Effects of anticoagulation on markers of activation of clotting following major orthopedic surgery.

INTRODUCTION: This study examines makers of activation of clotting following three chemoprophylactic regimens used for prevention of postoperative venous thromboembolic disease (TED) following high-risk surgery for TED. METHODS: Patients having elective primary knee or hip replacement surgery received variable dose warfarin (target international normalized ratios 2.0-2.5), 1 mg warfarin daily starting 7 days preoperatively or aspirin 325 mg daily starting on the day of surgery. Twelve patients in each group were treated for 28 ± 2 days. Thrombin-antithrombin (T-AT) and prothrombin fragment F1 + 2 were measured at baseline and postoperative days 3 and 28 ± 2. RESULTS: Thrombin-antithrombin and F1 + 2 on postoperative day 3 were equal for the study groups. By days 28 ± 2, variable dose warfarin therapy group suppressed production of F1 + 2 (P = 0.002) with no difference in the T-AT accumulation. F1 + 2 for other patients overlapped the normal range. CONCLUSION: The signals of activated clotting following surgery did not differentiate the three regimens on postoperative day 3. Variable dose warfarin was associated with suppression of F1 + 2 after 1 month of therapy, with no effect on accumulation of T-AT. Fixed low-dose warfarin started 7 days prior to surgery and aspirin are not inferior on postoperative day 3, but appear to be inferior over a longer treatment.

Autologous blood donation and subsequent blood use in patients undergoing total knee arthroplasty.

Autologous blood donation is designed to avoid complications from allogeneic blood, leaving units of blood in the general blood supply. It is unclear how efficient these programmes are in accomplishing these goals. It is unclear if autologous donation provokes increased need for any transfusion following surgery and whether it can be avoided in low-risk surgeries. Of 430 patients undergoing unilateral primary knee replacement arthroplasty over 12 months in our hospital, 309 had autologous donations and 121 did not. Of the 121 patients who did not donate, 36% completed surgery without transfusion, whereas only 17% of those who had autologous donations did so (P < 0.05). Age less than 65 years, higher baseline and postoperative haemoglobin levels were associated with lower transfusion rates. Patients who had autologous donations were approximately four times more likely to be transfused. As the number of autologous units donated increased, transfusions following surgery increased. Autologous donation did reduce allogeneic blood transfusions. Therefore, autologous blood donation for unilateral total knee arthroplasty is associated with overall increased transfusion rates, but with reduced need for allogeneic blood, independent of other clinical factors associated with transfusion. Therefore, there is need for reconsideration of these programmes relative to specific surgeries.

Treatment of factor XI inhibitor using recombinant activated factor VIIa.

A 30-year-old female with severe factor XI deficiency of 0-2% acquired factor XI inhibitor following many infusions for fresh frozen plasma (FFP) for surgical procedures starting at 4 years of age. Seven months before this inhibitor was diagnosed, surgery was complicated by prolonged bleeding resistant to FFP, requiring epsilon aminocaproic acid (EACA) and surgical packing. The inhibitor was measured at 2.2 Bethesda units, 7 months since the last FFP. The inhibitor was confirmed as specific anti-XI and anti-XIa binding by patient's IgG to immobilized factor XI and factor XIa from whole plasma and purified IgG. For repair of a painful anterior cruciate ligament (ACL) defect she was given recombinant factor VIIa (rVIIa) at 90 mug kg(-1), starting one-half hour preoperatively and continued every 2 h for 8 h when haemostasis was complete. Thereafter the rVIIa was given every 3 h for two doses, and then every 4 h for four doses at which time she was discharged on EACA which was continued for 6 days. There was excellent haemostasis during and following the surgery. There was no evidence of consumptive coagulopathy, with no change in the fibrinogen, platelet count, or D-D dimer; and no increase of platelet factor 4, beta-thromboglobulin, or prothrombin fragment F 1.2. The thrombin-antithrombin complex increased over baseline after 24 h. There was no postoperative deep vein thrombosis or pulmonary embolus. In this patient with a factor XI inhibitor, the recombinant factor VIIa was effective and safe, ensuring adequate haemostasis with no thrombotic complications. This product which was designed for patients with inhibitors to factor VIII or factor IX, and factor VII deficiency, has now been given successfully to four patients with factor XI inhibitors.

Combined paclitaxel, cisplatin, and etoposide for patients with previously untreated esophageal and gastroesophageal carcinomas.

BACKGROUND: Paclitaxel (T), etoposide (E), and cisplatin (P) are each active in gastric carcinoma, either as single agents or as part of a multidrug regimen. To the authors' knowledge, the combination of these three agents in the treatment of patients with esophageal or gastroesophageal carcinoma has not been previously studied. METHODS: Previously untreated patients with locally advanced carcinoma of the stomach, esophagus, or gastroesophageal (GE) junction received at least 2 cycles of TPE administered twice weekly for 3 weeks, with the cycle repeated every 28 days. Drug doses, administered over 3 hours on either Monday and Thursday or Tuesday and Friday, consisted of T 50 mg/m2/dose, P 15 mg/m2/dose, and E 40 mg/m2/dose. For patients with local disease only, subsequent therapy consisted of radiation with or without surgical resection. RESULTS: Twenty-five patients with gastric (10) or gastroesophageal or GE junction (15) carcinoma were treated. Eighteen had locally advanced disease and 7 had liver metastases at presentation. Hematologic toxicity, namely, Grade 3 anemia and neutropenia, was experienced by all patients. The median number of treatment cycles was 4 (range, 2-6). Three patients were not evaluable for response. All 22 evaluable patients responded; 3 were complete responders and 19 were partial responders. Eleven patients received radiation therapy with (6) or without (5) concomitant 5-fluorouracil, and 8 patients subsequently underwent surgical resection. Three of 8 patients had no tumor at surgery, 4 had minimal microscopic tumor at the primary site, and 3 had microscopic lymph node involvement. Twenty-three patients are alive, of whom 14 are without evidence of disease. Two patients with metastatic disease at presentation died at 9 and 29 months, respectively. The median survival was 12.5 months (range, 6 to 30+ months). CONCLUSIONS: Multifractionated TPE chemotherapy is a highly active regimen in gastric and gastroesophageal carcinoma. It could be evaluated in Phase III trials against other active regimens for the treatment of patients with this disease. The introduction of 5-fluorouracil could also be an interesting direction to explore because of its primary role in the treatment of patients with gastric and esophageal carcinoma.

Pilot study of ambulatory infusional ifosfamide admixed with carboplatin.

BACKGROUND: Ifosfamide and carboplatin are agents that have completed Phase I studies using a continuous infusion schedule for as long as 14 days. The in vitro compatibility of the two drugs allows for the simultaneous administration in an admixture, and a pilot study was undertaken to determine the feasibility and tolerability of the infusion schedule for the combination. METHODS: Ifosfamide at 500 mg/M2/day and carboplatin at 15 or 20 mg/M2/day were administered for 14-day cycles repeated at 28 days in 29 patients, with a total of 60 courses administered. RESULTS: Total cumulative dose per cycle was: ifosfamide 7.0 g/M2 and carboplatin 210-280 mg/M2. Hematuria developed in five patients, four of whom had prior urologic disease, severe thrombocytopenia, or pelvic radiation. In all patients, the hematuria was transient and inconsequential despite the absence of mesna. Grade 3 or 4 leukopenia was observed in eight patients with or without thrombocytopenia and delayed subsequent treatment cycles. Thrombocytopenia was less frequent (Grade 3, 2 patients: Grade 4, 1 patient). No significant episodes of sepsis or hemorrhage were noted. Anemia requiring transfusion developed in 12 of 29 patients. Twenty-one of the 29 patients had received prior chemotherapy. Five of seven previously untreated patients with non-small cell lung cancer achieved a complete (1) or partial (4) response. CONCLUSIONS: A continuous 14-day infusion of ifosfamide admixed with carboplatin is feasible in an ambulatory setting with no need for adding mesna for urologic protection and full dosage administration for each agent. Phase 2 studies in non-small cell lung cancer would be reasonable at the optimal doses of ifosfamide 500 mg/M2/day and carboplatin 15 mg/M2/day, and the potential exists for the introduction of additional agents, such as etoposide.

Considerations for using lower doses of warfarin.

Warfarin is a very effective anticoagulant when used in the standard dose; however, the definition of standard dose has become ambiguous as the importance of the thromboplastin used in the measure of the prothrombin times has been demonstrated. Full or "standard" anticoagulation with warfarin imposes a hemorrhagic risk that can be avoided using lower doses. The premise has now been established that less than standard doses are efficacious. What is yet to be determined, however, is how low the dose of warfarin may be while maintaining efficacy and in which clinical settings. These conclusions must be established cautiously in clinical settings before being advocated generally. More complete discussions of this topic as well as safer means of using warfarin in general are available.

Very low doses of warfarin can prevent thrombosis in central venous catheters. A randomized prospective trial.

OBJECTIVE: To determine whether very low doses of warfarin are useful in thrombosis prophylaxis in patients with central venous catheters. DESIGN: Patients at risk for thrombosis associated with chronic indwelling central venous catheters were prospectively and randomly assigned to receive or not to receive 1 mg of warfarin, beginning 3 days before catheter insertion and continuing for 90 days. Subclavian, innominate, and superior vena cava venograms were done at onset of thrombosis symptoms or after 90 days in the study. RESULTS: One hundred twenty-one patients entered the study, and 82 patients completed the study. Of 42 patients completing the study while receiving warfarin, 4 had venogram-proven thrombosis. All 4 had symptoms from thrombosis. Of 40 patients completing the study while not receiving warfarin, 15 had venogram-proven thrombosis, and 10 had symptoms from thrombosis (P less than 0.001). There were no measurable changes in the coagulation values assayed due to this warfarin dose, except in occasional patients who had become anorectic because of their disease or chemotherapy. CONCLUSIONS: Very low doses of warfarin can protect against thrombosis without inducing a hemorrhagic state. This approach may be applicable to other groups of patients.

A phase I study of thiotepa administered by short-term and protracted continuous intravenous infusion.

Forty-five patients received escalating dose rates of continuous infusion thio-triethylene thiophosphoramide (TEPA) for either five (26 patients) or 28 (19 patients) days. Dose rate limiting toxicity for the 5-day infusion was myelosuppression with leukocyte and platelet nadirs on days 21 and 28, respectively. The nadir was influenced by the presence and degree of liver disease. The optimal dose rate for 5-day infusion in the absence of liver disease was 12 mg/m2/d and was reduced to 8 mg/m2/d in patients with major liver disease. Dose rate limiting toxicity for the protracted 28-day infusion was leukopenia. The optimal dose rate for the 28-day infusion was 4 mg/m2/d. Pharmacologic studies included determination of plasma steady state concentrations (CSS) of thio-TEPA and TEPA. Dose rates up to 10 mg/m2/d produced thio-TEPA and TEPA CSS below the levels of detection of available analytical methodology, except in three patients infused at dose rates of 1, 2, and 4 mg/m2/d, respectively.

Four patients with myelodysplastic syndrome with translocation (1;7)(p11;p11) including one patient with independent clones del(7)q22) [corrected] and t(1;7)(q21;q11)

A translocation involving the short arm of chromosome #1 and the short arm of chromosome #7, [t(1;7)(p11;p11)] was present in four patients with myelodysplastic syndrome (MDS). Two of these patients had prior lymphoproliferative disorders and developed MDS following prolonged therapy with alkylating agents. One of the patients with prior therapy history has two additional independent abnormal clones: one with a partial deletion of the long arm of #7 and the other with t(1;7)(q21;q11). A third patient had a family history of leukemia in both the father and a brother, both of whom developed acute nonlymphocytic leukemia following an MDS phase. The last patient was an elderly woman with no predisposing features.

Monocyte adhesion to subendothelial components.

Human monocytes have been shown to penetrate the endothelial layer of large blood vessels and to adhere to the subendothelial basement membrane. To determine the active components of this process, we have studied the ability of monocytes to adhere to isolated components of the subendothelial matrix. Using a quantitative dot-blot adhesion assay, we find that monocytes adhere preferentially to immobilized laminin and elastin. The monocytes adhere less well to fibronectin and bind poorly or not at all to collagen types I and IV, or to heparan sulfate. Monocyte binding to elastin requires an intact, crosslinked molecule as no binding was observed to soluble, acid-alcohol elastin extracts, to pepsin or elastase digests of elastin, to tropoelastin monomer, or to desmosine/isodesmosine crosslinks. Similar binding profiles to elastin, laminin, and fibronectin were seen with the established human leukocyte cell line U937. The promyelocytic cell line HL60 adhered equally well to laminin but showed slightly reduced adhesion to elastin when compared with the fresh monocytes or U937 cells. Freshly isolated human erythrocytes did not demonstrate significant adhesion to fibronectin, laminin, or elastin.

Cyclosporin treatment for aplastic anemia: a case report demonstrating a second response to second exposure to cyclosporin.

Cyclosporin has been used in the treatment of aplastic anemia, often in combination with other drugs, making it difficult to make a clear distinction between the effects of cyclosporin and those of other treatments. This report demonstrates a clear response of a patient with aplastic anemia to single drug cyclosporin therapy.

Etoposide in combination with cytarabine, doxorubicin, and 6-thioguanine for treatment of acute nonlymphoblastic leukemia in a protocol adjusted for age.

Etoposide combined with cytarabine, doxorubicin, and 6-thioguanine was used to treat 34 patients with acute nonlymphoblastic leukemia (ANLL) in an age-adjusted protocol, with patients greater than 50 years old receiving fewer days of therapy. Complete remissions (CR) occurred in 85% of all patients (29 of 34 patients). Patients less than or equal to 50 years of age achieved a 94% CR rate (17 of 18 patients) compared to a 75% CR rate (12 of 16 patients) in older patients. Duration of remission was less for those greater than 50 years of age. The remission rate for primary ANLL was 86% (19 of 22 patients) and for secondary or relapsed ANLL was 83% (ten of 12 patients). Thus, this is effective therapy for primary and secondary or relapsed ANLL. When the days of therapy are reduced for older patients' age, the remissions are fewer and less durable.

Effect on platelet function of hypoalbuminemia in peritoneal dialysis.

Chronic renal failure is associated with functional platelet defects. Peritoneal dialysis is associated with improvement in platelet function. This study demonstrates that the hypoalbuminemia resulting from peritoneal dialysis may account for part of the improvement. Platelet aggregation was measured when plasma albumin was less than 3 g/dl and again when the albumin level was raised to greater than 4 g/dl. Normal albumin levels were associated with decreased platelet function when the slope of aggregation to ADP and epinephrine were used as the study parameters. Patients with peritoneal dialysis given albumin to correct their plasma albumin level also acquired reduced platelet aggregation.

Physiological changes in hemostasis associated with acute exercise.

Acute exercise enhances fibrinolytic (FA), factor VIII coagulant and factor VIII ristocetin cofactor activities, and increases the concentration of factor VIII-related antigen. Little is known concerning the mechanisms of these changes. To investigate possible relationships between exercise-induced changes in blood lactate, 2,3-diphosphoglycerate (DPG), and the hemostatic variables, a branching multistage treadmill protocol was used to exercise male volunteers to a maximum effort. Blood samples were drawn before, immediately post-, and 8 min postexercise. All hemostatic variables were significantly (P less than 0.05) increased postexercise. Highest values for factor VIII coagulant, factor VIII-related antigens and factor VIII ristocetin cofactor were observed at 8 min postexercise. Significant (P less than 0.001) correlations were found postexercise for lactate with factor VIII coagulant (r = 0.64), while no association between pre-, post-, or 8 min postexercise. Postexercise lactate demonstrated a significant correlation (r = +0.81), which was strengthened by including the preexercise high-density lipoprotein (HDL) concentrations (r = +0.87). Consequently, the expected postexercise FA may be calculated from the observed values for postexercise lactate and preexercise HDL. The correlations of lactate with postexercise FA and with postexercise factor VIII coagulant may reflect a common stimulus for these exercise-induced changes.

Prophylaxis against central vein thrombosis with low-dose warfarin.

Low-dose warfarin was given to patients to prevent venous thrombosis. Patients at greatest risk for having thrombi adjacent to central venous catheters were detected by the von Kaulla assay. Patients with normal von Kaulla assays had one thrombus per 1844 days at risk while those with accelerated von Kaulla assays had one thrombus per 500 days at risk. Low-dose warfarin therapy given to patients at high risk reduced the incidence of venous thrombosis from one thrombus per 251 days to one thrombus per 1617 days. Thus low doses of warfarin that do not prolong the prothrombin time appear to offer prophylaxis against venous thrombosis in patients at high risk for developing venous thrombosis adjacent to the central venous catheters.

Open heart surgery in patients with cold-reactive proteins.

The presence of cold-reactive proteins may pose special hazards to the patient about to undergo hypothermic cardiopulmonary bypass, topical myocardial cooling, and cold potassium cardioplegic arrest. The detection and characterization of such proteins, their potential adverse effects, and a proposed management protocol are discussed.

Response of protein C and protein C inhibitor to warfarin therapy in patient with combined deficiency of Factors V and VIII.

The role of Protein C in combined factor V/VIII deficiency was examined by reducing the Protein C concentration using warfarin therapy in a patient with the combined deficiency. The factor VIII deficiency was like Hemophilia-A, with deficiency of VIII:C and VIII:C(Ag), but normal VIIIR:Ag and VIIIR:cof. The factor V deficiency was due to loss of the V antigen. During warfarin therapy the Protein C level was reduced, but concentrations of factors V and VIII did not change. Protein C Inhibitor was normal throughout. Thus combined factor V/VIII deficiency is not related to Protein C levels.

Effects of low-dose warfarin on antithrombin III levels in morbidly obese patients.

Morbid obesity has been associated with increased risks for thrombotic diseases. Patients with morbid obesity are shown to have decreased activity and decreased concentration of antithrombin (AT) III. This deficit can be corrected by giving the patients low doses of the oral anticoagulant warfarin. The same beneficial effect was not observed in normal lean control volunteers in whom the levels of AT III were normal at all times. Thus, it may be possible to offer prophylactic protection against the effects of having depressed levels of AT III in patients at increased risk for thrombotic diseases without using full anticoagulant doses of warfarin, including morbidly obese patients.

Factor VIII complex in chronic renal failure: influence of protein C, fibrinolysis and diabetes mellitus.

Chronic renal failure causes elevations of factor VIII coagulant activity and Factor VIII-related antigen even before the patients enter chronic hemodialysis. The change from control of Factor VIII ristocetin cofactor does not reach significance. The elevations are not effected by entering onto hemodialysis. These parameters are the same for non-diabetic and diabetic patients. Protein C, plasminogen and total fibrinolytic capacity are normal in diabetic and non-diabetic patients, with or without hemodialysis for chronic renal failure. However, before entering onto hemodialysis some of these parameters had negative correlation coefficients with parts of the factor VIII complex among the diabetic and non-diabetic patients. These negative correlates turned positive after hemodialysis. Thus, there are differences in these catabolic mechanisms for factor VIII when hemodialysis is used for diabetic and non-diabetic patients with chronic renal failure.

Disseminated varicella-zoster virus infection with the syndrome of inappropriate antidiuretic hormone.

A patient with non-Hodgkin's lymphoma who was previously treated with chemotherapy and radiotherapy was seen with intestinal pseudoobstruction due to paralytic ileus associated with herpes zoster (varicella zoster) infection. The infection was accompanied by a polydermatomal rash with typical morphologic characteristics, followed by cutaneous dissemination and the syndrome of inappropriate antidiuretic hormone (SIADH), as well as myotomal paresis. The diagnosis was supported by cytology and by culture of the virus from the CSF. The isolation of the virus from the CSF, coupled with abnormalities of the patient's mental status and CSF, indicate that meningoencephalitis occurred and probably accounted for the SIADH. The patient had a spontaneous and complete recovery. To our knowledge, this is the first report of SIADH associated with herpes zoster infection.