External pneumatic compression and fibrinolysis in abdominal surgery

INTRODUCTION: External pneumatic compression (EPC) devices prevent lower extremity deep venous thrombosis by increasing venous flow and thereby reducing stasis. Early studies suggested that they also enhance systemic fibrinolytic activity and thus prevent thrombus formation; more recent studies have been conflicting. The hypothesis of this study was that EPC devices enhance systemic fibrinolysis or reduce postoperative fibrinolytic impairment in patients undergoing abdominal surgical procedures. METHODS: Each of 48 patients (98% male; mean age, 67 years) undergoing major intra-abdominal surgical procedures (36 bowel procedures, 12 aortic reconstructions) was prospectively randomized to one of three treatments for deep venous thrombosis prophylaxis: subcutaneous heparin injections (HEP group), use of a thigh-length sequential EPC device (EPC group), or both (HEP + EPC group). Antecubital venous samples were collected for measurement of systemic fibrinolytic activity on the day before surgery, after induction of anesthesia but before prophylaxis was initiated, and on postoperative days 1, 3, and 5. Fibrinolysis was assessed through measurement of the activities of the rate limiting fibrinolytic activator, tissue plasminogen activator, and its inhibitor plasminogen activator inhibitor-1 with amidolytic methods. RESULTS: On the day before surgery, plasminogen activator inhibitor-1 activity was elevated in all groups in comparison with that in age-matched and sex-matched controls (20.3 +/- 0.6 AU/mL). In the HEP group, plasminogen activator inhibitor-1 activity was further elevated above the value for the day before surgery on postoperative day 1 (28.5 +/- 4.3 AU/mL; P =.04) and postoperative day 3 (25.1 +/- 1.9 AU/mL; P =.07). No significant decrease in plasminogen activator inhibitor-1 activity occurred in either group treated with EPC devices in comparison with the HEP group at any time. There were no changes in tissue plasminogen activator activity postoperatively in the HEP group and no significant increases in either EPC group at any point. CONCLUSIONS: Reduced systemic fibrinolytic activity ("fibrinolytic shutdown") occurred in these patients after abdominal surgery; it was manifested as increased plasminogen activator inhibitor-1 activity. EPC devices did not enhance systemic fibrinolysis or prevent postoperative shutdown either by decreasing plasminogen activator inhibitor-1 activity or by increasing tissue plasminogen activator activity. These data suggest that EPC devices do not prevent deep venous thrombosis by fibrinolytic enhancement; effective prophylaxis is achieved only when the devices are used in a manner that reduces lower extremity venous stasis.     

The effect of cyclosporine on early graft function in human renal transplantation

The effect of cyclosporine and steroids on early renal allograft function and eventual graft outcome was analyzed in 100 recipients; 33 recipients of living related donor (LRD) and 67 recipients of cadaveric donor (CAD) allografts were studied. A concurrent population of 47 CAD recipients treated with azathioprine and steroids was used for comparison. Recipients received oral cyclosporine (14 mg/kg) 48 hours (LRD) or 6-12 hours (CAD) pretransplant. No cases of acute tubular necrosis (ATN) were observed in the LRD recipients. The incidence of posttransplant ATN was similar in the cyclosporine-treated (41%) and in the azathioprine-treated (45%) CAD recipients (P = ns). Cyclosporine-treated CAD kidneys preserved less than 24 hr experienced a lower rate of ATN (P less than .01) using simple cold storage (31%), as compared with hypothermic pulsatile perfusion (57%). One-month creatinine nadirs were higher in cyclosporine-treated than in azathioprine-treated recipients, using median values for each group. One-year actuarial patient survival for cyclosporine-treated LRD recipients was 97%; CAD recipients, 94%, and azathioprine-treated CAD recipients, 91%. Graft survival rates in the same groups were 91%, 76%, and 55%, respectively. The major causes of graft loss in cyclosporine-treated patients were nonimmunologic. It is concluded that cyclosporine and prednisone are a safe, efficacious combination for LRD and CAD renal transplantation. The possibility of nephrotoxicity leading to impaired graft function in the early posttransplant period should not preclude the administration of cyclosporine prior to alloantigen presentation.     

Progressive intermittent claudication is associated with impaired fibrinolysis

Purpose: Acute complications of atherosclerosis such as stroke and myocardial infarction are caused by thrombosis and may be associated with impaired fibrinolytic activity. The current study was performed to determine whether peripheral arterial disease (PAD) and its progression are also associated with impaired fibrinolysis, by measurement of tissue plasminogen activator (tPA, the activator of fibrinolysis) and its inhibitor plasminogen activator inhibitor-1 (PAI-1). Methods: The study group consisted of 80 men with a mean age of 69 years. This included 18 patients with mild intermittent claudication (MC, pain-free walking distance ≥200 meters) and 51 patients with severe claudication (SC, walking distance <200 meters). Eleven age- and sex-matched patients without PAD served as controls. All patients had measurements of serum tPA antigen using an enzyme-linked immunoadsorbent assay. Serum levels of tPA and PAI-1 activity were assayed with an amidolytic method. Mean ± SEM levels of the enzyme levels in patients with progressively more severe PAD were compared with normal controls. Results: Serum PAI-1 activity levels were significantly elevated in both PAD groups compared with normal controls (p < 0.02). There were no significant differences in the PAI-1 activity levels in groups with worsening degrees of PAD. There was a significant decrease in tPA activity levels in patients with SC (p = 0.01) relative to those with MC and the normal subjects. There was also a significant increase in tPA antigen level in the patients with SC compared with those with MC and the control subjects, as well as a significant inverse correlation between tPA antigen levels and pain-free walking time in patients with claudication (p = 0.001). Conclusions: All patients with PAD in this study had significant reductions in endogenous fibrinolytic activity. Patients with SC had more impaired fibrinolytic activity than those with MC and the control subjects, suggesting that the progression to more severe levels of PAD may be associated with worsening endogenous fibrinolysis. (J Vasc Surg 1998;27:645-50.)     

Urinary procoagulant and fibrinolytic activity in human glomerulonephritis. Relationship with renal function

Fibrin deposition in kidney is a common event in some forms of human and experimental glomerulonephritis, and is thought to result from local activation of blood coagulation and/or impaired removal by the fibrinolytic system. We studied the urinary procoagulant and fibrinolytic activities in 46 patients with renal disease (26 with IgA nephritis, 13 with other forms of glomerulonephritis and 7 with non-inflammatory kidney disease) and in 15 matched healthy subjects, as possible indicators of the coagulation-fibrinolysis balance in kidney. Procoagulant activity was slightly but not significantly increased in patients with serum creatinine levels higher than 1.5 mg/dl (group II) as compared with patients with normal creatinine (group I) and controls. It was identified as tissue factor by biological criteria (dependence on factor VII). Fibrinolysis studies showed that both plasminogen activator activity and urokinase antigen were significantly lower in group II than in group I patients and controls (P less than 0.0005). Reduced fibrinolytic activity in patients' urine was due to decreased excretion of urokinase since no inhibitor was detected by both fibrin autography and functional assay. No differences were found between patients and controls in plasma fibrinolytic activity, plasminogen activator inhibitor, and procoagulant activity of blood monocytes. The urinary changes in severe renal disease may reflect an unbalance of the coagulation-fibrinolysis equilibrium in kidney and might be of pathogenetic and clinical relevance.     

Improved fibrinolytic capacity after withdrawal of steroid immunosuppression in renal transplant recipients

BACKGROUND: Long-term steroid immunosuppression has been associated with the prothrombotic state observed in renal transplant (RT) patients, in whom both hypercoagulability due to an increase of von Willebrand factor/factor VIII complex, and impaired fibrinolysis due to PAI-1 excess have been demonstrated. Our aim was to investigate the effect of steroid withdrawal on fibrinolytic capacity in a group of RT patients. METHODS: The fibrinolytic study was performed in 28 RT patients under stable immunosuppression therapy with cyclosporine, azathioprine, and methylprednisolone; only 12 of these patients could repeat the study 6 months after steroid withdrawal. Euglobulin lysis time (ELT), tissue plasminogen activator activity (t-PA:act) and antigen (t-PA:Ag), PAI-1 activity (PAI-1:act), and antigen (PAI-1:Ag) were assayed on blood samples drawn before and 20 min after the venous occlusion test (VO). RESULTS: An hypofibrinolytic state due to a significant increase in PAI-1 levels was confirmed in RT patients receiving triple immunosuppression therapy. RT patient who stayed off steroids showed a significant shortening of ELT both before (P=0.01) and 20' after VO (P=0.005) at the 6-month control. Moreover, after steroid withdrawal, PAI-1:Ag levels decreased significantly (P=0.002) and normalized; in a similar manner PAI-1:act levels also showed a significant decrease both before (P=0.001), and after VO (P=0.0001). The prevalence of RT patients with impaired fibrinolytic capacity was as high as 83.3% during steroid treatment, and dropped to 16.7% after steroid withdrawal. CONCLUSIONS: Our findings confirm that steroid withdrawal may normalize impaired fibrinolytic capacity in RT patients; this improvement may further contribute to reduce the thrombotic risk associated with renal transplantation.     

Effect of activated protein C on impaired fibrinolysis in rats with obstructive jaundice.

We studied the effect of activated protein C (APC) on impaired fibrinolysis using a rat model in which disseminated intravascular coagulation (DIC) is induced by the intravenous injection of endotoxin in rats with obstructive jaundice. An intravenous injection of endotoxin in rats with obstructive jaundice resulted in pulmonary hemorrhages and a marked increase in the plasma levels of tissue-type plasminogen activator (t-PA) antigen and plasminogen activator inhibitor activity. Prophylaxis with APC before the injection of endotoxin resulted in a decrease of the number of lung hemorrhages and an accelerated release of t-PA antigen. Thus, DIC in obstructive jaundice may be due to impairment of fibrinolysis and an increased susceptibility of endothelial cells to endotoxin. APC may be effective as a treatment for patients with obstructive jaundice associated with DIC.     

Fibrinolytic defect in chronic back pain. A controlled study of plasminogen activator activity in 20 patients.

We analyzed the fibrinolytic system in patients with chronic low back pain using a venous occlusion test to stimulate fibrinolysis, and we subsequently determined the levels of tissue plasminogen activator (TPA) and fast-acting inhibitor of TPA (PAI). There were 20 patients with a mean age of 50 years. Two thirds had radiographically spinal stenosis. Scar tissue around the spinal nerves was seen in 11 cases. Thirteen patients had undergone back surgery, whereas 21 healthy subjects served as controls. In the basal samples, TPA activity was decreased in the patients while TPA antigen level was increased compared with the controls. No clear explanation for this defective function of TPA in the patients was obtained, because no difference was seen in PAI level in basal samples. After the venous occlusion, no difference was observed in TPA activity between the two groups excluding the constitutionally defective fibrinolytic system in the patients. However, our results confirm low basal fibrinolytic activity in patients with chronic low back pain with manifest spinal pathology.     

Diabetic retinopathy and the fibrinolytic system.

We found that patients with long-standing (greater than 10 years) diabetes who have not developed retinopathy had a significantly higher and almost normal fibrinolytic response to venous occlusion and also a higher spontaneous fibrinolytic activity than those who had developed retinopathy. In the latter, the low fibrinolytic activity of the blood was, however, not correlated to a low plasminogen activator activity of the vessel walls. Although generally lower than in controls, the activator activity of the vessel walls in the retinopathy group tended to be higher than in the rest, and in fact those with only minor vascular changes (microaneurysms) had a significantly higher activity than the other diabetics. The fibrinogen and alpha2-macroglobulin levels were higher in the retinopathy group. Thus multiple abnormalities of the fibrinolytic system were found to be related to diabetic microangiopathy.     

Impairment of the immune response to influenza vaccination in renal transplant recipients by cyclosporine, but not azathioprine

Influenza vaccination has been strongly recommended for immunosuppressed renal transplant recipients. However, immunosuppression may lead to impaired antibody responses. We studied the antibody response to an inactivated trivalent influenza vaccine in 59 renal transplant recipients with life-sustaining kidney function: 21 were on cyclosporine and prednisone, 38 on azathioprine and prednisone. Healthy volunteers (n = 29) and patients on hemodialysis (n = 28) served as controls. Despite comparable renal allograft function, cyclosporine-treated patients had a significantly lower immune response against influenza A viruses than azathioprine-treated patients, whether mean antibody levels, fourfold titer rise, or seroconversion to protective titers was analyzed. No significant differences in antibody responses were found between healthy controls and patients on azathioprine. The patients on hemodialysis showed an impaired response to vaccination. However, in contrast to the cyclosporine-treated patients, booster immunization proved valuable in this group.     

Plasma fibrinolytic capacity in renal transplant recipients: effect of steroid-free immunosuppression therapy

BACKGROUND: Cardiovascular disease is the most common cause of death among renal transplant recipients (RTRs). Impaired fibrinolytic capacity caused by an increase in plasminogen activator inhibitor type 1 (PAI-1) levels is involved in the onset of atherosclerosis and thrombotic complications. Long-term steroid treatment may induce arterial hypertension and metabolic and prothrombotic changes (including up-regulation of PAI-1 synthesis), which increase the cardiovascular risk. We evaluated plasma fibrinolytic behavior in two groups of RTRs treated with different immunosuppressive regimens. METHODS: Twenty-seven RTRs were randomized to receive long-term (17 patients) or perioperative short-term (10 patients) steroids in addition to immunosuppression with cyclosporine A plus everolimus (Certican; Novartis, Basel, Switzerland) (7 patients) or FK506 plus mycophenolate mofetil (20 patients). In each patient, fibrinolytic capacity was studied with the 20-min venous occlusion test 1 and 6 months after transplantation. The following were assayed: euglobulin lysis time, tissue-type plasminogen activator antigen, and PAI-1 antigen and activity. RESULTS: One month after transplantation, a severe impairment of fibrinolytic capacity, mainly caused by an increase in PAI-1 antigen and activity levels, was seen in patients with and without steroid treatment. Six months after transplantation, an improvement in fibrinolytic potential as the result of a decrease in PAI-1 levels was observed only in patients without steroid therapy. None of the steroid-treated patients demonstrated PAI-1 values correlating with body mass index, blood pressure, and metabolic parameters, thus confirming the effect of exogenous factors on PAI-1 expression. Moreover, all patients revealed a slight impairment of stimulated endothelial tissue-type plasminogen activator release, regardless of any steroid treatment, which was probably attributable to calcineurin inhibitor-induced endothelial dysfunction. CONCLUSIONS: Our study suggests that steroid-free immunosuppression is associated with a better fibrinolytic capacity in RTRs. This finding may contribute toward reducing the risk of cardiovascular events.     

Fibrinolytic responses to 1-desamino-8-D-arginine-vasopressin in patients with congenital nephrogenic diabetes insipidus

Fibrinolytic responses to infusion of 1-desamino-8-D-arginine-vasopressin (DDAVP) were assessed in 6 males with congenital nephrogenic diabetes insipidus (NDI), 6 carriers of the NDI gene and 6 normal control subjects. Tissue-type plasminogen activator (t-PA) activity and antigen increased significantly in normal subjects, while plasminogen activator inhibitor (PAI) activity decreased. None of these changes were observed in patients with NDI. In 2 female carriers, normal fibrinolytic responses were seen, while in the other carriers responses were delayed. These findings are consistent with the concept of a general V2-receptor defect in congenital NDI. DDAVP tests are of limited use in NDI carrier detection.     

Fibrinolytic defect in chronic back pain: A controlled study of plasminogen activator activity in 20 patients

We analyzed the fibrinolytic system in patients with chronic low back pain using a venous occlusion test to stimulate fibrinolysis, and we subsequently determined the levels of tissue plasminogen activator (TPA) and fast-acting inhibitor of TPA (PAI). There were 20 patients with a mean age of 50 years. Two thirds had radiographically spinal stenosis. Scar tissue around the spinal nerves was seen in 11 cases. Thirteen patients had undergone back surgery, whereas 21 healthy subjects served as controls. in the basal samples, TPA activity was decreased in the patients while TPA antigen level was increased cornpared with the controls. No clear explanation for this defective function of TPA in the patients was obtained, because no difference was seen in PAI level in basal samples. After the venous occlusion, no difference was observed in TPA activity between the two groups excluding the constitutionally defective fibrinolytic system in the patients. However, our results confirm low basal fibrinolytic activity in patients with chronic low back pain with manifest spinal pathology.     

The fibrinolytic effects of intermittent pneumatic compression: mechanism of enhanced fibrinolysis.

BACKGROUND AND OBJECTIVES: Intermittent pneumatic compression (IPC) is an effective form of deep vein thrombosis prophylaxis for general surgery patients. The antithrombotic effect of IPC is thought to be the result of increased venous velocity and stimulation of endogenous fibrinolysis. However, the mechanism of enhanced fibrinolytic activity and the relative effects on normal and postthrombotic veins have not been defined. The purposes of this study are 1) to quantify changes in fibrinolytic activity with IPC; 2) to study the mechanism of fibrinolytic enhancement with IPC; and 3) to evaluate whether postthrombotic patients have the same capacity for fibrinolytic enhancement with IPC as do normal subjects. METHODS: Twelve volunteers (6 normal and 6 postthrombotic) had 5 IPC devices applied for 120 minutes in random fashion, 1 per week x 5 weeks. The devices included single-chamber, sequential, foot, calf, and long-leg compression. Subjects had an indwelling antecubital venous cannula placed for blood drawn at baseline, 60, 120, and 180 minutes after IPC devices were applied. Global fibrinolytic activity (euglobulin fraction, fibrin plate assay), tissue plasminogen activator (tPA) antigen (Ag) and activity (Act), plasminogen activator inhibitor-1 (PAI-1) Ag and Act, alpha-2-antiplasmin-plasmin complexes, and von Willebrand factor (vWF) antigen were assayed. RESULTS: A striking elevation in fibrinolytic activity was noted at 180 minutes with all devices in normal subjects and postthrombotic patients (p = 0.01-0.0001); however, baseline and stimulated fibrinolytic activity was attenuated in postthrombotic patients (<0.03). The tPA-Act increased only in normal subjects (3.8 +/- 1.9%) (p = 0.057), despite a decrease in plasma tPA-Ag, which was observed in both normal subjects (-12.4 +/- 3.8%) (p = 0.009) and patients (-17.2 +/- 3.1%) (p = 0.001). PAI-1-Ag decreased in both normal subjects (-13.4 +/- 3.8%) (p = 0.007) and patients (-12.0 +/- 3.1%) (p = 0.013) with a marked reduction in PAI-1-Act in both normal subjects (p = 0.003) and patients (p = 0.004). There were no changes in vWF, and alpha-2-antiplasmin-plasmin complexes increased only in postthrombotic patients (p = 0.021). CONCLUSIONS: Stimulation of endogenous fibrinolytic activity occurs after IPC, both in normal subjects and postthrombotic patients; however, baseline and overall fibrinolytic response in postthrombotic patients is reduced. The mechanism of increased fibrinolytic activity is likely because of a reduction in PAI-1, with a resulting increase of tPA activity.     

Effect of treatment with cyclosporine versus azathioprine on incidence and severity of cytomegalovirus infection posttransplantation

The incidence and severity of cytomegalovirus (CMV) infection were evaluated in 24 renal transplant patients treated with steroids and cyclosporine and compared with 40 patients treated with steroids and azathioprine: 58% of patients receiving azathioprine and 33% of patients receiving cyclosporine required additional therapy with antithymocyte globulin (ATG) to treat steroid-resistant rejections. CMV antibody titers and cultures of urine and saliva were determined monthly for 4-6 months following transplant in all patients. Both the frequency of CMV infection (occurring in 58% of patients on steroids and cyclosporine and in 48% of patients on steroids and azathioprine) and its severity (21% of cyclosporine-treated patients and 22% of azathioprine-treated patients with symptoms) were similar in both groups. Use of ATG was associated with an increased incidence of CMV disease, especially for patients in the azathioprine group. Both the incidence of CMV disease, and the number of patients with symptoms in the azathioprine group were significantly lower when patients who had received ATG were excluded from analysis. When results were analyzed in just the cadaveric recipients in each group, the incidence and severity of CMV infection tended to be higher in azathioprine-treated patients compared with those maintained on cyclosporine. This could have been explained by the more frequent use of ATG in 84% of azathioprine maintained patients compared with 35% of cyclosporine-treated patients (P less than 0.002) since other factors, such as risk for CMV infection and Solumedrol dose for rejection were similar in both groups. The data demonstrate that ATG has a deleterious influence on the incidence and severity of CMV infection in renal transplant patients, even when the dosage of other immunosuppressive drugs is decreased during ATG therapy. Since patients treated with steroids and azathioprine tend to require ATG to treat steroid-resistant rejection more frequently than do patients on cyclosporine, this effect of ATG must be taken into account when evaluating CMV infection in patients on these two drug regimens.     

DOS SANTOS PAPER: Fibrinogen and fibrinolysis in blood and in the arterial wall: its role in advanced atherosclerotic disease

High plasma fibrinogen appears to be an important risk factor for the development of atherosclerosis. The aim of our study was to measure fibrinogen and fibrin degradation products (D-dimer), interleukin-6 tissue plasminogen activator, plasminogen activator inhibitor-1 and urokinase-type plasminogen activator in the plasma and arterial walls of 45 patients who had arterial surgery between April 1993 and November 1995. The arterial specimens were also examined by immunohistochemists for these same factors. The serum fibrinogen and fibrin degradation products were high in all patients, and fibrinolysis was depressed. Few leukocytes were seen in the arterial walls, which had poor fibrinolytic activity. Plasminogen-activator inhibitor activity in the wall was also reduced in the affected arterial walls. The abdominal aorta appeared to have the highest levels of fibrinogen and this may be related to its ability to form aneurysms. Fibrinogen may play an important role in the progression of atherosclerotic disease.     

Infectious complications with the use of cyclosporine versus azathioprine after cadaveric kidney transplantation

Infectious complications within 1 year of cadaveric kidney transplantation were compared in 45 patients treated with azathioprine, prednisone, and antilymphocyte globulin and 38 patients treated with cyclosporine and prednisone. Although there was no difference in the 1 year patient or graft survival rate, cyclosporine-treated patients had significantly fewer wound infections, infection-related transplant nephrectomies, and infection-related graft failures than azathioprine-treated patients. The cyclosporine-treated diabetic recipients had more nonviral pneumonias and opportunistic infections but fewer cases of infection-related transplant nephrectomy than did the azathioprine-treated diabetic patients. Our data suggest cyclosporine is associated with reduced infectious morbidity after cadaveric kidney transplantation in nondiabetic patients.     

Fibrinolytic capacity in hemodialysis patients treated with recombinant human erythropoietin.

A major adverse effect of recombinant human erythropoietin (r-HuEPO) in hemodialyzed patients are thrombotic events. Several reports on platelet function during r-HuEPO treatment have been published but less is known about fibrinolysis. In the present study, the fibrinolytic capacity was studied in 20 patients on maintenance hemodialysis and treated with r-HuEPO. The patients were randomized into two groups and investigated in a crossover design. r-HuEPO was administered intravenously and subcutaneously in each group and was given for 3 months, respectively. Plasma tissue plasminogen activator (t-PA) and released t-PA remained unaffected by r-HuEPO in both groups throughout the study. Tissue plasminogen activator inhibitor (PAI) increased in a cyclic way reaching peak values 4-6 weeks after the start of investigation and again 4-6 weeks after changing therapy. The increase in PAI was significant in the two groups (0.025 > p > 0.01). Tissue plasminogen antigen was low in the uremic patients. The influence of r-HuEPO on this parameter was not investigated. Compensatory changes in plasma levels of factor XII procoagulant activity, activated protein C and of alpha 2-antiplasmin were not observed. Thrombotic events occurred in 4 patients at peak values of PAI. Six patients required an increase in heparin dose simultaneously with the increase in PAI. Thus, r-HuEPO seemed to affect the fibrinolytic capacity of uremic patients.     

Fibrinolysis defect in long-term hemodialysis patients with type 2 diabetes mellitus and its relation to metabolic disorders

BACKGROUND/AIMS: Patients with chronic renal failure (CRF) secondary to diabetes mellitus show a high incidence of atherosclerosis with its thrombotic complications. Both CRF and type 2 diabetes mellitus (DM2) results in fibrinolysis defects causally related to atherogenesis and thrombogenesis. It is not well known whether or not and, if so, how fibrinolysis is altered in patients with both CRF and DM2. Our study was designed (1) to identify the fibrinolysis defect present in patients with DM2-mediated CRF and treated by long-term hemodialysis (DM2HD), and (2) to establish whether the fibrinolysis defect is related to the metabolic abnormalities observed in CRF or DM2. METHODS: Sixteen DM2HD patients and 23 healthy individuals (HI) had their euglobulin clot lysis time (ECLT), and tissue-type plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1) activities (act) and concentrations (ag) assessed before and after standard fibrinolytic stimulus (i.v. administration of 0.4 microg/kg BW 1-deamino-8-D-arginine vasopressin, DDAVP) along with metabolic status markers. RESULTS: DDAVP caused a significant shortening of ECLT, rises in tPA act and ag, and a significant decrease in PAI-1 act. PAI-1 ag declined significantly in HI, but not in DM2HD. A comparison of responses to DDAVP revealed the groups differed significantly in the change in PAI-1 ag. Whereas, in HI, PAI-1 ag decreased by 11.8 ng/ml, no decrease was seen in DM2HD (0.0 ng/ml) (p < 0.0001; medians given; unpaired Wilcoxon's test). Stepwise regression analysis showed the change in PAI-1 ag was highly group-specific (DM2HD vs. HI, regression coefficient 21.22; partial correlation 0.58; p < 0.0001) and, also dependent on the serum concentrations of apolipoprotein A-I (-32.41; -0.46; p < 0.01) and homocysteine (0.35; 0.36; p < 0.05). CONCLUSIONS: Patients with type 2 DM and CRF on long-term hemodialysis have a fibrinolysis defect manifesting itself after standard fibrinolytic stimulus by an insufficient decrease in PAI-1 concentrations. The defect is related to decreased serum levels of apolipoprotein A-I and increased serum levels of homocysteine. The defect might be a factor contributing to accelerated atherosclerosis and thrombotic complications in these patients.     

Hemostatic abnormalities in total artificial heart patients as detected by specific blood markers.

We retrospectively evaluated the hemostatic system of 13 patients during implantation (2 to 35 days) of the Jarvik 7-70 total artificial heart (TAH). Although all patients were clinically manageable while on the TAH, 5 had excessive generalized bleeding. After the heart transplant procedure, 2 patients had neurological events and 1 patient, thrombosis of the leg. While the patients were supported by the TAH, the routine coagulation assays (prothrombin time, activated partial thromboplastin time, fibrinogen, factor assays, and platelet count) showed slight abnormalities but no correlation to hemorrhagic or thrombotic events. In contrast, plasma and cellular activation markers, which are highly sensitive and specific for hypercoagulability, fibrinolysis, or platelet activation, revealed activation in all patients. Most striking was the marked activation of the fibrinolytic system (p less than 0.05 to 0.001). Correlations of individual patient data compared with the average TAH group response could be made between excessive enhancement of fibrinolysis (increased D-dimer and tissue plasminogen activator and decreased plasminogen activator inhibitor) and bleeding. A hypercoagulable state (increased fibrinogen and thrombin-antithrombin complex and decreased antithrombin III and protein C), decreased fibrinolysis (decreased tissue plasminogen activator and D-dimer), activated platelets (increased thromboxane B2), or combinations of these were associated with thrombosis. The hemostatic activation returned to normal 1 day after removal of the TAH. These data suggest that the patient with a TAH requires more sophisticated laboratory monitoring and individualized treatment for excessive fibrinolysis, hypercoagulable state, or platelet activation to avoid thrombotic and hemorrhagic complications.     

Glomerulotubular function in long-term renal allograft recipients. A comparison of conventional therapy with cyclosporine

Glomerular and tubular function were assessed, using a lithium clearance technique, in two groups of renal allograft recipients at least one year after transplantation. Group 1 comprised 14 patients receiving low-dose prednisolone and cyclosporine, and group 2, 14 patients receiving low-dose prednisolone and azathioprine. There were no significant differences in creatinine clearances between the two groups, although the clearances of lithium (which is absorbed almost exclusively from the proximal tubule) and sodium were significantly lower in the cyclosporine-treated group. Fractional lithium excretion was also significantly lower in group 1 than in group 2, but there was no significant difference in fractional sodium excretion. The absolute proximal reabsorption of sodium and water did not differ between the groups, although the fractional proximal reabsorption of sodium and water was significantly higher in group 1. In contrast, the distal reabsorption of sodium and of water was significantly lower in the cyclosporine-treated patients than in the azathioprine-treated patients; there were, however, no significant differences in the distal fractional reabsorptions of sodium and water between the two groups. In addition there was no correlation in group 1 between whole-blood cyclosporine levels or time since transplantation and any of the assessed parameters of renal function. These results indicate that tubular concentrating abnormalities in cyclosporine-treated renal allograft recipients are similar to those observed in rodent models of cyclosporine nephrotoxicity. They suggest that the pathogenesis of cyclosporine nephrotoxicity may be similar in renal allograft recipients to that in experimental models.