A raised beta 2-glycoprotein I level does not prolong the DRVVT.
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Blood Coagulation Tests↗
Biomedical subjects
S J Machin
Publications and source records attributed to S J Machin.
Contact factor proteases and the complexes formed with alpha 2-macroglobulin can interfere in protein C assays by cleaving amidolytic substrates.
Plasma from women taking combined oral contraceptives and cold-activated plasma contain proteases which cleave chromogenic substrates in protein C assays in the absence of protein C activators such as Protac. This spontaneous activity makes a background substraction necessary and makes protein C (PC) assays less accurate. We investigated two commonly used substrates < Glu-Pro-Arg-pNA (S-2366) and 2AcOH.H-D-Lys(Cbo)-Pro-Arg-pNA (PC substrate) and found that cold-activated normal and protein C-deficient plasmas gave absorbance values up to 300 times higher than buffer blanks. FXIa cleaves these substrates but activity was not blocked by corn or lima bean trypsin inhibitors, soy bean trypsin inhibitor (SBTI), hirudin or epsilon-amino-n-caproic acid (EACA). Kaolin activation of normal, FXI, FIX, FVIII, FVII and protein C-deficient, but not of FXII or prekallikrein (PKK)-deficient plasmas led to cleavage of chromogenic substrate for protein C. The protein C substrates were cleaved by purified kallikrein and alpha- and beta-FXIIa. Immunoabsorption with alpha 2-macroglobulin (alpha 2M) antibodies removed 60% of the alpha 2M and 70% of the activity on PC Substrate. Gel filtration of normal plasma on Sephadex G-150 gave a single peak of protein C activity and antigen in the included volume. After cold activation of the fractions, a second protein C-like peak appeared in the void volume, but with no detectable protein C antigen. This peak coincided with alpha 2M (chromogenic and ELISA) and plasma kallikrein (S-2302), but FXII (measured with a substrate insensitive to kallikrein) eluted separately.(ABSTRACT TRUNCATED AT 250 WORDS)
Amides↗
Some 'antiphospholipid antibodies' bind to beta 2-glycoprotein I in the absence of phospholipid.
Some antiphospholipid antibodies (aPL) only bind to anionic phospholipids in the presence of a serum cofactor, beta 2-glycoprotein I (beta 2GPI). Whether these aPL can bind to beta 2GPI in the absence of phospholipid is controversial. We have purified anticardiolipin antibodies (aCL) from the plasma of four patients and beta 2GPI from normal plasma by solid phase affinity methods. All four aCL bound to cardiolipin and phosphatidylserine in the presence of beta 2GPI but not in its absence. The binding of two of the antibodies to cardiolipin and phosphatidylserine at various concentrations of human beta 2GPI was compared with that obtained using 10% bovine serum. The two antibodies responded differently to increasing beta 2GPI concentrations, and binding to phosphatidylserine was relatively greater than to cardiolipin using human beta 2GPI. All four aCL bound to plastic plates coated with beta 2GPI in the absence of phospholipid, and beta 2GPI in the fluid phase had no effect on binding. Binding to beta 2GPI coated plates was increased equally when bovine serum or bovine albumin were used as the sample diluent in place of gelatine. These findings and those of others have important implications for the design of assays for antiphospholipid antibodies.
Antibodies, Anticardiolipin↗
The influence of therapeutic blocking of Gp IIb/IIIa on platelet alpha-granular fibrinogen.
Recent evidence suggests that platelet alpha-granule fibrinogen (fg) is derived from the plasma pool. Since platelets from patients with Type I Glanzmann's thrombasthenia (GT) are deficient in intracellular fibrinogen (fg) it was hypothesized that Gp IIb/IIIa could mediate the uptake of fg. To study the potential role of Gp IIb/IIIa in intracellular fg trafficking, the influence of therapeutic blocking of Gp IIb/IIIa on platelet fg was studied in 12 patients with stable ischaemic heart disease. Patients were either given a single intravenous dose of the monoclonal antibody 7E3 Fab (n = 4) or a combination of bolus and continuous infusion up to 24 (n = 3), 36 (n = 3) or 96 h (n = 2). All patients showed grossly prolonged bleeding times with a significant reduction of ex-vivo ADP induced aggregation. Although, surface Gp IIb/IIIa binding sites were consistently reduced in all patients, there was a variable but delayed decrease in platelet fg relative to vWf:Ag in only six out of the 12 patients studied. The reduction in fg appeared dependent upon both dosage and duration of Gp IIb/IIIa blockade. The study provides further evidence for the novel role of Gp IIb/IIIa in the intracellular trafficking of fg to platelet and megakaryocytic alpha-granules.
Adult↗
Guidelines for the use of fresh frozen plasma. British Committee for Standards in Haematology, Working Party of the Blood Transfusion Task Force.
Fresh frozen plasma should only be used to treat bleeding episodes or prepare patients for surgery in certain defined situations. Definite indications for the use of FFP: 1. Replacement of single coagulation factor deficiencies, where a specific or combined factor concentrate is unavailable. 2. Immediate reversal or warfarin effect. 3. Acute disseminated intravascular coagulation (DIC). 4. Thrombotic thrombocytopenic purpura (TTP). Conditional uses: FFP only indicated in the presence of bleeding and disturbed coagulation: 1. Massive transfusion. 2. Liver disease. 3. cardiopulmonary bypass surgery. 4. Special paediatric indications. No justification for the use of FFP: 1. Hypovolaemia. 2. Plasma exchange procedures. 3. 'Formula' replacement. 4. Nutritional support. 5. Treatment of immunodeficiency states.
Adult↗
Lack of specific binding of anticardiolipin antibodies to intact platelets.
The aims of this study were to investigate whether anticardiolipin antibodies (aCL) bind to intact (resting or activated) platelets in vitro. Suspensions of resting, activated (with a mixture of thrombin and collagen) and freeze-thawed platelets from healthy subjects were incubated with either affinity-purified aCL or pooled normal human immunoglobulin G (IgG). Platelet-bound IgG was measured by flow cytometric analysis of platelets incubated with a fluorescein-conjugated polyclonal goat anti-human IgG. There was no significant binding of IgG aCL to intact resting or activated platelets, while significant specific binding to freeze-thawed platelets was demonstrated. These results question the theory that aCL bind/activate intact platelets in vivo.
Adult↗
Teicoplanin and prophylaxis of Hickman catheter insertions.
A total of 88 patients with haematological malignancies who required Hickman catheters for intensive chemotherapy, were randomized to receive either a single bolus intravenous injection of teicoplanin, or no teicoplanin, immediately before insertion of a double lumen Hickman catheter. There was a lower incidence of catheter-related Gram-positive sepsis in patients receiving prophylactic teicoplanin. This benefit was particularly clear in patients who were already neutropenic at the time of catheter insertion. Prophylactic teicoplanin may, therefore, be useful as a routine procedure during the insertion of Hickman catheters for this group of patients.
Adult↗
Procoagulant changes induced by oral contraceptives are balanced by an increased fibrinolytic tendency.
Oral contraceptives caused increased fibrinogen, FVII, FX, and fibrinolysis. The latter was associated with elevated FXII and PKK, while C1-INH was decreased, ATIII and alpha 2M were unchanged; it could not be accounted for by changes in t-PA, u-PA, PAI, plasminogen, alpha 2-AP, proteins C or S. HCII and alpha 1-PI were increased and may regulate the availability of thrombin and FXIa. The increased FXII/PKK dependent fibrinolytic potential and HCII may offset any increase in thrombin generation, while alpha 1-PI limits intrinsic coagulation.
Adult↗
Lassa fever encephalopathy: clinical and laboratory findings.
Clinical and laboratory findings are reported in nine patients who developed acute encephalopathy during the course of Lassa fever. The encephalopathy manifested 3-17 days after disease onset with confusion, followed rapidly by tremor (seven patients), grand mal convulsions (seven), abnormal posturing (three) and coma (eight); focal neurological signs and evidence of raised intracranial pressure were not seen. Eight patients died, most commonly from respiratory arrest following a protracted fit. Development of encephalopathy did not correlate with the presence of virus in cerebrospinal fluid (CSF), nor with virus antibodies in CSF and/or serum; thus, neither direct cytopathic nor immune-mediated mechanisms seem to be involved in its pathogenesis.
Adolescent↗
Guidelines for testing and revised criteria for lupus anticoagulants. SSC Subcommittee for the Standardization of Lupus Anticoagulants.
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Autoantibodies↗
Changes in haemostasis after stopping the combined contraceptive pill: implications for major surgery.
OBJECTIVE: To investigate the changes in haemostasis in the three months immediately after stopping the combined contraceptive pill. DESIGN: Prospective randomised study. SETTING: Family planning centre in London. SUBJECTS: 24 women aged 35-45 investigated before, during, and after six months' use of combined oral contraceptives containing 30 micrograms ethinyl oestradiol together with the progestogens desogestrel or gestodene. MAIN OUTCOME MEASURES AND RESULTS: Blood samples were taken immediately before and after six months of oral contraceptive use and one, two, four, six, eight, and 12 weeks after the pill had been stopped. During the six months of oral contraceptive use the plasma concentration of factor X and fibrinogen increased and that of antithrombin III decreased. Between two and six weeks after stopping the pill a rebound phenomenon occurred with plasma concentrations of antithrombin III increasing (mean change from baseline at two weeks 0.06 IU/l and at six weeks 0.10 IU/l) and fibrinogen decreasing (0.26 g/l change at two weeks and 0.40 g/l at six weeks). Factor X concentrations fell gradually and the values at eight weeks were not significantly different from those found before the combined pill was started. CONCLUSION: The combined pill should be stopped at least four weeks before major surgery, which carries the risk of postoperative thrombosis, to allow the potentially prothrombotic haemostatic changes that occur during its use to be corrected.
Adult↗
A prospective randomized study of prophylactic teicoplanin to prevent early Hickman catheter-related sepsis in patients receiving intensive chemotherapy for haematological malignancies.
Eighty-eight patients with haematological malignancies requiring Hickman catheters for intensive chemotherapy were randomized to receive either one single bolus intravenous injection of teicoplanin or no teicoplanin immediately before insertion of a double lumen Hickman catheter. There were lower incidences of catheter-related Gram-positive sepsis in patients receiving prophylactic teicoplanin. There were less exit site infections, tunnel infections and catheter-related Gram-positive septicaemia. The benefit of prophylactic teicoplanin was observed especially among patients who were already neutropenic at the time of catheterization. All Gram-positive organisms isolated from the infected skin sites or from blood cultures taken from the Hickman catheters were sensitive to teicoplanin. No adverse reaction was reported in any of the patients in the prophylactic group. Prophylactic teicoplanin therefore may be used routinely for patients requiring insertion of Hickman catheters for intensive chemotherapy to reduce the early incidence of catheter-related sepsis, especially during the associated period of neutropenia following chemotherapy.
Adult↗
Detection of protein C deficiency during oral anticoagulant therapy--use of the protein C:factor VII ratio.
Laboratory diagnosis of protein C deficiency is complicated by the fact that many patients referred for investigation are already being treated with oral anticoagulants. Protein C and factor VII have similar half lives and by using the protein C:factor VII ratio we hoped to be able to detect protein C deficiency in patients receiving oral anticoagulants. We have studied activity levels of protein C and factor VII to produce protein C:factor VII activity ratios in 105 patients receiving oral anticoagulants, 42 normal subjects, and nine patients with known inherited protein C deficiency. The mean ratios for these groups were 1.38, 1.12 and 0.63 respectively. In patients receiving oral anticoagulants, the protein C level showed a poor correlation with the international normalized ratio (INR) value. Reference ranges for protein C at different levels of anticoagulation were therefore considered unsuitable for the identification of inherited protein C deficiency. Five patients with inherited protein C deficiency were studied with and without oral anticoagulation; their protein C:factor VII ratios remained relatively unchanged, despite alterations in the level of the individual proteins. These results suggest that measurement of the protein C:factor VII ratio may help to identify patients with inherited protein C deficiency whilst on oral anticoagulants.
Adolescent↗
The fibrinolytic response to venous occlusion and the natural anticoagulants in patients with antiphospholipid antibodies both with and without systemic lupus erythematosus.
Patients with systemic lupus erythematosus (SLE) have an increased risk of thrombosis and this is increased in the presence of antiphospholipid antibodies (APA). These APA are also associated with thrombosis in patients who do not have SLE. We compared haemostatic parameters in SLE patients with and without APA, and also compared patients who had APA but not SLE with healthy normal controls. No relationships between the natural anticoagulants, antithrombin III, heparin cofactor II, protein C and protein S, and the presence of APA were found. In the patients with SLE both tissue plasminogen activator antigen and plasminogen activator inhibitor (PAI) were increased, but these changes were not due to APA which had no effect on fibrinolysis in these patients. In the patients with APA who did not have SLE the fibrinolytic response to venous occlusion was reduced due to raised levels of PAI; similar changes have, however, been reported in some patients with idiopathic thrombosis.
Adolescent↗
Platelet aggregation is inhibited by a nitric oxide-like factor released from human neutrophils in vitro.
Thrombin-induced platelet aggregation was inhibited in vitro by washed human neutrophils. Aggregation was inhibited in a neutrophil concentration dependent manner but glutaraldehyde fixed neutrophils had no significant effect on platelet aggregation. The neutrophil-derived inhibitory factor had the pharmacological profile of nitric oxide. Its action was potentiated by both superoxide dismutase and M&B22, 948, a selective cyclic guanosine monophosphate (cyclic GMP) phosphodiesterase inhibitor. Haemoglobin lessened this inhibitory action of neutrophils. L-Arginine, the substrate for nitric oxide formation, enhanced inhibition, whereas, L-canavanine, a structural analogue of L-arginine, prevented it. Nitric oxide release by neutrophils antagonized platelet ATP secretion and thromboxane B2 release. Inhibition was mediated by nitric oxide activation of guanylate cyclase with a subsequent rise in cyclic GMP. When neutrophils were stimulated with formyl-met-leu-phe, there was a further increase in platelet cyclic GMP. This was enhanced by superoxide dismutase, but lessened by haemoglobin. Leukotriene B4 stimulation of neutrophils promoted inhibition of platelet aggregation. Leukotriene B4 alone had no direct effect on thrombin-induced aggregation of platelets. Platelets, when incubated with neutrophils and stimulated with calcium ionophore A23187, increased leukotriene B4 production by neutrophils in a platelet concentration dependent manner. Platelets alone were unable to release leukotriene B4. The action of platelets in haemostasis is modified as they come into contact with neutrophils. This may be an important physiological mechanism.
6-Ketoprostaglandin F1 alpha↗
Antibiotic treatment and associated prolonged prothrombin time.
The incidence and type of pathology causing a prolonged prothrombin time and clinical bleeding episodes were assessed in a multicentre study of 1109 patients receiving cefotetan, a N-methyl-thiotetrazole (NMTT), or equivalent antibiotics. There was no significant difference in the incidence of a prolonged prothrombin time (9.9% with cefotetan, 8.0% with comparable antibiotics) of clinical bleeding episodes. However, prothrombin time increases of greater than 12 seconds were significantly (p = 0.002) greater with cefotetan (3.8%) than with comparators (0.8%). In both antibiotic groups increases in prothrombin time were more likely following surgery and in patients who were older, with a high platelet count, low albumin, or higher urea and creatinine concentrations. All antibiotic treatment can be associated with prolonged prothrombin times and new agents should always be assessed in a large multicentre study before the practical, clinical importance of haemostatic defects can be defined.
Adolescent↗
Exchange transfusion of a patient with fulminant Lassa fever.
We report a patient with fulminant Lassa fever who responded dramatically to a 2.5-litre exchange transfusion of whole blood. On admission he was semicomatose with facial oedema and oral haemorrhage; his platelets showed markedly depressed aggregation to ADP; and his plasma inhibited the aggregation responses of normal platelets in vitro. Exchange transfusion resulted in rapid clinical improvement, recovery of platelet function, and disappearance of platelet-inhibitory activity in plasma. The patient died 2 weeks later from an acute encephalopathy. His initial response was sufficiently impressive to suggest that further evaluation of this therapeutic approach is justified in selected patients with overwhelming Lassa virus infection.
Adult↗
Total and free protein S in systemic lupus erythematosus.
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Adult↗