Recombinant tissue plasminogen activator (alteplase) for restoration of flow in occluded central venous access devices: a double-blind placebo-controlled trial--the Cardiovascular Thrombolytic to Open Occluded Lines (COOL) efficacy trial.

PURPOSE: Central venous access devices (CVADs) are a mainstay of current medical therapy but often become occluded by thrombus. Tissue plasminogen activator (alteplase), at a dose of 2 mg per 2 mL, has been shown to be effective in restoring flow to catheters proven by radiographic contrast injection to be occluded by thrombus. The purpose of this double-blind placebo-controlled multicenter trial was to determine the efficacy of alteplase in occluded catheters without earlier contrast injections or radiographic examinations. MATERIALS AND METHODS: Patients were eligible for inclusion if blood could not be withdrawn from their catheter after a period of normal function of at least 48 hours. Single or multiple catheters, peripherally inserted central catheters, catheters with valves, and implanted ports were eligible; catheters used for hemodialysis were not included. Patients were randomly assigned to one of two groups. In one group, patients received a first dose of 2 mg alteplase followed, if needed, by a second dose of 2 mg alteplase and a third dose of placebo. The other group received placebo first followed by one 2-mg dose of alteplase and then a second, if needed. Each dose was allowed to dwell for 2 hours and ability to withdraw blood from the catheter was reassessed. The endpoint was restoration of the ability to withdraw and infuse through the catheter. One hundred forty-nine patients were randomized: 74 received placebo first, 75 received alteplase first. RESULTS: After the first 2-hour treatment, function was restored to 74% in the alteplase arm and 17% in the placebo arm (P <.0001 compared to placebo). After one or two treatments, function was restored in 90% of patients. There were no serious study-drug-related adverse events, no intracranial hemorrhage, no major hemorrhage, and no embolic events. CONCLUSION: Infusion of alteplase appeared to be safe and effective in restoring flow to occluded catheters without need for pretreatment radiographic evaluation.

Techniques in dosing for thrombolysis of occluded central venous catheters.

Dosing of thrombolytic agents for restoration of flow to thrombotically occluded central venous catheters has been empiric. The lowest effective dose of any agent is not known. Given that none of the dosing regimens in current use has ever been found to be toxic, this is probably not a major clinical problem as long as the regimen is highly effective. Thrombolytic regimens differ in the type of drug, dose of drug, method of administration (injection versus prolonged infusion), and duration of administration. All of these variables are important in determining the efficacy, and possibly the toxicity, of a regimen. Active research is being conducted to determine the most effective ways of using the expanding number of thrombolytic medications that are now, or soon may be, on the market.

Organ dysfunction following stem cell transplantation: relationship to plasma cytokine concentrations.

Patients receiving high-dose preparation for stem cell transplantation are at risk for organ dysfunction (OD). Signs of early OD include hypoxia, mental status changes, and liver dysfunction. These early signs have not been correlated with potential cytokine mediators. We compared plasma concentrations of IL-6, TNF-alpha, and IL-10 in OD patients and controls. Cytokines were measured before preparation, 5 days before OD, day of OD, and 5 days after OD. TNF-alpha and IL-10 were not measurable prior to preparation. IL-10 was more likely to be measurable in OD patients than in controls 5 days prior to onset of OD (P = 0.039), on the day of OD (P = 0.023), and 5 days later (P < 0.0001). TNF-alpha was more likely to be measurable only on the day of OD (P = 0.0035). IL-6 was significantly elevated in OD patients at all time points. Patients who had measurable IL-6 on admission were 5.1 times more likely to develop OD (95% CI = 1.4-17.9; P = 0.011). Five days prior to OD for each 100 pg/ml increase in IL-6, patients were 2.75 times more likely to develop OD (95% CI = 1.3-5.8; P = 0.0087). The early elevation of IL-6 in patients who develop OD may help identify a high risk group where preventive therapies can be evaluated.

The multiple organ dysfunction syndrome in cancer patients undergoing hematopoietic stem cell transplantation.

In the past two decades, major improvements in antibiotics and other elements of supportive care have decreased the number and severity of complications of hematopoietic stem cell transplantation (HSCT). Despite these improvements, many subpopulations of transplant patients still have a significant morbidity and mortality. It is becoming increasingly clear that medical science does not have a good understanding of the pathophysiology of many of the common, potentially fatal complications in patients currently undergoing HSCT. As the mechanisms of these complications are subjected to increasingly more rigorous scrutiny, it is becoming clear that many of these complications are intimately connected one to another and are not isolated clinical disorders as previously thought. One hypothesis that can explain the close relationship between them is that most of the severe complications of HSCT are the result of a systemic inflammatory disorder that has escaped biologic control, an inflammatory process begun by the preparative regimen and perhaps added to by intercurrent infections, tumor cell death and other as yet unidentified stimuli (transfusions, medications?). If this is true, this syndrome would have many similarities with the multiple organ dysfunction syndrome (MODS) seen in critically ill non-transplant patients. As such, this hypothesis has two significant corollaries: (a) That looking for or empirically treating for a reversible organ specific cause of single organ dysfunction during HSCT (such as infectious pneumonia, intracranial hemorrhage, or acute infectious hepatitis) in any given patient is unlikely to be rewarding as the defect causing the organ dysfunction is often systemic at the time of its presentation, and (b) that MODS is the dose-limiting toxicity of our current preparative regimens, suggesting that when we understand its pathophysiology and develop therapies for MODS we will be able to escalate their intensity and, by doing so, cure more patients of their malignancy. Manipulation of the hemostatic system may prove to be one of these therapies, but there is little doubt that other interventions designed to modulate the inflammatory process will prove to be even more useful in this syndrome. Using the definitions of organ dysfunction outlined in this article, we can provide a basis for clinical monitoring of patients today and for use in interventional clinical trials in the future.

The pre-conditioning incidence of antiphospholipid antibodies is not significantly increased in patients with bone marrow transplant-related organ dysfunction.

Hepatic dysfunction resulting from hepatic veno-occlusive disease (VOD) is a common complication of bone marrow transplantation (BMT). Some investigators believe that hepatic dysfunction, along with pulmonary and central nervous system (CNS) dysfunction, is part of a systemic disorder called multiple organ dysfunction syndrome (MODS). Endothelial damage by pretransplant chemo-radiation and activation of hemostasis are considered early events in the development of hepatic VOD. The pathological mechanism leading to fibrous obliteration of hepatic vessels may also take place in pulmonary and CNS vessels. Since antiphospholipid antibodies (aPA) are associated with venous and arterial thrombosis, which can lead to vessel occlusion, we asked if the incidence of aPA before conditioning was greater in patients who developed MODS following BMT. Samples drawn before pretransplant chemo-radiation from 57 patients who subsequently developed MODS and 55 control patients who did not develop MODS were studied blindly for aPA by ELISA. The number of aPA-positive patients who developed MODS (10/57), compared to the number of aPA-positive patient controls who did not develop MODS (7/55) was not statistically significant (P = 0.48). Our data indicate that the incidence of aPA before conditioning was not greater in patients who developed MODS, including hepatic VOD, following BMT.

A prospective randomized double-blind trial of antithrombin III concentrate in the treatment of multiple-organ dysfunction syndrome during hematopoietic stem cell transplantation.

Many of the complications of high-dose therapy with hematopoietic stem cells are caused by or lead to the multiple-organ dysfunction syndrome (MODS). In hematopoietic stem cell transplantation (HSCT), acquired antithrombin III (ATIII) deficiency is independently associated with MODS to the exclusion of transplant type, preparative regimen, and bacteremia. In experimental settings, replacement of ATIII can ameliorate the severity of MODS that develops in response to a variety of pathologic stimuli, suggesting that ATIII supplementation might improve the clinical course of MODS in patients undergoing HSCT. We performed a study to determine if ATIII can improve the morbidity of MODS in HSCT. Forty-nine patients undergoing HSCT, who developed pulmonary dysfunction (oxygen saturation of <90%), central nervous system dysfunction (drop of >4 points in the mini-mental status exam), or hepatic dysfunction (bilirubin >34 micromol/L [2.0 mg%], weight gain of >5% over baseline, and abdominal pain, possibly of hepatic origin) with a concomitant ATIII activity of <84% were double-blind randomized to receive ATIII concentrate, 70 units/kg within 24 hours of recognition of initial organ dysfunction followed by 50 units/kg 8, 16, 48, and 72 hours later, or albumin placebo. The group randomized to ATIII had a lower severity-of-illness score (15.7 +/- 19.2 vs. 28.6 +/- 25.2, p = 0.03), shorter duration of hospitalization (14.9 +/- 16.7 vs. 25.7 /- 17.9 days, p = 0.03), and lower hospital charges ($138,700 +/- $23,500 vs. $206,400 +/- $34,000). ATIII concentrate was associated with improved morbidity of MODS in patients undergoing HSCT when given early in the evolution of the syndrome.

Normal saline versus heparin flush for maintaining central venous catheter patency during apheresis collection of peripheral blood stem cells (PBSC).

Thrombotic occlusion is frequently a complication of central venous catheters (CVCs). The original designers and producers of CVCs recommended heparin flush regimens to prevent thrombosis and maintain patency. This has become standard practice although no studies have demonstrated a relationship between heparin flushing and reduction of catheter thrombosis. Many consider the routine use of heparin flushing innocuous. However, serious complications including drug interactions and heparin induced thrombocytopenia and thrombosis syndrome (HITS) have been reported in association with heparin flushing. Numerous studies comparing heparin to saline flushing in peripheral devices suggest equal rates of thrombotic occlusions. The purpose of this study was to examine the incidence of thrombotic occlusions in CVCs using heparin compared to saline flushing. The study involved 78 cancer patients undergoing apheresis collection for peripheral blood stem cells; 29 received saline flushes and 49 received heparin (100 U/ml of saline) flushes. Study endpoints included slow apheresis flow rate (< 50 ml/min), urokinase use for thrombolysis, and radiographic evidence of catheter thrombosis. No significant differences were found for any endpoint between the two groups. These findings suggest saline may be as effective as heparin for maintaining patency of CVCs.

Autoimmune coagulation disorders.

The spontaneous onset of autoantibodies against circulating factors, including factors II, V, VII, VIII, IX, XI, XII, and XIII, is a phenomenon of unclear causes. It may occur in patients with no underlying disease process or may be antedated by autoimmune diseases and malignancies. The antibodies are almost always IgG and are most commonly directed at F VIII. They generally present with a bleeding diathesis in patients with no history of prior bleeding events. The laboratory abnormalities vary depending on whether the inhibitor involves the intrinsic or extrinsic pathway of coagulation, and the laboratory studies may vary depending on the technique used. Supportive measures are used initially but are generally not completely effective. Supportive measures are followed by blood products, such as recombinant human F VIII, porcine F VIII, or PCC/aPCC. There are limitations to each of these, however. If bleeding is severe and high titers of inhibitors are present, plasma-pheresis may lead to a temporary decrease in the titer but is short-lived. Immunosuppressive therapy should ultimately be attempted to suppress further antibody production. Spontaneous remission may occur with some of the inhibitors, primarily postpartum or drug related, for reasons not fully understood.

Antithrombin III in hematopoietic stem cell transplantation.

Many of the serious, potentially fatal complications of hematopoietic stem cell transplantation have similarities to the multiple organ dysfunction syndrome (MODS) in critically ill nontransplant patients. One of these similarities is the alteration in the hemostatic system in such a way as to lower the levels of the naturally occurring anticoagulant proteins, especially antithrombin III. As in MODS, the outcome of transplant patients with these complications correlates with the degree of change in antithrombin III levels. Preliminary studies suggest that antithrombin III concentrate in pharmacologic doses along with intensive supportive care efforts can improve the clinical outcome of patients with these transplant-related complications. Further work to confirm these findings and, it is hoped, provide insight into the mechanism of action of antithrombin III in this setting is obviously warranted. Until such studies are completed, however, the preponderance of evidence suggests that when subjected to a risk-benefit analysis, patients in the early stages of transplant-related complications would be better off receiving antithrombin III supplementation than not.

Determination of prothrombin activation fragments in young patients with inflammatory bowel disease.

OBJECTIVE: To assess coagulation cascade activation as a potential index of thromboembolic risk in inflammatory bowel disease (IBD). STUDY DESIGN: Fifty plasma samples were obtained during consecutive outpatient encounters with 29 patients (male:female = 20:9) with either Crohn's disease (CD) (n = 23) or ulcerative colitis (UC) (n = 6). Disease activity for CD was determined using the Pediatric Crohn's Disease Activity Index (PCDAI) and for UC using signs/symptoms and mucosal histology. Patients were grouped as active, recently active (not currently active but had been active within the previous 2 months), or inactive. Prothrombin fragment 1.2 (F1.2) was determined by enzyme-linked immunosorbent assay on plasma samples. Lab parameters were compared using the Kruskal-Wallis test with pairwise comparisons made using Wilcoxian rank sum test. RESULTS: Forty-three percent of samples taken during active phases of disease (13 of 30) had elevated prothrombin cleavage byproduct F1.2. Similarly, five of eight encounters (63%) with recently active IBD had elevated F1.2 values. In contrast, none of the patients with inactive disease exhibited F1.2 elevation. Median F1.2 levels in both the active (0.85 nM/L) and recently active (1.4 nM/L) patient groups were greater than that of the inactive group (0.6 nM/L; p < 0.05). CONCLUSIONS: Evidence of coagulation cascade activation in patients with active and recently active IBD suggests an increased risk of thrombogenesis during active disease that extends for a period of time after commencement of medications to induce remission in their disease process. It may be prudent to counsel patients to avoid risk factors associated with thrombotic phenomenon around the time of active IBD.

Treatment of veno-occlusive disease of the liver with bolus tissue plasminogen activator and continuous infusion antithrombin III concentrate.

Veno-occlusive disease (VOD) of the liver is a common complication of BMT and is accompanied by reduced levels of natural anticoagulants and by multi-organ dysfunction. We describe two cases of clinical VOD developing after autologous BMT and accompanied by ultrasonographic features of reversed portal venous flow. In both cases the patients had decreased levels of antithrombin (AT). Once the diagnosis of VOD was made, these patients were treated with tissue plasminogen activator (tPA) and continuous infusion AT. Each patient had radiographic and clinical resolution of VOD with the therapy. This novel treatment appears to have reversed the course of VOD without the increased risk of bleeding seen in the use of heparin therapy.

Induction of immune tolerance in a 7-year-old hemophiliac with an anaphylactoid inhibitor.

BACKGROUND: Anaphylactic reactions were a rare complication of low purity VIII concentrates, but not with high purity VIII concentrates. CASE: 7 y/o WM with severe hemophilia A, received only cryoprecipitate and monoclonally purified VIII concentrates; developed post-infusional urticaria. A 2-Bethesda-unit inhibitor was detected. Generalized urticaria and bronchospasm following factor developed as the titer increased. Skin tests demonstrated reactivity to plasma derived VIII, but not recombinant VIII (rhVIII). Attempts at desensitization using rhVIII failed. ELISA revealed an anti-VIII IgE antibody. He was treated with a modified tolerance regimen using rhVIII starting at 500 U/day with aggressive premedication. The dosage increased by 200 U weekly as tolerated to a maximum of 100 U/kg/d without symptoms. RESULTS: His antibody titer decreased rapidly once he started 100 U/kg/d. Six months later, the inhibitor was < 1 Bethesda unit. CONCLUSION: Immune tolerance induction using a graduated dosage of rhVIII was successful.

Multiple organ dysfunction syndrome in bone marrow transplantation.

OBJECTIVE: To define the frequency and outcome of organ dysfunction in bone marrow transplantation (BMT) and to determine if patients with organ dysfunction have lower levels of protein C (PC) and/or antithrombin III (ATIII) than those without organ dysfunction. DESIGN: Inception cohort of patients undergoing BMT, followed for 28 days, until hospital dismissal, or until death. SETTING: Bone marrow transplant department of a university hospital. PATIENTS: A total of 199 consecutive patients admitted for BMT. INTERVENTIONS: Standard supportive care was given to all patients. MAIN OUTCOME MEASURES: Definitions of organ dysfunction were arrived at prior to beginning the study. They include pulmonary, central nervous system (CNS), hepatic, and renal dysfunction. Protein C and ATIII levels were measured prior to beginning the preparative regimen and weekly thereafter. RESULTS: Single organ dysfunction, manifesting as pulmonary, CNS, or hepatic dysfunction, occurred in 93 (48.5%) of the 199 patients and was a strong predictor of multiple organ dysfunction syndrome (MODS) and death. Death occurred in 14 (7.0%) of the patients. Cause of death was precisely identified in only four patients. Low levels of either PC or ATIII were associated with death and pulmonary, CNS, and hepatic dysfunction. Multivariate analysis showed ATIII and PC levels were associated with single organ dysfunction independent of the type of transplant, the type of preparative regimen, and the presence of bacteremia. CONCLUSIONS: Single organ dysfunction during BMT is a marker for a systemic abnormality that has a high likelihood of progressing to MODS, similar to that seen in other critically ill patient populations. MODS is the leading cause of death in series of BMT patients. Low levels of ATIII and PC are markers of and may be involved in the pathogenesis of MODS in BMT.

Arm vein thrombosis.

With the advent of subclavian catheterization for the supportive care of a host of diseases, the incidence of axillosubclavian vein thrombosis (ASVT) is rising. Treatment of these patients is not standard. Spontaneous ASVT usually occurs in healthy young individuals, often results in long-term disability, and warrants aggressive intervention. Catheter-induced ASVT generally occurs in older individuals with other significant medical problems.

Pharmacokinetics of antithrombin concentrate during autologous hematopoietic stem cell transplantation.

Antithrombin is a naturally-occurring anticoagulant protein. Congenital deficiency of this protein predisposes to thrombotic complications. Acquired deficiency of antithrombin occurs in a variety of clinical circumstances, including hematopoietic stem cell transplantation (HSCT), and is associated with multiorgan failure and death in these situations. Normalization of antithrombin levels by infusion of concentrates of this protein has been found to be beneficial in many of these situations, but has not been routinely used in HSCT. Before antithrombin concentrates can be widely recommended in HSCT, its pharmacokinetics at various phases of the transplant process must be defined to allow estimation of the proper dose and dosing interval. To this end, the recovery and half-life of antithrombin concentrate was determined prior to and 7, 14 and 28 days after beginning the preparative regimen in nine patients with lymphoma undergoing HSCT. The recovery of the infused material was constant during the transplant hospitalization, averaging 2.0% per unit/kg. The half-life, however, dropped significantly during the latter half of the transplant procedure. The half-lives pre-chemotherapy and on day 7 were similar and averaged 20.4 h. On days 14 and 21 the the half-lives were significantly lower at 12.2 and 15.5 h, respectively. The drop in half-life during the transplant process will require antithrombin concentrate to be given more frequently during this time to maintain constant antithrombin levels.

Double-lumen inferior vena cava catheters for peripheral stem cell apheresis and transplantations.

No previously published studies have described double-lumen hemodialysis/apheresis catheters for use with continuous-flow apheresis collection of peripheral stem cell (PSC). We prospectively evaluated experiences with these catheters during both PSC collection and transplantation. Because of previously-described successful experiences with single-lumen apheresis catheters placed in the inferior vena cava, all catheters evaluated in this study were placed in this anatomic location. Our experience demonstrated high rates of thrombotic occlusion (65%) and catheter-related infections (15%). This method of access should not be considered optimal in its present state of use. Further investigation into preferred catheter design, anatomic location, and thrombosis prophylaxis during continuous-flow apheresis is warranted.

Are clinical signs accurate indicators of the cause of central venous catheter occlusion?

BACKGROUND: Two hundred dysfunctional central venous catheters used for total parenteral nutrition and administration of cancer chemotherapy were radiographically examined in order to objectively identify thrombotic occlusions as the cause of catheter dysfunction. METHODS: Outcomes of radiographic dye injections were compared with factors such as the inability to aspirate blood or to infuse fluids, catheter type, and duration of catheter placement. RESULTS: Catheter type and duration of placement were not significant factors for predicting the type of dysfunction. Failure to withdraw blood was associated with 96% of the thrombosed catheters; this was also associated with 65% of the catheters with nonthrombotic dysfunctions. Once the cause of catheter occlusion was correctly identified, 90% of the catheters were restored to normal function. CONCLUSIONS: Inability to withdraw blood from a catheter does not necessarily mean it is occluded by thrombus. Mechanical complications account for a significant portion of dysfunctional catheters.