Rivaroxaban versus aspirin for secondary prevention of ischaemic stroke in patients with cancer: a subgroup analysis of the NAVIGATE ESUS randomized trial.

BACKGROUND AND PURPOSE: Cancer is a frequent finding in ischaemic stroke patients. The frequency of cancer amongst participants in the NAVIGATE ESUS randomized trial and the distribution of outcome events during treatment with aspirin and rivaroxaban were investigated. METHODS: Trial participation required a recent embolic stroke of undetermined source. Patients' history of cancer was recorded at the time of study entry. During a mean follow-up of 11 months, the effects of aspirin and rivaroxaban treatment on recurrent ischaemic stroke, major bleeding and all-cause mortality were compared between patients with cancer and patients without cancer. RESULTS: Amongst 7213 randomized patients, 543 (7.5%) had cancer. Of all patients, 3609 were randomized to rivaroxaban [254 (7.0%) with cancer] and 3604 patients to aspirin [289 (8.0%) with cancer]. The annual rate of recurrent ischaemic stroke was 4.5% in non-cancer patients in the rivaroxaban arm and 4.6% in the aspirin arm [hazard ratio (HR) 0.98, 95% confidence interval (CI) 0.78-1.24]. In cancer patients, the rate of recurrent ischaemic stroke was 7.7% in the rivaroxaban arm and 5.4% in the aspirin arm (HR 1.43, 95% CI 0.71-2.87). Amongst cancer patients, the annual rate of major bleeds was non-significantly higher for rivaroxaban than aspirin (2.9% vs. 1.1%; HR 2.57, 95% CI 0.67-9.96; P for interaction 0.95). All-cause mortality was similar in both groups. CONCLUSIONS: Our exploratory analyses show that patients with embolic stroke of undetermined source and a history of cancer had similar rates of recurrent ischaemic strokes and all-cause mortality during aspirin and rivaroxaban treatments and that aspirin appeared safer than rivaroxaban in cancer patients regarding major bleeds. www.clinicaltrials.gov (NCT02313909).

Incidence of neuraxial haematoma after total hip or knee surgery: RECORD programme (rivaroxaban vs. enoxaparin).

BACKGROUND: Patients receiving anticoagulants could be at higher risk of compressive haematoma with neuraxial anaesthesia use. The phase III RECORD programme compared rivaroxaban with enoxaparin for prevention of venous thromboembolism after total hip or knee replacement surgery in more than 12,500 patients. This observational analysis evaluated the risk of neuraxial haematoma after neuraxial anaesthesia in patients receiving rivaroxaban or enoxaparin using pooled RECORD1-4 data. METHODS: The incidences of intraspinal bleeding or haemorrhagic puncture were recorded as part of the criteria for major bleeding (the primary safety outcome in the RECORD studies). Incidences of allogeneic transfusion and venous thromboembolism by type of anaesthesia were also recorded. RESULTS: No compressive haematomas occurred in rivaroxaban-treated patients (10 mg once daily started 6-8 h after surgery) who underwent neuraxial anaesthesia (n = 4086). Among enoxaparin-treated patients (n = 4090), one compressive spinal haematoma requiring laminectomy occurred after epidural catheter removal in an elderly female patient with renal insufficiency undergoing total knee replacement. Total venous thromboembolism rates did not differ according to type of anaesthesia. CONCLUSION: Although no issues were observed with the use of neuraxial anaesthesia in this population of 4086 patients receiving rivaroxaban after total hip or knee replacement, it is important to remain aware of the risk of compressive haematoma. This may be of particular concern in elderly patients with renal insufficiency receiving an anticoagulant predominantly eliminated via the kidneys.

The effects of rivaroxaban on the complications of surgery after total hip or knee replacement: results from the RECORD programme.

Post-operative complications after total hip or knee replacement can delay recovery, prolong hospitalisation, increase rates of re-admission and, in the most severe cases, lead to long-term disability or even death. In this analysis of pooled data from four large, randomised, phase III clinical trials that compared the oral, direct Factor Xa inhibitor rivaroxaban with subcutaneous enoxaparin for the prevention of venous thromboembolism after total hip or knee replacement (n = 12,729), the incidence of complications, including bleeding and adverse events related to surgery (such as wound infection, wound dehiscence and haemarthrosis) are reported. Interventions and procedures relating to surgery are also compared between the groups. Bleeding events, including excessive wound haematoma and surgical-site bleeding, occurred at similar rates in the rivaroxaban and enoxaparin groups. Over the total study duration, adverse surgical events occurred at a similar rate in the rivaroxaban group compared with the enoxaparin group after total knee replacement (2.26% vs. 2.69%, respectively) and total hip replacement (1.48% vs. 1.65%, respectively). Blood loss, wound drainage and transfusion requirements were also similar between the two groups. This analysis shows that the incidence of adverse surgical events with rivaroxaban was similar to enoxaparin.

Comparison of ximelagatran, an oral direct thrombin inhibitor, with enoxaparin for the prevention of venous thromboembolism following total hip replacement. A randomized, double-blind study.

BACKGROUND: Prophylaxis is recommended following total joint replacement because of the high risk of venous thromboembolism (VTE). Postoperative low-molecular-weight heparin (LMWH) reduces the incidence of venographically detected deep vein thrombosis (DVT) to about 10-15% in total hip replacement (THR) patients. Ximelagatran is a novel, oral direct thrombin inhibitor that selectively and competitively inhibits both free and clot-bound thrombin. We compared the efficacy and safety of ximelagatran with those of enoxaparin for the prevention of VTE in patients undergoing THR. METHODS: This was a prospective, randomized, multicenter, double-blind study conducted principally in the USA and Canada. Patients received fixed-dose oral ximelagatran 24 mg bid or subcutaneous enoxaparin 30 mg bid and matched placebo for 7-12 days; both regimens were initiated the morning after surgery. The incidence of VTE (by postoperative day 12) included thrombosis determined by mandatory venography of the leg on which surgery was performed and symptomatic, objectively proven DVT or pulmonary embolism (PE). VTE and bleeding events were interpreted by an independent central adjudication committee for primary analysis. RESULTS: Of the 1838 patients randomized, 1557 had either adequate venography or symptomatic, proven VTE (efficacy population). Overall rate of venography acceptable for evaluation was 85.4%. Overall rates of total VTE were 7.9% (62 of 782 patients) in the ximelagatran group and 4.6% (36 of 775 patients) in the enoxaparin group, with an absolute difference of 3.3% and a 95% confidence interval for the difference of 0.9% to 5.7%. Proximal DVT and/or PE occurred in 3.6% (28 of 782 patients) in the ximelagatran group and 1.2% (nine of 774 patients) in the enoxaparin group. Major bleeding events were observed in 0.8% (seven of 906) of the ximelagatran-treated patients and in 0.9% (eight of 910) of the enoxaparin-treated patients (P > 0.95). Non-inferiority of ximelagatran 24 mg bid based on a prespecified margin of 5% was not met, resulting in superiority of the enoxaparin regimen. CONCLUSIONS: Both ximelagatran and enoxaparin decreased the overall rate of VTE compared with that reported historically. However, in this study, enoxaparin 30 mg bid was more effective than ximelagatran 24 mg bid for prevention of VTE in THR. Oral ximelagatran was used without coagulation monitoring, was well tolerated, and had bleeding rates comparable to those of enoxaparin. Further refinement by testing a higher dose of ximelagatran in the patients undergoing THR is warranted.

Oral heparin administration with a novel drug delivery agent (SNAC) in healthy volunteers and patients undergoing elective total hip arthroplasty.

BACKGROUND: Unfractionated heparin (UFH) is safe and effective for thromboprophylaxis, but its use is limited to parenteral administration. A novel drug delivery agent (SNAC) has been developed to accomplish the oral delivery of heparin. OBJECTIVE: This report describes the foundation for dose selection and use of oral heparin/SNAC in patients undergoing elective total hip arthroplasty (THA). PATIENTS AND METHODS: To develop a treatment regimen for clinical study, a multiple dose Phase I pharmacokinetic (PK) study in healthy volunteers compared oral heparin/SNAC (90 000 U heparin) with subcutaneous UFH (5000 U). On this basis, we carried out a double-blind, randomized, multicenter study comparing subcutaneous UFH (5000 U) with oral heparin/SNAC at either 60 000 or 90 000 U heparin in 123 patients undergoing elective THA. Patients received, postoperatively, one of the three treatments every 8 h for a total of 12 doses and were followed for 35 days post surgery. RESULTS: In the Phase I study, anti-factor Xa activity peaked at 45-60 min following oral heparin/SNAC, returning to baseline at 4 h. RESULTS of the randomized trial in THA patients showed that venous thromboembolic events (n = 6), major bleeding events (n = 5) and need for transfusion (n = 23) were distributed evenly among the three treatment groups, UFH and both doses of oral heparin/SNAC. CONCLUSION: This is the first demonstration that oral heparin/SNAC can be safely delivered to the postoperative THA patient, and provides the basis for a larger clinical trial to assess the prophylactic efficacy of heparin/SNAC.

Prospective comparison of hemorrhagic complications after treatment with enoxaparin versus unfractionated heparin for unstable angina pectoris or non-ST-segment elevation acute myocardial infarction.

Patients with unstable angina pectoris (UAP) or non-ST-segment elevation acute myocardial infarction (AMI) are at risk of death or recurrent ischemic events, despite receiving aspirin and unfractionated heparin (UFH). This study investigates the effect of the low molecular weight heparin, enoxaparin, on the incidence of hemorrhage and thrombocytopenia in relation to baseline characteristics and subsequent invasive procedures. Rates of hemorrhage and thrombocytopenia were analyzed for UAP or non-ST-segment elevation AMI in patients included in the prospective, randomized, double-blind Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-wave Coronary Events (ESSENCE) study. Patients received either enoxaparin or UFH, plus aspirin, for 2 to 8 days. The overall rate of major hemorrhage (at 30 days) was comparable between the 2 groups (6.5% for enoxaparin vs. 7.0% for UFH, p = 0.6). The rate of major hemorrhage while on treatment was slightly higher in the enoxaparin group, but this was not significant (1.1% vs 0.7% for UFH, p = 0.204), as was the rate of major hemorrhage within 48 hours of coronary artery bypass grafting performed within 12 hours of treatment. However, the rate of minor hemorrhage was significantly higher in the enoxaparin group, with the majority being injection-site ecchymoses or hematomas (11.9% vs. 7.2% with UFH, p <0.001). Thrombocytopenia (platelet count <100,000 per mm(3)) occurred mainly in association with coronary bypass surgery, with a similar rate in both groups. Thus, enoxaparin is a well-tolerated alternative to UFH in the management of UAP or non-ST-segment elevation AMI. Despite the more effective antithrombotic effect, which results in fewer ischemic events, enoxaparin is not associated with an increase in the rate of major hemorrhagic complications, and is not significantly associated with thrombocytopenia, but is associated with an increase in minor injection site ecchymosis.

Comparison of the oral direct thrombin inhibitor ximelagatran with enoxaparin as prophylaxis against venous thromboembolism after total knee replacement: a phase 2 dose-finding study.

BACKGROUND: Up to one third of patients who undergo total knee replacement develop deep vein thrombosis after surgery despite receiving low-molecular-weight heparin prophylaxis. Ximelagatran is a novel direct inhibitor of free and clot-bound thrombin. METHODS: We performed a randomized, parallel, dose-finding study of 600 adults undergoing elective total knee replacement at 68 North American hospitals to determine the optimum dose of ximelagatran to use as prophylaxis against venous thromboembolism after total knee replacement. Patients received either ximelagatran twice daily by mouth in blinded fixed doses of 8, 12, 18, or 24 mg or open-label enoxaparin sodium, 30 mg, subcutaneously twice daily, starting 12 to 24 hours after surgery and continuing for 6 to 12 days. We measured the 6- to 12-day cumulative incidence of symptomatic or venographic deep vein thrombosis, symptomatic pulmonary embolism, and bleeding. RESULTS: A total of 594 patients received at least 1 dose of the study drug; 443 patients were evaluable for efficacy. Rates of overall venous thromboembolism (and proximal deep vein thrombosis or pulmonary embolism) for the 8-, 12-, 18-, and 24-mg doses of ximelagatran were 27% (6.6%), 19.8% (2.0%), 28.7% (5.8%), and 15.8% (3.2%), respectively. Rates of overall venous thromboembolism (22.7%) and proximal deep vein thrombosis or pulmonary embolism (3.1%) for enoxaparin did not differ significantly compared with 24-mg ximelagatran (overall difference, -6.9%; 95% confidence interval, -18.0% to 4.2%; P=.3). There was no major bleeding with administration of 24 mg of ximelagatran twice daily. CONCLUSION: Fixed-dose, unmonitored ximelagatran, 24 mg twice daily, given after surgery appears to be safe and effective oral prophylaxis against venous thromboembolism after total knee replacement.

Rapid assessment of glycoprotein IIb/IIIa blockade with the platelet function analyzer (PFA-100) during percutaneous coronary intervention.

BACKGROUND: The platelet function analyzer PFA-100 (Dade Behring, Miami, Fla) evaluates platelet function by determining the time to occlusion of an aperture in a membrane coated with collagen and adenosine diphosphate or epinephrine as whole blood flows under shear stress conditions. Platelet aggregation causes aperture occlusion, and results are reported as closure time (CT). Interindividual variability is observed in the level of platelet inhibition achieved with use of the current abciximab dosing regimen (0.25-mg/kg bolus + 10-microg/min infusion for 12 hours). The relationships between specific levels of platelet inhibition and clinical efficacy and safety have not been fully established. METHODS AND RESULTS: We prospectively studied platelet function in 27 patients receiving abciximab during percutaneous coronary intervention. This evaluation included determinations of platelet-rich plasma aggregometry, receptor occupancy studies (D3 assay), and CT measurements at baseline and 10 minutes, 4 hours, 12 hours, and 24 hours after the bolus. All patients received abciximab, aspirin, and heparin; patients undergoing coronary stent implantation received aspirin and ticlopidine after the procedure. CT results were reported within 10 minutes after initiation of testing. For 96% of patients, CT was 300 seconds (maximum CT) immediately after abciximab bolus and remained so throughout the infusion. At 24 hours we observed variable recovery from platelet inhibition and in 72% of patients CT returned to normal (< or =130 seconds). CONCLUSIONS: Findings with the PFA-100 were similar to results observed with platelet aggregometry and receptor occupancy measurements. Most patients treated with abciximab exhibit normalized platelet function at 24 hours despite moderate levels of receptor occupancy, suggesting dissociation between occupancy and function.

Clinical correlates and course of thrombocytopenia during percutaneous coronary intervention in the era of abciximab platelet glycoprotein IIb/IIIa blockade.

BACKGROUND: Thrombocytopenia is infrequently associated with abciximab therapy but may contribute to hemorrhagic risk. Factors associated with development of thrombocytopenia, the role of weight-adjustment in concomitant heparin administration, and clinical outcomes in patients with thrombocytopenia are not well defined. METHODS AND RESULTS: Pooled data from 3 placebo-controlled, randomized trials (EPIC, EPILOG, and EPISTENT) of abciximab therapy during percutaneous coronary intervention identified 178 patients (2. 4% of 7290 patients) in whom thrombocytopenia (platelet count <100 x 10(9)/L) developed after enrollment. Multivariate regression analysis identified age (>65 years; P <.001), weight (<90 kg; P =. 023), baseline platelet count (<200 x 10(9)/L; P <.001), abciximab therapy (P =.002), and enrollment into the EPIC trial (P <.001) to be associated with development of thrombocytopenia. Major and minor nonsurgical hemorrhage and transfusion were more frequent (all P <. 001) in thrombocytopenic patients. Although the primary composite clinical end point of these trials (death, myocardial infarction, or urgent revascularization to 30 days) was observed with similar frequency in patients with (11.2%) and those without (7.9%; P =.114) thrombocytopenia, 30-day mortality rate was higher in thrombocytopenic patients (8.4% vs 0.6%, respectively; P <.001). This excess mortality rate persisted after excluding patients in whom thrombocytopenia was first noted after the performance of coronary bypass surgery (4.8% vs 0.6%; P <.001). Among patients in whom thrombocytopenia developed during these trials, those who received prophylactic abciximab had fewer primary end point events (7.1% vs 23.1%; P =.056) and had a lower 30-day mortality rate (3.5% vs 15.4%; P =.048) than patients with thrombocytopenia who had received prophylactic placebo. CONCLUSIONS: Thrombocytopenia associated with abciximab therapy for percutaneous coronary intervention was more frequent in older, lighter-weight patients, those with lower baseline platelet counts, and in those patients who were enrolled into the EPIC trial. Both bleeding and transfusion events occur more frequently in patients with thrombocytopenia. Patients in whom thrombocytopenia developed during these trials had increased mortality rates to 30 days not attributable to the performance of coronary bypass surgery. Among patients with thrombocytopenia, those who received prophylactic abciximab had better clinical outcomes including survival than those who did not.

Efficacy of abciximab readministration in coronary intervention.

Abciximab, an Fab monoclonal antibody fragment that blocks the platelet glycoprotein IIb/IIIa receptor, is increasingly used as an adjunct to coronary intervention. Little is known, however, about the efficacy and safety of readministration of abciximab. This study examined and characterized outcomes of patients receiving abciximab for a second time. From April 1995 to June 1997, 164 consecutive patients were readministered abciximab at our 3 institutions. We retrospectively examined and analyzed in-hospital outcomes in this cohort. The median time to readministration was 95 days. The angiographic success rate of percutaneous intervention was 99.5%. Rates and 95% confidence intervals of in-hospital events were death 2% (0.7% to 6.1%), myocardial infarction 3% (1% to 7%), coronary bypass surgery 0% (0% to 2.2%), and intracranial hemorrhage 2% (0.4% to 5.3%). Severe thrombocytopenia was observed in 4% of patients (1.4% to 7.8%) after readministration. Allergic or anaphylactic reactions were not observed. Major bleeding was associated with excessive concomitant antithrombotic therapy. Patients undergoing readministration of abciximab within 2 weeks of first administration experienced a higher incidence of severe thrombocytopenia (12% vs. 2%, p = 0.046). Thus, abciximab remains clinically efficacious when readministered as an adjunct to percutaneous coronary intervention. However, concomitant heparin administration must be carefully monitored and warfarin therapy should be avoided. Vigilant surveillance for thrombocytopenia should be employed. Reduced dosing may be necessary when abciximab is readministered within days of the initial administration.

Current knowledge of the platelet glycoprotein IIb/IIIa receptor antagonists for the treatment of coronary artery disease.

Understanding of the pivotal role of the platelet surface membrane glycoprotein (GP) IIb/IIIa receptor in platelet aggregation at the injured coronary plaque in acute coronary syndromes has led to recent pharmacologic strategies that focus on inhibition of this final common pathway. Several intravenous medications directed specifically at this receptor (called platelet GP IIb/IIIa receptor antagonists; GPAs) have emerged. These include the human-murine chimeric monoclonal antibody Fab fragment abciximab, the peptide antagonist eptifibatide and the peptidomimetics tirofiban and lamifiban. To date, over 33,000 patients have been studied with these compounds in 11 large, randomized placebo controlled trials which have established the effectiveness of these drugs in conditions where platelet aggregation and thrombosis play major contributing roles such as in high-risk coronary intervention, myocardial infarction and unstable angina. GPAs have been proven to be effective in reducing ischemic complications when used as an adjunct to percutaneous coronary revascularization or the management of acute ischemic syndromes. They are well tolerated and safe, provided concomitant use with other antithrombotics (e.g. heparin) is carefully managed and platelet counts are monitored.

Clinical significance of thrombocytopenia during a non-ST-elevation acute coronary syndrome. The platelet glycoprotein IIb/IIIa in unstable angina: receptor suppression using integrilin therapy (PURSUIT) trial experience.

BACKGROUND: The significance of thrombocytopenia in patients experiencing an acute coronary syndrome (ACS) has not been examined systematically. We evaluated this condition in a large non-ST-elevation ACS clinical trial, with particular interest paid to its correlation with clinical outcomes. METHODS AND RESULTS: Patients presenting without persistent ST elevation during an ACS were randomized to receive a double-blind infusion of the platelet glycoprotein (GP) IIb/IIIa inhibitor eptifibatide or placebo in addition to other standard therapies including heparin and aspirin. The primary end point was death/nonfatal myocardial infarction (MI) at 30 days, whereas bleeding and stroke were the main safety outcomes. Thrombocytopenia (nadir platelet count <100x10(9)/L or <50% of baseline) occurred in 7.0% of enrolled patients. The time to onset was a median of 4 days in both treatment arms. Patients with thrombocytopenia were older, weighed less, were more likely nonwhite, and had more cardiac risk factors. These patients experienced significantly more bleeding events: they were more than twice as likely to experience moderate/severe bleeding after adjustment for confounders. Univariably, ischemic events (stroke, MI, and death) occurred significantly (P<0.001) more frequently in patients with thrombocytopenia; multivariable regression modeling preserved this association with death/nonfatal MI at 30 days. Neither the use of heparin or eptifibatide was found to independently increase thrombocytopenic risk. CONCLUSIONS: Although causality between thrombocytopenia and adverse clinical events could not be established definitively, thrombocytopenia was highly correlated with both bleeding and ischemic events, and the presence of this condition identified a more-at-risk patient population.

Modifiable risk factors for vascular access site complications in the IMPACT II Trial of angioplasty with versus without eptifibatide. Integrilin to Minimize Platelet Aggregation and Coronary Thrombosis.

OBJECTIVES: This study was designed to identify potential predictors of vascular access site (VAS) complications in the large-scale Integrilin to Minimize Platelet Aggregation and Coronary Thrombosis (IMPACT) II trial, which studied angioplasty with versus without a new glycoprotein (GP) IIb/IIIa receptor inhibitor (eptifibatide). BACKGROUND: GP IIb/IIIa receptor inhibition during coronary interventions has been associated with excess VAS complications. If other predictors of VAS complications could be identified, they might be manipulated to reduce complications. METHODS: A total of 4,010 patients undergoing percutaneous transluminal coronary revascularization (PTCR) were randomized into one of three bolus/20- to 24-h infusion arms: placebo bolus/placebo infusion; 135-microg/kg body weight eptifibatide bolus/0.5-microg/kg per min eptifibatide infusion; or 135-microg/kg eptifibatide bolus/0.75-microg/kg per min eptifibatide infusion. Heparin during the procedure was weight adjusted and stopped 4 h before sheaths were removed. Logistic regression modeling was used to identify independent predictors of VAS complications. RESULTS: VAS complications were more common in patients treated with eptifibatide (9.9% vs. 5.9% placebo-treated patients, p < 0.001). Multivariate analysis identified eptifibatide therapy (p < 0.0001), advanced age (p = 0.0001), longer time to sheath removal (p = 0.0002), stent placement (with intense post-stent anticoagulation) (p = 0.0004), female gender (p = 0.0006), PTCR within 24 h of thrombolytic therapy (p = 0.002), larger heparin doses during PTCR (p = 0.009), major coronary dissection (p = 0.03) and placement of a venous sheath (p = 0.04) as independent predictors of VAS complications. CONCLUSIONS: VAS complications may be reduced by early sheath removal, by avoiding placement of venous sheaths and by limiting heparin dosing to avoid excessive activated clotting times. Early sheath removal during inhibition of platelet aggregation by eptifibatide is feasible.

Efficacy and safety of low molecular weight heparin (ardeparin sodium) compared to warfarin for the prevention of venous thromboembolism after total knee replacement surgery: a double-blind, dose-ranging study. Ardeparin Arthroplasty Study Group.

UNLABELLED: We performed a double-blind, randomized clinical trial to compare the efficacy and safety of three different subcutaneous (s.c.) low molecular weight heparin doses (ardeparin sodium 25, 35, or 50 anti-Xa U/kg twice daily [BID]) to adjusted-dose warfarin (international normalized ratio [INR] = 2.0 to 3.0), as venous thromboembolism prophylaxis after total knee replacement surgery. The primary endpoint was total venous thromboembolism prevalence, defined as deep vein thrombosis discovered at postoperative venography of the operated leg, or symptomatic, objectively-documented pulmonary embolism. Of 860 patients randomized, 680 (79%) had an evaluable venogram or pulmonary embolism. The total venous thromboembolism prevalence was significantly greater among patients prophylaxed with warfarin compared to ardeparin 50 BID (38% vs 27%, p = 0.019); the prevalence among ardeparin 25 BID (37%) and 35 BID (28%) patients was similar to warfarin and ardeparin 50 BID patients, respectively. Overt bleeding occurred in 22 (7.9%) ardeparin 50 BID patients compared to 12 (4.4%) warfarin patients (p = 0.08), and in seven ardeparin 25 and 35 BID patients each (5.2% and 5.0%, respectively). Compared to the warfarin group, blood loss was significantly greater in the ardeparin 50 and 25 BID groups, and not different in the ardeparin 35 BID group. CONCLUSIONS: Postoperative, unmonitored, fixed-dose ardeparin 50 anti-Xa U/kg s.c. BID is significantly more effective than adjusted-dose warfarin for this indication. Although overt bleeding among warfarin and ardeparin 50 BID patients did not differ significantly, ardeparin 50 BID patients had significantly greater blood loss. Ardeparin 35 anti-Xa U/kg s.c.BID may provide efficacy similar to ardeparin 50 anti-Xa U/kg s.c. BID but with reduced bleeding.

Degradation of von Willebrand factor in patients with acquired clinical conditions in which there is heightened proteolysis.

The behavior of plasma von Willebrand factor (vWF) in patients with acute leukemia (n = 5), decompensated cirrhosis (n = 10), and acute pancreatitis (n = 5) was investigated to evaluate whether the systemic proteolytic states associated with these diseases had affected the structure and function of the molecule. vWF antigen and, to a lesser degree, ristocetin cofactor activity in patient plasma were high. Multimeric analysis of plasma vWF revealed loss of high molecular weight multimers. The subunit composition and proteolytic pattern of vWF immunopurified from patient plasmas and reduced were studied by sodium dodecyl sulfate (SDS)-polyacrylamide gel electrophoresis followed by transblotting and probing with monoclonal antibodies that distinguish cleavages caused by plasmin from those caused by other proteases. There was marked reduction of the relative concentration of the native vWF subunit of 225 Kd in all patient groups, indicating heightened cleavage of the protein. The concentrations of 189- and 140-Kd vWF fragments, normally present in plasma, were increased in cirrhosis and pancreatitis but not in leukemia. Novel fragments, ranging in size from less than 225 to approximately 120 Kd were present in leukemia and cirrhosis, including plasmin-generated fragments of 176 and 145 Kd. These data indicate that in clinical conditions in which there is heightened proteolysis vWF is degraded in vivo by plasmin and other proteases. Degraded vWF may be less effective than native vWF in supporting primary hemostasis, thereby being a cofactor in the multifactorial bleeding diathesis accompanying systemic proteolytic states.

Subunit composition of plasma von Willebrand factor in patients with the myeloproliferative syndrome.

In order to evaluate the role of proteolysis in acquired von Willebrand's disease (vWD) associated with the myeloproliferative syndrome, we have determined the relative quantity of von Willebrand factor (vWF) fragments as compared with the intact 225 kDa subunit in four patients. The plasma vWF of each individual lacked large multimers; each had a prolonged bleeding time; and both platelet and leukocyte counts were elevated. Plasma was obtained from blood drawn into 1 mmol/L leupeptin, 6 mmol/L N-ethylmaleimide, and 5 mmol/L EDTA to prevent in vitro proteolysis. vWF was isolated from plasma by immunoadsorbent chromatography, reduced, subjected to SDS-5% polyacrylamide gel electrophoresis, and immunoblotted with a mixture of 55 anti-vWF monoclonal antibodies. In three patients with essential thrombocytosis (ET) the 176 and 140 kDa fragments were increased in proportion to the intact 225 kDa subunit indicating increased proteolysis. Treatment of one ET patient with CCNU (Lomustine) decreased the platelet count and, to a lesser extent, the white blood cell count. This was associated with a correction of the bleeding time, a partial correction of the multimeric abnormality, and a lessening of vWF cleavage. In a patient with polycythemia rubra vera (PRV) the proportion of the 176 kDa fragment was increased to the upper limit of normal but there was no definite evidence of increased proteolysis. These studies provide evidence that proteolysis plays a role in the acquired von Willebrand's disease associated with the myeloproliferative syndrome. However, other mechanisms must also be considered.