monitoring devices. Clotting times were kept within the normal range--prothrombin time between 13 s and 14 s; partial thromboplastin time between 28 s and 30 s. Surgery was straightforward. The patient remained ventilated for 24 h and intravenous morphine (6 micrograms.kg-1.h-1) was used for nurse controlled analgesia. Afterwards, this was changed for patient controlled analgesia. Intravenous heparin was restarted 12 h after surgery and there were no complications postoperatively. Keeping the patient without anticoagulant therapy during this kind of surgery, was the less harmful option, taking into consideration that haemorrhage is inevitable and thromboembolism is a potential, though serious risk.     

Augmentation of the neuromuscular blocking effects of cisatracurium during desflurane, sevoflurane, isoflurane or total i.v. anaesthesia

We recently performed a laparoscopic cholecystectomy on three patients receiving preoperative oral anticoagulant therapy. The patients requiring anticoagulants for pre-existing cardiac conditions have the following risks at surgery: thromboembolism, hemorrhage, endocarditis, and cardiopulmonary dysfunction. In patients receiving anticoagulant therapy, one must thus maintain a balanced international normalized ratio of the prothrombin time to prevent thromboembolism or hemorrhage. Warfarin sodium was discontinued preoperatively in all patients. Heparin sodium was individualized according to each patient's risk of thromboembolism. As a result, these patients all underwent a laparoscopic cholecystectomy without complications. Attention was paid to achieve hemostasis in the operative field and the trocar inserted sites during the procedure. The administration of warfarin sodium was resumed on the first postoperative day in all patients. Restarting warfarin sodium early also helps to simplify postoperative management. A broad spectrum of antibiotic therapy was also used to reduce the risk of endocarditis. Each patient's cardiopulmonary function was carefully monitored. The minimal invasion experienced during a laparoscopic cholecystectomy may thus facilitate the management of gallstones in patients receiving systemic anticoagulation treatment based on the findings of this limited series.     

Treatment of coumarin-induced skin necrosis with a monoclonal antibody purified protein C concentrate

BACKGROUND AND DESIGN--Protein C is a vitamin K-dependent plasma protein that is converted to the serine protease activated protein C by the thrombin-thrombomodulin complex. Activated protein C functions as a natural anticoagulant by inactivating the cofactors of the coagulation cascade, factors Va and VIIIa. Coumarin (warfarin)-induced skin necrosis is thought to be due to a rapid elimination of protein C relative to other vitamin K-dependent factors during the initial phase of oral anticoagulation. We have used a highly purified protein C concentrate to treat a patient with acquired protein C deficiency who developed skin necrosis during the initial phase of oral anticoagulant therapy. OBSERVATIONS AND CONCLUSIONS--During protein C concentrate therapy, no further skin lesions appeared, and the healing process of necrotic areas was facilitated. Replacement therapy with protein C concentrate appears to be safe and effective as an adjunctive treatment for coumarin-induced skin necrosis.     

Prevention of hemorrhage and dental treatment of patients with congenital or acquired coagulopathies

The physiopathology of the hemorrhagic blood coagulation disorders caused by genetic or aquired problems is described. Among the former the most frequent ones include the hemophilia of type A-B and the von Willebrand disease, among the latter the use of oral anticoagulant constitutes the most frequent cause. If the are not subjected to an adequate haemostatic prophylaxis, both patients with hemophilia and von Willebrand disease present a serious haemorrhagic risk as a consequence of dental practice. As far as the use of anticoagulants is concerned, a periodical monitoring of the time of prothrombin (PT) is needed to find the right dosage (TP between 20%-30% or INR--international normalized radio between 2 and 3.5). Values over this range cause an increase of the hemorrhagic risk, while lower values involve an increased risk of thrombotic events. According to the authors the patients with the hemorrhagic diathesis show a precise handicap, caused both by his illness and by environmental elements, such as the fear of doctors for the haemorrhagic complications consequent to a therapeutical operation, fear that often leads to neglect important medical measures, in particular dental measures. The specialized dental surgeon has to mantain a strict cooperation with the hematologist in order to arrange an appropriate procedure of the prophylaxis. As far as the hemostatic prophylaxis is concerned, the use of the dermopressin (DDAVP), in patients with hemophilia A and von Willebrand disease, guarantees the realisation of dental practice without hemorrhagic risk. On the contrary, the use of the tranhexanic acid on patients in an anticoagulant oral treatment gives hemostatic security and makes it possible to carry on the therapy and the out-patient treatment.     

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.     

Oral anticoagulant prophylaxis and epidural catheter removal

BACKGROUND AND OBJECTIVES: The use of regional anesthesia in patients receiving anticoagulants is controversial. The purpose of this review is to document the incidence of neurologic complications with insertion and removal of an epidural catheter in patients receiving oral anticoagulants and antiplatelet medication. METHODS: A retrospective review was made of the charts of 459 patients who underwent hip pinning or hip or knee replacement under regional anesthesia and received postoperative epidural analgesia and warfarin thromboembolism prophylaxis. The number of patients receiving preoperative antiplatelet therapy and warfarin, as well as baseline coagulation parameters, was documented. For patients who had postoperative epidural analgesia, the prothrombin time on the day of epidural catheter removal was obtained. Neurologic complications during the hospital stay were noted. RESULTS: Spinal anesthesia was administered to 47 patients and epidural anesthesia and postoperative analgesia to 412. Before surgery, antiplatelet therapy was given to 270 and warfarin to 180 patients, with some patients receiving both. The mean +/- SD preoperative prothrombin and partial thromboplastin times were 10.8 +/- 1.2 seconds (normal, 9.6-11.1 seconds) and 27.5 +/- 3.5 seconds (normal, 24.6-33.2 seconds), respectively. Blood on needle or catheter insertion was noted in 21 patients, all of whom were taking antiplatelet medication and/or warfarin. Epidural catheters remained postoperatively for a mean of 43.6 +/- 12.5 hours (range 5-118 hours). The mean prothrombin time on the day of epidural catheter removal was 14.1 +/- 3.2 seconds. Four postoperative peripheral neuropathies were detected. There was no clinical evidence of spinal hematoma in any patient. CONCLUSIONS: Epidural catheter placement and removal in patients taking oral anticoagulants appears to be safe. Careful monitoring of the patient for evidence of spinal hematoma after epidural catheter removal is recommended.     

Current recommendations for warfarin therapy. Use and monitoring

With the aging population, the use of warfarin will continue to increase. The introduction of new thromboplastins with International Sensitivity Indices (ISI) of 1.0 to 1.5 has improved the efficacy of monitoring warfarin therapy with the prothrombin time (PT). Increasingly, outpatient oral anticoagulant clinics and home testing are the sites for PT monitoring.     

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.     

The effect of N-alkyloxycarbonyl group on the anticonvulsant activities of N-alkyloxycarbonyl-alpha-aminoglutarimides

The aim of this study was to determine the effect of heparin therapy on the international normalized ratio (INR). In vitro heparin sensitivity curves were created using normal and warfarinized plasma samples from patients. The INR results were measured with each of two reagents. In addition, a comparison of INR values with these two reagents was performed on plasma from patients receiving therapeutic heparin and warfarin. The INR values were measured before and after heparin removal with a heparin adsorbent system. While one of the reagents was found to be sensitive to even low levels of therapeutic heparin, the other thromboplastin was resistant up to at least 0.9 U/mL. The INR values determined for patients with one of the reagents were found to be erroneously elevated by an average of 16%. The error ranged from 2% to 55% depending on the in vivo heparin concentration. With the other reagent, the INR values were not substantially affected by heparin. Previous studies have described the effect or lack thereof of heparin on the prothrombin time. The present study demonstrates that the degree to which INR results are prolonged by heparin therapy depends on the reagent formulation. As the therapeutic index for monitoring warfarin is relatively narrow (2.0-3.0), an INR value that is falsely elevated due to reagent sensitivity may precipitate premature cessation of heparin therapy and place certain patients at risk for recurrent thrombosis in the short term.     

Experimental kallikrein gene therapy in hypertension, cardiovascular and renal diseases

Argatroban, a direct thrombin inhibitor, is used clinically because of its safe and effective antithrombotic action. This drug of low molecular weight shows reversible inhibition of thrombin irrespective of whether thrombin is fibrin-bound or soluble. Optimal anticoagulant effects can easily be attained by monitoring with the activated partial thromboplastin time or whole-blood activated clotting time when a therapeutic range of argatroban equivalent to that of heparin is used. The antithrombotic action is simply detected with a chromogenic substrate assay. The clinical use of the drug in Japan was approved for the treatment of chronic peripheral arterial obstructive disease and acute ischemic stroke. For coronary artery disease in patients with deficiency of antithrombin activities attributable to either antithrombin III or heparin cofactor II deficiency, argatroban is effective as an anticoagulant. Acute coronary occlusion during and after percutaneous transluminal coronary angioplasty can be treated by argatroban as an alternative to heparin. The presence of platelets activated by a trace amount of thrombin is evidenced by modified methods of platelet aggregometry in acute ischemic stroke. Therefore, argatroban can render the platelets insensitive against the platelet hyperaggregation enhanced by thrombin.     

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.