High Expression of ENO1 and Low Levels of Circulating Anti-ENO1 Autoantibodies in Patients with Myelodysplastic Neoplasms and Acute Myeloid Leukaemia.

In solid tumours, high expression of the glycolytic enzyme, α-enolase (ENO1), predicts for poor patient overall survival (OS), and circulating autoantibodies to ENO1 correlate positively with diagnosis and negatively with advanced disease. Although ENO1 is one of the most highly expressed genes in acute myeloid leukaemia (AML), its potential role as a biomarker in AML or its precursor, myelodysplastic neoplasms (MDS), has not been investigated. A meta-analysis of nine AML online datasets (n = 1419 patients) revealed that high ENO1 expression predicts for poor OS (HR = 1.22, 95% CI: 1.10-1.34, p < 0.001). Additionally, when compared to AML in remission (n = 5), ENO1 protein detected by immunohistochemistry was significantly higher at diagnosis in bone marrow from both AML (n = 5, p < 0.01) and MDS patients (n = 12, p < 0.05), and did not correlate with percentage of blasts (r = 0.28, p = 0.21). AML patients (n = 34) had lower circulating levels of ENO1 autoantibodies detected by ELISA compared to 26 MDS and 18 controls (p = 0.003). However, there was no difference in OS between AML patients with high vs. low levels of anti-ENO1 autoantibodies (p = 0.77). BM immunostaining for ENO1 and patient monitoring of anti-ENO1 autoantibody levels may be useful biomarkers for MDS and AML.

A comparative evaluation of three consecutive artificial intelligence algorithms released by Techcyte for identification of blasts and white blood cells in abnormal peripheral blood films.

INTRODUCTION: Digital pathology artificial intelligence (AI) platforms have the capacity to improve over time through "deep machine learning." We have previously reported on the accuracy of peripheral white blood cell (WBC) differential and blast identification by Techcyte (Techcyte, Inc., Orem, UT, USA), a digital scanner-agnostic web-based system for blood film reporting. The aim of the current study was to compare AI protocols released over time to assess improvement in cell identification. METHODS: WBC differentials were performed using Techcyte's online AI software on the same 124 digitized abnormal peripheral blood films (including 64 acute and 22 chronic leukaemias) in 2019 (AI1), 2020 (AI2), and 2022 (AI3), with no reassignment by a morphologist at any time point. AI results were correlated to the "gold standard" of manual microscopy, and comparison of Lin's concordance coefficients (LCC) and sensitivity and specificity of blast identification were used to determine the superior AI version. RESULTS: AI correlations (r) with manual microscopy for individual cell types ranged from 0.50-0.90 (AI1), 0.66-0.86 (AI2) and 0.71-0.91 (AI3). AI3 concordance with manual microscopy was significantly improved compared to AI1 for identification of neutrophils (LCC AI3 = 0.86 vs. AI1 = 0.77, p = 0.03), total granulocytes (LCC AI3 = 0.92 vs. AI1 = 0.82, p = 0.0008), immature granulocytes (LCC AI3 = 0.67 vs. AI1 = 0.38, p = 0.0014), and promyelocytes (LCC AI3 = 0.53 vs. AI1 = 0.16, p = 0.0008). Sensitivity for blast identification (n = 65 slides) improved from 97% (AI1), to 98% (AI2), to 100% (AI3), while blast specificity decreased from 24% (AI1), to 14% (AI2) to 12% (AI3). CONCLUSION: Techcyte AI has shown significant improvement in cell identification over time and maintains high sensitivity for blast identification in malignant films.

Indian Polyvalent Antivenom Accelerates Recovery From Venom-Induced Consumption Coagulopathy (VICC) in Sri Lankan Russell's Viper (Daboia russelii) Envenoming.

Background: Venom-induced consumption coagulopathy (VICC) is an important clinical consequence of Russell's viper (Daboia russelii) envenoming. There is limited evidence for antivenom effectiveness in resolving VICC. We aimed to compare the recovery of VICC in patients who received and did not receive antivenom following Russell's viper envenoming. Patients and Methods: This was a non-randomized observational study comparing patients with VICC from Russell's viper envenoming given antivenom for systemic envenoming and those not given antivenom. Antivenom administration was decided by the treating physicians. We included 44 patients with confirmed Russell's viper bites with one or more International Normalized Ratio (INR) value ≥ 1.5 (VICC). We compared five patients who did not receive antivenom with 39 patients who did receive antivenom. The primary outcome was the proportion of patients with an INR < 1.5 by 48 h post-bite. Results: The antivenom group had higher peak serum venom concentrations [median (IQR) = 272 (96-1,076) ng/mL versus 21 (8-58) ng/mL] and more severe VICC compared to the no antivenom group. Twenty seven of 39 patients (69%) in the antivenom group had an INR < 1.5 at 48 h post-bite compared to none of the five patients (0%) in the no antivenom group (absolute difference: 69%; 95%CI: 13 to 83%; p = 0.006; Fisher's exact test). The fibrinogen recovered in 32 of 39 patients (82%) in the antivenom group compared to one of five patients (20%) in the no antivenom group (absolute difference 62%; 95% CI: 28 to 95%; p = 0.001; Fisher's exact test). Both INR and fibrinogen were significantly improved between 24 and 48 h post-bite in the antivenom group compared to the no antivenom group. Conclusion: Antivenom accelerated the recovery of VICC in patients with Russell's viper envenoming, compared to no recovery in a smaller group of patients with milder VICC not receiving antivenom. This supports the efficacy of antivenom in patients with VICC.

White blood cell evaluation in haematological malignancies using a web-based digital microscopy platform.

INTRODUCTION: Digital microscopy systems are beginning to replace traditional light microscopes for morphologic analysis of blood films, but these are geographically restricted to individual computers and technically limited by manufacturer's constraints. We explored the use of a scanner-agnostic web-based artificial intelligence (AI) system to assess the accuracy of white blood cell (WBC) differentials and blast identification in haematological malignancies. METHODS: Digitized images of 20 normal and 124 abnormal peripheral blood films were uploaded to the web-based platform (Techcyte©) and WBC differentials performed using the online AI software. Digital images were viewed for accuracy and manual cell reassignment was performed where necessary. Results were correlated to the 'gold standard' of manual microscopy for each WBC class, and sensitivity and specificity of blast identification were calculated. RESULTS: The AI digital differential was very strongly correlated to microscopy (r > .8) for most normal cell types and did not require any manual reassignment. The AI digital differential was less reliable for abnormal blood films (r = .50-.87), but could be greatly improved by manual assessment of digital images for most cell types (r > .95) with the exception of immature granulocytes (r = .62). For blast identification, initial AI digital differentials showed 96% sensitivity and 25% specificity, which was improved to 99% and 84%, respectively, after manual digital review. CONCLUSIONS: The Techcyte platform allowed remote viewing and manual analysis of digitized slides that was comparable to microscopy. The AI software produced adequate WBC differentials for normal films and had high sensitivity for blast identification in malignant films.

A simplified method to calculate telomere length from Southern blot images of terminal restriction fragment lengths.

Southern blotting of DNA terminal restriction fragment lengths is the gold standard for measuring mean telomere length. Analysis of the final image is a crucial step in this process, however, current techniques are cumbersome and prone to error. Here we present a simple and accurate method for analyzing telomere smears. Basic 2D gel imaging software was used to automatically subtract background, generate standard curves and calculate net intensity and MW at each position (i) along the telomere smear. Our method required no statistical software or major data manipulation and correctly classified >80% of 18 samples as having short, medium or long telomeres compared with 33-72% using other methods.

Procoagulant snake venoms have differential effects in animal plasmas: Implications for antivenom testing in animal models.

BACKGROUND: Animal models are used to test toxic effects of snake venoms/toxins and the antivenom required to neutralise them. However, venoms that cause clinically relevant coagulopathy in humans may have differential effects in animals. We aimed to investigate the effect of different procoagulant snake venoms on various animal plasmas. METHODS: Prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen and D-dimer levels were measured in seven animal plasmas (human, rabbit, cat, guinea pig, pig, cow and rat). In vitro clotting times were then used to calculate the effective concentration (EC50) in each plasma for four snake venoms with different procoagulant toxins: Pseudonaja textilis, Daboia russelli, Echis carinatus and Calloselasma rhodostoma. RESULTS: Compared to human, PT and aPTT were similar for rat, rabbit and pig, but double for cat and cow, while guinea pig had similar aPTT but double PT. Fibrinogen and D-dimer levels were similar for all species. Human and rabbit plasmas had the lowest EC50 for P. textilis (0.1 and 0.4 µg/ml), D. russelli (0.4 and 0.1 µg/ml), E. carinatus (0.6 and 0.1 µg/ml) venoms respectively, while cat plasma had the lowest EC50 for C. rhodostoma (11 µg/ml) venom. Cow, rat, pig and guinea pig plasmas were highly resistant to all four venoms with EC50 10-fold that of human. CONCLUSIONS: Different animal plasmas have varying susceptibility to procoagulant venoms, and excepting rabbits, animal models are not appropriate to test procoagulant activity. In vitro assays on human plasma should instead be adopted for this purpose.

Venom Concentrations and Clotting Factor Levels in a Prospective Cohort of Russell's Viper Bites with Coagulopathy.

BACKGROUND: Russell's viper envenoming is a major problem in South Asia and causes venom induced consumption coagulopathy. This study aimed to investigate the kinetics and dynamics of venom and clotting function in Russell's viper envenoming. METHODOLOGY/PRINCIPAL FINDINGS: In a prospective cohort of 146 patients with Russell's viper envenoming, we measured venom concentrations, international normalised ratio [INR], prothrombin time (PT), activated partial thromboplastin time (aPTT), coagulation factors I, II, V, VII, VIII, IX and X, and von Willebrand factor antigen. The median age was 39 y (16-82 y) and 111 were male. The median peak INR was 6.8 (interquartile range [IQR]: 3.7 to >13), associated with low fibrinogen [median,<0.01 g/L; IQR: <0.01-0.9 g/L), low factor V levels [median,<5%; IQR: <5-4%], low factor VIII levels [median,40%; IQR: 12-79%] and low factor X levels [median, 48%; IQR: 29-67%]. There were smaller reductions in factors II, IX and VII over time. All factors recovered over 48 h post-antivenom. The median INR remained >3 at 6 h post-antivenom but had reduced to <2, by 24 h. The aPTT had also returned to close to normal (<50 sec) at 24 h. Factor VII, VIII and IX levels were unusually high pre-antivenom, median peak concentrations of 393%, 307% and 468% respectively. Pre-antivenom venom concentrations and the INR (r = 0.20, p = 0.02) and aPTT (r = 0.19, p = 0.03) were correlated (non-parametric Spearman analysis). CONCLUSIONS: Russell's viper coagulopathy results in prolonged aPTT, INR, low fibrinogen, factors V, VIII and X which recover over 48 h. Severity of clotting abnormalities was associated with venom concentrations.

Detection of venom after antivenom is not associated with persistent coagulopathy in a prospective cohort of Russell's viper (Daboia russelii) envenomings.

BACKGROUND: Venom recurrence or persistence in the circulation after antivenom treatment has been documented many times in viper envenoming. However, it has not been associated with clinical recurrence for many snakes, including Russell's viper (Daboia spp.). We compare the recovery of coagulopathy to the recurrence or persistence of venom in patients with Russell's viper envenoming. METHODOLOGY/PRINCIPAL FINDINGS: The study included patients with Russell's viper (D. russelii) envenoming presenting over a 30 month period who had Russell's viper venom detected by enzyme immunoassay. Demographics, information on the snake bite, and clinical effects were collected for all patients. All patients had serum collected for venom specific enzyme immunoassay and citrate plasma to measure fibrinogen levels and prothrombin time (international normalised ratio; INR). Patients with venom recurrence/persistence were compared to those with no detectable recurrence of venom. There were 55 patients with confirmed Russell's viper envenoming and coagulopathy with low fibrinogen concentrations: 31 with venom recurrence/persistence, and 24 with no venom detected post-antivenom. Fibrinogen concentrations increased and INR decreased after antivenom in both the recurrence and non-recurrence patients. Clinical features, laboratory parameters, antivenom dose and length of hospital were similar for both groups. Pre-antivenom venom concentrations were higher in patients with venom recurrence/persistence with a median venom concentration of 385 ng/mL (16-1521 ng/mL) compared to 128 ng/mL (14-1492 ng/mL; p = 0.008). CONCLUSION: Recurrence of Russell's viper venom was not associated with a recurrence of coagulopathy and length of hospital stay. Further work is required to determine if the detection of venom recurrence is due to the venom specific enzyme immunoassay detecting both venom-antivenom complexes as well as free venom.

Reduction of prothrombin and Factor V levels following supplementation with omega-3 fatty acids is sex dependent: a randomised controlled study.

BACKGROUND: LCn-3PUFA comprised of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) offer cardioprotection involving a decrease in coagulant activity; however, the evidence is equivocal. We have previously demonstrated that the acute (24 h) effects and chronic (4 weeks) effects of LCn-3PUFA supplementation on platelet aggregation in human subjects are sex specific. This study investigated the mechanisms of the sex-dependent effects of LCn-3PUFA with 4 weeks supplementation of EPA-rich vs. DHA-rich oils on procoagulant and platelet activity in healthy subjects. DESIGN: A double-blinded, placebo-controlled randomised trial was conducted in 94 healthy adults: male (n=41) and female (n=53). Platelet coagulation parameters including factors I, II, V, VII, VIII, IX, X, vWF:Ag and endogenous thrombin potential were measured at baseline and 4 weeks postsupplementation with EPA-rich or DHA-rich oil capsules. RESULTS: We have previously reported that platelet aggregation is specifically reduced by supplementation with EPA in males and DHA in females. This sex-specific effect was also observed for decreases in plasma levels of Factor II (-7.9 ± 3.8%, P=.026), Factor V (-6.5 ± 4.5%, P=.022) and vWF:Ag (-7.3 ± 2.1%, P=.034) and was most pronounced in males supplemented with EPA. In contrast, DHA-mediated reduction in platelet aggregation in females was not accompanied by any significant changes in the coagulation parameters tested. CONCLUSION: Significant interactions between sex and specific LCn-3PUFA exist to reduce procoagulant activity differentially in males vs. females and could have profound effects on managing risk of thrombotic disease.

Comparative sensitivity of commercially available aPTT reagents to mulga snake (Pseudechis australis) venom.

This study aimed to determine the relative sensitivity of activated partial thromboplastin time (aPTT) reagents to the anticoagulant effects of phospholipases in mulga snake (Pseudechis australis) venom.Twenty-one haematology laboratories participating in the Royal College of Pathologists of Australasia Quality Assurance Programs were sent human plasma samples spiked with mulga venom (n=25 total results). Results for 17 patients with mulga snake envenoming were available through the Australian Snakebite Project.Only 12 of 25 venom spiked samples returned an abnormally prolonged aPTT. Tests performed with Dade Actin FS (n=7) did not identify any of the spiked samples as abnormal. Although clotting times were significantly prolonged using the lupus anticoagulant sensitive Actin FSL (n=5, p=0.043), only one was reported as abnormal. Only laboratories using TriniCLOT aPTT S (n=6), HemosIL APTT SP (n=2) and Stago PTT-A (n=1) consistently recorded the spiked sample as being above the upper normal reference interval. Abnormally prolonged aPTTs were recorded for four of eight patients whose tests were performed with Actin FSL, five of eight patients with TriniCLOT aPTT HS, and three of three patients using TriniCLOT aPTT S.We conclude that some reagents used for routine aPTT testing are relatively insensitive to the anticoagulant effects of mulga snake venom. Tests performed with these reagents should be interpreted with caution.

Variable plasma levels of Factor V Leiden correlate with circulating platelet microparticles in carriers of Factor V Leiden.

INTRODUCTION: Inheritance of Factor V Leiden (FVL) is associated with an increased but variable level of risk for thrombosis. We have previously shown that FVL heterozygotes have elevated levels of circulating pro-coagulant microparticles (MP). Here we sought to determine if these subjects differed in their plasma levels of FVL and if this was related to MP concentrations and/or history of thrombosis. MATERIALS AND METHODS: The Hemoclot Quanti. V-L clotting assay was used to specifically measure FVL in plasma samples from 44 known carriers (12M, 32F; aged 46±13years). Circulating MP were quantified by flow cytometry using fluorochrome conjugated antibodies to platelet (CD41a), leukocyte (CD45), and endothelial (CD62e) surface markers, and MP prothrombinase activity was determined by ELISA. RESULTS: The cohort was found to have a mean FVL of 49.5±5.6% and this was positively correlated to the total number of circulating CD41a+MP (R=0.31, p=0.03) but not to other MP subsets or to MP prothrombinase activity. The amount of FVL relative to normal factor V (FVL/FV clotting ratio) was calculated and found to be highly variable, ranging from 0.37 to 0.69, and significantly correlated with a history of thrombosis (n=14; p=0.04). CONCLUSIONS: This is the first study to investigate the relationship between varying levels of FVL and plasma derived MP. These results are consistent with our previous findings of an increase in MP levels in carriers of FVL as compared to controls, and suggest a role for FVL/FV ratio in predicting risk of thrombosis in carriers of FVL.

Circulating microparticles are elevated in carriers of factor V Leiden.

INTRODUCTION: Microparticles (MP) are small membrane bound cellular particles that play an important role in thrombosis. This study was carried out to evaluate if increased numbers or procoagulant potential of circulating MP contribute to the heterogeneity in occurrence of thrombosis in heterozygotes carrying Factor V Leiden (FVL) mutation. METHODS: Levels of circulating platelet (CD41a), endothelial (CD62e) as well as leukocyte (CD45) derived MP from 45 FVL heterozygous individuals were enumerated by flow cytometry and compared with normal controls. Functional studies included enzyme linked immunoassay based prothrombinase activity (ELISA) and modified dilute Russell Viper venom test (DRVVT). RESULTS: Circulating MP were significantly higher in the FVL cohort compared to the controls (median=2100 vs. 1508 MP/microl, respectively p=0.0021).All subsets of MP (platelet, endothelial and leukocyte) were significantly elevated in the FVL group, the most striking disparity seen in the number of CD45 positive leukocyte MP. Despite the differences in the number of MP between the controls and FVL cohorts, there was no significant difference in the prothrombinase activity recorded by the ELISA (2.0 vs 2.4 PS equivalents; p=0.7374) or clotting time assessed by the DRVVT (47 vs 46 sec, p=0.8118). When the FVL cohort was considered alone there was no significant difference in MP parameters between FVL subjects with or without a history of thrombosis. CONCLUSIONS: This is the first study on circulating MP levels in subjects who are heterozygote for factor V Leiden. We report that circulating platelet and leukocyte MP are elevated in carriers of this mutation and may be important contributors to risk of thrombosis.

Quantification of hTERT splice variants in melanoma by SYBR green real-time polymerase chain reaction indicates a negative regulatory role for the beta deletion variant.

Telomerase activity is primarily determined by transcriptional regulation of the catalytic subunit, human telomerase reverse transcriptase (hTERT). Several mRNA splice variants for hTERT have been identified, but it is not clear if telomerase activity is determined by the absolute or relative levels of full-length (functional) and variant hTERT transcripts. We have developed an SYBR green-based reverse transcription-quantitative polymerase chain reaction assay for the enumeration of the four common hTERT mRNA variants and correlated these with telomerase activity and telomere length in 24 human melanoma cell lines. All except five of the lines expressed four hTERT transcripts, with an overall significant level of co-occurrence between absolute mRNA levels of full-length alpha+/beta+ hTERT and the three splice variants alpha-/beta+, alpha+/beta-, and alpha-/beta-. On average, alpha+/beta+ made up the majority (48.1%) of transcripts, followed by alpha+/beta- (44.6%), alpha-/beta- (4.4%), and alpha-/beta+ (2.9%). Telomerase activity ranged from 1 to 247 relative telomerase activity and correlated most strongly with the absolute amount of alpha+/beta+ (R = 0.791, P = .000004) and the relative amount of alpha+/beta- (R = -0.465, P = .022). This study shows that telomerase activity in melanoma cells is best determined by the absolute expression of full-length hTERT mRNA and indicates a role for the hTERT beta deletion variant in the negative regulation of enzyme activity.

Polymorphisms of the tissue factor pathway inhibitor gene are associated with venous thromboembolism in the antiphospholipid syndrome and carriers of factor V Leiden.

Polymorphisms within the tissue factor pathway inhibitor (TFPI) gene may determine TFPI expression and increase the risk of venous thromboembolism (VTE) in predisposed individuals. We tested this hypothesis by comparing TFPI activity and the frequency of common TFPI polymorphisms, -33T->C, -399C->T and -287T->C, in patients with antiphospholipid syndrome (APS) (n = 24) or factor V Leiden (n = 44) who had a history of VTE (n = 26), compared with those without VTE (n = 42) and also with normal control individuals (n = 56). TFPI activity was measured using a modified amidolytic assay and genotypes were determined by polymerase chain reaction and restriction fragment length polymorphism. We found that only APS patients with a history of venous thrombosis had TFPI activity levels significantly different from control individuals (1.77 +/- 0.60 vs 0.77 +/- 0.19 U/ml; P = 0.0001), and this was associated with inheritance of the TFPI -33C allele (1.70 +/- 0.72 U/ml for TC/CC genotypes vs 0.97 +/- 0.56 U/ml for TT; P = 0.01). Multivariate analysis of APS and factor V Leiden patients revealed that the greatest independent contributor to VTE was TFPI activity (adjusted odds ratio = 16.84; 95% confidence interval = 2.47-114.36, P = 0.004), while inheritance of either the TFPI -33C or -399T alleles each increased the odds of VTE by nearly 13 times (95% confidence interval = 2.39-69.91, P = 0.003; and 95% confidence interval = 2.25-71.23, P = 0.004, respectively). These results indicate that the TFPI -33T->C and -399C->T polymorphisms are significantly associated with venous thrombosis in the presence of other risk factors, especially APS, and may be clinically relevant in patients who are prone to hypercoagulability.

Identification of a novel single nucleotide polymorphism in the first tandem repeat sequence of the thymidylate synthase 2R allele.

Thymidylate synthase (TS) activity is an important determinant of response to chemotherapy with fluoropyrimidine prodrugs and its expression is largely determined by the number of functional upstream stimulatory factor (USF) E-box consensus elements present in the 5'regulatory region of the TYMS gene. Two known polymorphisms in this area, a variable number of tandem repeat (VNTR) consisting of 2 or 3 repeats (2R/3R) of a 28-bp sequence and a further G > C single nucleotide substitution within the second repeat of the 3R, result in genotypes with between 2 and 4 functional repeats in most humans. Here, we identify a further G > C SNP in the first repeat of the TYMS 2R allele, which effectively abolishes the only functional USF protein binding site in this promoter. The frequency of the new allele was found to be 4.2% (95% CI = 1.4-9.6%), accounting for 8.8% (95% CI = 2.9-19.3%) of all 2R alleles in our patient cohort. Thus, we observed that the lowest number of inherited functional binding sites is 1 instead of 2 as previously thought, and could potentially be 0 in a homozygous individual. This would severely decrease TS expression and may have implications for predicting efficacy and toxicity of therapy with commonly used fluorouracil-based therapy regimes.

Genetic variations in benzene metabolism and susceptibility to multiple myeloma.

We have previously shown that deficiency in the biotransformation enzyme glutathione-S-transferase theta (GSTT1) is a risk factor for multiple myeloma (MM). The present case-control study of 102 MM patients and 205 controls revealed a significant trend in increasing risk of MM with inheritance of multiple putative 'high risk' genetic variants in related pathways of benzene detoxification. Individuals who carried polymorphisms for GSTT1 null and/or high activity microsomal epoxide hydrolase (mEH 113YY+139HR or 113YY+139RR or 113YH+139RR) and/or low activity NAD(P)H:quinone oxidoreductase 1 (NQO1 187PS/SS) were 1.65, 2.49 and 13 times more likely to have MM (P(trend)=0.001).

Endogenous thrombin potential for predicting risk of venous thromboembolism in carriers of factor V Leiden.

Measurement of endogenous thrombin potential (ETP) detects hypercoagulability and can be used to identify activated protein C resistance due to factor V Leiden (FVL). However, not all carriers of FVL suffer thrombosis and therefore we sought to determine if the test for ETP could be modified in such a way as to enable detection of FVL patients who were at increased risk of venous thromboembolism. Protac, an activator of both protein C and factor V, was incorporated into the traditional thrombin generation reaction and ratios (reaction with Protac:reaction without Protac) were calculated. Plasma samples from 42 FVL heterozygotes (12 with a history of thrombosis and 30 with no prior thrombosis) and 38 controls (non-FVL with no history of thrombosis) were analysed. The mean ETP ratio was significantly higher in FVL heterozygotes (0.90 +/- 0.06) compared to normal controls (0.41 +/- 0.10; p = 0.00004). Multivariate analysis indicated that the average ETP ratio was significantly and inversely correlated with factor V levels in FVL heterozygotes (p = 0.002) but not controls. Within the FVL group, patients with a history of thrombosis had higher ETP ratios (0.92 +/- 0.06) compared to those without (0.89 +/- 0.05), however, this did not reach statistical significance (p = 0.09). Further investigation into the use of ETP for detecting risk of thrombosis in people who are genetically predisposed is warranted. The recent introduction of diagnostic ETP measurements in the form of the calibrated automated thrombin generation from Thrombinoscope and the TechnoThrombin from Baxter should facilitate such studies.

Xenobiotic gene polymorphisms and susceptibility to multiple myeloma.

Genetic variations in the activity of xenobiotic enzymes may predict susceptibility to multiple myeloma (MM). In a case-control study, 90 Australian Caucasians with MM had significantly higher incidences of GST T1 null, PON1 BB and NAT2 slow acetylation genotypes, but no difference in polymorphism frequencies for GST M1, NAT1, and CYP1A1 when compared to 205 controls.