The clinical significance of differences between point-of-care and laboratory INR methods in over-anticoagulated patients

Introduction

Patients receiving warfarin are at increased risk of bleeding when their International Normalised Ratio (INR) > 4.5. Although not standardised above 4.5 the INR is measured in over-anticoagulated patients, consequently we have examined the reliability of INR results ≥ 4.5. We assessed: the relationship between different prothrombin time systems for INRs > 4.5; the relationships between the INR and levels of vitamin K-dependent coagulation factors (VKD-CF) and thrombin generation test (TGT) parameters; and the impact that variation in results would have on warfarin dosing.

Methods

INRs were performed using a CoaguChek XS Plus point-of-care (POC) device (measuring range 0.6-8.0). For POC INRs ≥ 4.5, laboratory INRs were also measured using a recombinant tissue factor (rTF) and a rabbit brain (RBT) thromboplastin.

Results

There was good correlation between POC (INR ≥ 4.5, < 8.0) and Lab INRs (rTF n = 154, rs = 0.87, p < 0.0001; RBT n = 102, rs = 0.76, p < 0.0001); and significant correlations between each of the VKD-CF and the INR, the strongest being with FVII (POC INR rs = -0.53 p < 0.0001; Lab rTF-INR rs = -0.70 p < 0.0001). TGT peak thrombin and ETP also showed good correlations with INR values (R² > 0.71). Using POC and Lab rTF-INR, 109/154 (71%), or POC and Lab RBT-INR 75/102 (74%) results exhibited dosage concordance and/or were within 0.5 INR units. In the remaining patients variation in warfarin dosing was generally slight.

Conclusions

Our data suggest that CoaguChek XS Plus INRs > 4.5 and < 8.0 are comparable to laboratory INRs (both methods) and it is probably unnecessary to perform laboratory INRs for clinical management of patients with INRs > 4.5 including those > 8.0.     

Continuous thrombin infusion leads to a bleeding phenotype in sheep

Background

In addition to a recognized role in the coagulation cascade and haemostasis, thrombin is known to have multiple functions. We aimed to establish an ovine model to study thrombin effects in vivo.

Methods

Thrombin (0.0004-0.42 IU/kg/min) was continuously infused in Austrian Mountain Sheep over five hours in the dose escalation study (n = 5 animals; 15 experiments). In the dose verification study animals received 0.42 IU/kg/min of thrombin vs. saline solution in a cross-over design (n = 3 animals; 7 experiments).

Results

Thrombin at an infusion rate of 0.42 IU/kg/min decreased fibrinogen levels by 75% (p < 0.001) and increased degradation products of the fibrinogen beta-chain as shown in a proteomic analysis. Thrombin decreased platelet counts by 36% (p = 0.006), prolonged thrombin time by 70% (p = 0.012) and activated partial thromboplastin time by 32%. Interestingly, thrombin infusion significantly increased the activity of coagulation factors V and X (p < 0.05) and decreased the activity of the coagulation factors VIII and XIII (p < 0.05). Accordingly, thrombin displayed predominantly anti-coagulant and anti-platelet effects: 1) thrombin prolonged clotting time/clot formation time 7-fold (p = 0.019) and induced a 65% decrease in maximal clot firmness (p < 0.001); 2) thrombin reduced collagen- induced platelet aggregation by 85% and prolonged collagen/adenosine diphosphate closure time 3-fold; and 3) thrombin caused lung haemorrhage but not thromboembolism.

Conclusion

Protracted intravenous infusion of thrombin over a period of five hours offers a new experimental model to study thrombin effects in a large animal species.     

Depressive symptoms, perceived social support, and prothrombotic measures in patients with venous thromboembolism

Introduction

Psychosocial factors have been associated with both a prothrombotic state and an increased risk of venous thromboembolism (VTE). We examined the relation of depressive symptoms and social support with D-dimer, an integrative measure of enhanced coagulation activity, and several additional prothrombotic measures in patients with VTE.

Methods

We studied 173 patients with a previous deep venous thrombosis and/or pulmonary embolism (mean age ± SD 45 ± 14 years, 55% men). Clinical and lab assessments took place ≥ 3 months after VTE and ≥ 1 month after discontinuation of oral anticoagulants. The patients rated depressive symptoms and social support by validated questionnaires.

Results

After adjusting for sociodemographic and medical covariates, interactions emerged between depressive symptoms and social support for D-dimer (p = 0.012) and aPTT (p = 0.002). As opposed to patients with high levels of social support, those with low levels of social support showed a direct association of depressive symptoms with D-dimer (r = 0.19, p = 0.014) and an inverse relationship with aPTT (r = -0.14, p < 0.09). Depressive symptoms were associated with levels of thrombin-antithrombin complex (r = 0.19, p = 0.016). Greater social support was associated with prolonged aPTT (r = 0.16, p = 0.046). There were no significant associations of depressive symptoms and social support with D-dimer, fibrinogen, FII:C, FV:C, FVII:C, FVIII:C, FX:C, INR, and thrombin time.

Conclusions

Depressive symptoms are associated with enhanced coagulation activity in patients with VTE, particularly so in those who perceive low levels of social support. Conversely, high levels of social support may contribute directly and through buffering the effect of depressive symptoms to attenuated clotting activity in VTE patients.     

Plasma factor and inhibitor composition contributes to thrombin generation dynamics in patients with acute or previous cerebrovascular events

Introduction

More than 80% of cerebrovascular events are ischemic and largely thromboembolic by nature. We evaluated whether plasma factor composition and thrombin generation dynamics might be a contributor to the thrombotic phenotype of ischemic cerebrovascular events.

Materials and Methods

We studied (1) 100 patients with acute ischemic stroke (n = 50) or transient ischemic attack (TIA) (n = 50) within the first 24 hours from symptom onset, and (2) 100 individuals 1 to 4 years following ischemic stroke (n = 50) or TIA (n = 50). The tissue factor pathway to thrombin generation was simulated with a mathematical model using plasma levels of clotting factors (F)II, V, VII, VIII, IX, X, antithrombin and free tissue factor pathway inhibitor (TFPI).

Results

The plasma levels of free TFPI, FII, FVIII, and FX were higher, while antithrombin was lower, in the acute patients compared to the previous event group (all p ≤ 0.02). Thrombin generation during acute events was enhanced, with an 11% faster maximum rate, a 15% higher maximum level and a 26% larger total production (all p < 0.01). The increased thrombin generation in acute patients was determined by higher FII and lower antithrombin, while increased free TFPI mediated this effect. When the groups are classified by etiology, all stroke sub-types except cardioembolic have increased TFPI and decreased AT and total thrombin produced.

Conclusion

Augmented thrombin generation in acute stroke/TIA is to some extent determined by altered plasma levels of coagulation factors.     

Activated protein C plasma levels in the fasting and postprandial states among patients with previous unprovoked venous thromboembolism

Introduction

The protein C anticoagulant system is of major importance in the regulation of thrombotic risk, but it is not known whether low plasma levels of activated protein C (APC) in vivo reflect a compromised anticoagulant situation with increased thrombotic risk. Previous studies have reported low, normal or increased plasma APC levels in unselected patients with venous thromboembolism (VTE).

Materials and methods

We performed a population-based, case-control study in patients with a previous history of unprovoked VTE and subjected the participants to a standard fat tolerance test (1 g fat/kg body weight) in order to promote physiological coagulation activation.

Results

VTE patients had higher BMI (28.3 ± 4.4 kg/m² versus 26.3 ± 3.9 kg/m², p = 0.045) and greater waist circumference (98.2 ± 12.5 cm versus 93.4 ± 13.4 cm, p = 0.041) than age and sex matched controls. APC levels were equal in fasting plasma (3.00 ± 0.74 ng/ml and 2.99 ± 0.60 ng/ml, p = 0.66) but higher in postprandial plasma (3.18 ± 0.57 ng/ml and 2.81 ± 0.38 ng/ml, p = 0.008) collected from VTE patients and controls, respectively. Endogenous thrombin generation in plasma following a standardized meal, assessed by thrombin-antithrombin complex (TAT), increased similarly in both groups, whereas APC increased only among the VTE patients during the postprandial state. Plasma levels of APC increased linearly with TAT in the postprandial state (p for linear trend = 0.012).

Conclusions

Our findings fail to support the hypothesis that low APC levels are linked to increased thrombotic risk in unprovoked VTE, and they suggest that plasma APC is a biomarker of thrombin generation.     

An experimental model to study isolated effects of thrombin in vivo

Background

In addition to a recognized role in the coagulation cascade and haemostasis, thrombin is known to have multiple functions. We hypothesized that protracted intravenous infusion of thrombin at steady state will allow to study isolated thrombin effects in vivo.

Methods

Thrombin (0.05-0.9 U/kg/min) was continuously infused in Sprague Dawley rats over five hours (n = 38). The study consisted of three parts: dose escalation (n = 21), dose verification (n = 5) and a parallel group study to investigate whether thrombin effects can be antagonised by concomitant infusion of lepirudin (n = 12).

Results

A thrombin dose of 0.9 U/kg/min decreased platelet counts by 70% compared to the control group (median 230 × 10^9/L vs. 752 × 10^9/L; p = 0.041). In accordance, infusion of 0.9 U/kg/min of thrombin decreased fibrinogen level by 75% compared to the control group (56 mg/dl vs. 220 mg/dl; p = 0.046). Cumulative thrombin doses of ≥ 0.1 U/kg/min caused bleedings but not thromboembolic events. Thrombin at doses ≥ 0.15 U/kg/min was lethal in four cases (30%). Platelet counts and fibrinogen levels after thrombin infusion correlated with bleeding events and mortality. Administration of thrombin at cumulative doses of 0.3-0.9 U/kg/min was associated with a 3 to 6.5 -fold increase in IL-6 levels (139-306 pg/ml vs. 47 pg/ml, p < 0.05). In contrast, thrombin infusion did not alter other markers of inflammation (IL-10, MCP-1 or TNF-alpha). In addition, lepirudin prevented thrombin- induced thrombocytopenia.

Conclusion

Protracted intravenous infusion of thrombin offers a new experimental model, where consumption of fibrinogen and platelets correlates with bleedings and mortality. Infusion of thrombin increased only IL-6 levels but not other cytokines.     

Tissue factor-induced Thrombin Generation in the Fasting and Postprandial State among Elderly Survivors of Myocardial Infarction

Introduction

Tissue factor (TF)-induced thrombin generation (TG) ex vivo has been suggested to be an important method to assess thrombotic risk. No studies have investigated the impact of postprandial lipemia on TF-induced TG. Since myocardial infarction (MI) is associated with elevated postprandial levels of triglycerides, we hypothesized a differential impact of postprandial lipemia on coagulation activation in MI-patients and healthy controls.

Material and Methods

Elderly survivors of acute MI (n = 44) and healthy age-and sex matched controls (n = 43) underwent a fat tolerance test (1 gram per kg body weight) to assess coagulation activation during postprandial lipemia.

Results

The incremental area under the curve (AUCi) for serum triglycerides was higher in MI-patients than in healthy age-and sex matched controls (5.64 ± 0.52 mmol/L?h and 3.94 ± 0.39 mmol/L?h, p = 0.012) during the postprandial phase. Subsequent endogenous activation of coagulation, assessed by FVIIa and thrombin generation (F1 + 2), was similar among groups and not related to levels of triglycerides during the postprandial phase. Healthy individuals had a gradual decline in TF-induced thrombin generation ex vivo, assessed by endogenous thrombin potential (ETP) (AUCi = - 542.4 ± 71.4 nM?min?h, p < 0.001), whereas MI-patients retained their ETP (AUCi = 127.4 ± 89.0 nM?min?h, p = 0.47) in plasma during the postprandial phase (p for group difference = 0.005).

Conclusions

MI-patients had elevated postprandial lipemia and retained their ability for TF-induced TG in plasma ex vivo in the postprandial phase, whereas the capacity gradually decreased in healthy individuals. Further studies are warranted to reveal underlying mechanism(s) and clinical implications.     

The relationship between monoclonal gammopathy of undetermined significance and venous thromboembolic disease

Introduction

Monoclonal gammopathy of undetermined significance (MGUS) has been proposed to be a risk factor for venous thromboembolic disease (VTE). However, no series published to date has been population-based or included a control group with similar comorbidities to people with MGUS.

Patients/Methods

We reviewed the records of all the male veterans in a single VA healthcare system with MGUS between January 1, 1996 and December 31, 2005. We compared the rate of VTE in 166 patients with MGUS with the rate of VTE in an age-matched control group of 465 patients who had tested negative for monoclonal gammopathy by serum protein electrophoresis (SPEP).

Results

The VTE rate in the MGUS group was 2.2 per 100 person-years, which was not significantly different from the rate in the control group, 1.4 per 100 person-years (HR 1.38, CI 0.63-3.01, p = 0.42). Most VTE events occurred within 4 months of the diagnosis of MGUS. In univariate analysis, albumin level (HR 0.21, CI 0.1-0.41, p < 0.001), abnormal leukocyte count (HR 2.53, CI 1.09-5.86, p = 0.03), and history of prior VTE (HR 4.41, CI 1.69-11.54, p = 0.003) were associated with increased risk of VTE. On multivariate analysis, albumin level and history of prior VTE remained significant, but presence of MGUS was still not significantly associated with VTE risk.

Conclusion

Our results suggest that the increased rate of VTE in people with MGUS may be primarily due to other underlying conditions that led to testing for a monoclonal gammopathy rather than to the monoclonal gammopathy itself.     

Increased thrombin generation in women with a history of preeclampsia

Introduction

Women with a history of preeclampsia have an increased risk for cardiovascular disease in later life. We evaluated thrombogenic characteristics of women with a previous history of preeclampsia, expressed in levels of thrombin generation, number of microparticles and related to menstrual cycle and endothelial function, measured as flow-mediated dilatation.

Materials and methods

We included 18 primipara women with a history of preeclampsia and 17 healthy primipara controls, 15 (± 3) months after the index pregnancy. Thrombin generation was measured by tissue factor triggered assay, microparticle levels were measured by flow cytometry and the endothelial function was previously examined by measuring flow-mediated dilatation by high-resolution ultrasound, during follicular and luteal phases of the menstrual cycle.

Results

Women with previous preeclampsia produced more total amount of thrombin as calculated from thrombin max, thrombin potential and max slope levels p < 0.05, 0.01 and 0.01 respectively. Platelet derived microparticle levels were higher in women with a history of preeclampsia, p = 0.07. Flow-mediated dilatation was significantly decreased in comparison to healthy controls (p < 0.0001). There were no variation in levels of thrombin, microparticles and flow-mediated dilatation during the menstrual phases.

Conclusion

Women with a history of preeclampsia show signs of hypercoagulability as indicated by higher thrombin generation and higher platelet derived microparticle levels. Since these women were investigated more than one year after delivery, these results may be indicative of an increased risk of cardiovascular events later in life.     

Prothrombotic changes with acute psychological stress: combined effect of hemoconcentration and genuine coagulation activation

Introduction

Acute psychosocial stress accelerates blood coagulation and elicits hemoconcentration which mechanisms are implicated in acute coronary thrombotic events. We investigated the extent to which the change in prothrombotic measures with acute stress reflects hemoconcentration and genuine activation of coagulation.

Material and methods

Twenty-one middle-aged healthy men underwent three sessions of a combined speech and mental arithmetic task with one-week intervals. Coagulation and plasma volume were assessed at baseline, immediately post-stress, and 45 min post-stress at sessions one and three. Measures of both visits were aggregated to enhance robustness of individual biological stress responses. Changes in eight coagulation measures with and without adjustment for simultaneous plasma volume shift were compared.

Results

From baseline to immediately post-stress, unadjusted levels of fibrinogen (p = 0.028), clotting factor VII activity (FVII:C) (p = 0.001), FVIII:C (p < 0.001), FXII:C (p < 0.001), and von Willebrand factor (VWF) (p = 0.008) all increased. Taking into account hemoconcentration, fibrinogen (p = 0.020) and FVII:C levels (p = 0.001) decreased, activated partial prothrombin time (APPT) shortened (p < 0.001) and prothrombin time (PT) was prolonged (p < 0.001). Between baseline and 45 min post-stress, unadjusted (p = 0.050) and adjusted (p = 0.001) FVIII:C levels increased, adjusted APTT was prolonged (p = 0.017), and adjusted PT was shortened (p = 0.033). D-dimer levels did not significantly change over time.

Conclusions

Adjustment for stress-hemoconcentration altered the course of unadjusted levels of several prothrombotic factors. After adjustment for hemoconcentration, APPT was shortened immediately post-stress, whereas 45 min post-stress, FVIII:C was increased and PT was shortened. Procoagulant changes to acute stress may reflect both hemoconcentration and genuine activation of coagulation molecules and pathways.     

Compliance of antithrombotic management at a tertiary paediatric hospital with international guidelines: a 100-Day audit

Background

Increased levels of factor VIII occur as a response to vascular injury and/or inflammation, and may increase thrombotic risks. In contrast, factor VIII deficiency poses a major hemostatic challenge. The role of factor VIII in modulating hemostasis/thrombosis was investigated in plasma models of hypocoagulable and hypercoagulable state using thrombin generation (TG) assay.

Methods

TG was performed in undiluted/diluted control, FVIII-deficient, FVIII-deficient with low antithrombin (AT activity, ~ 59%), and factor XI-deficient plasma samples using relipidated tissue factor (TF, 2 pM) or dilute Actin as activators. The impact of elevated FVIII on TG was simulated by adding Humate-P (0 to 3 U/ml) to the above plasma samples. In fondaparinux (1 μg/ml) treated plasma with normal or lower AT activity effects of Humate-P vs. 60 nM of recombinant activated factor VII (rFVIIa) were also evaluated.

Results

Humate-P increased TG concentration dependently in undiluted and diluted control plasma with TF activation. With Actin activation, only the concentration dependent shortening of lag time, but no change in peak thrombin was observed. In FVIII-deficient, FVIII-deficient with low AT, and FXI-deficient samples, 3 U/ml of Humate-P increased TG, and decreased its onset with either activator. The reduced peak thrombin due to fondaparinux was reversed with Humate-P (3 U/ml) more than with rFVIIa. Elevated FVIII levels seem to favor intrinsic tenase formation and antagonize fondaparinux because anti-FIXa aptamer added to fondaparinux effectively attenuated TG.

Conclusion

Elevated FVIII supports the propagation of TG via intrinsic tenase formation under low TF condition, factor XI deficiency or in the presence of fondaparinux.     

Endogenous thrombin potential (ETP) in plasma from patients with AMI during antithrombotic treatment

Background

The beneficial impact of warfarin in preventing new events after AMI is well established. Decrease in thrombin generation seems to be the key element in anticoagulant treatment.

Objectives

The aims were to investigate the effect of warfarin and platelet inhibition on thrombin generation, assessed by the endogenous thrombin potential (ETP), and study the relation between coagulation parameters and ETP in patients with AMI.

Patients/Methods

In the present sub-study of the WARIS II trial, patients with AMI were randomly assigned to treatment with aspirin 160 mg/d (n = 57), aspirin 75 mg/d and warfarin (INR 2.0-2.5) (n = 68) or warfarin (INR 2.8-4.2) (n = 61). Fasting blood samples were collected from patients at discharge from hospital and after 6 weeks treatment.

Results

Correlation analyses showed that both ETP and peak thrombin levels were significantly correlated with Factor VII Ag (r = 0.38 and 0.36 respectively, p < 0.01 for both) and with F1+2 (r = 0.26 and 0.23 respectively, p = 0.01 for both) at baseline. Antithrombotic treatment for 6 weeks caused a highly significant inhibition of ETP in patients treated with warfarin (− 28% ± 5%, p < 0.001), and patients treated with aspirin/warfarin (− 24% ± 8%, p = 0.04). Similarly, peak thrombin levels were reduced in patients treated with warfarin (− 18% ± 7%, p = 0.049) and aspirin/warfarin (− 19% ± 5%, p = 0.029), whereas an increase (12% ± 4%, p = 0.029) occurred during aspirin treatment alone. F1+2 levels decreased by 64% and 58% in the warfarin and aspirin/warfarin groups, respectively (p = 0.001 for both).

Conclusions

In patients with AMI, warfarin significantly reduced the endogenous thrombin generation and the potential to generate thrombin in plasma ex vivo, whereas aspirin alone had no effect on thrombin generation in vivo or ex vivo, assessed by ETP.     

Simultaneous thrombin and plasmin generation capacities in normal and abnormal states of coagulation and fibrinolysis in children and adults

Introduction

Thrombin and plasmin are the key enzymes involved in coagulation and fibrinolysis, respectively. Plasma coagulative and fibrinolytic potentials in normal children and adults, and in representative pathologically altered hemostatic states, were evaluated via simultaneous assessment of thrombin and plasmin generation.

Materials and Methods

An assay of Simultaneous Thrombin and Plasmin generation (STP) was developed to measure thrombin and plasmin in plasma using individual fluorometric substrates. Coagulation is initiated with dilute tissue factor, phospholipid, and calcium in platelet-poor plasma; fibrinolysis is accelerated via tissue plasminogen activator (tPA). Abnormal states of hemostasis were investigated.

Results

STP assay reproducibility and normal adult and pediatric values for measured and calculated parameters have been established. Onset of both thrombin and plasmin generation was significantly delayed in children relative to adults (p < 0.001) and the maximum amplitudes of thrombin and plasmin generation were less in children than adults (p < 0.01). No significant differences were measured among pediatric age groups. The most profound impairments in thrombin generation were observed for extrinsic and common pathway factor deficiencies, with the exception of afibrinogenemia. Plasmin generation was severely impaired in deficiencies of fibrinogen and plasminogen as well as with decreased tPA reagent concentration and addition of aminocaproic acid. Plasmin generation was greatly enhanced by alpha-2-antiplasmin deficiency and excess tPA reagent.

Conclusion

Simultaneous assessment of thrombin and plasmin generation in plasma shows promise for affording an enhanced understanding of overall coagulative and fibrinolytic functions in physiological and pathologically altered states of hemostasis in children and adults.     

Platelet activation and endogenous thrombin potential in pre-eclampsia

Introduction

Platelets and the coagulation system may be involved in the pathogenesis of pre-eclampsia. We investigated whether platelet and coagulation activation markers, are elevated in pre-eclampsia.

Materials/methods

Case-control study in which activated platelets, platelet-monocyte/ neutrophil aggregates, platelet microparticles (measured by flow cytometry) and four markers of thrombin generation capacity (endogenous thrombin potential (ETP), peak height, lag time and time to peak) using the Calibrated Automated Thrombogram system were assessed in pregnant women of similar gestational age with (n = 46) and without (n = 46) pre-eclampsia, and in healthy non-pregnant women (n = 42).

Results

The percentage of, CD62P+ platelets (p = 0.013), CD62P+ platelet microparticles (p = 0.029) and platelet-monocyte aggregates (p = 0.019) were significantly higher in women with pre-eclampsia than the pregnant controls. Both groups of pregnant women had significantly higher ETP and peak height (p  < 0.001) than the healthy non pregnant group and the women with pre-eclampsia had significantly higher ETP and peak height (p < 0.001) than the normotensive pregnant controls.

Conclusion

In the most comprehensive laboratory analysis to date, we found evidence of both platelet and coagulation activation in women with pre-eclampsia.     

Venous thromboembolism risk assessment and thromboprophylaxis among hospitalized acute medical patients in China - the RAMP study

Background

In developed countries, hospitalized patients with acute medical conditions are at significant risk for venous thromboembolism (VTE). Little is known about VTE risk and prophylaxis practices in China.

Objective

To determine the VTE risk and the frequency of recommended VTE prophylaxis in hospitalized Chinese patients with acute medical conditions.

Methods

Multi-center, cross-sectional, observational study. Eligibility criteria: ≥ 30 years, admitted to an intensive care unit (ICU)/coronary care unit (CCU) for acute medical illness, had ≥ 1 VTE risk factor/1 disease that predisposes to VTE, and provided informed consent. We used 2004 American College of Chest Physicians (ACCP) evidence-based consensus guidelines to assess VTE risk and the frequency of recommended VTE prophylaxis.

Results

1247 patients from 19 hospitals in 11 cities across 11 provinces of China were enrolled from July 2007 to June 2008. 57.3% patients had > 2 VTE risk factors. Only 20.2% received ACCP-recommended VTE prophylaxis (CCU patients: 22.7%, ICU patients: 16.9%, p = 0.0117).

Limitations

Excluding some patients with VTE risk factors did not allow assessment of the prevalence of VTE risk in the acute hospital-care setting. We could not determine whether the duration of prophylaxis complied with the ACCP recommendations. Our results may not be representative of hospitals in small cities/rural areas in China.

Conclusions

The prevalence of VTE risk factors in Chinese patients was similar to that in developed countries; however, only a small proportion of eligible patients received the recommended VTE prophylaxis. Our findings highlight the need for dissemination and implementation of appropriate VTE prophylaxis guidelines in China.     

Impact of thromboprophylaxis guidelines on clinical outcomes following total hip and total knee replacement

Background

The American College of Chest Physicians (ACCP) guidelines recommends thromboprophylaxis for total hip replacement (THR) and total knee replacement (TKR) patients. We examined alignment with ACCP thromboprophylaxis guidelines among THR/TKR patients, and compared symptomatic venous thromboembolism (VTE), bleeding event rates and risk factors for VTE between patients receiving ACCP-recommended thromboprophylaxis (‘ACCP’) and those who did not (‘non-ACCP’).

Methods

This retrospective observational study used a large US health plan claims database that was linked to an inpatient database containing detailed inpatient medication use and a database containing date-of-death information. Patients who had THR/TKR surgery between April 01, 2004 and December 31, 2006 were included. Comparisons of VTE and bleeding events between ACCP and non-ACCP patients were analyzed using chi-squared tests and multivariate logistic regression.

Results

Of 3,497 linked patients, 1,395 (40%) received ACCP recommended thromboprophylaxis. Of the patients who received non-ACCP recommended prophylaxis the majority (81%) received shorter than the recommended minimum 10 day prophylaxis and 118 (5.6%) of patients received no prophylaxis. Overall, non-ACCP patients were almost twice as likely to experience an incident DVT (3.76% versus 2.01%, p = 0.003) and more than eight times as likely to experience an incident PE (1.19% versus 0.14%, p = 0.001) relative to ACCP patients; there were no statistically significant difference in bleeding rates. Multivariate logistic regression indicated that the odds of a VTE event were significantly lower for ACCP patients (DVT: OR = 0.54; p = 0.006; PE: OR = 0.12; p = 0.004).

Conclusions

This study offers a unique perspective on ‘real-world’ thromboprophylaxis patterns and associated outcomes in THR and TKR patients in the US. It suggests that only 40% of THR/TKR patients receive ACCP-recommended thromboprophylaxis and that not receiving ACCP thromboprophylaxis is an independent risk factor for both DVT and PE.     

Clinical characteristics of patients with factor V Leiden or prothrombin G20210A and a first episode of venous thromboembolism. Findings from the RIETE Registry

Background

The clinical characteristics of patients with factor V Leiden or prothrombin G20210A presenting with a first episode of venous thromboembolism (VTE) have not been thoroughly studied.

Methods

RIETE is an ongoing registry of consecutive patients with acute VTE. We compared the clinical characteristics of patients with factor V Leiden, prothrombin G20210A, or no thrombophilia, at presentation with a first episode of VTE.

Results

As of May 2009, 22428 patients had been enrolled with a first episode of VTE. Of these, 345 had factor V Leiden, 261 had prothrombin G20210A, and 2399 tested negative. Sixty-two percent of the VTE episodes in women with factor V Leiden or prothrombin G20210A (40% in men) were associated with an acquired risk factor. Among women, pregnancy or contraceptive use accounted for 63% and 67% of such risk factors. Patients with factor V Leiden presented with pulmonary embolism (PE) less likely than those with prothrombin G20210A (31% vs. 51%; p < 0.001) or with negative testing (31% vs. 45%, p < 0.001). In addition, PE patients with Factor V Leiden presented with hypoxaemia (Sat O₂ levels < 90%) less likely than those with prothrombin G20210A (4.5% vs. 17%; p < 0.001) or with no thrombophilia (4.5% vs. 20%; p < 0.001).

Conclusions

Most VTE episodes in women (not men) with factor V Leiden or prothrombin G20210A were associated with an acquired risk factor (mostly pregnancy or contraceptive use). Only 4.5% of patients with factor V Leiden presenting with acute PE had hypoxaemia.     

Incidence and characteristics of asymptomatic distal deep vein thrombosis unexpectedly found at admission in an Internal Medicine setting

Introduction

Lower limb deep vein thrombosis (DVT) is the most frequent clinical manifestation of venous thromboembolism (VTE) and can involve proximal or distal veins. Distal DVT (dDVT) is often asymptomatic and data about its incidence and prognosis are scanty, especially in high risk medical inpatients. Therefore, no consensus exists on the value of detecting and treating dDVTs. Aim of study was to evaluate incidence and characteristics of asymptomatic isolated dDVT at admission in an Internal Medicine department.

Materials and methods

Consecutive patients hospitalized for acute medical illnesses, in whom VTE was not the admission diagnosis, underwent Doppler Ultrasonography. For all patients with dDVT standard treatment with therapeutic doses of low molecular weight heparin or fondaparinux was proposed. Follow-up visits were scheduled at 1, 6 and 12 weeks.

Results

One-hundred-fifty-four patients were enrolled. In 4.5% a proximal DVT and in 16.2% an asymptomatic dDVT were found. Female sex, elevated age and renal and electrolyte abnormalities were significantly associated to dDVT (p = 0.014, p = 0.009 and p = 0.046, respectively). Only low degree of mobility (LDM) was independently associated to dDVT [OR 7.97 (95%CI 2.42-26.27), p = 0.001)]. A high mortality rate, not for VTE-related causes, was found, especially in the first week, among dDVT patients.

Conclusions

We found a high incidence of clinically silent dDVTs. LDM evaluation could be useful to select patients at high risk in whom to perform a search for dDVT.     

Partial versus complete factor VIII inhibition in a mouse model of venous thrombosis

Introduction

Partial inhibition of Factor VIII (FVIII) may provide antithrombotic efficacy whilst avoiding excessive anticoagulation.

Materials and Methods

We studied the anticoagulant effects of a partial (TB-402) and a complete (BO2C11) FVIII-inhibiting monoclonal antibody (MAb) on FVIII, aPTT, thrombin generation and fibrin deposition in a flow chamber model. The antithrombotic efficacy of TB-402 and BO2C11 was compared in a mouse model of venous thrombosis.

Results

Both in vitro and ex vivo, the maximally achievable FVIII inhibition by TB-402 was about 25 to 30%. The degree of inhibition reached a plateau in vitro at 0.316 μg/mL and ex vivo after administering 0.1 mg/kg and higher doses. BO2C11 strongly inhibited FVIII:C, up to 91% at 100 μg/mL in vitro, and by 88% ex vivo 1 hour after administering 1 mg/kg to the mice.Whereas BO2C11 also markedly prolonged the aPTT and completely inhibited thrombin generation in vitro and ex vivo, the effect of TB-402 on the aPTT and on thrombin generation was limited. Similarly, in a dynamic flow chamber model, TB-402 and BO2C11 inhibited tissue factor-induced human fibrin deposition by 40% and 76%, respectively.In a mouse model of FeCl₃-induced venous thrombosis, TB-402 (1 mg/kg) inhibited thrombus formation to the same extent as BO2C11 (2 mg/kg) and enoxaparin (5 mg/kg), with a mean (± SD) occlusion time of 51 ± 13 minutes for TB-402, compared to 28 ± 6 minutes for the controls, 51 ± 13 minutes for BO2C11 and 55 ± 11 minutes for enoxaparin.

Conclusions

In this mouse model of venular thrombosis, partial FVIII inhibition yielded similar antithrombotic effects as nearly complete FVIII inhibition. These preclinical data are indicative of a therapeutic potential of partial FVIII inhibition in the management of venous thromboembolism.     

Stent implantation in the superficial femoral artery: Short thrombelastometry-derived coagulation times identify patients with late in-stent restenosis

Introduction

The mechanisms of restenosis, the recurrence of luminal narrowing, are complex and incompletely understood to date. Thrombin, the pivotal enzyme in haemostasis, presumably contributes to the formation of in-stent restenosis (ISR). It was therefore the aim of our study to investigate whether blood coagulation/thrombin generation plays a critical role in the formation of ISR in peripheral artery disease patients with stent angioplasty in the superficial femoral artery.

Materials and Methods

We aimed to examine in this retrospective study whether patients with high-degree restenosis (50-75% lumen diameter reduction, n = 20) are in a hypercoaguable state implying enhanced readiness to generate thrombin compared to patients with low-degree restenosis (< 50% lumen diameter reduction, n = 14).

Results

The coagulation tests calibrated automated thrombography, activated partial thromboplastin time, platelet aggregation, platelet adhesion, fibrinogen, and microparticles’ procoagulant activity did not indicate a different coagulation status in the two patient groups. However, the thrombelastometry-derived value Coagulation Time (CT) was significantly shorter in the high-degree restenosis group (p = 0.012), indicating a hypercoagulable state of patients with high-degree restenosis. Under our experimental conditions, CTs shorter than 444.5 s identify patients at high risk (sensitivity = 95%) for luminal narrowing.

Conclusions

Our study supports the assumption that blood coagulation/thrombin generation plays a critical role in the development of ISR in peripheral arteries after stent insertion and that the thrombelastometry-derived CT might be a suitable value to identify peripheral artery disease patients at risk for development of high-degree in-stent restenosis in the superficial femoral artery.