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Papers by Marilyn Johnston

Blood, Jan 15, 1992

To determine whether an association exists between the presence of antiphospholipid antibodies an... more To determine whether an association exists between the presence of antiphospholipid antibodies and pregnancy loss, a cross-sectional study was performed. Consecutive women who were referred to three outpatient rheumatology clinics and who had systemic lupus erythematosus (SLE) and a history of one or more pregnancies were evaluated. Patients were interviewed to determine outcomes of all previous pregnancies. Blood was taken on two separate occasions at least 3 months apart to test for the presence of the lupus anticoagulant and anticardiolipin antibodies; on both occasions, five tests of the lupus anticoagulant, with well-defined normal ranges, and an enzyme-linked immunosorbent assay to measure IgG anticardiolipin antibodies were performed. Patients were considered to be positive for the lupus anticoagulant if one or more tests was abnormal on both occasions and positive for anticardiolipin antibodies if the test was abnormal on both occasions. Forty-two women were studied. Statist...

Thrombosis and haemostasis, 2002

Local ISI calibration has been proposed to improve INR accuracy and inter-laboratory precision. W... more Local ISI calibration has been proposed to improve INR accuracy and inter-laboratory precision. We evaluated the affect of local PT calibration on INR precision and accuracy using six levels of frozen plasma calibrants prepared and pooled from normal donors and patients stabilized on sodium warfarin (coumarin) based oral anticoagulant therapy (OAT). Reference prothrombin time (PT) and INR values were assigned to these calibrants in accordance with World Health Organization (WHO) procedure using rTF 95 international reference preparation (IRP) of thromboplastin (human recombinant). These calibrants, along with five similarly characterized individual OAT patient plasmas, were distributed to 127 laboratories in a multi-center study. Calibrant plasmas were evaluated and INR's subsequently determined on the 5 OAT test samples using: 1) the ISI and MNPT in place before the study (the local system), 2) the locally calibrated ISI value (local system with ISI calibration) and 3) a PT-INR...

Blood, Jan 15, 1995

The clinical relevance of antiphospholipid antibodies (APLA) in patients without systemic lupus e... more The clinical relevance of antiphospholipid antibodies (APLA) in patients without systemic lupus erythematosus who have venous thromboembolism (VTE) in unknown. Limited evidence suggests that there is an association between the presence of APLA and both initial and recurrent episodes of VTE and that patients with APLA and VTE are resistant to warfarin therapy. Unselected patients with a first episode of clinically suspected deep vein thrombosis or pulmonary embolism were evaluated with objective tests for VTE and with laboratory tests for APLA; the latter included tests for the lupus anticoagulant (LA) and anticardiolipin antibodies (ACLA). Patients with VTE were treated with anticoagulant therapy and observed during and after discontinuation of anticoagulants for symptomatic recurrence of VTE. There was a strong association between LA and VTE (odds ratio, 9.4; 95% confidence interval [CI], 2.1 to 46.2) and 9 to 65 (14%; 95% CI, 7% to 25%) patients with VTE had LA. There was no assoc...

Blood, 1987

The investigation of many hemostatic defects in the newborn is limited by the lack of normal refe... more The investigation of many hemostatic defects in the newborn is limited by the lack of normal reference values. This study was designed to determine the postnatal development of the human coagulation system in the healthy full-term infant. Consecutive mothers of healthy full-term infants born at St Joseph's Hospital in the city of Hamilton were approached for consent. One hundred eighteen full-term infants (37 to 42 weeks' gestational age) were entered into the study. Demographic information and a 2-mL blood sample were obtained in the postnatal period on days 1, 5, 30, 90, and 180. Between 40 and 79 full-term infants were studied on each day for each of the coagulation tests. Plasma was fractionated and stored at -70 degrees C for batch assaying of the following tests: prothrombin time, activated partial thromboplastin time, thrombin clotting time, and factor assays (biologic): fibrinogen, II, V, VII, VIII, IX, X, XI, XII, and high-molecular weight kininogen. Factor XIII sub...

Transfusion, 2009

BACKGROUND: Plasma transfusion is standard therapy for urgent warfarin reversal in the United Sta... more BACKGROUND: Plasma transfusion is standard therapy for urgent warfarin reversal in the United States. "Four-factor" prothrombin complex concentrate (PCC), available in Europe, has advantages over plasma therapy for warfarin reversal; however, only "three-factor" PCCs (containing relatively low Factor [F]VII) are available in the United States. STUDY DESIGN AND METHODS: The efficacy of a three-factor PCC for urgent warfarin reversal was evaluated in 40 patients presenting with supratherapeutic international normalized ratio (ST-INR > 5.0) with bleeding (n = 29) or at high risk for bleeding (n = 11). In 13 patients, pre-and posttherapy vitamin K-dependent factors were assayed. Historical controls (n = 42) treated with plasma alone were used for rate of ST-INR correction comparison. RESULTS: Treatment with plasma alone (mean, 3.6 units) lowered the INR to less than 3.0 in 63 percent of historical controls. Low-dose (25 U/kg) and high-dose (50 U/kg) PCC alone lowered INR to less than 3.0 in 50 and 43 percent of patients, respectively. Additional transfusion of a small amount of plasma (mean, 2.1 units) increased the rate of achieving an INR of less than 3.0 to 89 and 88 percent for low-and high-dose PCC therapy, respectively. FII, F IX, and FX increments were similar for PCC-treated patients with or without supplemental plasma; FVII was significantly higher in the PCC plus plasma group compared to the PCC-only group (p = 0.001). CONCLUSION: Three-factor PCC does not satisfactorily lower ST-INR due to low FVII content. Infusion of a small amount of plasma increases the likelihood of satisfactory INR lowering. ABBREVIATIONS: PCC(s) = prothrombin complex concentrate(s); ST-INR = supratherapeutic international normalized ratio; TAT = thrombin-antithrombin; TP = thawed plasma. PO = orally; IV = intravenous.

Thrombosis Research, 2002

The issue of whether long-term sodium warfarin therapy results in decreased bone density is contr... more The issue of whether long-term sodium warfarin therapy results in decreased bone density is controversial. To address this question, we randomized rats to once daily subcutaneous injections of either sodium warfarin (0.20 or 0.25 mg/kg) or saline for 28 days and monitored the effects on bone, both biomechanically and by histomorphometric analysis. In addition, the anticoagulant status of both saline- and warfarin-treated rats were monitored throughout the course of the experiment by measuring the prothrombin time, expressed as international normalized ratios (INRs). Rats treated with 0.25 mg/kg warfarin demonstrated INRs of approximately 2.6, while rats treated with either 0.20 mg/kg warfarin or saline were found to have INRs of 1.3 and 1.0, respectively. Biomechanical testing of the right femur of rats treated with 0.25 mg/kg warfarin demonstrated that warfarin caused an 8% reduction in bone strength as measured by maximum tolerated load. A similar reduction in the biomechanical parameters of energy to break (P<.0001) and force at break point (P<.005) was also observed. Histomorphometric analysis of the left femur of warfarin-treated rats revealed a 17% reduction in cancellous bone volume. This was accompanied by a 60% decrease in osteoblast surface, as well as an 80% reduction in osteoid surface. In contrast, warfarin treatment had the opposite effect on osteoclast surface, which was 35% higher following warfarin treatment. Based on these observations, we conclude that clinically relevant doses of warfarin decrease femoral bone strength and cancellous bone volume, both by decreasing the rate of bone formation and increasing the rate of bone resorption.

Thrombosis Research, 2000

Recent studies have found that hormone replacement therapy (HRT) is associated with a two- to fou... more Recent studies have found that hormone replacement therapy (HRT) is associated with a two- to fourfold increased risk of venous thromboembolism, but the thrombogenic mechanism of HRT remains unclear. To investigate whether HRT use induces a procoagulant state, we undertook a prospective cohort study in postmenopausal women to investigate the effects of 3 months of treatment with oral HRT (conjugated equine estrogen 0.625 mg daily and medroxyprogesterone 2.5 mg daily) on markers of thrombin generation (prothrombin fragment 1+2, thrombin-antithrombin complexes), fibrinolytic potential (plasminogen activator inhibitor-1 (PAI-1) activity), and activated protein C (APC) resistance. In addition, we reviewed the literature for studies investigating the effects of HRT on markers of thrombin generation and fibrinolytic potential. In 12 patients who received HRT for a mean of 3.8 months, there was no significant effect of HRT on levels of F1+2, thrombin-antithrombin complexes, or the APC ratio. HRT use had the greatest effect on PAI-1 activity (mean difference = -3.75 UI/mL; 95% confidence interval: - 8.9, 1.1) compared to other coagulation parameters, but this did not attain statistical significance (p = 0.12). In the literature review, the effects of HRT on markers of thrombin generation were inconsistent across studies. There was a consistent pattern of increased fibrinolytic potential with HRT use associated with one marker (PAI-1), but not with another marker (tissue plasminogen activator antigen). We conclude that there is a lack of consistent evidence that the increased risk of venous thromboembolism associated with HRT use is due to a procoagulant state related to increased thrombin generation, decreased fibrinolytic potential, or acquired APC resistance.

New England Journal of Medicine, 1999

New England Journal of Medicine, 1987

To determine the extent to which autologous blood that has been donated in advance ("pre... more To determine the extent to which autologous blood that has been donated in advance ("predeposited") is used in patients undergoing elective surgery and to assess whether predonation decreases the use of homologous blood and the demand on the blood supply, we studied 4996 patients undergoing elective surgery at 18 tertiary care hospitals. Cross-matched blood was ordered for 1287 patients (26 percent), and of these, 590 (46 percent) were considered eligible for predepositing blood. Only 5 percent (32) of the eligible patients actually predeposited blood, indicating that predonation is not widely used. Of those who predeposited, only 13 percent (4 of 32) subsequently received homologous blood, as compared with 36 percent (199 of 558) of those who did not predeposit (P less than 0.01). Among the 199 patients who did not predeposit but required transfusion, we estimate that predonation could have avoided homologous transfusion in as many as 68 percent. If all eligible patients had predeposited autologous blood, they could have supplied as much as 72 percent of their own transfused red cells. The blood for as much as 10 percent of all red-cell transfusions could have been predonated by and transfused into the patients undergoing elective surgery. Greater use of predonation would not only reduce the demand on the blood supply by decreasing the need for homologous transfusion, but would probably also reduce the risk of hepatitis and other transfusion-associated illnesses.

Journal of Thrombosis and Haemostasis, 2004

Gent M for the SOFAST Investigators. Comparison of 1 month with 3 months of anticoagulation for a... more Gent M for the SOFAST Investigators. Comparison of 1 month with 3 months of anticoagulation for a first episode of venous thromboembolism associated with a transient risk factor. J Thromb Haemost 2004; 2: 743-9.

Journal of thrombosis and haemostasis : JTH, 2010

The role of D-dimer in excluding deep vein thrombosis (DVT) in pregnancy is currently uncertain. ... more The role of D-dimer in excluding deep vein thrombosis (DVT) in pregnancy is currently uncertain. We hypothesized that the specificity of sensitive D-dimer assays could be improved without compromising sensitivity by using higher D-dimer cut-off values.

British Journal of Haematology, 1994

Recombinant human erythropoietin (EPO) therapy has been shown to increase red blood cell (RBC) pr... more Recombinant human erythropoietin (EPO) therapy has been shown to increase red blood cell (RBC) production and facilitate autologous blood donation before elective surgery. However, recent reports have suggested that surgery and/or EPO therapy may suppress endogenous erythropoietin secretion in response to anaemia. We therefore analysed the haemoglobi/erythropoietin relationship preoperatively and postoperatively in 71 autologous blood donors subjected to aggressive phlebotomy and six treatments with either EPO (150U/kg. n = 16, 300U/kg, n = 18. or 600U/kg, n = 19) or placebo (n = 18). Using

Archives of Internal Medicine, 2001

D-Dimer, a cross-linked fibrin degradation product, has a high sensitivity in patients with suspe... more D-Dimer, a cross-linked fibrin degradation product, has a high sensitivity in patients with suspected venous thrombosis. Traditional latex D-dimer assays, however, have not been sufficiently sensitive to exclude venous thromboembolism. To determine the clinical utility of a latex D-dimer assay (MDA D-Dimer; Organon Teknika Corporation, Durham, NC) in patients with suspected venous thromboembolism, we conducted a retrospective cohort study involving 595 unselected patients at 4 tertiary care hospitals. Patients had blood drawn for performance of the D-dimer assay and underwent objective testing for venous thromboembolism. Pretest probability was determined using validated models in 571 patients. Patients were classified as venous thromboembolism positive or negative according to results of objective tests and 3-month follow-up. The sensitivities, specificities, predictive values, and negative likelihood ratios of the assay were calculated for all patients and for subgroups of patients with known cancer or a low, moderate, or high pretest probability of venous thromboembolism. The prevalence of venous thromboembolism was 19.0% (113/595). Of those who had a pretest probability assessment, 35.9% had a low pretest probability, 49.7% a moderate pretest probability, and 14.4% a high pretest probability. Using a discriminant value of 0.50 microg fibrinogen equivalent units per milliliter, the assay showed an overall sensitivity of 96%, a negative predictive value of 98%, a specificity of 45%, and a negative likelihood ratio of 0.09. In patients with a low or moderate pretest probability, the sensitivity, negative predictive value, and negative likelihood ratio were 97%, 99%, and 0.07, respectively. The MDA D-Dimer assay is the first latex agglutination assay with sufficient sensitivity to be clinically useful in the exclusion of venous thromboembolism. A negative result has the potential to be used as the sole test to exclude venous thromboembolism in patients with a low or moderate pretest probability of disease.

Archives of Internal Medicine, 2001

The commonly recommended therapeutic range for patients receiving unfractionated heparin of 1.5 t... more The commonly recommended therapeutic range for patients receiving unfractionated heparin of 1.5 to 2.5 times the control activated partial thromboplastin time (aPTT) is not universally applicable. It has been suggested that the therapeutic range for each aPTT reagent should be based on plasma heparin levels. We sought to identify an aPTT ratio that corresponds to therapeutic anti-factor Xa heparin levels for combinations of several reagents and coagulometers that are commonly used.

The Annals of Thoracic Surgery, 1990

Annals of Emergency Medicine, 2003

Background: Because clinical diagnosis is inaccurate, objective testing is usually considered nec... more Background: Because clinical diagnosis is inaccurate, objective testing is usually considered necessary when patients present with suspected deep venous thrombosis (DVT).

The American Journal of Medicine, 1995

In order to determine whether there is a relationship between acquired free protein S deficiency ... more In order to determine whether there is a relationship between acquired free protein S deficiency and increased thrombin generation, we performed a cross-sectional study of patients with systemic lupus erythematosus (SLE). Plasma samples were assayed for free protein S and were correlated to levels of prothrombin fragments (F1 + 2); an elevated level of F1 + 2 was used as a surrogate marker for a prothrombotic state. Assays for anticardiolipin antibodies (ACA) and lupus anticoagulant (LA) were performed on two separate blood samples taken at least 3 months apart in order to detect the presence of antiphospholipid antibodies. Of the 36 subjects, 9 had reduced free protein S levels compared to 0 of 21 controls (P = 0.01) and the mean free protein S level was significantly lower in the SLE population than in controls (0.30 +/- 0.08 U/mL versus 0.43 +/- 0.10 U/mL, P < 0.001). Of the 24 subjects with antiphospholipid antibodies, 9 had reduced free protein S levels, compared to 0 of 12 subjects without antiphospholipid antibodies (P = .01). The mean F1 + 2 level was significantly higher in study subjects with reduced free protein S levels than in those with normal free protein S levels (1.22 +/- 0.50 nmol/L versus 0.78 +/- 0.27 nmol/L, P = 0.05). This study confirms an association between antiphospholipid antibodies and reduced free protein S levels and demonstrates that patients with SLE and acquired free protein S deficiency generate more thrombin than patients with SLE and normal free protein S levels. Further studies are needed to determine whether the thrombotic diathesis associated with the presence of antiphospholipid antibodies is directly caused by the concomitant presence of acquired free protein S deficiency.

The American Journal of Medicine, 1996

... PT Toy, RG Strauss and LC Stehling et al., Predeposited autologous blood for elective surgery... more ... PT Toy, RG Strauss and LC Stehling et al., Predeposited autologous blood for elective surgery, A national multicenter study, N Engl J ... TR Love, WG Hendren, DD O'Keefe and WM Daggett, Transfusion of predonated autologous blood in elective cardiac surgery, Ann Thorac Surg ...

Thrombosis and Haemostasis, 2005

Abnormalities of the Protein C (PC) pathway are found in the majority of patients with thrombophi... more Abnormalities of the Protein C (PC) pathway are found in the majority of patients with thrombophilia. ProC Global is a coagulation assay that reflects the net effect of the PC pathway by measuring the activated partial thromboplastin time (APTT) of patient and control plasma, before and after activation of endogenous PC by Protac, a snake venom. Previous studies have suggested that abnormalities in this test are associated with an increased risk of venous thromboembolism (VTE). A retrospective analysis was performed using frozen plasma samples from 140 patients with confirmed VTE to determine whether an abnormal ProC Global result (in the presence and in the absence of known abnormalities in the PC pathway) is a predictor of initial and recurrent VTE. Patients were tested for the presence of activated protein C resistance, Factor V Leiden, PC and protein S (PS) deficiency, and non-specific inhibitor positivity. Mean ProC Global results were significantly lower in patients with recurrent VTE than in patients without recurrent VTE. The association between abnormal ProC Global result and recurrent VTE showed a strong trend, before (odds ratio, OR 3.6) and after (OR 3.1) exclusion of known thrombophilic abnormalities. Patients with a first episode of idiopathic VTE also expressed significant lower ProC Global results than those with secondary VTE. After exclusion of known PC pathway abnormalities, there was a statistically significant association between abnormal ProC Global and initial idiopathic VTE (p=0.04). These results suggest that ProC Global may serve as a predictor of recurrent VTE and potentially for first episode of idiopathic VTE. ProC Global may help identify patients at increased risk of initial and recurrent VTE.

Blood, Jan 15, 1992

To determine whether an association exists between the presence of antiphospholipid antibodies an... more To determine whether an association exists between the presence of antiphospholipid antibodies and pregnancy loss, a cross-sectional study was performed. Consecutive women who were referred to three outpatient rheumatology clinics and who had systemic lupus erythematosus (SLE) and a history of one or more pregnancies were evaluated. Patients were interviewed to determine outcomes of all previous pregnancies. Blood was taken on two separate occasions at least 3 months apart to test for the presence of the lupus anticoagulant and anticardiolipin antibodies; on both occasions, five tests of the lupus anticoagulant, with well-defined normal ranges, and an enzyme-linked immunosorbent assay to measure IgG anticardiolipin antibodies were performed. Patients were considered to be positive for the lupus anticoagulant if one or more tests was abnormal on both occasions and positive for anticardiolipin antibodies if the test was abnormal on both occasions. Forty-two women were studied. Statist...

Thrombosis and haemostasis, 2002

Local ISI calibration has been proposed to improve INR accuracy and inter-laboratory precision. W... more Local ISI calibration has been proposed to improve INR accuracy and inter-laboratory precision. We evaluated the affect of local PT calibration on INR precision and accuracy using six levels of frozen plasma calibrants prepared and pooled from normal donors and patients stabilized on sodium warfarin (coumarin) based oral anticoagulant therapy (OAT). Reference prothrombin time (PT) and INR values were assigned to these calibrants in accordance with World Health Organization (WHO) procedure using rTF 95 international reference preparation (IRP) of thromboplastin (human recombinant). These calibrants, along with five similarly characterized individual OAT patient plasmas, were distributed to 127 laboratories in a multi-center study. Calibrant plasmas were evaluated and INR's subsequently determined on the 5 OAT test samples using: 1) the ISI and MNPT in place before the study (the local system), 2) the locally calibrated ISI value (local system with ISI calibration) and 3) a PT-INR...

Blood, Jan 15, 1995

The clinical relevance of antiphospholipid antibodies (APLA) in patients without systemic lupus e... more The clinical relevance of antiphospholipid antibodies (APLA) in patients without systemic lupus erythematosus who have venous thromboembolism (VTE) in unknown. Limited evidence suggests that there is an association between the presence of APLA and both initial and recurrent episodes of VTE and that patients with APLA and VTE are resistant to warfarin therapy. Unselected patients with a first episode of clinically suspected deep vein thrombosis or pulmonary embolism were evaluated with objective tests for VTE and with laboratory tests for APLA; the latter included tests for the lupus anticoagulant (LA) and anticardiolipin antibodies (ACLA). Patients with VTE were treated with anticoagulant therapy and observed during and after discontinuation of anticoagulants for symptomatic recurrence of VTE. There was a strong association between LA and VTE (odds ratio, 9.4; 95% confidence interval [CI], 2.1 to 46.2) and 9 to 65 (14%; 95% CI, 7% to 25%) patients with VTE had LA. There was no assoc...

Blood, 1987

The investigation of many hemostatic defects in the newborn is limited by the lack of normal refe... more The investigation of many hemostatic defects in the newborn is limited by the lack of normal reference values. This study was designed to determine the postnatal development of the human coagulation system in the healthy full-term infant. Consecutive mothers of healthy full-term infants born at St Joseph's Hospital in the city of Hamilton were approached for consent. One hundred eighteen full-term infants (37 to 42 weeks' gestational age) were entered into the study. Demographic information and a 2-mL blood sample were obtained in the postnatal period on days 1, 5, 30, 90, and 180. Between 40 and 79 full-term infants were studied on each day for each of the coagulation tests. Plasma was fractionated and stored at -70 degrees C for batch assaying of the following tests: prothrombin time, activated partial thromboplastin time, thrombin clotting time, and factor assays (biologic): fibrinogen, II, V, VII, VIII, IX, X, XI, XII, and high-molecular weight kininogen. Factor XIII sub...

Transfusion, 2009

BACKGROUND: Plasma transfusion is standard therapy for urgent warfarin reversal in the United Sta... more BACKGROUND: Plasma transfusion is standard therapy for urgent warfarin reversal in the United States. "Four-factor" prothrombin complex concentrate (PCC), available in Europe, has advantages over plasma therapy for warfarin reversal; however, only "three-factor" PCCs (containing relatively low Factor [F]VII) are available in the United States. STUDY DESIGN AND METHODS: The efficacy of a three-factor PCC for urgent warfarin reversal was evaluated in 40 patients presenting with supratherapeutic international normalized ratio (ST-INR > 5.0) with bleeding (n = 29) or at high risk for bleeding (n = 11). In 13 patients, pre-and posttherapy vitamin K-dependent factors were assayed. Historical controls (n = 42) treated with plasma alone were used for rate of ST-INR correction comparison. RESULTS: Treatment with plasma alone (mean, 3.6 units) lowered the INR to less than 3.0 in 63 percent of historical controls. Low-dose (25 U/kg) and high-dose (50 U/kg) PCC alone lowered INR to less than 3.0 in 50 and 43 percent of patients, respectively. Additional transfusion of a small amount of plasma (mean, 2.1 units) increased the rate of achieving an INR of less than 3.0 to 89 and 88 percent for low-and high-dose PCC therapy, respectively. FII, F IX, and FX increments were similar for PCC-treated patients with or without supplemental plasma; FVII was significantly higher in the PCC plus plasma group compared to the PCC-only group (p = 0.001). CONCLUSION: Three-factor PCC does not satisfactorily lower ST-INR due to low FVII content. Infusion of a small amount of plasma increases the likelihood of satisfactory INR lowering. ABBREVIATIONS: PCC(s) = prothrombin complex concentrate(s); ST-INR = supratherapeutic international normalized ratio; TAT = thrombin-antithrombin; TP = thawed plasma. PO = orally; IV = intravenous.

Thrombosis Research, 2002

The issue of whether long-term sodium warfarin therapy results in decreased bone density is contr... more The issue of whether long-term sodium warfarin therapy results in decreased bone density is controversial. To address this question, we randomized rats to once daily subcutaneous injections of either sodium warfarin (0.20 or 0.25 mg/kg) or saline for 28 days and monitored the effects on bone, both biomechanically and by histomorphometric analysis. In addition, the anticoagulant status of both saline- and warfarin-treated rats were monitored throughout the course of the experiment by measuring the prothrombin time, expressed as international normalized ratios (INRs). Rats treated with 0.25 mg/kg warfarin demonstrated INRs of approximately 2.6, while rats treated with either 0.20 mg/kg warfarin or saline were found to have INRs of 1.3 and 1.0, respectively. Biomechanical testing of the right femur of rats treated with 0.25 mg/kg warfarin demonstrated that warfarin caused an 8% reduction in bone strength as measured by maximum tolerated load. A similar reduction in the biomechanical parameters of energy to break (P<.0001) and force at break point (P<.005) was also observed. Histomorphometric analysis of the left femur of warfarin-treated rats revealed a 17% reduction in cancellous bone volume. This was accompanied by a 60% decrease in osteoblast surface, as well as an 80% reduction in osteoid surface. In contrast, warfarin treatment had the opposite effect on osteoclast surface, which was 35% higher following warfarin treatment. Based on these observations, we conclude that clinically relevant doses of warfarin decrease femoral bone strength and cancellous bone volume, both by decreasing the rate of bone formation and increasing the rate of bone resorption.

Thrombosis Research, 2000

Recent studies have found that hormone replacement therapy (HRT) is associated with a two- to fou... more Recent studies have found that hormone replacement therapy (HRT) is associated with a two- to fourfold increased risk of venous thromboembolism, but the thrombogenic mechanism of HRT remains unclear. To investigate whether HRT use induces a procoagulant state, we undertook a prospective cohort study in postmenopausal women to investigate the effects of 3 months of treatment with oral HRT (conjugated equine estrogen 0.625 mg daily and medroxyprogesterone 2.5 mg daily) on markers of thrombin generation (prothrombin fragment 1+2, thrombin-antithrombin complexes), fibrinolytic potential (plasminogen activator inhibitor-1 (PAI-1) activity), and activated protein C (APC) resistance. In addition, we reviewed the literature for studies investigating the effects of HRT on markers of thrombin generation and fibrinolytic potential. In 12 patients who received HRT for a mean of 3.8 months, there was no significant effect of HRT on levels of F1+2, thrombin-antithrombin complexes, or the APC ratio. HRT use had the greatest effect on PAI-1 activity (mean difference = -3.75 UI/mL; 95% confidence interval: - 8.9, 1.1) compared to other coagulation parameters, but this did not attain statistical significance (p = 0.12). In the literature review, the effects of HRT on markers of thrombin generation were inconsistent across studies. There was a consistent pattern of increased fibrinolytic potential with HRT use associated with one marker (PAI-1), but not with another marker (tissue plasminogen activator antigen). We conclude that there is a lack of consistent evidence that the increased risk of venous thromboembolism associated with HRT use is due to a procoagulant state related to increased thrombin generation, decreased fibrinolytic potential, or acquired APC resistance.

New England Journal of Medicine, 1999

New England Journal of Medicine, 1987

To determine the extent to which autologous blood that has been donated in advance ("pre... more To determine the extent to which autologous blood that has been donated in advance ("predeposited") is used in patients undergoing elective surgery and to assess whether predonation decreases the use of homologous blood and the demand on the blood supply, we studied 4996 patients undergoing elective surgery at 18 tertiary care hospitals. Cross-matched blood was ordered for 1287 patients (26 percent), and of these, 590 (46 percent) were considered eligible for predepositing blood. Only 5 percent (32) of the eligible patients actually predeposited blood, indicating that predonation is not widely used. Of those who predeposited, only 13 percent (4 of 32) subsequently received homologous blood, as compared with 36 percent (199 of 558) of those who did not predeposit (P less than 0.01). Among the 199 patients who did not predeposit but required transfusion, we estimate that predonation could have avoided homologous transfusion in as many as 68 percent. If all eligible patients had predeposited autologous blood, they could have supplied as much as 72 percent of their own transfused red cells. The blood for as much as 10 percent of all red-cell transfusions could have been predonated by and transfused into the patients undergoing elective surgery. Greater use of predonation would not only reduce the demand on the blood supply by decreasing the need for homologous transfusion, but would probably also reduce the risk of hepatitis and other transfusion-associated illnesses.

Journal of Thrombosis and Haemostasis, 2004

Gent M for the SOFAST Investigators. Comparison of 1 month with 3 months of anticoagulation for a... more Gent M for the SOFAST Investigators. Comparison of 1 month with 3 months of anticoagulation for a first episode of venous thromboembolism associated with a transient risk factor. J Thromb Haemost 2004; 2: 743-9.

Journal of thrombosis and haemostasis : JTH, 2010

The role of D-dimer in excluding deep vein thrombosis (DVT) in pregnancy is currently uncertain. ... more The role of D-dimer in excluding deep vein thrombosis (DVT) in pregnancy is currently uncertain. We hypothesized that the specificity of sensitive D-dimer assays could be improved without compromising sensitivity by using higher D-dimer cut-off values.

British Journal of Haematology, 1994

Recombinant human erythropoietin (EPO) therapy has been shown to increase red blood cell (RBC) pr... more Recombinant human erythropoietin (EPO) therapy has been shown to increase red blood cell (RBC) production and facilitate autologous blood donation before elective surgery. However, recent reports have suggested that surgery and/or EPO therapy may suppress endogenous erythropoietin secretion in response to anaemia. We therefore analysed the haemoglobi/erythropoietin relationship preoperatively and postoperatively in 71 autologous blood donors subjected to aggressive phlebotomy and six treatments with either EPO (150U/kg. n = 16, 300U/kg, n = 18. or 600U/kg, n = 19) or placebo (n = 18). Using

Archives of Internal Medicine, 2001

D-Dimer, a cross-linked fibrin degradation product, has a high sensitivity in patients with suspe... more D-Dimer, a cross-linked fibrin degradation product, has a high sensitivity in patients with suspected venous thrombosis. Traditional latex D-dimer assays, however, have not been sufficiently sensitive to exclude venous thromboembolism. To determine the clinical utility of a latex D-dimer assay (MDA D-Dimer; Organon Teknika Corporation, Durham, NC) in patients with suspected venous thromboembolism, we conducted a retrospective cohort study involving 595 unselected patients at 4 tertiary care hospitals. Patients had blood drawn for performance of the D-dimer assay and underwent objective testing for venous thromboembolism. Pretest probability was determined using validated models in 571 patients. Patients were classified as venous thromboembolism positive or negative according to results of objective tests and 3-month follow-up. The sensitivities, specificities, predictive values, and negative likelihood ratios of the assay were calculated for all patients and for subgroups of patients with known cancer or a low, moderate, or high pretest probability of venous thromboembolism. The prevalence of venous thromboembolism was 19.0% (113/595). Of those who had a pretest probability assessment, 35.9% had a low pretest probability, 49.7% a moderate pretest probability, and 14.4% a high pretest probability. Using a discriminant value of 0.50 microg fibrinogen equivalent units per milliliter, the assay showed an overall sensitivity of 96%, a negative predictive value of 98%, a specificity of 45%, and a negative likelihood ratio of 0.09. In patients with a low or moderate pretest probability, the sensitivity, negative predictive value, and negative likelihood ratio were 97%, 99%, and 0.07, respectively. The MDA D-Dimer assay is the first latex agglutination assay with sufficient sensitivity to be clinically useful in the exclusion of venous thromboembolism. A negative result has the potential to be used as the sole test to exclude venous thromboembolism in patients with a low or moderate pretest probability of disease.

Archives of Internal Medicine, 2001

The commonly recommended therapeutic range for patients receiving unfractionated heparin of 1.5 t... more The commonly recommended therapeutic range for patients receiving unfractionated heparin of 1.5 to 2.5 times the control activated partial thromboplastin time (aPTT) is not universally applicable. It has been suggested that the therapeutic range for each aPTT reagent should be based on plasma heparin levels. We sought to identify an aPTT ratio that corresponds to therapeutic anti-factor Xa heparin levels for combinations of several reagents and coagulometers that are commonly used.

The Annals of Thoracic Surgery, 1990

Annals of Emergency Medicine, 2003

Background: Because clinical diagnosis is inaccurate, objective testing is usually considered nec... more Background: Because clinical diagnosis is inaccurate, objective testing is usually considered necessary when patients present with suspected deep venous thrombosis (DVT).

The American Journal of Medicine, 1995

In order to determine whether there is a relationship between acquired free protein S deficiency ... more In order to determine whether there is a relationship between acquired free protein S deficiency and increased thrombin generation, we performed a cross-sectional study of patients with systemic lupus erythematosus (SLE). Plasma samples were assayed for free protein S and were correlated to levels of prothrombin fragments (F1 + 2); an elevated level of F1 + 2 was used as a surrogate marker for a prothrombotic state. Assays for anticardiolipin antibodies (ACA) and lupus anticoagulant (LA) were performed on two separate blood samples taken at least 3 months apart in order to detect the presence of antiphospholipid antibodies. Of the 36 subjects, 9 had reduced free protein S levels compared to 0 of 21 controls (P = 0.01) and the mean free protein S level was significantly lower in the SLE population than in controls (0.30 +/- 0.08 U/mL versus 0.43 +/- 0.10 U/mL, P < 0.001). Of the 24 subjects with antiphospholipid antibodies, 9 had reduced free protein S levels, compared to 0 of 12 subjects without antiphospholipid antibodies (P = .01). The mean F1 + 2 level was significantly higher in study subjects with reduced free protein S levels than in those with normal free protein S levels (1.22 +/- 0.50 nmol/L versus 0.78 +/- 0.27 nmol/L, P = 0.05). This study confirms an association between antiphospholipid antibodies and reduced free protein S levels and demonstrates that patients with SLE and acquired free protein S deficiency generate more thrombin than patients with SLE and normal free protein S levels. Further studies are needed to determine whether the thrombotic diathesis associated with the presence of antiphospholipid antibodies is directly caused by the concomitant presence of acquired free protein S deficiency.

The American Journal of Medicine, 1996

... PT Toy, RG Strauss and LC Stehling et al., Predeposited autologous blood for elective surgery... more ... PT Toy, RG Strauss and LC Stehling et al., Predeposited autologous blood for elective surgery, A national multicenter study, N Engl J ... TR Love, WG Hendren, DD O'Keefe and WM Daggett, Transfusion of predonated autologous blood in elective cardiac surgery, Ann Thorac Surg ...

Thrombosis and Haemostasis, 2005

Abnormalities of the Protein C (PC) pathway are found in the majority of patients with thrombophi... more Abnormalities of the Protein C (PC) pathway are found in the majority of patients with thrombophilia. ProC Global is a coagulation assay that reflects the net effect of the PC pathway by measuring the activated partial thromboplastin time (APTT) of patient and control plasma, before and after activation of endogenous PC by Protac, a snake venom. Previous studies have suggested that abnormalities in this test are associated with an increased risk of venous thromboembolism (VTE). A retrospective analysis was performed using frozen plasma samples from 140 patients with confirmed VTE to determine whether an abnormal ProC Global result (in the presence and in the absence of known abnormalities in the PC pathway) is a predictor of initial and recurrent VTE. Patients were tested for the presence of activated protein C resistance, Factor V Leiden, PC and protein S (PS) deficiency, and non-specific inhibitor positivity. Mean ProC Global results were significantly lower in patients with recurrent VTE than in patients without recurrent VTE. The association between abnormal ProC Global result and recurrent VTE showed a strong trend, before (odds ratio, OR 3.6) and after (OR 3.1) exclusion of known thrombophilic abnormalities. Patients with a first episode of idiopathic VTE also expressed significant lower ProC Global results than those with secondary VTE. After exclusion of known PC pathway abnormalities, there was a statistically significant association between abnormal ProC Global and initial idiopathic VTE (p=0.04). These results suggest that ProC Global may serve as a predictor of recurrent VTE and potentially for first episode of idiopathic VTE. ProC Global may help identify patients at increased risk of initial and recurrent VTE.