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1.  Determination of APTT factor sensitivity – the misguiding guideline 
The Clinical and Laboratory Standards Institute (CLSI) has produced a guideline detailing how to determine the activated partial thromboplastin time’s (APTT) sensitivity to clotting factor deficiencies, by mixing normal and deficient plasmas. Using the guideline, we determined the factor sensitivity of two APTT reagents.
APTTs were performed using Actin FS and Actin FSL on a Sysmex CS-5100 analyser. The quality of factor-deficient and reference plasmas from three commercial sources was assessed by assaying each of the clotting factors within the plasmas and by performing thrombin generation tests (TGT).
Testing samples from 50 normal healthy subjects gave a two-standard deviation range of 21.8–29.2 s for Actin FS and 23.5–29.3 s for Actin FSL. The upper limits of these ranges were subsequently used to determine APTT factor sensitivity. Assay of factor levels within the deficient plasmas demonstrated that they were specifically deficient in a single factor, with most other factors in the range 50–150 iu/dL (Technoclone factor VII-deficient plasma has 26 iu/dL factor IX). APTTs performed on mixtures of normal and deficient plasmas gave diverse sensitivity to factor deficiencies dependent on the sources of deficient plasma. TGT studies on the deficient plasmas revealed that the potential to generate thrombin was not solely associated with the levels of their component clotting factors.
Determination of APTT factor sensitivity in accordance with the CLSI guideline can give inconsistent and misleading results.
PMCID: PMC4229062  PMID: 23718922
APTT; plasma clotting factors
2.  Self-monitoring of oral anticoagulation: does it work outside trial conditions? 
Journal of Clinical Pathology  2009;62(2):168-171.
Patient self-monitoring (PSM) of oral anticoagulation therapy (OAT) can improve anticoagulant control, but poor uptake and high dropout rates have prompted suggestions that PSM is suitable for only a minority of patients in the UK.
To determine whether PSM could be a viable alternative to regular hospital anticoagulant clinic attendance, if offered from the start of treatment.
318 consecutive patients referred, for the first time, to an anticoagulation clinic were assessed for eligibility using established criteria. Patients electing for PSM attended training and, following successful assessment, performed a capillary blood INR every two weeks or more frequently if directed to do so by the anticoagulation clinic. Primary outcome measures were uptake of PSM and the percentage time in target therapeutic INR range (TIR) compared to patients electing for routine clinic care.
Of 318 patients referred for OAT, 188 were eligible for PSM. 84 (26%) elected to self-monitor, of whom 72 (23%) remained self-monitoring or had completed their course of treatment at the end of the audit. Self-monitoring patients had significantly better anticoagulant control than those receiving routine hospital anticoagulation clinic care (TIR 71% vs 60%, p = 0.003) and significantly less time outside critical limits, ie, INR <1.5 or >5.0 (0.45% vs 2.04%, p = 0.008).
Patients offered PSM from the start of treatment show increased uptake compared to previous UK studies and a level of oral anticoagulation control comparable to that reported in previous clinical trials.
PMCID: PMC2629005  PMID: 19181634
4.  Prothrombin time derived fibrinogen determination on Sysmex CA-6000. 
Journal of Clinical Pathology  1998;51(6):462-466.
AIM: To evaluate PT derived fibrinogen determinations with reference to the Clauss fibrinogen assay using a Sysmex CA-6000 random access coagulation analyser. METHODS: Samples were analysed from normal subjects (n = 20), patients with renal or liver dysfunction (n = 25), critically ill patients (n = 25), patients receiving oral anticoagulant treatment (n = 50), and patients with a haemoglobinopathy (n = 127). Prothrombin times were performed using two thromboplastins: one derived from rabbit brain (Dade: Thromboplastin IS) and the other from recombinant human tissue factor (Dade: Innovin). Fibrinogen was assayed by the Clauss method using a commercial kit (Dade: Fibrinogen). RESULTS: The relation between Clauss fibrinogen and PT derived fibrinogen was found to be dependent on the patient's clinical group and source of the thromboplastin used. When the data from the above sample groups were pooled there was still a significant difference (p < 0.001) between Clauss fibrinogen and PT derived fibrinogen, irrespective of thromboplastin used. CONCLUSIONS: It is unsafe to use the PT derived fibrinogen for patient monitoring owing to non-uniform variability in response to clinical status and reagent employed; however, it may prove to be a useful screening test in a research environment for estimating fibrinogen levels among defined patient groups.
PMCID: PMC500750  PMID: 9771446
5.  The Taipan snake venom time: a new test for lupus anticoagulant. 
Journal of Clinical Pathology  1994;47(6):497-501.
AIMS--To develop a specific test for lupus anticoagulant activity with reduced sensitivity to coagulation factor deficiency that would be suitable for analysis of plasmas from patients receiving oral anticoagulants. METHODS--A coagulation test based on the Taipan snake venom time (TSVT) with a platelet neutralisation procedure (PNP) was developed and compared with dilute Russell's viper venom time (DRVVT). The TSVT was used to test plasmas from patients receiving oral anticoagulant or heparin with mild liver dysfunction and with documented lupus anticoagulant. RESULTS--The optimised conditions for the TSVT were established and a reference range was determined in normal healthy subjects. Results were considered positive for lupus anticoagulant if the ratio was > or = 1.1 and was reduced by > or = 10% or to < 1.1 in the PNP. In 43 samples from patients receiving oral anticoagulants there was no correlation between level of anticoagulation and TSVT, and only seven samples had increased TSVTs. Of these, five corrected on mixing with normal plasma and two gave equivocal results. The patients with mild liver dysfunction all had normal TSVTs. The TSVT in plasmas from patients receiving heparin correlated with the heparin concentrations (as measured by the APTT, r2 = 0.81). Some anticoagulated plasmas showed correction in the PNP and were regarded as false positive. Fourteen of 17 patients known to have lupus anticoagulant (on the basis of DRVVT results) were also positive by the TSVT; two of the remaining three were borderline and one was negative. CONCLUSIONS--The TSVT showed satisfactory intra-assay precision and reasonable sensitivity to lupus anticoagulant, compared with the DRVVT. The TSVT was influenced by the presence of heparin but was not sensitive to the effects of oral anticoagulant. Like other lupus anticoagulant tests, it does not seem to have a 100% detection rate, but this may be due to the presence of lupus anticoagulant subtypes with distinct activities or the requirement of cofactors other than prothrombin or beta 2 glycoprotein-I.
PMCID: PMC494726  PMID: 8063928
7.  Acquired pseudo-pseudo Bernard-Soulier syndrome complicating Gaucher's disease. 
Journal of Clinical Pathology  1994;47(2):162-165.
AIMS--To investigate the abnormality in platelet function in two patients with type I Gaucher's disease causing a chronic bleeding tendency despite normalisation of the platelet count after spleen removal. METHODS--Routine laboratory methods were used to assess baseline coagulation. Platelet aggregometry was used to assess platelet responses to a range of agonists, and abnormalities were further assessed in mixing experiments using washed platelets and patients' plasma. RESULTS--Platelets from both patients with Gaucher's disease failed to agglutinate to ristocetin, despite normal platelet surface glycoprotein (GP) Ib and plasma von Willebrand factor activity. The agglutination of normal washed platelets was abolished by incubation in patient plasma. The inhibitory activity did not lie in the IgG fraction of patient plasma, and was found to be loosely associated with the patient platelet surface. CONCLUSIONS--The inhibition of ristocetin induced platelet agglutination in patients with Gaucher's disease causes a prolonged skin bleeding time. This could be due to the accumulated glucocerebroside in the plasma coating the platelet membrane. It is suggested that the term pseudo-pseudo Bernard-Soulier syndrome would be appropriate, as on initial screening, the abnormality has the features of Bernard-Soulier syndrome, but further investigation shows normal plasma von Willebrand activity and platelet surface GP Ib concentrations. The inhibitory activity is not due to a platelet specific antibody as is the case in pseudo-Bernard Soulier syndrome.
PMCID: PMC501834  PMID: 8132832
9.  Role of beta 2-glycoprotein I and anti-phospholipid antibodies in activation of protein C in vitro. 
Journal of Clinical Pathology  1993;46(10):908-911.
AIMS--To investigate the effect of beta 2-glycoprotein I (beta 2 GPI) on the thrombin/thrombomodulin dependent activation of protein C; and to determine whether beta 2 GPI dependent anticardiolipin antibodies have any effect. METHODS--Protein C was activated by thrombin in the presence of thrombomodulin and phospholipid vesicles in an in vitro system. The effect of adding purified beta 2 GPI to this system was observed. Affinity purified anticardiolipin antibodies and total IgG from patients with anticardiolipin antibodies and the lupus anticoagulant were studied for their effects on protein C activation in the presence and absence of beta 2 GPI. RESULTS--beta 2-Glycoprotein I had no effect on the activity of preformed activated protein C. When the phospholipid vesicles were incubated with beta 2 GPI before the addition of protein C, the activation of protein C was inhibited in a dose dependent manner. With phosphatidylserine:phosphatidylcholine vesicles at a concentration of 1 microM:2 microM, beta 2 GPI began to inhibit the reaction at a concentration of 15 nM, and at 4 microM (the normal plasma concentration) the activation of protein C was reduced to 40%. Anticardiolipin antibodies had no demonstrable effect. CONCLUSIONS--beta 2-Glycoprotein I inhibits protein C activation in an in vitro system. Its physiological role is unknown but it has potential procoagulant as well as anticoagulant properties. An effect of antiphospholipid antibodies on protein C activation, which might explain their association with thrombosis, could not be shown.
PMCID: PMC501616  PMID: 8227406
10.  Lupus anticoagulant activity of some antiphospholipid antibodies against phospholipid bound beta 2 glycoprotein I. 
Journal of Clinical Pathology  1993;46(7):665-667.
AIMS--To determine whether beta 2 glycoprotein I (beta 2GPI) dependent anticardiolipin (aCL) antibodies detected in solid phase enzyme linked immunosorbent assays can also have lupus anticoagulant activity. METHODS--Six anticardiolipin antibodies were affinity purified from patients with these antibodies and lupus anticoagulant activity in their plasma. RESULTS--The anticardiolipin antibodies bound only to anionic phospholipids in the presence of beta 2GPI and bound to beta 2GPI in the absence of phospholipids. Four out of six had lupus anticoagulant activity in the dilute Russell viper venom time test. CONCLUSIONS--The results show that some beta 2GPI dependent aCL are lupus anticoagulants. It is unclear why only some should have lupus anticoagulant activity while others do not.
PMCID: PMC501399  PMID: 8157757
11.  Antibiotic treatment and associated prolonged prothrombin time. 
Journal of Clinical Pathology  1991;44(9):738-741.
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.
PMCID: PMC496719  PMID: 1918399
12.  Exchange transfusion of a patient with fulminant Lassa fever. 
Postgraduate Medical Journal  1991;67(784):193-194.
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.
PMCID: PMC2398981  PMID: 2041853
13.  Routine measurement of fibrinogen concentration. 
BMJ : British Medical Journal  1993;307(6909):882-883.
PMCID: PMC1679028  PMID: 8241845
14.  Changes in haemostasis after stopping the combined contraceptive pill: implications for major surgery. 
BMJ : British Medical Journal  1991;302(6771):269-271.
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.
PMCID: PMC1668968  PMID: 1998792
15.  Prolonged post-operative bleeding due to an acquired von Willebrand syndrome. 
Postgraduate Medical Journal  1987;63(744):901-902.
Acquired von Willebrand syndrome is a rare cause of post-operative bleeding, and should be considered in all such cases, in spite of previous uneventful surgical challenge.
PMCID: PMC2428609  PMID: 3128779
16.  ABC of transfusion. Massive blood transfusion. 
BMJ : British Medical Journal  1990;300(6717):107-109.
PMCID: PMC1662019  PMID: 2105753
17.  Detection of important abnormalities of the differential count using the Coulter STKR blood counter. 
Journal of Clinical Pathology  1989;42(7):772-776.
An assessment of the three part differential provided by the Coulter STKR blood counter showed good correlation when compared with an 800 cell manual differential. Satisfactory flagging of eosinophilia, basophilia, and the presence of immature cells was found. The use of variables derived from the STKR in conjunction with interpretive reporting and user-defined flagging enabled this department to reduce considerably the numbers of films requiring manual differential counts.
PMCID: PMC1142033  PMID: 2760236
19.  Lupus anticoagulant, anticardiolipin antibodies, and human immunodeficiency virus in haemophilia. 
Journal of Clinical Pathology  1989;42(6):629-633.
The prevalence of lupus anticoagulant, using the dilute Russell's viper venom time (DRVT), was determined in 22 patients with mild to severe haemophilia A to see if there was any association with the presence of viral disease. Twelve haemophiliacs (58%) were lupus anticoagulant positive, with a mean patient:control ratio of 1.24 (range 1.15-1.52, normal range 0.84-1.06 which partially corrected with lysed, washed platelets). Nine of these patients were IgG or IgM, or both, anticardiolipin antibody positive and nine were human immunodeficiency virus (HIV) antibody positive, but associations between lupus anticoagulant, anticardiolipin antibodies, and HIV antibody positivity were not significant. Mixing studies of normal plasma and immune depleted factor VIII deficient plasma showed that the DRVT ratio increased when the factor VIII concentration fell below 0.15 IU/ml. There was no significant association between plasma factor VIII concentration and positive DRVT results in haemophiliacs. The addition of porcine factor VIII concentrate produced no correction in eight of the 12 with DRVTs indicative of lupus anticoagulant, suggesting that these were prolonged by antiphospholipid activity. It is concluded that the presence of lupus anticoagulant and anticardiolipin antibodies in haemophiliacs may represent an antiphospholipid response to viraemic challenge, not only to HIV but also to other viral antigens, and that a very low factor VIII concentration may produce a false positive DRVT result.
PMCID: PMC1141992  PMID: 2500459
20.  Familial occurrence of the antiphospholipid syndrome. 
Journal of Clinical Pathology  1989;42(5):495-497.
In a family of four the whole spectrum of antiphospholipid and associated antibodies was present but without evidence of connective tissue disease. All four members had anticardiolipin antibodies; two had a confirmed lupus anticoagulant. Thrombocytopenia was severe in one and associated with a high titre of antiplatelet antibody, while another member was found to have a positive antiglobulin test. One member also had a low protein C concentration while two had decreased concentration of protein S. Factors that predispose to these antibodies may be environmental as well as genetic. In view of the well known association of spontaneous thrombotic events with some of these antibodies the prognosis for the family members must be guarded.
PMCID: PMC1141955  PMID: 2499608
22.  Effects of N-methyl-thiotetrazole cephalosporin on haemostasis in patients with reduced serum vitamin K1 concentrations. 
Journal of Clinical Pathology  1986;39(11):1245-1249.
Two patients with low random serum vitamin K1 concentrations but with normal prothrombin times and normal biological assays of the vitamin K dependent coagulation proteins were treated with an N-methyl-thiotetrazole cephalosporin (cefotetan) postoperatively. Four to six days later both patients developed a prolonged prothrombin time and a noticeable and specific lowering of the clotting activities of factors II, VII, IX and X, though the serum vitamin K1 concentrations remained unchanged. Crossed immunoelectrophoresis of prothrombin showed the appearance of a second peak corresponding to descarboxyprothrombin (PIVKA II). These abnormalities corrected after vitamin K administration. These data are consistent with the hypothesis that cephalosporins with an N-methyl-thiotetrazole side chain inhibit the hepatic utilisation of vitamin K but that this only causes hypoprothrombinaemia when liver reserves of vitamin K are low.
PMCID: PMC1140772  PMID: 3466904
23.  Time trends in prevalence of cervical cytological abnormality in women attending a sexually transmitted diseases clinic and their relationship to trends in sexual activity and specific infections. 
British Journal of Cancer  1986;54(4):669-675.
Trends in prevalence of cytological evidence of cervical intraepithelial neoplasia (CIN) and cervical infection with human papilloma virus (HPV), as indicated by HPV infection and dyskeratosis, were studied in 2,992 new attenders at a sexually transmitted diseases (STD) clinic between 1978 and 1982. Crude prevalence of CIN increased from 1.3% to 4.3% (P less than 0.001) and crude prevalence of HPV infection increased from 2.8% to 9.3% (P less than 0.001). Age adjustment had little effect on these trends. Review, in 1984-85, of samples of smears taken in 1978 and 1982 showed that recognition of koilocytosis by the laboratory had increased substantially over time while a tendency had developed to downgrade nuclear changes in the presence of koilocytosis. Correction of the 1978 and 1982 smear results to the 1984-85 classifications suggested that prevalence of koilocytosis had increased little (from 13.4% to 16.1%, P = 0.20) while there had been a substantial real increase in CIN (0.8% to 2.4%, P less than 0.001). To try to explain the trend in CIN, other characteristics of a sample of attenders at the STD clinic were studied. There were no appreciable trends in prevalence of past STD, number of sexual partners in the last 3 months, method of contraception, genital warts and culture of N. gonorrhoea, T. vaginalis, C. albicans and Chlamydia sp. from the vagina. There was an increase in the proportions in socioeconomic group I, as classified by postcode of residence (17.0% to 26.9%, P = 0.04), referred as contacts rather than with symptoms (24.0% to 41.6%, P less than 0.001), with a clinical diagnosis of genital herpes (5.0% to 8.6%, P = 0.08) and with herpes virus cultured from the cervix (2.1% to 6.3%, P = 0.03). The trend in prevalence of herpes virus infection was not explained by the other trends. It may explain the trend in prevalence of CIN.
PMCID: PMC2001504  PMID: 3022781
25.  Laboratory investigation of platelet function: a review of methodology. 
Journal of Clinical Pathology  1986;39(7):701-712.
Over the past decade interest in and knowledge about the role of platelets in the haemostatic process and in various pathological conditions has continued to grow. The scope of laboratory methodology to investigate platelet function in clinical haemorrhagic and thrombotic disorders in the specialised haemostasis unit has also proportionally widened. After highlighting the physiological processes of the role of platelets in the haemostatic mechanism this brief review comments critically on the available routine techniques used to study platelet function in patients who present primarily with a bleeding tendency.
PMCID: PMC500028  PMID: 2942578

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