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A Pilot Study of Subcutaneous Recombinant Hirudin (HBW 023) in the Treatment of Deep Vein Thrombosis
Abstract
Recombinant hirudin, a pure, specific antithrombin could be more effective than heparin in the treatment of deep vein thrombosis, but its short half-life requires constant intravenous infusion, whereas subcutaneous administration of recombinant hirudin can ensure stable and prolonged plasma levels. The aim of our study was to assess the pharmacokinetics, the results on the coagulation variables, and the safety of a recombinant hirudin (HBW 023) administered subcutaneously in patients suffering from deep vein thrombosis.
Recombinant hirudin (HBW 023) was administered subcutaneously to 10 patients with recent deep vein thrombosis, at a dose of 0.75 mg/kg of body weight twice daily for 5 days, after which standard heparin and acenocoumarol were introduced. Bilateral lower limb venography, and pulmonary angiography, and/or ventilation-perfusion lung scan were carried out on day 1 prior to recombinant hirudin injection and repeated on day 5. aPTT and recombinant hirudin plasma levels were serially assessed after the 1st and the 10th injections. Prothrombin fragments 1 + 2, thrombin-antithrombin III complexes, fibrin degradation products were collected on days 1 and 5.
Clinical evolution was uneventful in all but one patient who had a probable recurrence of pulmonary embolism on day 4. No hemorrhagic complication, no untoward biological event was observed. On days 5, Marder score was unchanged or had decreased. Plasma levels of recombinant hirudin peaked in between 3 and 4 h following the injection. aPTT values paralleled, and were significantly correlated with plasma levels of recombinant hirudin on day 1 as well on day 5 (r = 0.903, r = 0.948 respectively). Fragment 1 + 2, and thrombin antithrombin complexes non-significantly decreased from day 1 to day 5.
Subcutaneous administration of recombinant hirudin ensures prolonged stable plasma levels of recombinant hirudin which results in efficient anticoagulation. A dose-ranging study conducted with subcutaneous recombinant hirudin in comparison to conventional heparin therapy may answer the question as to efficacy.
... Recombinant hirudin (r-hirudin) is almost as effective and safe as heparin for the prophylaxis of venous thrombosis in total hip replacement 2 and for the treatment of myocardial infarction, 3 unstable angina, 4 and deep vein thrombosis. 5 It is the drug of choice for the anticoagulant treatment of patients with heparin-induced thrombocytopenia (HIT) and thromboembolic complications because it is a non-heparin anticoagulant with specific antithrombin potency, which thus enables rapid anticoagulation. 6,7 As polypeptides, hirudins may elicit an immunological response in humans; this may also be due to the long phylogenetic distance from invertebrates. ...
Heparin-induced thrombocytopenia is a less common but severe side effect of heparin therapy. Heparin-induced IgG antibody was elucidated to be the main isotype and the most pathogenic antibody in the pathophysiology. As the patients are at high risk of developing thrombotic events, the confirmation of clinical diagnosis and avoidance of heparin reexposure are important and desirable. A fluorescence-linked immunofiltration assay (FLIFA) was developed for the determination of heparin-induced IgG in heparin-induced thrombocytopenia (HIT) type II patients. A high frequency of heparin-induced IgG in heparin-induced thrombocytopenia type II patients can be detected using the novel antigen assay. The immediate determination of pathogenic heparin-induced IgG may be a useful tool for the rapid diagnosis of heparin- induced thrombocytopenia type II that could facilitate further management of the patients.
... Bei klinischen Untersuchungen (Thrombolyse bei Myokardinfarkt [1][2][3], Thromboseprophylaxe [4], Hämodialyse [7,8], instabile Angina pectoris und perkutane transluminale Koronarangioplastie [12, 13, 2l], Therapie tiefer Venenthrombosen [22], disseminierte intravasale Gerinnung [23], kardiochirurgische Eingriffe [24,25]) wurden zur Kontrolle und Steuerung der Hirudintherapie mehrheitlich Globalteste verwendet. Neben der aktivierten Gerinnungszeit (ACT) wurde insbesondere die aktivierte partielle Thromboplastinzeit (APTT) eingesetzt [24]. ...
... In zahlreichen Studien wurde die Anwendung von Hirudin geprüft, so bei der Behandlung der disseminierten intravasalen Gerinnung [56,65], der tiefen Beinvenenthrombose [66,71], der Angina pectoris [81,82], des akuten Myokardinfarkts [1,2,62] und schließlich auch der Heparin-induzierten Thrombozytopenie [29]. Hirudin erwies sich als ein dem Heparin vergleichbares Antikoagulans. ...
Rekombinantes Hirudin ist ein sehr potenter direkter Thrombinantagonist, der zur Behandlung einer Heparin-induzierten Thrombozytopenie eingesetzt wird. Da Hirudin hauptsächlich renal eliminiert wird, ist seine Halbwertszeit bei Patienten mit eingeschränkter Nierenfunktion stark verlängert. Diese Patienten sind daher verstärkt durch Blutungskomplikationen gefährdet, zumal bisher noch kein klinisch verfügbares Antidot bekannt ist. Um Hirudin auch bei niereninsuffizienten Patienten einsetzen zu können, sind Informationen zur Hirudinfiltration verschiedener Hämodialysatoren von großem Interesse.
In der vorliegenden Studie wurden mit einem Rezirkulationsmodell acht verschiedene in der Klinik häufig verwendete Low-Flux- und High-Flux-Dialysatoren hinsichtlich ihrer Filtrationseigenschaften für Hirudin charakterisiert. Alle verwendeten High-Flux-Dialysemembranen filtrierten Hirudin. Dabei zeigte der Polysulfon-Dialysator mit einem Siebkoeffizienten (SK) von 0,97 in den Vollblutexperimenten die besten Filtrationseigenschaften. Während auch die Dialysatoren aus Polyarylethersulfon (SK=0,73) und Polymethylmethacrylat (SK=0,75) eine gute Hirudinfiltration zeigten, lag der Siebkoeffizient bei Verwendung des Polyamid-Dialysators mit 0,49 deutlich unter dem der anderen getesteten Dialysatoren. Keiner der untersuchten Low-Flux-Dialysatoren aus Cuprophan, Hämophan, Polysulfon und Polymethylmethacrylat wies eine relevante Hirudinfiltration auf.
Um die Hirudinkonzentration im Falle einer Blutungskomplikation oder Überdosierung zu senken, ist demnach eine Hämofiltration mit High-Flux-Dialysatoren aus Polysulfon am besten geeignet. Im Rahmen von Nierenersatzverfahren mit Hirudin als Antikoagulans können sowohl Low- als auch High-Flux-Membranen verwendet werden. Dabei sollte die Hirudindosierung insbesondere an die Permeabilität des eingesetzten Filters, aber auch an die jeweilige klinische Situation des Patienten angepaßt werden.
... Its terminal half-life in young healthy volunteers is about 1.3 hours. The bioavailability of the drug is also almost 100% with subcutaneous (sc) administration, with peak plasma drug concentration achieved in 3-4 hours (Verstraete et al 1993;Schiele et al 1994). ...
Lepirudin, a recombinant hirudin, is a direct irreversible thrombin inhibitor by binding to both free and clot-bound thrombin. It is approved for treatment of heparin-induced thrombocytopenia (HIT), which is a serious antibody-mediated drug reaction mostly associated with the use of unfractionated heparin. Clinical experience during the last 10 years has proved the efficacy of lepirudin in the management of HIT. The major route of elimination of lepirudin is the kidney, accounting for approximately 90% of its systemic clearance. The most important adverse reactions are bleeding and the induction of immunologic reactions. The risk of bleeding can be reduced by implementing an optimal monitoring and dose adjustment strategy, particularly in patients undergoing cardiopulmonary bypass surgery and in those with impaired renal function. Development of antihirudin antibodies may enhance the anticoagulant effect of lepirudin. Anaphylactic reactions associated with lepirudin therapy are rare. The lack of an antidote against lepirudin is still a concern, particularly during cardiopulmonary bypass surgery with a heart-lung machine and during artificial renal support. Currently, hemofiltration using high-flux filter systems is the only available and valid means to manage hirudin overdose. Nevertheless, the drug can be safely used if meticulous monitoring strategy is installed.
... Peak aPTT values, were measured 2 h (1´5±2´5 h) after the s.c. r-hirudin injection as recommended by Schiele et al (1994). The ECT ratios were calculated as the normal ECT (55 s) divided by the individual value. ...
We prospectively investigated 27 patients with heparin-induced thrombocytopenia (HIT) type II who were subsequently treated with r-hirudin. Patients with venous or arterial thromboembolism were treated with activated partial thromboplastin time (aPTT)-controlled intravenous r-hirudin (n = 19; mean 19.3 d) followed by subcutaneous r-hirudin (n = 6; mean 22.5 d) and oral anticoagulation. Patients without thromboembolism were treated with subcutaneous r-hirudin (n = 8; mean 25.9 d). Four patients were readmitted to subcutaneous r-hirudin for a mean duration of 32 d. The incidence of r-hirudin antibodies was 84% for intravenously treated patients and 50% in subcutaneously treated patients. The patients (n = 27) showed a 74% overall incidence of r-hirudin antibodies, mainly of the IgG-subclass, without seroconversion before day 6 and after day 32 of r-hirudin treatment or during r-hirudin treatment. None of the patients showed onset or recurrence of venous or arterial thromboembolism, systemic allergic reactions or IgE-antibody development.
During intravenous and subcutaneous administration of r-hirudin the aPTT and the ecarin clotting time was increased in the antibody-positive patients compared to antibody-negative patients. Therefore we assume that r-hirudin antibodies may reduce r-hirudin metabolism.
... After injection of 0.75 mg/kg SC, a peak lepirudin concentration of Ϸ0.7 g/mL occurs in 3 to 4 hours. 18 Renal clearance and degradation account for Ϸ90% of the systemic clearance. The t 1/2 of lepirudin lengthens with deterioration of renal function 19,20 to up to 150 hours. ...
Clinical applications for recombinant hirudins have been investigated for the past 10 years. The first indication for which a hirudin-lepirudin-has been approved is treatment of heparin-induced thrombocytopenia (HIT). Also, the recently completed trials for use of lepirudin in unstable angina indicate a potentially new indication. This review describes pharmacology and clinical applications of lepirudin with an emphasis on HIT and unstable angina. An overview of usage of lepirudin in acute coronary syndromes is given, as well as a summary of rare indications for lepirudin, such as extracorporeal circulation, for which comprehensive data are lacking.
... route involves r- hirudins: lepirudin and desiru- din. 9,[17][18][19][20][21] Lepirudin is identical to natural hirudin except for the substi- tution of leucine for isoleucine at the N-terminal end and the removal of a sulfate group on the tyrosine at posi- tion 63. Similarly, desirudin is identi- cal to hirudin except that it lacks a sulfate on tyrosine at position 63. ...
The development of thrombosis within a diseased artery or vein is responsible for acute coronary syndromes, deep venous thrombosis, pulmonary embolism, cerebral vascular accidents, and limb and bowel ischemia. Thrombin plays a central role in the process of thrombosis. Heparin, which is currently the mainstay of antithrombotic therapy for the acute phase of all of these clinical syndromes, is only partially effective. The limitations of heparin therapy may be linked to several features of its mode of action, which may be overcome by the use of direct thrombin inhibitors, a new class of agents that specifically and potently antagonize the actions of thrombin.
Der medizinische Blutegel (Hirudo medicinalis), ein blutsaugender Parasit, eröffnet durch einen Y-förmigen Biß der 3 bezahnten Kiefer Blutgefäße in der Unterhautregion seiner Opfer. Durch die Benetzung der Wundränder mit dem Sekret der kranialen Speicheldrüsen des Blutegels wird die Wunde offengehalten und gleichzeitig das gesaugte Blut antikoaguliert. Haycraft (1884), Franz und Jacobi (1904) haben bereits Ende des vergangenen Jahrhunderts das wirksame Prinzip des Speichelsekretes untersucht und ihm den Namen Hirudin gegeben. 1926 verwendete Haas ein Hirudinpräparat erstmalig als Antikoagulans bei einem Hämodialyseversuch am Menschen. In den 50er und 60er Jahren erfolgte die weitere Reinigung und biochemische Charakterisierung von Hirudin. In den 80er Jahren wurde nach Sequenzierung die gentechnologische Herstellung eingeleitet und die pharmakologische Wertbestimmung bei Versuchstieren und am Menschen durchgeführt.
Lepirudin is a recombinant hirudin derived from yeast. Natural hirudin, a family of highly homologous polypeptides, is produced in trace amounts by the leech, . Hirudo medicinalis. The biosynthetic lepirudin is identical to natural hirudin except for substitution of leucine for an N-terminal isoleucine and the absence of a sulfate group on tyrosine-63. Lepirudin is a .
Objective: To evaluate the efficacy and safety of Shuxuetong injection in the treatment of deep vein thrombosis. Methods: Patients with deep vein thrombosis in the lower extremity (n = 92) were randomly divided into 2 groups, and treated with slow intravenous infusion of Shuxuetong injection (n = 46) and low molecular weight beparin (control, n = 46), respectively. The changes in coagulation indexes (PT, APTT, INR and FIB) were observed before and after the treatments. Results: After treatment with Shuxuetong injection for 2 weeks, the changes in coagulation indexes (including APTT and PT) were prolonged, and the content of fibrinogen was reduced. Conclusion: Shuxuetong injection is effective and safe for the treatment of deep vein thrombosis, which may result from anticoagulation and reduction of fibrinogen.
Lepirudin is a recombinant hirudin derived from transfected yeast cells. The hirudins are direct thrombin inhibitors which render the thrombin molecule incapable of promoting fibrin formation and catalysing other haemostatic reactions.
In initial studies, parenteral lepirudin has shown promising efficacy as an antithrombotic agent. Lepirudin increased or maintained platelet counts at normal baseline values while maintaining adequate anticoagulation in patients with heparin-induced thrombocytopenia (HIT), and has not been associated with the development of immune-mediated thrombocytopenia.
Preliminary studies in patients with deep vein thrombosis (DVT) suggest that lepirudin may be more effective than unfractionated heparin (UFH) at preventing pulmonary perfusion defects. In patients with unstable angina pectoris, preliminary data also showed lepirudin to be significantly more effective than UFH according to the combined incidence of cardiovascular mortality, new acute myocardial infarction (AMI) or refractory angina. However, additional studies involving larger patient numbers are necessary before firm conclusions can be made regarding the relative efficacy of lepirudin in these indications. Similarly, promising but limited data on the use of lepirudin during haemodialysis or heart surgery and in patients with disseminated intravascular coagulation (DIC) require further confirmation.
Bleeding complications and the possible induction of allergic or anaphylactic reactions are the most serious adverse events associated with lepirudin therapy. Major bleeding complication rates appear to be similar with lepirudin and UFH monotherapy; however, lepirudin may be associated with an increased incidence of minor bleeding including bruising.
Initial encouraging results showing an improvement in coronary artery patency with high-dose lepirudin versus UFH as an adjunct to thrombolytic therapy in patients with AMI were subsequently overshadowed by reports of a high incidence of major bleeding events including cerebral haemorrhage among lepirudin recipients. Moreover, at lower doses which did not produce an unacceptably high incidence of haemorrhagic complications, lepirudin appeared to have only a small efficacy advantage over UFH.
Conclusions: Lepirudin has shown promising activity as an antithrombotic agent and may be a suitable substitute anticoagulant for heparin in patients with HIT. The narrow therapeutic window of lepirudin makes it difficult to assess the role of this agent when used as an adjunct to thrombolytic therapy in patients with AMI. However, initial data suggest that lepirudin may be a potentially useful agent in the management of patients with unstable angina, DVT or DIC and in preventing thrombus formation in extracorporeal circuits. Further studies should more fully elucidate the efficacy of lepirudin in these indications.
Pharmacodynamic Properties
Lepirudin is a recombinant hirudin derived from transfected yeast cells, which directly inhibits thrombin. In contrast to that of heparin, the antithrombotic mechanism of action of the hirudins is independent of the presence of antithrombin and instead involves the formation of a stable noncovalent complex between the hirudin and thrombin molecules. This renders the thrombin molecule incapable of promoting fibrin formation and catalysing other haemostatic reactions such as activation of clotting factors V, VIII and XIII and thrombin-induced platelet aggregation. Importantly, the hirudins appear to inhibit not only free but also clot-bound thrombin which continues to have prothrombotic activity. However, they appear to have a limited inhibitory effect on the generation of thrombin from prothrombin.
Lepirudin has demonstrated antithrombotic activity in several animal models of thrombosis and was more effective than unfractionated heparin (UFH) at inhibiting thrombin formation in the hamster femoral vein model of mural thrombosis and in a baboon model of cardiopulmonary bypass (CPB). Lepirudin also prevented disseminated clotting in animal models of disseminated intravascular coagulation (DIC) and reduced elevated plasma levels of fibrin/fibrinogen degradation products, D-dimer, thrombin-antithrombin complex and plasmin α2-antiplasmin complex in patients with DIC.
Thrombin-induced platelet activation was inhibited by lepirudin in blood taken from healthy volunteers during bleeding; however, platelet aggregation induced by endogenously generated thrombin after intrinsic activation of platelet-rich plasma was inhibited less efficiently.
Inhibition of thrombin by lepirudin results in a dose-dependent prolongation of the activated partial thromboplastin time (aPTT); this coagulation parameter is currently used to monitor the anticoagulant activity of lepirudin. However, problems of standardisation and reports of wide interindividual variability of aPTT ratios among lepirudin-treated patients suggest that aPTT may not be the optimal marker.
Positive lepirudin antibody titres developed in 38 of 82 patients (46.3%) with heparin-induced thrombocytopenia (HIT) after ≥6 days’ treatment with lepirudin and resulted in a prolongation of aPTT values to >100 seconds in 3 patients. Limited data are available on re-exposure of patients to lepirudin; however, 4 patients with antilepirudin antibodies treated with a second course of lepirudin did not develop allergic reactions.
Pharmacokinetic Profile
Lepirudin is rapidly distributed throughout the extracellular compartment after intravenous administration; its plasma pharmacokinetics are best described by a 2-compartment model. In contrast, the pharmacokinetic profile of lepirudin after subcutaneous administration best fits a 1-compartment model with an absorption phase. There was no evidence of drug accumulation following repeated subcutaneous (0.5 or 1.0 mg/kg/day) or intravenous administration of lepirudin (0.1 or 0.2 mg/kg/day) to healthy young volunteers. Similarly, significant drug accumulation was not evident after subcutaneous administration of lepirudin 0.75 mg/kg twice daily for 5 days to patients with deep vein thrombosis (DVT).
Volume of distribution determinations at steady state ranged from 13.3 to 22.4L, suggesting that lepirudin is primarily confined to the extracellular space.
Lepirudin is excreted predominantly by the kidney and undergoes minimal, if any, hepatic metabolism. The terminal elimination half-life (t1/2β) of lepirudin after subcutaneous administration (1.6 to 2.6 hours) is longer than that after intravenous administration (0.8 to 2 hours). This difference has been ascribed to a slower absorption rate of lepirudin from subcutaneous tissue. Renal clearance accounted for approximately 40 to 45% of the systemic clearance of an intravenously administered dose of lepirudin.
In patients with renal impairment, the renal clearance of lepirudin is reduced. Dosage adjustments are recommended in these patients. Alterations in the pharmacokinetics of lepirudin (t1/2β 3.5 hours; renal clearance 3.4 L/h) after subcutaneous administration to healthy elderly volunteers was also attributed to reduced renal function and/or delayed absorption of the drug from subcutaneous tissue. Renal clearance of lepirudin was also slightly reduced in the elderly after intravenous administration of the drug (3.7 L/h).
A good correlation between plasma lepirudin concentrations and increases in aPTT values from normal control values has been reported. Maximum aPTT values generally correlate well with peak plasma drug concentrations and were achieved 10 minutes, 3 to 6 hours and 2 to 3 hours, respectively, after administration of lepirudin by intravenous bolus injection, intravenous infusion or subcutaneous injection.
Therapeutic Efficacy
At present, efficacy data on lepirudin as an antithrombotic agent are available from a limited number of studies in patients with HIT, unstable angina, DVT and acute myocardial infarction (AMI) and in patients undergoing haemodialysis or CPB.
Lepirudin may be a suitable substitute anticoagulant for heparin in patients with HIT who require further anticoagulation. Platelet counts increased after 3 to 6 days of lepirudin therapy without the development of thromboembolic or haemorrhagic complications in 1 small study in patients with HIT. In a larger multicentre study (n = 82), platelet counts were increased or maintained at normal baseline values while maintaining adequate anticoagulation in 64.6% of patients with HIT treated with a range of lepirudin dosages. A final evaluation of the results of another study of a similar design is awaited with interest.
In patients with DVT, pulmonary perfusion defects were statistically significantly less frequent during 5 days’ treatment with subcutaneous lepirudin (0.75, 1.25 or 2 mg/kg twice daily; n = 91) than during 5 days of intravenous UFH (5000IU bolus plus 1250 IU/h infusion; n = 30) [3 to 9 vs 27%]. However, too few clinical embolic events in this study precluded any firm conclusions regarding the efficacy of lepirudin relative to that of UFH. Moreover, assessment of existing thromboemboli by phlebography revealed no significant difference between lepirudin and UFH, with the majority of thrombi showing no change. Data on the efficacy of lepirudin in the prophylaxis of DVT are currently limited to the results of 1 small study in patients undergoing hip replacement surgery which reported no cases of DVT, pulmonary embolism or bleeding during lepirudin therapy.
Although not conclusive, data are accumulating on the use of lepirudin in the treatment of patients with unstable angina. According to the results of the OASIS I study, the combined incidence of cardiovascular mortality, new AMI or refractory angina was statistically significantly lower with medium-dose intravenous lepirudin (0.4 mg/kg bolus plus 0.15 mg/kg/h; n = 267) than with intravenous UFH (5000IU bolus plus 1000 or 1200 IU/h; n = 371) [3 vs 6.5%]. Despite an increase in ischaemic events approximately 8 days after the cessation of lepirudin therapy, differences in the combined incidence of various ischaemic events in favour of lepirudin did persist during long term follow-up (180 days); however, these differences were statistically significant only for the combined incidence of cardiovascular death, new AMI and refractory or severe angina without revascularisation (19.7 vs 27.3%).
A limited number of patients (n = 40) with unstable angina have also received lepirudin as a periprocedural antithrombotic therapy during coronary angioplasty. In these patients, high-dose intravenous lepirudin (0.5 mg/kg bolus plus 0.04 to 0.24 mg/kg/h for 48 hours) was as effective as UFH (150 IU/kg plus 7 to 20 IU/kg/h for 48 hours) in the prevention of early restenosis and was associated with a lower incidence of cardiac events (death, AMI, acute occlusion or emergency intervention).
Lepirudin appears to have a narrow therapeutic window when used as an adjunct to thrombolytic therapy in patients with AMI. In the HIT-SK study, high-dose intravenous lepirudin (0.4 mg/kg bolus plus 0.15 mg/kg/h for 48 to 72 hours) as an adjunct to streptokinase produced a statistically significantly higher early, complete and sustained patency rate than UFH (76.9 vs 42.0%) but was associated with a high incidence of major bleeding events (26.7%). Although treatment with lower doses of lepirudin was associated with a positive risk/benefit ratio and a lower rate of major bleeding events, the improvement in early, complete and sustained coronary artery patency was somewhat lower (50 to 61.4%). In the HIT-III study, patient recruitment was stopped prematurely because of an unexpectedly high incidence of intracranial haemorrhage with high-dose lepirudin therapy as an adjunct to alteplase (3.4 vs 0% in the UFH group) and the study results also revealed a higher overall 30-day mortality rate with lepirudin (9.5 vs 5.2%).
Promising results from 3 small studies (total n = 36) also suggest that lepirudin is able to prevent clotting within extracorporeal circuits. In patients undergoing haemodialysis, lepirudin was at least as effective as UFH at preventing coagulation and was also associated with a lower incidence of platelet deposition on the inlet of the artificial kidney. Similarly successful anticoagulation has been reported with lepirudin during CPB.
Tolerability
The most important adverse events associated with lepirudin therapy are bleeding complications and possible allergic or anaphylactic reactions. However, further studies are required to more fully characterise the tolerability profile of lepirudin.
In patients with HIT treated with lepirudin (n = 125), the rates of total and major bleeding events were 39 and 11%, respectively. Wound bleeding (9% of patients), haematoma and haematuria (each 7%), puncture site bleeds (6%), epistaxis (4%), rectal bleeding and postoperative haemothorax (each 3%) and vaginal bleeding (2%) were the most frequent bleeding complications among 198 lepirudin-treated patients with HIT. Other bleeding events including gastrointestinal, oesophageal and lung bleeding and haematemesis occurred with an incidence of ≤1%.
Available data from 2 comparative studies suggest that the incidence of major bleeding with lepirudin monotherapy is similar to that reported with UFH alone. However, minor bleeding events such as skin bruising and oozing at puncture sites appear to be more frequent with lepirudin than with UFH therapy.
Notably, the potential for bleeding appears to be greater when lepirudin is used in combination with thrombolytic therapy. Indeed, reports of an unacceptably high rate of intracerebral haemorrhage among patients treated with high-dose lepirudin as an adjunct to alteplase resulted in the premature termination of the HIT-III study.
Allergic reactions have been reported in patients treated with lepirudin and have included cutaneous reactions, anaphylaxis, pruritus, hot flushes, isolated chills, cough, dyspnoea, bronchospasm, stridor, oedema of the face, tongue or larynx and angioedema. Injection site reactions have been reported rarely in patients treated with lepirudin.
Dosage and Abddministration
Lepirudin is indicated for the treatment of adult patients with confirmed HIT and thromboembolic disease requiring parenteral antithrombotic therapy. Dosage recommendations for the use of lepirudin in patients with DVT, unstable angina, AMI and DIC or during CPB or haemodialysis are not available.
In patients with HIT, the dosage regimen for lepirudin consists of an initial intravenous bolus dose of 0.4 mg/kg followed by 0.15 mg/kg/h administered as a continuous intravenous infusion for 2 to 10 days or longer if necessary. For patients weighing >110kg, the dosage of lepirudin should not be increased beyond the 110kg bodyweight dose (44mg intravenous bolus dose followed by 16.5 mg/h continuous intravenous infusion). In patients with renal impairment [creatinine clearance ≤3.6 L/h (≤60 ml/min)] dosage reduction is necessary.
The aPTT value, which should be monitored 4 hours after the start of therapy and at least once daily thereafter, should be used to adjust the lepirudin infusion rate. The therapeutic target range for aPTT is dependent on the test reagent used and varies between 1.5- and 3-fold (for Actin FS® and Neothromtin® reagents) and 1.5- and 2.5-fold prolongation (for all other reagents) of the normal control value. Dosage modification is necessary if an aPTT value is confirmed to be above or below the target range.
Prior reduction of the lepirudin dose to achieve an aPTT ratio of just above 1.5 is necessary if a patient is to receive oral anticoagulation with a coumarin derivative after treatment with lepirudin. Administration of lepirudin should then be stopped when an international normalised ratio (INR) of 2.0 is reached.
Lepirudin is contraindicated in pregnant or lactating women and in patients with a known sensitivity to hirudins. Lepirudin should also be used with caution in patients who are receiving concomitant treatment with thrombolytics or coumarin derivatives because of a potential increased risk of bleeding. A careful risk-benefit assessment should be made before administering lepirudin to patients with a possible bleeding tendency. Because of a possible enhanced anticoagulant effect of lepirudin, strict monitoring of aPTT is essential in patients who develop anti-lepirudin antibodies.
No specific antidote is available at present for the treatment of bleeding associated with lepirudin overdosage. In case of overdosage, blood transfusion may be necessary and current guidelines for shock therapy should be followed.
Recombinant hirudins have a definite role in the treatment of patients with heparin-induced thrombocytopenia (HIT). The most important adverse effects are haemorrhages and the induction of antihirudin antibodies. Major haemorrhages were not significantly increased in patients with HIT compared with a historical control group, but prospective data comparing hirudin and heparinoids such as danaparoid are lacking. The definition of the optimal method for monitoring and the availability of an antidote for hirudin would probably increase safety with this drug. To date, haemofiltration using high-flux filter systems is the only way to remove an overdosage of hirudin from the circulation. In patients with renal impairment requiring hirudin treatment, it therefore seems safer to start with a low dose that is subsequently adjusted according to the activated partial prothromboplastin time or ecarin clotting time.
Even in special circumstances, such as cardiopulmonary bypass or dialysis, hirudins can be applied successfully if care is taken to monitor their effects meticulously.
There are many other indications in which hirudins have shown feasibility (e.g. acute coronary syndromes) but available data preclude definite conclusions.
Hirudin and its derivatives represent the first parenteral anticoagulants introduced since the discovery of heparin in the early 1900s. Hirudin, the naturally occurring anticoagulant of the leech, is a single peptide chain of 65 amino acids with a molecular weight of about 7000. Recombinant technology has developed methods to produce recombinant forms of hirudin (r-hirudin) in sufficient quantities for therapeutic use.
Hirudin is a potent thrombin-specific inhibitor that forms equimolar complexes with thrombin. It represents a new anticoagulant agent in a field in which heparin has been the only available drug for many years. In contrast to heparin, hirudin does not require antithrombin III as a cofactor, is not inactivated by antiheparin proteins, has no direct effects on platelets and may also inactivate thrombin bound to clot or the subendothelium.
In humans, experience with r-hirudin in preventing or treating venous thromboembolism is very preliminary. However, r-hirudin achieved promising results in patients with unstable angina, or following coronary angioplasty. In patients with acute myocardial infarction, 3 important clinical trials were stopped because of an excess of bleeding complications. At present, the discovery of a r-hirudin regimen that is more efficacious than heparin and at least as safe needs a reappraisal of the drug in further trials.
In recent times, research on novel thrombin inhibitors, the exploration of the applications of oral thrombin inhibitors and the development of therapeutically useful low molecular weight competitive factor Xa inhibitors is receiving significant and growing attention. This chapter discusses the development of recently described specific small molecule direct thrombin inhibitors in addition to summarizing the recent clinical experiences with direct thrombin inhibitors. Finally, the chapter discusses the novel approaches to inhibit factor Xa, the enzyme within the prothrombinase complex, ultimately responsible for the conversion of inactive prothrombin to the procoagulant thrombin. The blood coagulation system involves the conversion of a variety of inactive enzymes (zymogens) into active enzymes and is the target of existing anti-coagulant drugs. Thrombin, a serine protease with trypsin-like specificity, plays a pivotal role in the coagulation cascade through the final conversion of fibrinogen to fibrin. Thrombin is also the most potent platelet agonist known and, therefore, positions thrombin as a central mediator in both thrombosis and in normal hemostasis. The major classes of compounds that are currently used as anti-coagulants all indirectly inhibit the activity of thrombin. Heparin, through its action on the plasma proteins, anti-thrombin III and heparin cofactor II, indirectly inhibits thrombin in addition to other proteases. Side effects, limitations of efficacy, and bleeding complications with these agents have stimulated the search for novel, more direct, and specific inhibitors of key coagulation enzymes.
Zusammenfassung
Thrombininhibitoren sind als Antikoagulans für spezielle Indikationen zur Therapie zugelassen. Studien, in denen diese Medikamente mit anderen Antikoagulantien verglichen wurden, zeigten z.B. auch bei Patienten mit Myokardinfarkt, instabiler Angina, tiefer Venenthrombose, disseminierter intravasaler Gerinnung und extrakorporaler Zirkulation Vorteile. Bei therapeutischer Dosierung ist ein Monitoring notwendig, für welches die aktivierte partielle Thromboplastinzeit (APTT) und Modifikationen der aktivierten Gerinnungszeit (ACT) verwendet wurden. In vielen Studien konnte jedoch gezeigt werden, dass diese Tests nicht sensitiv genug sind, um Spiegel im therapeutischen oder toxischen Bereich zu überwachen. Die Tests weisen bei gleicher Dosierung große interindividuelle Schwankungen auf, weswegen häufig eine Ratio angegeben wird. Die Korrelation mit den Ergebnissen der Ecarin-Gerinnungszeit (ECT), enzymimmunologischen und chromogenen Substrattests ist schlecht. Eine Bestimmung der Plasmaspiegel mit Hilfe chromogener Substrattests ist an Analysatoren oder als Bedside-Methode mit kleinen Photometern möglich. Diese Tests sind sehr präzise, weisen einen weiten Messbereich auf und werden nicht durch Heparin und Antithrombin gestört. Sie zeigen eine gute Korrelation mit der ECT. Die ECT kann aus Vollblut oder Plasma bestimmt werden, abhängig davon, ob eine mechanische oder eine optische Detektion der Gerinnungszeit verwendet wird. Die ECT kann ebenfalls als Bedside-Methode durchgeführt werden. Die Impräzisionen und der Messbereich des Tests sind mit denen der chromogenen Methoden vergleichbar. Testeinschränkungen sind nicht bekannt. Chromogene Tests oder die ECT sind für das Monitoring der Therapie mit Thrombininhibitoren am besten geeignet. Die APTT sollte nur dann verwendet werden, wenn keine anderen Methoden verfügbar sind.
The approach to take in trying to establish or disprove a diagnosis of pulmonary embolism in the presence of deep vein thrombosis is the subject of some controversy nowadays. Systematic perfusion lung scan can be proposed, given the mediocre specificity of the clinical symptoms of embolism or the high frequency of asymptomatic pulmonary embolism. This strategy, however, is not validated in terms of cost-efficacy. In practical terms, favourable evolution and the low rate of recurrent embolism observed with a well executed anticoagulant treatment pleads against systematic scintigraphy. Because of its moderate sensitivity, systematic echocardiography probably should not be an element of the assessment of asymptomatic pulmonary embolism. The advent of spiral CT scan in the management of such patients could however make it necessary to reconsider this position, by allowing complete venous and pulmonary examination in thrombo-embolic disease.
As the final enzyme in the activation of the coagulation system, the serine protease, thrombin, is believed to be an important target for the development of new anticoagulant/antithrombotic drugs. Direct thrombin inhibitors are either derived from natural sources, such as hirudin or are chemically synthesised, such as argatroban. The coupling of hirudin or parts of it with other entities leads to novel agents with different pharmacokinetic and pharmacodynamic characteristics, such as polyethylene glycol (PEG)-hirudin or the hirulogs. Due to the reversible or irreversible inactivation of the enzyme, thrombin inhibitors exert strong anticoagulant effects that can be measured in global clotting assays. Furthermore, these compounds inhibit thrombin-induced platelet reactions and influence other cellular, receptor-mediated actions of thrombin, e.g., on vascular cells. Directly acting thrombin inhibitors prevent blood clotting and are also capable of inhibiting clot-associated thrombin; however, they do not effectively block the further generation of the enzyme. Comprehensive experimental studies suggest that thrombin inhibitors may be effective drugs in a wide range of intravascular thrombus formation, also including the inhibition of vascular restenosis. Recent clinical trials revealed the effectiveness of direct thrombin inhibitors in various thrombotic and cardiovascular indications, but also a tendency to an increased risk of bleeding complications. At present, thrombin inhibitors are the most promising class of drugs for the initial therapy of patients with heparin-induced thrombocytopaenia (HIT) or the heparin-induced thrombocytopaenia and thrombosis syndrome (HITTS). They are also useful for the management of venous thrombosis and for acute ischaemic syndromes as well as for invasive procedures. However, with regard to the long-term outcome, a superiority of thrombin inhibitors over heparin has not yet been demonstrated. Several important issues, such as monitoring, pharmacological antagonism and drug interactions will also play an important role in the development of these new drugs. Further clinical trials are required to confirm the effectiveness of direct thrombin inhibitors in the prophylaxis and treatment of various thromboembolic and cardiovascular disorders.
Deep venous thrombosis (DVT) in the lower limb has been defined to be located in intrafascial veins, either in the deep veins of the calf (calf vein thrombosis) or the more proximal veins, including popliteal, superficial femoral, common femoral, and iliac veins. Thrombosis located in extrafascial veins (e.g., in varicosities of the saphenous vein) has been defined as thrombophlebitis. If thrombophlebitis affects the great saphenous vein in the thigh, it may, however, extend into the deep veins via the junction into the common femoral vein, thereby giving rise to pulmonary embolism (PE).Calf vein thrombosis may be asymptomatic, but these thrombi may also damage the valves of the deep venous system and when affecting several veins may cause late sequelae, such as postthrombotic syndrome. Thrombi also can extend proximally and become dangerous.40 Venous thrombi produce clinical symptoms (swelling, pain, and discoloration) because they obstruct venous outflow, cause inflammation of the vessel wall or perivascular tissue, or may become symptomatic by embolizing into the pulmonary circulation.The aims of treatment of DVT consist of several elements. In the acute phase, treatment is targeted at
Arresting thrombus growth, thereby preventing recurrent thrombotic disease in the chronic phase.Limiting progressive swelling of the leg, thereby preventing an increase of compartmental pressure possibly leading to phlegmasia cerulea dolens, venous gangrene, and limb loss.Dissolving or removing the clot, thereby preventing venous dysfunction or postthrombotic syndrome later on.Preventing embolization, thereby preventing secondary hypertension in the chronic phase.
To observe the clinical curative effects of lower extremity deep venous thrombosis (DVT) postoperative fracture treated by maixuekang capsule and low molecular heparin calcium (Subilin).
From Feb 2008 to Apr 2010, 214 cases of lower extremity DVT postoperative fracture were randomly divided into experimental group and control group. The 107 cases of them were treated by maixuekang capsule based on the comprehensive treatment.
The 89 cases were cured and improved in the observation group, but 18 cases were ineffectiveness. The 66 cases were cured and improved in the control group, but 41 cases were ineffectiveness. Maixuekang capsule group had 83. 18% (89/107) total effective rate and 61.68% (66/107) total effective rate in the control group. There was significant difference between the two groups (P < 0.05). After the treatment, the perimeter between the suffered limb and the healthy one was significantly reduced, the blood rheology examination had been improved significantly. There was also significant difference between the two groups (P < 0.05).
Maixuekang capsule for lower extremity deep vein thrombasis has good effect It has both thrombolytic and anticoagulant effects for lower extremity DVT postoperative fracture treated by maixuekang capsule and low molecular heparin calcium (Subilin). It's a recommended treatment.
Hirudin is a direct thrombin inhibitor that has potential mechanistic advantages over indirect inhibitors. Peptides containing the RGD motif competitively inhibit binding of fibrinogen to glycoprotein IIb/IIIa on platelets, thus inhibiting platelet aggregation. A novel hirudin derivative, recombinant RGD-hirudin (r-RGD-hirudin), was engineered by fusing the tripeptide RGD sequence to the native hirudin. We tested the antithrombotic effect of r-RGD-hirudin using a carotid artery reconstruction model in rabbits.
A fusion gene encoding r-RGD-hirudin was constructed and expressed at high levels in Pichia pastoris. Following traumatic injury and anastomosis, 42 New Zealand White rabbits were randomized to receive normal saline, abciximab, wild-type hirudin, or r-RGD-hirudin. Fibrinogen concentration, aPTT, TT, PT, and PAGm were measured prior to and following the operation. Carotid angiography and pathological examination of the anastomotic site were performed to compare patency rates among the groups.
The r-RGD-hirudin significantly prolonged aPTT, TT, PT and inhibited PAGm following carotid anastomosis in rabbits. The median dose of r-RGD-hirudin (0.5 mg/kg) had a therapeutic effect equal to that of wild-type hirudin (1.0 mg/kg) and higher than that of abciximab (0.2 mg/kg) with regard to patency rates.
Compared to wild-type hirudin or antiplatelet agent, the novel anticoagulant, r-RGD-hirudin was capable of inhibiting both thrombin activity and platelet aggregation, and was demonstrated to be effective in the prevention of thrombosis.
To report the use of subcutaneous lepirudin in an obese patient with heparin resistance.
A 34-year-old morbidly obese male (weight 145 kg) presented with hypoxia on postoperative day 1 following a sigmoid colectomy. A continuous unfractionated heparin infusion was started for a suspected pulmonary embolism. Doses were escalated without therapeutic activated partial thromboplastin time (aPTT) response and an antithrombin (AT) level was obtained. The AT level was reported as 78% (reference range 85-120%). Computed tomography angiography ruled out pulmonary embolism and lepirudin 50 mg administered subcutaneously twice daily was started (serum creatinine 1.3 mg/dL) for prevention of venous thromboembolism. The resulting aPTT values were therapeutic (63 and 60 sec, reference range 24-34, therapeutic heparin range 55-85). The dose was adjusted to 25 mg twice daily. aPTT values were 35 and 48 seconds. His serum creatinine increased to 1.6 mg/dL and minor bleeding was noted. The dose was decreased to 25 mg once daily, with resulting aPTT values of 31, 39, and 41 seconds. The patient was discharged to home without development of venous thromboembolism, as confirmed by duplex ultrasonography.
Commonly administered anticoagulants, such as unfractionated heparin, low-molecular-weight heparins, and fondaparinux, exert their effect by complexing with AT and thrombin (Factor IIa), activating AT and preventing thrombin from exerting coagulation effect. Without AT present, these drugs have little effect on inhibiting the coagulation cascade. Lepirudin is a synthetic irreversible direct thrombin inhibitor and does not rely on AT to exert its anticoagulation action. It can be given subcutaneously and is eliminated primarily by the kidneys. Dosage adjustments for both renal function and obesity need to be considered and aPTT should be monitored.
In obese patients or those with heparin resistance, subcutaneous lepirudin can be monitored and the regimen adjusted based on aPTT values. Further studies are warranted to maximize efficacy and define dosing.
Tick anticoagulant peptide (TAP) is a potent and selective inhibitor of factor Xa. TAP has shown good antithrombotic efficacy in experimental animal models of disseminated intravascular coagulation and venous and arterial thrombogenesis. In the present study we evaluated the effect of recombinant TAP (rTAP) on acute thrombus formation in human nonanticoagulated blood triggered either by tissue factor (TF) or by collagen at arterial shear conditions. The main goal was to establish the role of factor Xa in thrombus formation by use of an optimal inhibitory concentration of rTAP. Blood was drawn directly from an antecubital vein by a pump over the respective thrombogenic surfaces, which were positioned in a parallel-plate perfusion chamber. rTAP was mixed homogeneously into the flowing blood by a heparin-coated device positioned proximal to the perfusion chamber. The passage of blood through this device caused minor activation of coagulation but little activation of platelets. Fibrinopeptide A and beta-thromboglobulin levels after 5 minutes of blood perfusion were, on average, 14 ng/mL and 45 IU/mL, respectively. rTAP at a plasma concentration of 0.90 mumol/L completely inhibited TF/factor VIIa-dependent thrombus formation at wall shear rates of 650 and 2600 s-1. These shear conditions are comparable to those in medium-sized arteries and in moderately stenosed small arteries, respectively. In contrast to the TF-coated surface, rTAP was less efficient in reducing collagen-induced thrombus formation. While a significant reduction of 53% was observed at 650 s-1, thrombus formation at 2600 s-1 was not affected by rTAP.(ABSTRACT TRUNCATED AT 250 WORDS)
Heparin‐induced thrombocytopenia is a rare but severe complication of heparin therapy that can result in severe venous or arterial thromboembolic events and whose treatment remains partially unanswered. Recombinant hirudin is potentially effective as an antithrombotic treatment in the management of heparin‐induced thrombocytopenia, given its potent antithrombin effects without known interaction with platelets. We report the results obtained with intravenous recombinant hirudin (HBW 023) administered on a compassionate basis to patients suffering from heparin‐induced thrombocytopenia.
Six patients suffering from heparin‐induced thrombocytopenia were submitted to intravenous recombinant hirudin (HBW 023) administered at a dose of 0.05 mg/kg/hr after an initial bolus injection of 0.07 mg/kg in the case of a venous thromboembolic event, and at a dose of 0.15 mg/kg/hr with the same initial bolus injection in the case of an arterial thromboembolic event. Whenever possible, oral anticoagulation with acenocoumarol was introduced at the same time as recombinant hirudin, which was interrupted as soon as the international normalized ratio reached 3. Clinical events, particularly thromboembolism and bleeding, were noted; activated partial thromboplastin time (aPTT), and platelet count were assessed throughout the administration of recombinant hirudin.
Heparins responsible for heparin‐induced thrombocytopenia were porcine sodium or calcium heparinate in four cases, nadroparin in one case, and enoxaparin in one case. Thrombocytopenia was discovered on routine systematic platelet count in two patients and after the occurrence of arterial and venous thromboembolism in two patients, respectively. After discontinuation of heparin and the onset of recombinant hirudin, clinical evolution was uneventful in all patients, with no recurrence of thromboembolism, limb amputation, or hemorrhagic complication. The aPTT ratio varied from 1.8 to 3.5 (median 2.4) throughout administration of recombinant hirudin. Platelet count rose from nadir (median value 60 × 10 ⁹ 15 to 90) to above 100 × 10 ⁹ /L in every patient within 3–6 days (median 5), after discontinuation of heparin.
Intravenous administration of recombinant hirudin ensured safe anticoagulation in patients with heparin‐induced thrombocytopenia and made it possible to wait for oral anticoagulation to become efficient and platelet count to return to normal values without occurrence or recurrence of thromboembolism.
This review aims to discuss recent developments in antithrombotic therapy. New and specific inhibitors of platelet dependent thrombosis appear to moderately improve the outcome in coronary vascular disease. Further studies will need to address the cost-benefit ratio of this additional intervention. Hirudin and analogues are potent inhibitors of thrombin, and are clinically efficious, but at current dosage levels still complicated by bleeding. Low molecular weight heparin have markedly improved the efficacy of prevention and treatment of venous thromboembolism.
Percutaneous transluminal coronary angioplasty (PTCA) has become a mainstay in the treatment of ischemic heart disease, with an estimated 300,000 procedures performed annually in the United States. Despite significant advances in reducing the acute complications of percutaneous revascularization procedures with periprocedural medications and better techniques, chronic restenosis of dilated lesions remains a serious and frequent problem, occurring in 30% to 50% of cases. With a peak incidence between 1 and 4 months after PTCA, restenosis has been thought to reflect an exaggerated healing response to balloon injury, in which platelets and other cells secrete mitogens that induce smooth muscle cells from the media to migrate to and proliferate in the intima, compromising the coronary lumen and invoking ischemic symptoms. Several factors, including remodeling with compensatory arterial enlargement, normalization of wall shear stress, and recoil, are also likely to play key roles. Based on these concepts, several pharmacological approaches directed at reducing the incidence of restenosis have been investigated. Although studies frequently report suppression of neointimal proliferation in animal models of balloon vascular injury, few drug approaches have met with clear success in clinical trials. This can be explained in several ways, including mistaken understandings of the pathophysiology of restenosis, gross histopathological dissimilarities between animal vascular injury models and clinical restenosis, and inadequate dosing. This report proposes to extensively review the vast literature on the subject to serve as a guide for clinicians to the pathophysiology of restenosis and the pharmacotherapeutic management of patients after PTCA and coronary atherectomy. Those drug approaches that currently show the most clinical promise and that warrant further investigation will be highlighted.
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.
Hirudin is a small protein with strong thrombin inhibition that may be antigenic. The generation and disappearance of anti-hirudin antibodies were investigated in patients with heparin-induced thrombocytopenia who were treated with recombinant hirudin (r-hirudin) for >/=5 days.
The IgA, IgE, IgG, and IgM isotypes of anti-hirudin antibodies were determined by ELISA before and after the start of r-hirudin therapy. A total of 56% of patients (13 of 23) developed >/=1 antibody isotype during therapy. No IgE antibodies were generated. IgA, IgG, and IgM antibodies were detected in 30% (7 of 23), 52% (12 of 23), and 17% (4 of 23) of patients, respectively. Four patients generated only IgG, 2 patients developed either IgM or IgG and IgM, 5 patients IgG and IgA, and 2 patients IgG, IgM, and IgA antibodies. IgM antibodies disappeared within 8 days of the cessation of r-hirudin. IgA and IgG antibodies disappeared within 1 year in all but 1 patient. Binding of purified IgG to r-hirudin in IgG antibody-positive patients (n=7) was demonstrated by competitive ELISA for r-hirudin. Of the 7 IgG antibody samples, 1 each neutralized or enhanced the anticoagulant activity of r-hirudin.
R-hirudin may be antigenic in patients with heparin-induced thrombocytopenia. More comprehensive investigations will be required to determine the biological relevance of this and to establish the antibody-generation pattern in other diseases.
Introduction
Unfractionated heparin (UFH) and low molecular weight heparin (LMWH) are the most widely used anticoagulants when parenteral anticoagulation with a short half-life is required. Both can be administered subcutaneously and intravenously, and both have been shown to be effective in a variety of clinical settings.1 UFH has several limitations. One is its poor bioavailability after subcutaneous injection and the marked variability in its anticoagulant response in patients with an acute thromboembolic complication.2,3 Another major issue associated with UFH is the induction of heparin-induced thrombocytopenia (HIT). Both limitations are closely linked,4 as the underlying cause is the high density of negative charges on the heparin molecule and its molecular weight. Both are responsible for the binding of heparin to plasma proteins other than antithrombin (AT), such as platelet factor 4 (PF4) and to several cell types. This leads to heparin-platelet interaction, the formation of HIT antigen (i.e., PF4/heparin complexes), and inhibition of the anticoagulant effect of heparin (aPTT-nonresponder).
We prospectively studied 15 patients suffering from acute heparin-induced thrombocytopenia (HIT) type II with and without thromboembolic events and 4 patients with anamnestically known HIT type II recurrently requiring thromboprophylaxis in order to develop new therapeutic strategies by subcutaneous recombinant hirudin administration. Patients with acute venous or arterial thromboembolism were treated with aPTT-controlled intravenous (mean: 19.3 days) followed by subcutaneous r-hirudin (mean: 22.5 days). Patients without thromboembolism were treated with subcutaneous r-hirudin (mean: 25.9 days). Four patients were readmitted to subcutaneous r-hirudin (mean: 32 days). When r-hirudin was administered subcutaneously following intravenous treatment, mean baseline (prior to the injection) and mean peak (1.5-2.5 hours after the injection) aPTT ratios were 1.1 (+/-0.2) to 1.7 (+/-0.48) and 2. 48 (+/-0.43) to 2.52 (+/-0.4) times normal value, respectively. Mean baseline and mean peak ECT ratios were 1.2 (+/-0.12) to 1.9 (+/-0. 22) and 2.2 (+/-0.25) to 2.6 (+/-0.11) times the upper normal value, respectively. When r-hirudin was initially administered subcutaneously, mean baseline and mean peak aPTT ratios were 1.41 (+/-0.25) to 1.61 (+/-00.28) and 1.88 (+/-0.26) to 2.06 (+/-0.09) times the normal value, respectively. Mean baseline and mean peak ECT ratios were 1.25 (+/-0.2) to 1.5 (+/-0.38) and 2.01 (+/-0.21) to 2.23 (+/-0.25) times the upper limit of normal, respectively. Patients who received recurrent subcutaneous r-hirudin had mean baseline and peak aPTT values of 1.5 (+/-0.35) to 1.75 (+/-0.156) and 2.0 (+/-0.33) to 2.1 (+/-0.18) times the normal value, respectively. Mean baseline and peak ECT ratios were 1.3 (+/-0.26) to 1.65 (+/-0.09) and 1.94 (+/-0.256) to 2.7 (+/-0.23) times the upper limit of normal, respectively. The overall cumulative incidence of r-hirudin antibodies was 12/19 (63%) with a significant accumulation of r-hirudin in antibody-positive patients compared to antibody-negative patients (p<0.05). No patient suffered a new thromboembolic or major bleeding event. Subcutaneous administration of recombinant hirudin provides a long-term thromboprophylaxis regimen in HIT type II patients after passivation of acute thromboembolism.
The interaction between malignant cell growth and the coagulation and fibrinolysis system has been a well known phenomenon for decades. During recent years, this area of research has received new attention. Experimental data suggest a role for the coagulation and fibrinolysis system in tumor development, progression and metastasis. Also, clinical research suggests that targeting the coagulation system or fibrinolysis system might influence the course of malignant disease beneficially. This paper reviews data on various hemostatic and fibrinolytic parameters in malignancy; the possible use of such parameters as risk markers in oncology patients; and possible targets of anti-neoplastic therapies using anticoagulant and/or antifibrinolytic strategies. Current evidence suggests that the tissue factor/factor VIIa pathway mediates the most abundant procoagulant stimulus in malignancy via the increase in thrombin generation. Tissue factor has been suggested to mediate pro-metastatic properties via coagulation-dependent and coagulation-independent pathways; tissue factor has also been implicated in tumor neo-angiogenesis. However, so far no model has been validated that would allow the use of tissue factor in its soluble or insoluble form as a marker for risk stratification in tumor patients. On the other hand, there is now good evidence that parts of the fibrinolytic system, such as urokinase-type plasminogen activator and its receptor ("uPAR"), can be used as strong predictors of outcome in several types of cancer, specifically breast cancer. Observation of various treatment options in patients with thromboembolic disease and cancer as well as attempts to use anticoagulants and/or therapies modulating the fibrinolytic system as anti-neoplastic treatment strategies have yielded exciting results. These data indicate that anticoagulant therapy, and specifically low molecular weight heparin therapy, is likely to have anti-neoplastic effects; and that their use in addition to chemotherapy will probably improve outcome of tumor treatment in certain types of cancer. However, the body of clinical data is still relatively small and the question whether or not we should routinely consider the coagulation and/or fibrinolysis system as therapeutic targets in cancer patients is yet to be answered.
Initially, patients with deep vein thrombosis (DVT) should be treated with a 5- to 7-day course of heparin or low-molecular-weight heparin (LMWH). They can be administered LMWH as outpatients. Patients with extensive iliofemoral thrombosis, major pulmonary embolism, or concomitant medical illness, and those at high risk for bleeding, should be treated as inpatients. Thrombolytic therapy may be considered for patients with extensive iliofemoral thrombosis if there is no contraindication to the use of thrombolytic drugs. Oral anticoagulants can be started within 24 hours of the initiation of heparin or LMWH. Warfarin is started at a dose of 5 mg, and subsequent doses are given in amounts sufficient to achieve an international normalized ratio of 2.0 to 3.0. Inferior vena caval filters should be considered for patients with overt bleeding or for those at high risk for hemorrhage. Warfarin can be used for secondary prophylaxis in most patients. Patients in whom there are contraindications to the use of oral anticoagulants and patients in whom recurrent venous thromboembolism (VTE) develops while they are receiving therapeutic doses of warfarin can be safely and effectively treated with LMWH. Patients with idiopathic DVT should be treated with anticoagulants for at least 6 months. Those with calf DVT or proximal DVT that complicates surgery or medical illness can be treated with anticoagulants for 6 weeks and 3 months, respectively, provided that there are no ongoing risk factors for recurrent VTE. Oral anticoagulants are teratogenic and should be avoided by patients who are pregnant; unfractionated heparin or LMWH are safe alternatives. Unfractionated heparin, LMWH, and oral anticoagulants can be safely administered to nursing mothers.
We report here a case of recurrent venous and arterial thromboembolism, Trousseau's syndrome, in a cancer patient who developed heparin-induced thrombocytopenia. She was treated with lepirudin and after establishing the patient-specific half-life for subcutaneous lepirudin, she was successfully maintained on this therapy for more than eight months.
To our knowledge this case represents the longest reported use of subcutaneous lepirudin.
Thrombocytopenia is a frequent comorbid condition in many in hospital patients. In some patients, drugs are the cause of low platelet counts. While cytotoxic effects of anti-tumor therapy are the most frequent cause, immune mechanisms should also be considered. This review addresses thrombocytopenias in four groups. Heparin-dependent thrombocytopenia (HIT), by far the most frequent drug-induced immune-mediated type of thrombocytopenia, has a unique pathogenesis and clinical consequences. HIT is a clinicopathological syndrome in which antibodies mostly directed against a multimolecular complex of platelet factor 4 and heparin cause paradoxical thromboembolic complications. The mechanisms through which heparin can enhance thrombin generation are discussed and treatment alternatives for affected patients are presented in detail. It is of primary importance to recognize these patients as early as possible and to substitute heparin with a compatible anticoagulatory drug, such as hirudin, danaparoid or argatroban. Patients seem to benefit from therapeutic doses of alternative treatment rather than from low-dose prophylactic doses. With the increasing use of glycoprotein (GP) IIb/IIIa inhibitors in patients with acute coronary syndromes, thrombocytopenias are increasingly recognized as an adverse effect of these drugs. Up to 4% of treated patients are affected. Most important, pseudothrombocytopenia, a laboratory artefact, is as frequent as real drug-induced thrombocytopenia and must be excluded before changes in treatment are considered. The pathogenesis of these thrombocytopenias is still debated; an immune mechanism involving preformed antibodies is likely. However, since these antibodies are also detectable in a high percentage of normal controls and of patients not developing thrombocytopenia, their impact is still unclear. Patients with real thrombocytopenia are at an increased risk of bleeding; treatment consists of cessation of the GP IIb/IIIa inhibitor and platelet transfusions in cases of severe hemorrhage. Classic immune thrombocytopenia can be induced by some drugs, e.g. gold, which trigger anti-platelet antibodies indistinguishable from platelet autoantibodies found in autoimmune thrombocytopenia. Drug-induced and drug-dependent immune thrombocytopenia is induced by antibodies recognizing an epitope on platelet GP formed after binding of a drug to a platelet glycoprotein. Still unresolved is whether antibody binding is the consequence of a conformational change of the antigen, the antibody, or both. These antibodies typically react with monomorphic epitopes on platelet GP, but only in the presence of the drug or a metabolite. Although several platelet GP have been identified as antibody target (GPIb/IX, GPV, GP IIb/IIIa), antibodies in an individual patient are highly specific for a single GP. Clinically, these patients present with very low platelet counts and acute, sometimes severe, hemorrhage. Treatment is restricted to withdrawal of the drug and symptomatic treatment of bleeding.
To describe heparin-induced thrombocytopenia (HIT or HIT-2), an immune-mediated adverse reaction to heparin or low-molecular-weight heparin. Available treatment options and considerations in developing a therapy approach are discussed.
A search of the National Library of Medicine (1992-June 2001) was done to identify pertinent literature. Additional references were reviewed from selected articles.
Articles related to laboratory recognition and treatment options of HIT, including the use of agents in selected clinical conditions, were reviewed and included.
HIT is a rare but potentially severe adverse reaction to heparin that was, until recently, poorly understood and had limited treatment options. Recent advances describing the recognition and clinical manifestations of immune-mediated HIT, including recently available antithrombotic treatment options, have dramatically changed outcomes for patients having this syndrome.
Outpatient treatment of deep venous thrombosis has gained widespread acceptance and is facilitated by the use of subcutaneous low molecular weight heparins (LMWH). We report two patients in whom subcutaneous lepirudin was used for long term anticoagulation after heart transplant or surgical pulmonary embolectomy because treatment with LMWH or warfarin was contraindicated, unsuccessful, or impractical. Neither bleeding complications nor recurrent thromboses developed. Subcutaneous lepirudin may be safely and effectively employed for the outpatient treatment of venous thrombosis in selected cases including patients with heparin-induced thrombocytopenia and in those who fail LMWH.
Since recombinant hirudin (r-hirudin) has become available, several studies have been published on hirudin for prophylaxis and treatment of thromboembolic complications. Vr-hirudin was shown to be superior even to low-molecular-weight heparin (LMWH) for prophylaxis of deep venous thrombosis (DVT), especially in high-risk patients. Consequently, r-hirudin was expected to be more effective than heparins are in the treatment of thromboembolic events. Vr-hirudin was proved to be safe and efficacious in the therapy of thromboembolic events. However, no benefit could be shown in comparison with heparin. In contrast, in patients suffering from HIT type II, r-hirudin is the drug of choice for the therapy of thromboembolic complications.
Direct thrombin inhibitors are available for prophylactic as well as therapeutic purposes. Application of hirudin in therapeutic doses has been shown to require drug monitoring. Currently, most experience is available for recombinant hirudin, but the principle aspects of drug monitoring are the same for all direct thrombin inhibitors. Most frequently, activated partial thromboplastin time (aPTT) and modifications of the activated clotting time (ACT) have been used for the monitoring of hirudin therapy. However, these methods are insensitive at plasma levels higher than 0.6 mg/L of hirudin, so that overdoses may be missed despite monitoring. Correlations between ecarin clotting time (ECT), enzyme immunoassays, and chromogenic substrate assays on one side and global tests on the other side are poor. Fully automated chromogenic substrate-based assays, also available as point-of-care tests (POCT), are more precise and sensitive and are not disturbed by interferents such as heparin and antithrombin. Good correlations can be observed between chromogenic assays and the ECT performed in plasma or whole blood samples. ECT can also be determined with POCT systems. Test characteristics such as imprecision and measuring range are comparable to those of the chromogenic assays. In conclusion, therapy with direct thrombin inhibitors should be monitored with chromogenic assays or ECT.
Ximelagatran is a novel, oral direct thrombin inhibitor that is currently being investigated for the prophylaxis and treatment of thromboembolic events. This study evaluated the pharmacokinetics, pharmacodynamics, and clinical effects of melagatran, the active form of ximelagatran, in patients with both deep vein thrombosis (DVT) and pulmonary embolism (PE).
In this open-label study, 12 patients received a fixed dose of 48 mg oral ximelagatran twice daily for 6-9 days. Plasma samples were collected for determination of melagatran concentrations and scintigraphic changes and adverse events were recorded.
Peak plasma concentrations of melagatran were attained approximately 2 h after administration of ximelagatran. Melagatran plasma concentration profiles were similar on Days 1, 2, and 6-9. Plasma activated partial thromboplastin time increased following administration of ximelagatran and reached a peak that was approximately twofold higher than the predose activated partial thromboplastin time and correlated with melagatran plasma concentrations (R(2) = 0.69). All but one patient (with malignancy) showed regressed or unchanged lung scintigraphic findings, and six of these demonstrated no, or only minor, perfusion defects at central evaluation after 6-9 days of ximelagatran treatment. Clinical symptoms, including chest pain, dyspnoea, cough, and oedema, and pain in the affected leg, were improved. Ximelagatran was well tolerated with no deaths or severe bleeding events reported during treatment.
Treatment with a fixed dose of oral ximelagatran, used without routine coagulation monitoring, showed reproducible pharmacokinetics and pharmacodynamics with a rapid onset of action and promising clinical results in patients with pulmonary embolism.
We report the case of a 71 old woman presenting a bilateral massive pulmonary embolism with intraventricular right thrombus complicating heparin induced thrombocytopenia (HIT) persistent after one month of conventional anticoagulant processing. We underline the effectiveness of lepirudin (Refludan) in the curative processing of pulmonary embolism allowing here to avoid a complex surgical thromboembolectomy. We evoke the place of this molecule in the curative therapeutic strategy of HIT with thrombotic phenomena.
This randomized, controlled, multicentre study evaluated the efficacy and tolerability of the oral direct thrombin inhibitor ximelagatran, compared with a low-molecular-weight heparin (dalteparin) followed by warfarin, in the treatment of deep vein thrombosis (DVT) of the lower extremity. Patients with acute DVT received oral ximelagatran (24, 36, 48 or 60 mg twice daily) or dalteparin and warfarin for 2 weeks. Evaluation of paired venograms from 295 of 350 patients showed regression of the thrombus in 69% of patients treated with ximelagatran and 69% of patients treated with dalteparin and warfarin. Progression was observed in 8% and 3% of patients, respectively. Changes in thrombus size according to the Marder score were similar in all groups. Treatment discontinuation due to bleeding occurred in two patients receiving ximelagatran (24- and 36-mg groups) and in two patients receiving dalteparin and warfarin. Reduction in pain, edema and circumference of the affected leg was similar in all groups. Oral ximelagatran appears to be a promising alternative to current anticoagulant therapy to limit the progression of acute DVT, and it seems to possess a wide therapeutic window.
Recombinant (r)-hirudin is a specific inhibitor of thrombin that is independent of the activity of antithrombin.
To evaluate pharmacokinetic properties and coagulatory changes of r-hirudin in healthy horses.
Two clinically healthy horses received a single i.v. bolus of 0.4 mg/kg bwt r-hirudin and 6 clinically healthy horses received the same dose subcutaneously (subcut.) q. 12 h for 3 days. Coagulation times and r-hirudin plasma concentration were determined over 720 mins and 3 days after i.v. and subcut. administration, respectively.
In all horses, treatment with r-hirudin was not associated with systemic or local side effects. After i.v. injection, the 2 horses showed an elimination half-life of 58 and 80 mins, respectively. After subcut. administration, maximum plasma concentration of r-hirudin occurred at 128 +/- 55 mins and declined with a terminal half-life of 561 +/- 364 mins. Maximum response of activated partial thromboplastin time (aPTT) occurred 1.5 h after administration of r-hirudin. A prolongation of 1.9 +/- 0.2 times the pretreatment value was noted.
Pharmacokinetics of r-hirudin in healthy horses were similar to those in man and other animal species.
The results of this study indicate that r-hirudin can be used in horses, but further studies should be performed in order to prove its effectiveness in diseased horses.
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