Detection of intravascular coagulation.

A method is described for the measurement of soluble thrombin-altered fibrinogen (circulating fibrin) in human plasma. This method is dependent upon the enzymatic incorporation of glycine ethyl ester-(14)C (GEE-(14)C) into circulating fibrin by the action of the fibrin-stabilizing enzyme, factor XIII. The mean incorporation of GEE-(14)C into the fibrinogen of normal human plasma controls was 167 +/-47 dpm/mg fibrinogen. The addition of 0.03 NIH U/ml of thrombin to normal human plasma resulted in a two to threefold increase in the incorporation of GEE-(14)C into the fibrinogen. The addition of plasmin split products of fibrinogen to normal plasma did not increase the incorporation of GEE-(14)C unless these products were also exposed to thrombin. The addition of plasmin split products of a fibrin clot resulted in only minimal increase in the incorporation of GEE-(14)C (57 dpm/mg fibrinogen) at 37.5% concentration. The method was therefore sensitive to thrombin alterations of fibrinogen but insensitive to plasmin alterations of fibrinogen and fibrin.Clinically, the method was found to provide useful information for the diagnosis and treatment of disseminated intravascular coagulation in two patients with meningococcemia, two patients with Rocky Mountain spotted fever, and three patients in whom therapeutic abortions were induced by the injection of hypertonic saline.

Treatment of nonmetastatic osteosarcoma of the extremity with preoperative and postoperative chemotherapy: a report from the Children's Cancer Group.

PURPOSE: The specific aims of this study were to improve event-free survival (EFS) in patients with newly diagnosed nonmetastatic osteosarcoma of an extremity using the histologic response to neoadjuvant chemotherapy to determine postoperative chemotherapy; to evaluate a uniform histologic grading system that measures tumor response; and to identify patient characteristics that might influence EFS and survival. PATIENTS AND METHODS: Two hundred sixty-eight patients with nonmetastatic osteosarcoma of the extremity were entered between August 1983 and October 1986. Preoperative chemotherapy consisted of four courses of high-dose methotrexate (MTX) and one course of bleomycin, cyclophosphamide, and dactinomycin (BCD). Histologic response to preoperative chemotherapy was determined by morphometric analysis. Good histologic responders (< 5% residual viable tumor) were treated postoperatively with MTX, BCD, and doxorubicin (DOX); poor histologic responders were treated with BCD, DOX, and cisplatin (CDDP). RESULTS: The 8-year EFS and survival rates were 53% and 60%, respectively. Two hundred six patients had their tumors assessed for histologic response: 28% displayed a good histologic response to preoperative chemotherapy. Good histologic responders had an 8-year postoperative EFS rate of 81% and survival rate of 87%; those with a poor histologic response had an 8-year postoperative EFS rate of 46% and survival rate of 52%. A primary tumor site in the proximal humerus or proximal femur and an elevated serum alkaline phosphatase level were associated with an increased risk of an adverse event, whereas the type of surgical procedure was not. CONCLUSION: EFS and survival appear to be directly related to histologic response to neoadjuvant chemotherapy.

Cost-effectiveness of a shared-management delivery system for the care of children with cancer.

Costs of two alternative methods for obtaining comparable quality outpatient care for pediatric cancer patients were examined. Costs incurred in obtaining care from specialists, "specialist-management," were compared to costs incurred in obtaining "shared-management," care provided by specialists and primary physicians combined. Shared-management medical costs for outpatient care were 10% less than they would have been had the care been obtained from specialists. The nonmedical costs of transportation, parking, food away from home, and lost productivity or income were all less under the shared-management medical care delivery system than they would have been had specialist management been utilized. The total estimated cost differences between the alternative systems for the delivery of outpatient care ($2,191.34) represents for shared management a mean saving per patient of approximately 29% in direct out-of-pocket expenses and a 59% savings in the indirect costs of lost income or productivity. A total theoretical mean 41% saving per patient was shown to accrue through the use of shared management.

Physician incentives for shared management of childhood cancer patients.

Four years' experiences of 69 primary care physicians who delivered more than 70% of the chemotherapy to 174 children with cancer were assessed. Five academic pediatric oncologists were responsible for diagnosis, assignment to a clinical trial protocol, and overall management. The academicians saw the patients at diagnosis and at regularly scheduled intervals but provided care for less than 30% of the outpatient visits. Factors examined included: (1) why the primary care physicians agreed to participate in the care of these patients, (2) how they thought their participation affected the patient and the patient's family, (3) how participation affected their personal and professional development, (4) how participation affected their practice, (5) what their perceptions were concerning the merits of traditional specialist management, and (6) their overall evaluation of the Iowa shared-management program. The initial agreement by primary care physicians to participate in shared management was related to their perception that it would improve the overall care of their patients. The physicians agreed that the program saved the family time and money, was of educational value, personally satisfying, and not economically detrimental to their practice. They did not identify areas where specialist management had clear advantages over shared management and none reported dissatisfaction with this management program.

Health outcomes of a community-based therapy program for children with cancer--a shared-management approach.

Critical to providing cancer therapy to children in rural areas is finding dependable sources of therapy near the patients' homes. In this study, comparison was made of 668 visits by 24 patients to nearby private practitioners, who carried out 70% of the therapy, with 712 visits by 22 other patients for whom all care was managed by pediatric hematologist-oncologists. There was no significant difference by Wilcoxon rank sum test between the two groups in the accuracy with which protocol rules were followed, in the incidence of neutropenia, infection, fever, thrombocytopenia, drug toxicity, or the proportion of days hospitalized. The findings indicate that the private practitioners participating in a shared-management system were a dependable resource for providing 70% of the total cancer therapy to these patients.

The animal models for hemorrhage and thrombosis in the neonate.

Animal models have added significantly to our understanding of adult hemorrhagic and thrombotic diseases. Few models, however, have been developed for studies of the hemostatic disorders in the fetus and newborn. This report reviews the current information on animal models of fetal and neonatal hemostasis. The requirements of a relevant model are addressed and previous studies using fetal and neonatal animal models are reviewed. A recommendation of a single animal for all studies of fetal and neonatal hemostasis is not possible. However, the lamb has been the most frequently studied and appears to provide relevant information regarding normal development and the factors which may adversely influence hemostasis in the fetus and newborn. Animal models, in contrast to in vitro experiments, provide a means of studying the entire spectrum of biologic consequences that results from a single experimentally induced alteration. In the "Introduction to the Study of Experimental Medicine" Claude Bernard commented "I not only conclude that experiments made on animals from the physiological, pathological, and therapeutic points of view have results that are applicable to theoretic medicine, but I think that without such comparative study of animals, practical medicine can never acquire a scientific character". In the area of blood coagulation, animal models have added significantly to our understanding of the pathophysiology of hemorrhage and thrombosis. There are animal models for both congenital and acquired bleeding disorders including factor VII, VIII, IX, X, XI, and fibrinogen deficiency; as well as von Willebrand's disease and disorders of platelet function.(ABSTRACT TRUNCATED AT 250 WORDS)

Home treatment of mild to moderate bleeding episodes using recombinant factor VIIa (Novoseven) in haemophiliacs with inhibitors.

OBJECTIVE: To assess the safety and efficacy of a fixed dose of recombinant activated factor VII (rFVIIa; NovoSeven) in the home setting for mild to moderately severe joint, muscle; and mucocutaneous bleeding episodes in patients with haemophilia A or B with inhibitors. DESIGN: Multicentre, open-label, single arm, phase III study of one year duration. METHODS; Patients or their caregivers administered up to three doses of rFVIIa (90 microg/kg i.v.) at 3 h intervals within 8 h of the onset of a mild to moderate bleeding episode. Once the subject considered that rFVIIa had been "effective" with regard to haemostasis (after 1-3 injections), one further (maintenance) dose of rFVIIa was administered. RESULTS: Of 60 patients enrolled, 56 experienced at least one bleed, and 46 completed the one year study. 614 of 877 bleeds (70%) were evaluable according to protocol definitions. Haemostasis was rated as "effective" in 92% (566/614) of evaluable bleeds after a mean of 2.2 injections. For successfully treated episodes, the time from onset of bleeding until administration of the first injection was 1.1+/-2.0 h (mean+/-SD). Twenty-four hours after initial successful response, haemostasis was reported as having been maintained in 95% of cases. Efficacy was comparable for muscle, joint and target joint, and mucocutaneous bleeding episodes. In an intent-to-treat analysis of all 877 bleeding events, efficacy outcomes were equivalent to the evaluable bleeds, with an effective response in 88% of treated episodes. Treatment-related adverse events occurred in 32 (3% of all) bleeding episodes and consisted of re-bleeds/new bleeds in more than 50% (18/32) of these events. A single episode of superficial thrombophlebitis was the only thrombotic complication encountered, and there were no patient withdrawals due to adverse events. Development of FVII(a) antibodies could not be detected, and hypersensitivity reactions to rFVIIa were not reported. CONCLUSION: rFVIIa is effective and well tolerated when used in the home setting to treat mild to moderate bleeding episodes in patients with haemophilia A or B with inhibitors.

Detection of fibrin monomer. Comparison of the immune precipitate method with the serial-dilution protamine sulfate test and the ethanol gel test.

In a previous publication, a method for measuring fibrin monomer in plasma with the use of an immune precipitate of fibrinogen was described. The method was found to be more sensitive to unstabilized fibrin monomer than the serial-dilution protamine sulfate test, or the ethanol gel test, and detected fibrin in a mixture of the plasmin digestion products of fibrin. In the present study the sensitivity of the immune precipitate method for detecting specific plasmin digestion products of fibrin X, Y, D, and E, its sensitivity for stabilized fibrin monomer complexes, and its sensitivity for fibrin retaining B-peptide were measured and compared with the corresponding sensitivities of the serial-dilution protamine sulfate test and the ethanol gel test for detecting these same products. The immune precipitate method was found to be highly sensitive to stabilized fibrin monomer complexes and to fibrin retaining B-peptide; to be significantly less sensitive to the plasmin digestion fragments X, Y, and E; and to be insensitive to fragment D. The serial-dilution protamine sulfate test and the ethanol gel test were found to be insensitive to all of the plasmin digestion products of fibrin and less sensitive to the other fibrin complexes.

An intrinsic coagulation pathway inhibitor in a 3-year-old child.

An intrinsic coagulation pathway inhibitor with acitivty against factor XI was detected in the plasma of a 3-year-old child, following a respiratory infection. The inhibitor was present transiently, but it was clinically significant and was manifiested by extensive bruises. Abnormalities of clotting and the bruising tendency disappeared simultaneously without treatment before the inhibitor could be definitively characterized. It was possibly the consequence of an adenovirus infection, as an elevated adenovirus titer was demonstrated in the patient's blood. It is possible that inhibitors of this type are more common sequelae of viral infections than realized, and perhaps a systematic effort should be made to detect them and to define their etiology and mechanism of action.

Shared management of children with cancer.

OBJECTIVE: To determine the risks and benefits of university-based pediatric oncologists and community-based primary care physicians sharing the management of children with cancer. DESIGN: Physicians participating in shared management of children with cancer were surveyed, and the outcomes of the children were measured. SETTING AND PARTICIPANTS: One hundred thirty-seven community-based primary care physicians participated in the management of the 226 children with cancer in Iowa and western Illinois during the past 15 years. The survival of the 226 children was compared with that of 240 randomly selected children treated using the identical treatment protocols but treated only by pediatric oncologists. INTERVENTION: A 7-point Likert scale questionnaire was completed by 97 (71%) of the participating primary care physicians. RESULTS AND OUTCOME MEASURES: There were no differences in the survival of children using shared management compared with those treated only by pediatric oncologists. Primary care physicians believed that shared management is of economic and psychosocial benefit to patients, improves the treatment choices available to patients, does not require excessive time, and does not result in loss of practice income. The system strengthens the primary care physicians' relationships with oncologists and results in additional referrals to the university-based pediatric oncologists. It is of educational value, is personally satisfying, and provides relief from the stress associated with caring for these families. Primary care physicians would like to see this system expanded to include other children with special health care needs. CONCLUSION: The shared-management approach to care is a viable attractive option of health care provision for children.

Adequate anticoagulation during cardiopulmonary bypass determined by activated clotting time and the appearance of fibrin monomer.

The adequacy of anticoagulation during 2 hours of cardiopulmonary bypass at 30 degrees C in 9 rhesus monkeys was determined by measuring the whole-blood activated clotting time (ACT) and by noting the appearance of thrombin-altered fibrin (fibrin monomer) and the relative consumption of clotting factors. Factor V and VIII, the heparin cofactor, antithrombin III, prothrombin time, partial thromboplastin time, ACT, platelets, hematocrit, fibrinogen, and fibrin monomer were determined prior to heparinization and after protamine. In 6 of 9 experiments, fibrin monomer became positive in the plasma during cardiopulmonary bypass (CPB), indicating that active coagulation was occurring. In 5 of the 6 animals, initial ACT was less than 400 seconds, and fibrin monomer appeared within the first 30 minutes of bypass. In 1 animal with an initial ACT of 439 seconds, fibrin monomer appeared after 60 minutes of bypass, at which time the ACT was less than 400 seconds. An abnormal level of fibrin monomer was not detected in 5 pediatric patients with an ACT greater than 450 seconds during CPB. Our experimental study and clinical data suggest that the lower limit, as measured by the ACT, for anticoagulant effect to provide coagulation-free CPB is at least 400 seconds.

Coagulation changes following vasectomy: a study in primates.

Thirty vasectomized rhesus monkeys were tested for changes in coagulation factors that might reflect an increased incidence of thrombosis. The results of tests on these monkeys were compared with results of tests on 18 control rhesus monkeys; there were no significant differences between control and vasectomized animals for any of the parameters tested. One vasectomized animal had increased levels of fibrin monomer in his plasma on repeated samples, but no evidence of thrombosis on postmortem examination.

PIP: This study attempted to determine whether fibrin monomer complexes, or other alterations of coagulation factor activities that might predispose to thrombosis, were present in 30 vasectomized Rhesus monkeys that had had bilateral vasectomies 1-11 years earlier. Blood coagulation factors, prothrombin, factors V and VIII, fibrogen, and antithrombin III, are consumed when blood coagulation occurs. If consumption of these factors is in excess of the individual's ability to synthesize them, a decreased concentration results. No significant decreases in activities of any consumable clotting factors were found. If intravascular coagulation is present, certain products of coagulation may be present in the blood even though consumable factors remain normal. Products of intravascular coagulation include fibrin monomer and plasmin digestion products of fibrin. No significant differences in average values of fibrin monomer and fibrin digestion products in control and vasectomized animals were found. 1 animal had increased fibrin monomer, but on postmortem examination, no evidence of intravascular thrombosis was seen.

Human coagulation factor FVIIa (recombinant) in the management of limb-threatening bleeds unresponsive to alternative therapies: results from the NovoSeven emergency-use programme in patients with severe haemophilia or with acquired inhibitors.

This open-label, emergency-use study evaluated the efficacy and safety of activated human coagulation factor VIIa (recombinant) (rFVIIa) (NovoSeven; Novo Nordisk Pharmaceuticals, Inc., New Jersey, USA) in treating limb-threatening joint or muscle bleeds in 17 patients with haemophilia A or B and six patients with acquired inhibitors to factor VIII or factor IX. All patients had previously failed on one or more alternative therapies. rFVIIa administration was effective or partially effective in controlling joint or muscle bleeds in 34 out of 35 (97%) bleeding episodes; in 23 patients, 14 of 17 (82%) muscle bleeds and 16 of 18 (89%) joint bleeds were effectively controlled. These findings suggest that rFVIIa is an effective and well-tolerated therapeutic option in the management of joint or muscle haemorrhage in patients with haemophilia and in patients with acquired inhibitors.

Intelligence and achievement testing in childhood cancer: three years postdiagnosis.

Intellectual and educational testing, employing primarily the Wechsler Intelligence Scale for Children-Revised (WISC-R) and the Wide Range Achievement Test (WRAT), was administered to two groups of children, one with acute lymphoblastic leukemia (ALL), the other with a solid tumor (ST) which did not invade or involve the central nervous system (CNS). Initial testing was completed within 30 days following diagnosis and repeated one year and three years later. Separate ANOVA procedures on the ALL and ST patients were completed, with followup ANOVA procedures for two age groups. The ALL patients declined significantly on WISC-R vocabulary (p less than 0.05) and Full Scale IQ (p less than 0.05), but no significant changes were obtained from the ST patients. Separation of the ALL group into two age groups, less than 8 years and greater than or equal to 8 years revealed significant declines in the younger group on Verbal IQ, Performance IQ, Full Scale IQ, and WRAT arithmetic. However, no significant declines were observed in the older ALL group. The results suggest that declines in ability and achievement are limited to those ALL patients treated with CNS prophylaxis at relatively young ages.

Diagnosis and treatment of coagulopathy in the newborn.

Appropriate management of the bleeding newborn is easily accomplished by first assessing the clinical circumstances under which the bleeding occurs. Having determined the clinical circumstances, knowledge of the pathophysiology of disseminated intravascular coagulation, liver failure, vitamin K deficiency, and hemophilia coupled with knowledge of the normal levels of coagulation factor activities at birth leads to selection of appropriate laboratory tests to confirm the etiology of the bleeding. Once the etiology is confirmed, treatment requires management of associated clinical conditions and replacement of vitamin K and/or deficient coagulation factors.

Effect of metabolic acidosis on fetal renal haemodynamics.

The effects of metabolic acidosis on renal haemodynamics and intrarenal blood flow distribution was studied in two groups of chronically-catheterized fetal sheep between 122 and 130 days of gestation. One group (experimental group) was studied before and during infusion of 1.1 M lactic acid, whereas the second group received on infusion of dextrose 5% (w/v) in water and served as a time-control group. Infusion of lactic acid for 2 h decreased fetal arterial pH from 7.37 +/- 0.01 to 6.95 +/- 0.02, did not change arterial blood pressure, but produced a significant decrease in renal blood flow (41 +/- 3 to 33 +/- 7 ml/min, P less than 0.05) and a significant increase in renal vascular resistance (1.42 +/- 0.13 to 1.86 +/- 0.18 mmHg/ml/min, P less than 0.05). Moreover, a significant decline in cortical blood flow was also observed in the outer portion of the renal cortex during lactic acidosis. Taken together, these results suggest that metabolic acidosis produces significant changes in fetal renal haemodynamics not associated with changes in arterial blood pressure.