The incidence and risk factors of recurrent venous thromboembolism during pregnancy

Introduction

Recurrent venous thromboembolism (VTE) during pregnancy is a challenging topic with relatively few publications. The aim of this study was to identify the incidence and the risk factors of recurrent antepartum VTE in women with a history of at least one previous VTE episode.

Materials and Methods

This observational cohort study involved 270 pregnant women (369 pregnancies) with at least one previous episode of VTE. The risk factors of recurrent antepartum VTE were identified by using group A (women without recurrent venous thromboembolism VTE) as a control group for group B (women with recurrent VTE despite LMWH (low molecular weight heparin) prophylaxis) and C (women with VTE recurrence in early pregnancy before the planned initiation of LMWH prophylaxis).

Results and Conclusions

The incidence of recurrent VTE was 7.6% (n = 28).Twelve recurrent VTEs in ten women (3.3%) developed during early pregnancy before initiation of LMWH and sixteen recurrent VTEs (4.3%) developed in 15 women despite LMWH prophylaxis.In women with recurrent antepartum VTE, the incidence of a history of two or more previous VTEs (group A vs. B: 5.7% vs. 40.0%, p < 0.001; group A vs. C: 5.7% vs. 30.0%, p = 0.022), previous VTE in connection with antiphospholipid antibody syndrome (group A vs. B: 2.6% vs. 20.0%, p = 0.012) and a history of VTE related to hormonal risk factors (group A vs. B: 60.4% vs. 93.3%, p = 0.011) was significantly higher compared to those with successful LMWH-prophylaxis. The percentage of the women with long-term anticoagulation was also significantly higher among the women with recurrent antepartum VTE (group A vs. B: 7.6% vs. 46.7%, p < 0.001) compared to those with successful LMWH-prophylaxis. The risk of antepartum recurrent VTE is considerable in women with a history of two or more previous VTEs, antiphospholipid antibody syndrome or long-term anticoagulation. The antepartum prophylaxis with prophylactic dose of LMWH or even with intermediate dose of LMWH might not be sufficient in this high-risk population.     

The effect of major surgery,low doses of heparin and thromboembolism on plasma antithrombin. Comparison of immediate thrombin inhibiting capacity and the antithrombin III content

Antithrombin in plasma was studied by two different methods in a group of patients undergoing major surgery and taking part in a double-blind investigation on low-dose heparin treatment. The AT III results (Mancini method) were only slightly affected by thromboembolism which is in agreement with earlier findings. The immediate thrombin inhibiting capacity using a chromogenic tripeptide as substrate was, however, found to increase in connection with thromboembolism. The fact that the low doses of heparin given to the patients have no effect on any of the antithrombin methods used and that clinical effect was achieved, suggests that the prophylactic effect may depend on inhibition of earlier stages in the development of thrombosis.     

缺血性脑卒中早期复发的临床特点和危险因素预测

目的：探讨缺血性脑卒中患者早期复发的临床特点和危险因素。方法：对594例缺血性脑卒中在30天内复发的22例患者进行了临床分析和病例－对照研究。结果：早期复发率为3．7％（22／594），其中脑血栓复发率为3．3％（18／552），脑栓塞复发率为9．5％（4／42）。72．73％（16／22）复发在原患侧，多为同类型脑卒中复发（86．36％，19／22）。经统计学分析发现高血压、TIA史与复发有显著关系（OR＝4．9，OR＝7．1），而缺血性心脏病、糖尿病、入院时高血糖、房颤、高血脂、吸烟、颈部血管斑块与复发无显著关系。结论：缺血性脑卒中早期复发多为同类型脑卒中、同部位的复发，高血压、TIA史可能为脑卒中早期复发的重要危险因素。     

Incidence and risk factors of symptomatic venous thromboembolism related to implanted ports in cancer patients

Introduction

The true incidence of symptomatic implanted port related venous thromboembolism (VTE) in cancer patients is unclear and there is very limited data on its associated risk factors.

Materials and methods

We performed a retrospective cohort study of consecutive cancer outpatients who received an ultrasound guided implanted port insertion for the administration of chemotherapy. The primary outcome measure was symptomatic VTE. Univariable and multivariable logistic regression analyses were used to identify risk factors for symptomatic VTE.

Results

A total of 400 cancer patients with a newly inserted implanted port for deliverance of chemotherapy were included in the study. Median age was 58 years (range of 21 to 85 years) and 120 (30%) were males. Patients were followed for a median of 12 months and none received thrombophrophylaxis. Of the 400 patients included in the analysis, 34 patients (8.5%; 95% CI: 6.0 to 11.7%) had symptomatic VTE (16 DVTs, 16 PEs, and 2 with both). In the univariate analyses, metastatic disease, male gender and right sided implanted port insertion were significantly associated with the risk of VTE. In the multiple-variable analysis, male gender (OR 2.17, p = 0.04) and presence of metastases (OR 8.22, p < 0.01) were the two significant independent predictors of implanted port related VTE.

Conclusion

Symptomatic VTE is a frequent complication in cancer patients with implanted port receiving chemotherapy. Gender and presence of metastatic disease are independent risk factors for symptomatic VTE. Future trials assessing the role of thromboprophylaxis among these higher risk patients are needed.     

Symptomatic venous thromboembolism in acute leukemia. Incidence, risk factors, and impact on prognosis

The association between malignant disorders and occurrence of venous thromboembolism is well established. Patients with cancer and venous thromboembolism have adverse prognosis. No systematic study on the incidence and prognostic impact of venous thromboembolism in acute leukemia has been performed as yet. We retrospectively evaluated the incidence of symptomatic venous thromboembolism before chemotherapy in 719 patients (371 males and 348 females, median age of 57.4 years), diagnosed with acute leukemia [534 with acute myelogenous leukemia, 185 with acute lymphoblastic leukemia]. Furthermore, the relationship of venous thromboembolism to clinical and laboratory parameters and its impact on prognosis was assessed. Fifteen patients (2.09%) had venous thromboembolism (objectively confirmed in 13 patients) in close temporal relationship to the onset of acute leukemia. The incidence of venous thromboembolism was the same in acute myelogenous and lymphoblastic leukemia. In five patients, pulmonary embolism was documented. Venous thromboembolism occurred in all subtypes of acute leukemia, but was most common in promyelocytic leukemia. All but one patient were treated with anticoagulants. No patient died from treatment-related bleedings or venous thromboembolism. Overall, survival, disease-free survival, and remission duration did not differ between the patient groups with and without venous thromboembolism. In contrast to solid tumors, venous thromboembolism before or at diagnosis of acute leukemia is not associated with poor prognosis.     

Thrombophilic abnormalities and recurrence of venous thromboembolism in patients treated with standardized anticoagulant treatment

INTRODUCTION: Whether patients with hereditary or acquired thrombophilia have an increased risk for recurrence of venous thromboembolism (deep vein thrombosis and/or pulmonary embolism) is still controversial. The aim of this study was to evaluate the incidence of recurrence of venous thromboembolism in patients with and without thrombophilic abnormalities treated with standardized anticoagulant treatment. MATERIAL AND METHODS: Database was from a prospective multicenter randomized study aimed at evaluating the long-term clinical benefit of extending to 1 year the 3-month oral anticoagulant treatment after a first episode of idiopathic proximal deep vein thrombosis. The screening for thrombophilia included antithrombin, protein C, protein S deficiencies, resistance to activated protein C and/or factor V R506Q mutation, the mutation 20210GA of the prothrombin gene, hyperhomocysteinemia and antiphospholipid antibodies. The diagnosis of venous thromboembolism recurrence was done by objective tests and adjudicated by a panel unaware of the results of the thrombophilia screening. RESULTS: A screening for thrombophilic abnormalities was performed in 195 patients. Twenty of 57 (35.1%) thrombophilic patients experienced a recurrence of venous thromboembolism as compared with 29 of 138 (21.0%) patients without thrombophilia (HR=1.78, 95% CI 1.002-3.140, p=0.046). The difference in VTE recurrence between patients with and without thrombophilia was accounted for by those who received 3 months of oral anticoagulation (HR=3.21, 95% CI 1.349-7.616, p=0.008). No difference between thrombophilic and non-thrombophilic patients was observed in the time interval from the index episode to recurrent venous thromboembolism (29.1+/-23.9 and 30.6+/-19.8 months, respectively). CONCLUSIONS: Thrombophilic abnormalities are associated with an increased risk of venous thromboembolism recurrence. The role of thrombophilia in the long-term management of venous thromboembolism should be addressed in prospective management studies.     

Modification of an amidolytic heparin assay to express protein-bound heparin and to correct for the effect of antithrombin III concentration

A modification of an anti-Xa assay for plasma heparin has been devised using a low molecular weight dextran sulfate that competitively binds protein heparin neutralizers and displaces masked heparin. The addition of 0.12 mg dextran sulfate per ml of plasma permits heparin, neutralized by the products of platelet aggregation, to recover full functional activity against Xa. The assay will permit a more accurate assessment of both exogenous plasma heparin and endogenous heparin-like activity in blood samples collected with varying techniques. A further modification is proposed employing polybrene to neutralize the plasma heparin-like material providing a concurrent control for each sample that increases accuracy by eliminating the effect of varying AT-III levels which have anti-Xa activity.     

Increased risk of recurrent venous thromboembolism during hormone replacement therapy--results of the randomized, double-blind, placebo-controlled estrogen in venous thromboembolism trial (EVTET)

Recent observational studies suggest a 2-4 fold increased risk of venous thromboembolism (VTE) in women taking hormone replacement therapy (HRT). The present study was started before publication of these studies, and the aim was to determine if HRT alters the risk of VTE in high risk women. The study was a randomized. double-blind, and placebo-controlled clinical trial with a double-triangular sequential design. Females with previously verified VTE were randomized to 2 mg estradiol plus 1 mg norethisterone acetate, 1 tablet daily (n = 71) or placebo (n = 69). The primary outcome was recurrent deep venous thrombosis (DVT) or pulmonary embolism (PE). Between 1996 and 1998 a total of 140 women were included. The study was terminated prematurely based on the results of circumstantial evidence emerging during the trial. Eight women in the HRT group and one woman in the placebo group developed VTE. The incidence of VTE was 10.7% in the HRT group and 2.3% in the placebo group. In the HRT group, all events happened within 261 days after inclusion. The sequential design did not stop the study, but strongly indicated a difference between the two groups. Our data strongly suggests that women who have previously suffered a VTE have an increased risk of recurrence on HRT. This treatment should therefore be avoided in this patient group if possible. The results also support those of recent epidemiological studies, which also indicate increased risk of VTE in non-selected female populations during HRT.     

Prognostic factors for recurrence of venous thromboembolism (VTE) or bleeding during long-term secondary prevention of VTE with ximelagatran

The oral direct thrombin inhibitor ximelagatran (24 mg twice daily) has been shown to significantly reduce the incidence of recurrent venous thromboembolism (VTE) vs. placebo over 18 months, with no significant influence on bleeding (THRIVE III). The influence of potential prognostic factors on the risk of recurrent VTE or major and/or minor bleeding and their impact on ximelagatran treatment was evaluated in the THRIVE III study population. The effect of sex, age, body weight, renal function, malignancy, type of initial VTE event, and history of previous VTE events was investigated in the intention-to-treat population using Cox proportionate hazard modelling. Ximelagatran was administered to 612 patients and placebo to 611 patients. Within the placebo group, risk of recurrent VTE was higher among men than women (hazard ratio [HR]: 2.50,95% confidence interval [CI] 1.49,4.17), and in patients with one or more than one previous VTE event (HR: 1.73,95% CI 1.00, 2.99). There was a higher risk of bleeding among women than men in both the ximelagatran (HR: 1.49, 95% CI 1.06, 2.09) and placebo (HR: 1.48, 95% CI 1.01, 2.15) groups, and in placebo-treated patients with an initial pulmonary embolism (HR: 1.53, 95% CI 1.06,2.23) compared to those with initial deep vein thrombosis. There were no significant interactions between treatment effect and any of the potential prognostic factors. In conclusion, the superior efficacy of ximelagatran vs. placebo was maintained in all subgroups. Long-term use of oral ximelagatran, without coagulation monitoring or dose adjustment, should be feasible and well tolerated in a wide cross-section of patients for the secondary prevention of VTE.     

Lithium and risk of cardiovascular disease,dementia and venous thromboembolism

Objective

To determine if long-term lithium treatment is associated with protective effects or increased risk of vascular, neurological, and renal disorders.

Methods

Using nationwide registers, we included all citizens of Finland with dispensations of lithium for three or more consecutive years between 1995 and 2016. We identified 9698 cases and matched 96,507 controls without lithium treatment. Studied outcomes were vascular, neurological, renal disorders, and suicide. Analyses were performed applying Cox proportional hazards modeling in full cohort and in further subcohort analysis of individuals with a comparable diagnosis of mood or psychotic disorder.

Results

Lithium users had a significantly higher overall disease burden compared to matched population controls, including a higher risk of cardiovascular and cerebrovascular disorders and dementia. However, compared to individuals with a diagnosis of mood or psychotic disorders without lithium treatment, we observed a lower risk of cardiovascular and cerebrovascular disorders (HR = 0.80, 99% CI = 0.73–0.89), and no significant difference for dementia (HR = 1.15, 99% CI = 0.99-1.33), in lithium users. Pulmonary embolism was more common in the lithium-treated cases both in comparison to the general population (HR = 2.86, 99% CI = 2.42–3.37) and in comparison to the psychiatric subcohort (HR = 1.68, 99% CI = 1.31–2.17). Similarly, the risks of Parkinson's disease and kidney disease were higher in both comparisons.

Conclusions

We conclude that individuals prescribed lithium have a lower risk of cardiovascular and cerebrovascular disease, but no marked effect on dementia, compared to individuals with a mood or psychotic disorder not prescribed lithium. Venous thromboembolism, Parkinson's disease, and kidney disease were significantly more prevalent in individuals prescribed lithium.     

The ABO blood group genotype and factor VIII levels as independent risk factors for venous thromboembolism

Factor VIII (FVIII), von Willebrand factor (vWF) and the ABO blood groups have been associated with thrombosis. The ABO locus has functional effects on vWF and FVIII levels and is genetically correlated with FVIII, vWF and thrombosis. We carried out a case-control study to assess the role of FVIII, vWF and ABO types on thrombotic risk. We analyzed 250 patients with venous thrombosis and 250 unrelated controls. FVIII, vWF and other factors related to thrombophilia were measured, ABO groups were analyzed by genotyping. FVIII and vWF were higher in non-O individuals. Group O was more frequent in the controls (44.3% v 23.3%; difference 21.1%; 95% CI: 13.0-29.3%) and Group A in patients (59.2% v. 41.5%; difference 17.7%, 95% CI: 9.1-26.4%). Individuals carrying the A1 allele had a higher risk of thrombosis (OR 2.6; 95% CI, 1.8-3.8). The risk attributed to vWF disappeared after adjusting for the ABO group. Patients with FVIII above the 90th percentile had a high thrombotic risk (adjusted OR 3.7; 95% CI, 2.1-6.5), and a high risk of recurrence (OR 2.3; 95% CI: 1.3-4.1). In conclusion, high FVIII levels and non-O blood groups, likely those with the A1 allele, are independent risk factors for venous thromboembolism and should be considered in evaluating of thrombophilia.     

The consumption of antithrombin III during coagulation, its consequences for the calculation of prothrombinase activity and the standardisation of heparin activity.

The decay rate of thrombin in plasma is shown to be linearly proportional to the concentration of antithrombin III (AT III), not only in the absence but also in the presence of heparin. This is a consequence of partitioning of heparin between AT III and other plasma proteins. In previous articles were calculated the prothrombin converting activity assuming a fixed concentration of AT III. Since AT III is consumed during the clotting process, prothrombinase activity is more accurately approximated using an algorithm that counts with the decrease of the AT III concentration. It is shown this leads to higher prothrombinase activities. The (absence of) inhibition of prothrombin conversion by prothrombinase in the presence of heparins found with the previous method is also found using the new algorithm. From the results presented it is evident that characteristic parameters of heparin action have to be normalised to the AT III concentration. On this basis we define a Standard Independent Unit of the antithrombin activity of heparin.     

The effect of sulfation on the anticoagulant and antithrombin III-binding properties of a heparin fraction with low affinity for antithrombin III

Heparin with low affinity for antithrombin III (ATIII) and devoid of anticoagulant activity was chemically oversulfated and fractionated by affinity for ATIII. The oversulfated material showed ATIII binding properties, as monitored by intrinsic fluorescence enhancement of ATIII. The fluorescence increase was comparable to that of the AT III high affinity fraction of native heparin. The estimated dissociation constants however, showed a 10-fold weaker binding of the oversulfated material to ATIII, Kd = 6.4 x 10(-8) M, as compared to native heparin, Kd = 0.63 x 10(-8) M. Concomitant with the binding-induced allosteric change in ATIII, the oversulfated material stimulated the ATIII-thrombin and ATIII-factor Xa reactions. The high affinity fractions of native heparin and the sulfated material were almost equally effective in enhancing the rate of thrombin neutralization by ATIII. However, a 3-fold faster rate of factor Xa inactivation was found with the native high affinity material.     

Enhancement by heparin of thrombin-induced antithrombin III proteolysis: Its relation to the molecular weight and anticoagulant activity of heparin

Previous findings indicated that binding of heparin to antithrombin III (AT III) facilitates thrombin-induced proteolysis of the inhibitor. We now studied this property of heparin in regard to its molecular weight and anticoagulant activity. Commercial heparin was resolved on Sephadex G-200 into six fractions of decreasing molecular weight. From each fraction high affinity (HA) heparin was isolated by chromatography on AT III-Sepharose and examined in reaction of α-thrombin with a molar excess of ¹²⁵I AT III. Proteolysis of the inhibitor was assessed by SDS polyacreylamide gel electrophoresis. In the presence of the HA heparin from 18% to 38% of AT III participating in reaction appeared in the form of inactive 50,000-dalton fragment, as opposed to 7% of AT III fragmented in the absence of heparin. Although the ability to potentiate proteolysis was at its peak in the medium-molecular-size heparin fraction, the amount of degraded inhibitor relative to anticoagulant activity increased with decreasing molecular weight of the polysaccharide. These findings are consistant with the possibility that the ability of bound heparin to facilitate the cleavage of AT III by thrombin is generally less contingent upon secondary characteristics of the polysaccharide than the anticoagulant activity.     

Pre- and postoperative levels of antithrombin III with special reference to thromboembolism after total hip replacement

A prospective study of antithrombin III, determined by electroimmunochemical assay or an amidolytical method, was carried out with special reference to thromboembolism after total hip replacement. Two hundred and seven patients were randomly allocated to thromboembolic prophylaxis with dextran 70 or low dose heparin combined with dihydroergotamine. Deep vein thrombosis determined by phlebography of the operated leg or pulmonary embolism diagnosed with perfusion/ventilation scintigraphy developed in 51% of the total material and did not differ significantly between the two groups of prophylaxis or between patients with a preoperative At III below normal and those with a normal value. The correlation between the two assay methods for At III was 0.61. An initial, postoperative decrease in At III was noted with a parallel fall in hematocrit and fibrinogen, later followed by an increase of the plasma proteins. It is concluded that the immediate postoperative decrease of At III is mostly due to hemodilution.