Blood material interactions--implications for clinicians.
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Biomedical subjects
Publications and source records attributed to C D Forbes.
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Consideration of biomaterials for blood-contacting applications should take into account blood-biomaterial interactions, factors influencing the blood response and evaluation procedures. Examination of blood-biomaterial interactions indicates that relevant features are protein adsorption, platelet reactions, intrinsic coagulation, fibrinolytic activity, erythrocytes, leucocytes and complement activation. Factors influencing the blood response to a biomaterial in clinical application are the biomaterial structure, the presence of an antithrombotic agent, the patient status as determined by the disease and drug therapy, and the nature of the application. Evaluation options for biomaterials are clinical, in vivo, ex vivo and in vitro, with ex vivo and in vitro procedures relevant for biomaterial development.
The increasing use of biomaterials in blood-contacting applications underlines the importance of an enhanced understanding of the interactions of blood with foreign surfaces. These interactions constitute a complex response involving the possible participation of proteins, platelets, the intrinsic coagulation, the fibrinolytic system, erythrocytes, leucocytes and the complement system. Interpretation of blood-biomaterial interactions and the development of improved biomaterials require the utilisation of in vitro, ex vivo or in vivo blood compatibility assessment procedures, although there is no ideal procedure for linking assessment to the potential clinical performance of a material. In clinical application, foreign surfaces represent only one of the factors influencing the blood response, with the response also influenced by the presence of antithrombotic agents, the blood condition and the nature of the application.
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A principal objective of monitoring the blood response in procedures such as hemodialysis and cardiopulmonary bypass is to achieve an enhanced understanding of the relationship between blood component alterations and the biomaterials employed. The aim in a study of blood-biomaterial interactions of deriving a correlation between a characteristic of the biomaterial and a representative parameter of the blood response can be influenced in a clinical situation by antithrombotic agents, multimaterial contact, device utilization, blood condition, drug therapy, and the nature of the application. The selection of parameters representative of the blood response may require a compromise between the advantages of multiparameter assessment and the benefit of measuring a single parameter by a consistent methodology. Representative parameters are protein adsorption, platelet reactions, intrinsic coagulation and the contact activation phase, fibrinolysis, leukocyte alterations, and complement activation. Assessment during clinical application can be approached by consideration of blood response patterns.
Coronary heart disease has been described as Scotland's national disease and ways of reducing its incidence are therefore of paramount importance especially in younger males. A recent British Medical Journal paper has indicated that general practitioners can make little impact on patients' lifestyles. This paper shows that a cohort of Scottish men (Social Class III-V) responded well (80%) to offers of screening for risk factors of CHD, continued to attend for review and showed highly significant changes in their risk factor profiles. A committed enthusiastic primary care team have shown the potential for reducing coronary risk factors in so-called healthy men.
An automated filtration technique has been used to investigate the effect of dipyridamole (DP) on red blood cell deformability in patients identified as having rigid red cells. They were patients on haemodialysis (HD) for chronic renal failure (n = 18), patients with peripheral vascular disease (PVD, n = 23) and controls (hospital outpatients, n = 33). Leucocytes and platelets were removed from heparinised blood by filtration through Imugard wool. Washed red cell suspensions in buffer at 5% haematocrit, without or with 5 microM DP, were filtered through Nuclepore Hemafil Membranes with 4.7 microns pores. The initial steady state relative filtration pressure (iRFP) was used to assess cell deformability. A low iRFP value reflects increased deformability and vice versa. The mean iRFP values were 0.33, 0.393 and 0.403 for controls, PVD and HD patients respectively, indicating that the red cells in the two groups of patients were significantly more rigid. DP reduced the iRFP to 0.266, 0.278 and 0.263 for controls, PVD and HD patients respectively. The results suggest that DP may be beneficial when red cell rigidity contributes to impaired microvascular perfusion.
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Available pre-clinical techniques of assessing severity of untoward reaction by blood following contact with haemodialysis membranes do not account for the effects of dialysate and flow characteristics in the observed blood changes. A miniature flat sheet dialyser that considered these effects was prepared and tested in both in-vitro and ex-vivo circuits. Changes in platelets and leucocytes in heparinised human blood in-vitro tests did not distinguish regenerated cellulose (Cuprophan 150PM) membrane from a synthetic membrane, a copolymer of acrylonitrile and sodium methyl sulphonate (AN69S). Ex-vivo tests using rats showed more marked leucocyte (41.3%) and platelet (43.1%) depletion by Cuprophan 150PM than AN69S after 90 minutes of dialysis. Leucocyte and platelet loss due to AN69S were 26.9% and 13.4% respectively. In addition, Cuprophan 150PM membranes exhibited high affinity for leucocytes and platelets in both in-vitro and ex-vivo tests compared to AN69S membranes which were primarily covered with erythrocytes. Application of simulated in-use techniques in preclinical evaluation of blood compatibility membranes that are used in extra-corporeal treatment are recommended.
Plasma viscosity, molecular markers of activated coagulation and fibrinolysis (fibrinopeptides A and B beta 15-42), coagulation factors (fibrinogen and factor VII) and antiplasmins were measured in 529 men aged 35-54 years and related to new angina pectoris (n = 117) and to coronary risk factors in controls without angina (n = 412). Five major risk factors (cigarette-smoking, blood pressure, cholesterol, triglyceride and body mass index) were each associated with increases in plasma viscosity, coagulation factors, and imbalance of coagulation over fibrinolysis (increased ratio of fibrinopeptide A/fibrinopeptide B beta 15-42). Increased viscosity and fibrinogen in smokers were partly reversed in ex-smokers, but the imbalance of coagulation and fibrinolysis persisted. Cholesterol and triglyceride were also associated with increased antiplasmin activity. In men with angina, only fibrinogen was elevated compared to controls. We suggest that increased plasma viscosity and an imbalance of coagulation over fibrinolysis may be mechanisms by which known risk factors promote arterial thrombosis, but are not present in stable angina.
56 haemophiliacs selected on the basis of HIV-1 antibody status, liver disease grade and mean annual dose of clotting factor concentrate used were studied. Spontaneous and stimulated IgG and IgM production in vitro were measured. HIV-1 infection was associated with increased spontaneous immunoglobulin production and an impaired response to pokeweed mitogen and Staph Aureus protein A. Implying a shift in the proportions of partially and fully activated B cells. In the absence of HIV-1 infection there was a shift to a greater proportion of partially activated B cells in patients with severe liver disease. The remainder had in vitro immunoglobulin production comparable to controls. B cell abnormalities occur early in the course of HIV-1 infection. Liver disease and not clotting factor concentrate treatment cause B cell abnormalities in the absence of HIV-1 infection in haemophilia.
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STUDY OBJECTIVE: The aim was to investigate the effects of dipyridamole, aspirin, and a combination of dipyridamole plus aspirin on platelet aggregation in whole blood, PGI2 generation, and red cell deformability ex vivo. SUBJECTS: were 16 male volunteers, aged 22-39 years, mean age, 26.6 years. DESIGN: This was a randomised, double blind, placebo controlled trial. The volunteer received each of the following treatments 10 days apart: dipyridamole 200 mg; aspirin 300 mg; dipyridamole 200 mg plus aspirin 300 mg; matched placebos. MEASUREMENTS AND MAIN RESULTS: Blood was taken for platelet function tests, PGI2 metabolite assay, and red cell deformability before and 2 h after the trial dose was taken. Platelet aggregation was quantified by measuring the fall in single platelet count after stimulation with 2 micrograms.ml-1 collagen or 50 nM platelet activating factor (PAF), or by rollermixing aliquots of blood to initiate spontaneous aggregation. The platelet function tests were completed at 37 degrees C within 10 min of venepuncture. The stable metabolite of PGI2, 6-keto PGF1 alpha, was measured in serum. There was inhibition of spontaneous platelet aggregation by dipyridamole (p less than 0.004), aspirin (p less than 0.005), and the combination of dipyridamole plus aspirin (p less than 0.0001) as compared with placebo. PAF induced platelet aggregation was inhibited by dipyridamole (p less than 0.002) and the combination of dipyridamole plus aspirin (p less than 0.0001) but aspirin alone had no inhibitory effect. Collagen induced platelet aggregation was inhibited by all three treatments: dipyridamole (p less than 0.06), aspirin (p less than 0.0001), and the combination of dipyridamole plus aspirin (p less than 0.0001). PGI2 generation was markedly inhibited by aspirin (p less than 0.0001) and the combination doses (p less than 0.0001) but was unaffected by dipyridamole alone. Of the three active treatments, only dipyridamole alone significantly (p less than 0.001) increased red cell deformability; there was a modest decrease in red cell deformability with aspirin. CONCLUSIONS: The results with PAF support the view that dipyridamole inhibits platelet activation by more than one mechanism; the effect on collagen induced and spontaneous platelet aggregation suggests that the effect of the combination doses is additive and that on red cell deformability the synergy is negative.
OBJECTIVE: To review the obstetric and gynaecological problems in women with congenital coagulopathies. DESIGN: Retrospective review. SETTING: Regional Adult Haemophilia Unit, Glasgow Royal Infirmary. SUBJECTS: All women in contact with the Unit over a period of 30 years, comprising eight with von Willebrand's disease, 18 obligate carriers of haemophilia A and five obligate carriers of Christmas disease. Each woman was interviewed and details of their obstetric and gynaecological histories were obtained and their case records were reviewed. MAIN OUTCOME MEASURES: Haemostatic changes associated with pregnancy and gynaecological problems. RESULTS: In 14 pregnancies in seven patients with von Willebrand's disease, there were four primary and four secondary post-partum haemorrhages and a large perineal haematoma complicating an episiotomy. These problems arose despite the endogenous rise in factor VIIIc seen with pregnancy. All women seen with von Willebrand's disease complained of menorrhagia and had been referred to gynaecologists. Treatment included danazol, tranexamic acid and the contraceptive pill. Diagnostic curettage resulted in severe haemorrhage in one woman and two women with pelvic pain and dyspareunia were found to have spontaneous broad ligament haematomas, one requiring surgery. In 43 pregnancies in obligate carriers of haemophilia A and Christmas disease there were five post-partum haemorrhages and a large perineal haematoma. CONCLUSION: In von Willebrand's disease it should be noted that adequate laboratory correction of factor VIIIc levels does not ensure clinical haemostasis; hence platelet function should also be measured. Patients with congenital coagulopathies pose particular problems for the obstetrician and gynaecologist and should be managed in close association with the local haemophilia centre.
A retrospective cohort study of 14,457 workers at an aircraft maintenance facility was undertaken to evaluate mortality associated with exposures in their workplace. The purpose was to determine whether working with solvents, particularly trichloroethylene, posed any excess risk of mortality. The study group consisted of all civilian employees who worked for at least one year at Hill Air Force Base, Utah, between 1 January 1952 and 31 December 1956. Work histories were obtained from records at the National Personnel Records Centre, St. Louis, Missouri, and the cohort was followed up for ascertainment of vital state until 31 December 1982. Observed deaths among white people were compared with the expected number of deaths, based on the Utah white population, and adjusted for age, sex, and calendar period. Significant deficits occurred for mortality from all causes (SMR 92, 95% confidence interval (95% CI) 90-95), all malignant neoplasms (SMR 90, 95% CI 83-97), ischaemic heart disease (SMR 93, 95% CI 88-98), non-malignant respiratory disease (SMR 87, 95% CI 76-98), and accidents (SMR 61, 95% CI 52-70). Mortality was raised for multiple myeloma (MM) in white women (SMR 236, 95% CI 87-514), non-Hodgkin's lymphoma (NHL) in white women (SMR 212, 95% CI 102-390), and cancer of the biliary passages and liver in white men dying after 1980 (SMR 358, 95% CI 116-836). Detailed analysis of the 6929 employees occupationally exposed to trichloroethylene, the most widely used solvent at the base during the 1950s and 1960s, did not show any significant or persuasive association between several measures of exposure to trichloroethylene and any excess of cancer. Women employed in departments in which fabric cleaning and parachute repair operations were performed had more deaths than expected from MM and NHL. The inconsistent mortality patterns by sex, multiple and overlapping exposures, and small numbers made it difficult to ascribe these excesses to any particular substance. Hypothesis generating results are presented by a variety of exposures for causes of death not showing excesses in the overall cohort.