Intensive initial oral anticoagulation and shorter heparin treatment in deep vein thrombosis

In order to investigate whether a more intensive initial oral anticoagulation still would be safe and effective, we performed a prospective randomized study in patients with deep vein thrombosis. They received either the conventional regimen of oral anticoagulation ("low-dose") and heparin or a more intense oral anticoagulation ("high-dose") with a shorter period of heparin treatment. In the first part of the study 129 patients were randomized. The "low-dose" group reached a stable therapeutic prothrombin complex (PT)-level after 4.3 and the "high-dose" group after 3.3 days. Heparin was discontinued after 6.0 and 5.0 days respectively. There was no difference in significant hemorrhage between the groups, and no clinical signs of progression of the thrombosis. In the second part of the study another 40 patients were randomized, followed with coagulation factor II, VII, IX and X and with repeated venograms. A stable therapeutic PT-level was achieved after 4.4 ("low-dose") and 3.7 ("high-dose") days, and heparin was discontinued after 5.4 and 4.4 days respectively. There were no clinical hemorrhages, the activity of the coagulation factors had dropped to the same level in both groups at the time when heparin was discontinued and no thromboembolic complications occurred. Our oral anticoagulation regimen with heparin treatment for an average of 4.4-5 days seems safe and reduces in-patient costs.     

Anticoagulation therapy in cerebral sinovenous thrombosis and ulcerative colitis in children

We describe four pediatric patients with ulcerative colitis and cerebral sinovenous thrombosis and review the pediatric and adult literature on the treatment of sinovenous thrombosis. All of our patients had headache as the initial complaint with onset during an ulcerative colitis flare. Evaluation for hypercoagulable states revealed heterozygosity for prothrombin gene mutation and increased homocysteine level in one patient and mild elevation of anticardiolipin antibodies in two patients. Treatment in the acute period included thrombolysis, heparin, and low-molecular-weight heparin. Chronic therapy included warfarin, low-molecular-weight heparin, and aspirin. Peripheral vein thrombosis occurred in two patients while not on antiplatelet or anticoagulation therapy. Neurologic outcome was positive in this series without complications of therapy, suggesting that aggressive therapy should be considered. Although anticoagulation therapy of sinovenous thrombosis is controversial, particularly in the context of intestinal hemorrhage, it can be beneficial given the possibility of an ongoing hypercoagulable state.     

Treatment of patients with acute deep vein thrombosis and/or pulmonary embolism: Efficacy and safety of non-VKA oral anticoagulants in selected populations

Venous thromboembolism (VTE), comprising deep vein thrombosis (DVT) and pulmonary embolism (PE), presents a large clinical burden. Prompt, effective and sustained anticoagulation is vital because of the risk of recurrent events, including life-threatening PE, and complications such as post-thrombotic syndrome and chronic thromboembolic pulmonary hypertension. Dual-drug standard therapy is effective; however, parenteral low molecular weight heparin, coupled with routine coagulation monitoring and dose adjustment of vitamin K antagonists (VKAs), presents challenges for patients and healthcare providers. Non-VKA oral anticoagulants provide a simplified option for VTE treatment. Phase III studies have investigated rivaroxaban and apixaban as single-drug approaches, and edoxaban and dabigatran in conjunction with initial heparin therapy. These agents demonstrated non-inferiority to standard therapy, and most showed significant reductions in major bleeding. However, clinical information is limited in patient subgroups, e.g. fragile patients or patients with renal impairment or cancer, who may be at higher risk of bleeding and/or VTE. A prespecified pooled analysis of the EINSTEIN DVT and EINSTEIN PE studies (8281 patients), undertaken to evaluate clinical outcomes with rivaroxaban versus standard therapy, confirmed the non-inferiority of rivaroxaban, with significant reductions in major bleeding and fewer intracranial and retroperitoneal bleeding events. Consistent efficacy and safety were observed with rivaroxaban, irrespective of fragility, cancer or clot severity. The introduction of the non-VKA oral anticoagulants and approval of rivaroxaban in the EU, US and Canada for the treatment and secondary prevention of DVT and PE offer the potential for improvements in effective care across a broad spectrum of patients with VTE.     

Treatment of venous thromboembolism in cancer patients

The management of deep vein thrombosis (DVT) and pulmonary embolism (PE) in patients with cancer can be a clinical dilemma. Comorbid conditions, warfarin failure, difficult venous access, and a high bleeding risk are some of the factors that often complicate anticoagulant therapy in these patients. In addition, the use of central venous access devices is increasing but the optimal treatment of catheter-related thrombosis remains controversial. Unfractionated heparin (UFH) is the traditional standard for the initial treatment of venous thromboembolism (VTE) but low molecular weight heparins (LMWHs) have been shown to be equally safe and effective in hemodynamically stable patients. For long-term treatment or secondary prophylaxis, vitamin K antagonists remain the mainstay treatment. However, the inconvenience and narrow therapeutic window of oral anticoagulants make extended therapy unattractive and problematic. As a result, LMWHs are being evaluated as an alternative for long-term therapy. New antithrombotic agents are being tested in clinical trials and may have the potential to replace conventional treatment. The role of inferior vena cava filters in cancer patients remains ill defined but these devices remain the treatment of choice in patients with contraindications for anticoagulant therapy.     

Safety and efficacy of Direct Oral Anticoagulants in cerebral venous thrombosis: A meta-analysis

Cerebral venous thrombosis (CVT) is caused by partial or complete occlusion of the major cerebral venous sinuses or the smaller feeding cortical veins which predispose to the risk of venous infarction and hemorrhage. Current guidelines recommend treating CVT with either low-molecular-weight heparin (LMWH) or unfractionated heparin (UFH) followed by an oral vitamin K antagonist (VKA) for 3–12 months. Direct oral anticoagulants (DOACs) have already established benefit over warfarin as a long-term treatment of symptomatic venous thromboembolic disorder like deep vein thrombosis (DVT), and pulmonary embolism (PE) given its equal efficacy and better safety profile. The benefit of DOACs over warfarin as a long-term anticoagulation for CVT has likewise been extensively studied, yet it has not been approved as first-line therapy in the current practice. We therefore performed a systematic review and meta-analysis of relevant studies to generate robust evidence regarding the safety and efficacy of DOACs in CVT. This meta-analysis demonstrates that the use of DOACs in CVT has similar efficacy and safety compared to VKAs with better recanalization rate.     

Thrombolysis in deep vein thrombosis: is there still an indication?

The most accepted therapy for DVT consists of anticoagulation with unfractionated heparin or low molecular weight heparin, followed by variable duration oral anticoagulation but thrombolytic therapy has been proposed in addition to standard anticoagulation. This paper reviews the literature on post thrombotic syndrome, the natural history of vein patency after therapy, and we perform a systematic review, using accepted standards for meta-analysis, to determine the outcomes when thrombolytic therapy is used to treat DVT. We demonstrate that thrombolytic therapy for DVT results in a significant increase in the risk of major hemorrhage and a significant increase in the rate of vein patency. However, although thrombolytic therapy is advantageous over anticoagulation as measured by early vein patency, a benefit in terms of a reduction in PTS risk, is unproven. Our review also shows that there is no evidence that there is a difference in efficacy between thrombolytic agents or that local therapy differs from systemic therapy. Finally, the potential role of catheter directed therapy is unknown since appropriate trials have not been performed but it is reasonable to use catheter directed therapy in patients with phlegmasia cerulea dolens. We conclude that more work is needed to define the role of thrombolytic therapy but it is too early to abandon this therapeutic modality.     

Managing pulmonary embolism from presentation to extended treatment

Pulmonary embolism (PE) remains a major healthcare problem. PE presents with a variety of non-specific symptoms, and confirmation of diagnosis involves the use of clinical risk scores, scanning techniques and laboratory tests. Treatment choice is informed by the risk of sudden death, with high-risk patients recommended to receive thrombolytic therapy or thrombectomy. Patients with less severe presentations are given anticoagulant therapy, traditionally with parenteral heparins in the acute phase of treatment, transitioning to oral vitamin K antagonists (VKAs). The limitations of these agents and the introduction of non-VKA oral anticoagulants challenge this paradigm. To date, clinical studies of four non-VKA oral anticoagulants to treat acute thrombosis have been published, and rivaroxaban is now approved for treatment and prevention of PE (and deep vein thrombosis). Rivaroxaban and apixaban alone, and dabigatran and edoxaban after parenteral anticoagulant induction, were non-inferior to enoxaparin/VKA for the prevention of recurrent venous thromboembolism; the risk of major bleeding was similar with dabigatran and edoxaban and significantly reduced with rivaroxaban and apixaban. Patients with an initial PE are recommended to receive continued anticoagulation for 3 months or longer, depending on individual risk factors, and studies of non-VKA oral anticoagulants have shown a continued benefit for up to 2 years, without a significantly increased risk of major bleeding. Given that the non-VKA oral anticoagulants are given at fixed doses without the need for routine coagulation monitoring, their adoption is likely to ease the burden on both PE patients and healthcare practitioners when longer-term or extended anticoagulation is warranted.     

Recurrent venous thromboembolism in a Spanish population: incidence, risk factors, and management in a hospital setting

The major concern in the management of venous thromboembolism is the propagation of thrombus and rethrombosis. The incidence of recurrences and the duration of oral anticoagulant therapy in these patients are still controversial. The aim of this study was to determine the incidence, timing, and outcome of further thrombotic events after an initial episode of venous thromboembolism in a hospital setting. In addition, we evaluated potential risk factors for all these outcomes. This was designed as a retrospective analysis of all patients admitted to our Center with an episode of deep vein thrombosis and/or pulmonary embolism between 1986 and 1996. The patients included in the study had to be treated with unfractionated heparin or low molecular weight heparin, followed by at least 3 months of oral anticoagulants. Natural and acquired hemostasis inhibitors were assayed in patients aged less than 50 years. A total of 290 patients with a first episode of venous thromboembolism were included in the study. A total of 33 patients (11.9%, 95% confidence interval. 7.4-14.6) had recurrent episodes. The cumulative incidence of recurrent venous thromboembolism after 2, 5, and 10 years was 7.68, 10, and 12.4%, respectively. The incidence of rethrombosis was significantly higher in patients with idiopathic venous thromboembolism than in patients with secondary thrombosis. Abnormalities of hemostasis were found in 54.5% (95% confidence interval, 37.6-71.4) of the patients with recurrences and under the age of 50 years. Three of seven patients who stopped anticoagulant therapy after the second episode presented a third thrombotic event. In our study population, those patients with idiopathic venous thromboembolism seem to have an increased risk of recurrence. The second thrombotic episode occurs more frequently during the following 2 years after cessation of anticoagulation therapy. Our findings strongly support the use of long-term anticoagulant therapy in patients with recurrent venous thromboembolism.     

Post-thrombotic syndrome after primary event of deep venous thrombosis 10 to 20 years ago

AIMS: We investigated the impact of the extent of primary deep venous thrombosis (DVT) and recurrent thrombotic events in accordance to other presumed prognostic factors for long-term clinical outcome after first DVT. PATIENTS AND METHODS: All consecutive in-patients, who were treated following first acute DVT between January 1, 1978 and December 31, 1988 at the Department of Angiology were identified by admission lists. Localisation, extent of primary DVT, etiology and concomitant pulmonary embolism (PE) at the time of initial presentation and occurrence of post-thrombotic syndrome (PTS) at follow-up visits were assessed by chart review. The duration and quality of the compression therapy, as well as the accuracy of the oral anticoagulant (OAC) treatment were documented. Recurrence of thrombosis embolism and/or PE with respect to the intensity of OAC was analyzed. Patients were invited to participate in clinical reinvestigation. Patients' history and clinical stage of PTS were re-evaluated and patients were asked for compliance in wearing compression stockings. A survey concerning restriction in quality of life was conducted. Hemodynamic measurements by strain-gauge plethysmography (SGP) were performed. RESULTS: One hundred and sixty-one patients were eligible for the study. Out of these 132 patients, 82% suffered from the PTS, defined as signs of chronic venous insufficiency (CVI) secondary to DVT of the lower limbs: 74 patients (46%) presented with clinical stage I after Widmer, 47 patients (29%) with clinical stage II and 11 patients (7%) with clinical stage III. No sign of PTS was seen in 29 patients (18%). The mean follow-up period of 6.6 years was statistically not different between the three severity groups of PTS. The severity of clinical symptoms was significantly associated with the recurrence of ipsilateral thrombosis (n = 26/16%). Highest risk for developing severe PTS was seen after four-level DVT and deep vein thrombosis of the lower leg. Patients having had a non-sufficient OAC (Hepatoquick > 25% in more than 50% of measurements) exhibited worse progradient clinical stages. Besides the high rate of bleeding complications after thrombolytic therapy, this strategy did not show more efficiency in prevention of development of severe PTS than heparin therapy alone. CONCLUSION: Our results show that primary four-level DVT, calf vein thrombosis, recurrence of ipsilateral DVT and a non-sufficient oral anticoagulation are of prognostic significance for developing clinically relevant PTS within 10 to 20 years after first DVT.     

Treatment of subclavian-axillary vein thrombosis: long-term outcome of anticoagulation versus systemic thrombolysis

Objective: To investigate long-term clinical and morphological outcome of patients with subclavian–axillary vein thrombosis treated with systemic thrombolysis compared to anticoagulation in a retrospective, nonrandomised study. Methods: We studied 95 consecutive inpatients with subclavian–axillary vein thrombosis treated either with systemic urokinase thrombolysis and subsequent oral anticoagulation (n=33) or with anticoagulation only (n=62). Anticoagulation was performed with heparin and phenprocoumon. Patients were followed for median 40 months (IQR 14 to 94) for symptomatic upper extremity post-thrombotic syndrome and for venous recanalisation by duplex ultrasound. Results: Primary technical success rate of the systemic thrombolysis was 88% (n=29) with seven peri-intervention bleeding complications (21%). No complication was observed in patients with anticoagulation only (p<0.0001). At the time of follow-up, duplex sonography showed a thrombotic subclavian vein in 40 of 83 patients (48%), but only 9 of 95 patients (10%) had a symptomatic upper extremity post-thrombotic syndrome. Patients with systemic thrombolysis exhibited a 60% adjusted reduced risk for a thrombotic subclavian vein at the time of follow-up compared to patients with anticoagulation only (95% CI: 0.2 to 0.9, p=0.03). However, the frequency of symptomatic post-thrombotic syndrome after thrombolysis and anticoagulation was similar (adjusted p=0.6). Conclusion: Systemic thrombolysis of subclavian–axillary vein thrombosis has an acceptable primary technical success rate and improves venous recanalisation rates compared to anticoagulation. However, the high rate of complications during thrombolysis and the lack of clinical benefit suggest that conservative treatment may be favoured.     

Heparin in der Akutphase des ischämischen Schlaganfalls

Therapy with low- or high-dose heparin in acute stroke is changing. Despite several clinical studies (>20), some with quite large numbers of patients, no statistically significant benefit was found for the clinical endpoints of death and functional outcome. This negative result remains even when considering the preventive effect of high-dose heparin on secondary acute embolic events (e.g., cardiac emboli-arrhythmia) and low-dose heparin on venous thrombosis. Based on study results, most reviews and therapy recommendations for the treatment of acute stroke generally decline the use of high-dose heparins and heparinoids with full anticoagulation for improving outcome or preventing secondary embolic events as well as low-dose applications for venous thrombosis prophylaxis. This paper reviews the literature and presents the data of a standardised survey on coagulation therapy in acute stroke patients from all university and major stroke units in Germany (n=33). Contrary to the restrictive recommendations, therapy with heparin is firmly established in most stroke units. Full anticoagulation with heparin ("full dose") is performed on selected patients in 32/33 stroke units (97%). The selection criteria and thus the frequency of high-dose heparin use varies widely among the different centers. Almost all German stroke units (97%) routinely use low-dose heparin to prevent venous thrombosis and pulmonary embolism.The heparin agents and dosage, however, vary. These data correspond to those from the USA and Canada,where daily routine also departs from evidence-based treatment recommendations. That may be due to individual pathophysiological and aetiological considerations and of course the low acceptance of treatment recommendations based on classic, randomised trials. This underlines the need for new concepts (e.g.observational trials, continuous registers, etc.) addressing the adaptation of study-related conditions to the much more complex situation of daily routine (with risk/benefit, safety, and economic variables).     

Unsolved issues in the treatment of pulmonary embolism

The three most controversial and unsolved issues in the treatment of pulmonary embolism (PE) are: (1) the role of thrombolysis, (2) the role of low molecular weight heparin and length of hospital stay, and (3) the optimal duration of anticoagulation. The trend is to use thrombolysis more frequently, to administer low molecular weight heparin and shorten the hospitalization duration in low-risk patients, and to give prolonged courses of anticoagulation with warfarin. PE thrombolysis appears most beneficial in patients at high risk of adverse clinical outcomes in whom the potential hazards of bleeding can be justified by the danger of conservative management with anticoagulation alone. With respect to utilizing low molecular weight heparin as a way of shortening the duration of hospitalization, there are no data to warrant this approach. The current FDA mandate for symptomatic PE patients is to administer intravenous unfractionated heparin administered as a bridge to therapeutic warfarin. Finally, the optimal duration of anticoagulation following acute PE remains mired in controversy. Despite the high rate of recurrent venous thrombosis after discontinuation of anticoagulation, there are currently insufficient data to recommend indefinite warfarin therapy.     

Vernet's Syndrome Associated with Internal Jugular Vein Thrombosis

Our objective is to present a case of Vernet's syndrome (cranial nerve (CN) IX, X, and XI palsy) associated with cerebral venous thrombosis (CVT) in an internal jugular vein. The patient presented with acutely developed dysphagia. The weakness of the left sternocleidomastoid and trapezius muscles was observed. The initial magnetic resonance imaging and computed tomography (CT) with contrast enhancement showed contrast-filling defect in the left internal jugular vein inside the jugular foramen. The magnetic resonance venography with contrast enhancement revealed a partial filling defect in the left sigmoid sinus and total occlusion of the left internal jugular vein. Under the diagnosis of CVT associated with CN IX, X palsy, anticoagulation therapy with low-molecular-weighted heparin was initiated. Despite the continued anticoagulation therapy for 3 months, neither the burden of thrombosis in the left sigmoid sinus and internal jugular vein on neck CT nor dysphagia symptoms improved. Clinicians need to be aware of internal jugular venous thrombosis as one of the differential diagnoses in Vernet's syndrome in patients in a hypercoagulable state. Further reporting of similar cases is needed to confirm the association between CVT and Vernet's syndrome.     

Optimal dosing of subcutaneous unfractionated heparin for the treatment of deep vein thrombosis

Twice-daily, inpatient, subcutaneous unfractionated heparin is at least as effective and safe as continuous intravenous unfractionated heparin for the treatment of acute deep vein thrombosis. Subcutaneous unfractionated heparin therefore may be suitable for outpatient treatment of deep vein thrombosis. The purpose of this study was to develop a dosing nomogram for a dose each 12 hours (2 doses per day) 12-hourly subcutaneous unfractionated heparin that is suitable for outpatient treatment of acute deep vein thrombosis. A cohort study was performed in patients with acute deep vein thrombosis in two phases. In both phases, the first subcutaneous loading dose of unfractionated heparin was 317 U/kg, and the second dose was 231 U/kg. The activated partial thromboplastin time was measured daily, 6 hours after the morning injection, and subsequent doses of unfractionated heparin were adjusted according to a nomogram, which was modified for phase II. Warfarin was started with unfractionated heparin. In phase I (14 outpatients), activated partial thromboplastin time results were frequently subtherapeutic (9:14) the day after starting unfractionated heparin (day 1), and were frequently supratherapeutic (27:40) after the first 2 days of unfractionated heparin therapy. In phase II (21 patients), to explain the frequently subtherapeutic activated partial thromboplastin time results that were obtained on day 1, the activated partial thromboplastin time results were measured after the initial loading dose. Mean activated partial thromboplastin time results of 86 and 61 seconds were obtained 6 and 12 hours after this dose, suggesting that 317 U/kg is a suitable subcutaneous loading dose. In contrast to phase I, in phase II, unfractionated heparin dose was not increased on day 1 in response to a low activated partial thromboplastin time result. This reduced the frequency of supratherapeutic activated partial thromboplastin time results during the early days of therapy without increasing the frequency of subtherapeutic results. Warfarin therapy had a substantal effect on the activated partial thromboplastin time that appeared to account for a high frequency of supratherapeutic results during the later days of unfractionated heparin therapy; the activated partial thromboplastin time increased by 20 seconds (95% CI, 14–27 seconds) with each increase in the International Normalized Ratio of 1.0. We had limited success at developing a dosing nomogram for subcutaneous unfractionated heparin that reliably achieved activated partial thromboplastin time results within the therapeutic range. However, as oral anticoagulants directly increased activated partial thromboplastin time results, we suggest that adjusting unfractionated heparin dose to achieve prespecified activated partial thromboplastin time results may not be appropriate in patients who are receiving concomitant warfarin therapy.     

Initial treatment of venous thromboembolism

Immediate anticoagulant treatment is essential to reduce morbidity and mortality in patients with acute venous thromboembolism (VTE). Currently, rapid anticoagulation can only be achieved with parenteral anticoagulants, such as heparin or low-molecular-weight heparin (LMWH). Weight-adjusted LMWH is the treatment of choice, because it produces predictable anticoagulation and does not require coagulation monitoring. If heparin is used, the activated partial thromboplastin time must be monitored and the heparin dose adjusted to ensure a therapeutic level of anticoagulation. Heparin is recommended for patients with renal impairment and for those at high risk of bleeding. The selective factor Xa inhibitor fondaparinux is a recently introduced alternative to heparin or LMWH for initial VTE treatment. Heparin, LMWH, or fondaparinux should be given for at least five to seven days. Vitamin K antagonists should be initiated on the first day, or as soon as possible, in patients who are candidates for an oral anticoagulant. An oral anticoagulant agent to be used without laboratory monitoring for both acute and long-term treatment of VTE remains an unsolved clinical need in the treatment of VTE.     

Managing the therapeutic dilemma: patients with spontaneous intracerebral hemorrhage and urgent need for anticoagulation

Physicians face a therapeutic dilemma in patients with acute hemorrhagic stroke requiring long-term, high-intensity anticoagulants because this treatment increases the risk of intracranial hemorrhage (ICH) 8- to 11-fold. We retrospectively studied 15 patients with ICH which occurred under anticoagulation with phenprocoumon, with an international normalized ratio (INR) of 2.5–6.5 on admission. Hemispheric, thalamic, cerebellar, intraventricular, or subarachnoid hemorrhage without aneurysm occurred. Absolute indications for anticoagulation were double, mitral, or aortic valve replacement, combined mitral valve failure with atrial fibrillation and atrial enlargement, internal carotid artery-jugular vein graft, frequently recurring deep vein thrombosis with risk of pulmonary embolism, and severe nontreatable ischemic heart disease. As soon as the diagnosis of ICH was established, INR normalization was attempted in all patients by administration of prothrombin complex, fresh frozen plasma, or vitamin K. After giving phenprocoumon antagonists (and neurosurgical therapy in four patients) heparin administration was started. Nine patients received full-dose intravenous and six low-dose subcutaneous heparin. The following observations were made: (a) All patients with effective, full-dose heparin treatment with a 1.5- to 2-fold elevation in partial thromboplastin time after normalization of the INR were discharged without complication. (b) Three of four of the patients with only incomplete correction of the INR (> 1.35) experienced relevant rebleeding within 3 days (all patients with an INR higher than 1.5), two of whom were on full-dose heparin. (c) Three of seven of the patients with normalized INR and without significant PTT elevation developed severe cerebral embolism. Although our data are based on a retrospective analysis, they support treatment with intravenous heparin (partial thromboplastin time 1.5–2 times baseline value) after normalization of the INR in patients with an ICH and an urgent need for anticoagulation. Received: 1 September 1999/Received in revised form: 28 October 1999/Accepted: 19 November 1999     

Treatment and prophylaxis of venous thromboembolism during pregnancy

The treatment and prevention of deep vein thrombosis (DVT) and pulmonary embolism (PE) in pregnant patients is challenging for several reasons. Coumarins can cause embryopathy and other adverse effects in the fetus. Although unfractionated heparin and low-molecular-weight heparins, the cornerstones of initial therapy, are safe for the fetus, they can have significant maternal side effects, including osteoporosis and thrombocytopenia. Because they must be given parenterally, long-term administration is inconvenient. Further, although low-molecular-weight heparins probably cause less maternal osteoporosis and thrombocytopenia than unfractionated heparin, the appropriate dosing regimens for prevention and treatment of thrombosis during pregnancy have not been established. In addition, there is a paucity of reliable information on the incidence of venous thromboembolism and the risk of recurrent thrombosis during pregnancy. This paper briefly reviews the areas of controversy and provides recommendations for the treatment and prophylaxis of acute deep vein thrombosis and pulmonary embolism in pregnant patients.     

Hormonal contraceptives as a risk factor for cerebral venous and sinus thrombosis

This review will focus on recent developments in our understanding of cerebral venous and sinus thrombosis (CVST), as a side effect of combined oral contraceptives (COCs) use. Case-control studies have shown an increased risk of CVST in women who use COCs, especially third-generation contraceptives that contain gestodene or desogestrel. Several studies have indicated that the combination of COCs and thrombophilia greatly increased the risk of CVST, particularly in women with hyperhomocysteinaemia, factor V Leiden and the prothrombin-gene mutation. Women with thrombophilia who developed CVST while taking oral contraceptives should be definitively advised to stop using COCs. These patients should be considered for preventive therapy with low doses of heparin in prothrombotic situations such as bed rest or pregnancy, and the duration of anticoagulation should be considered on a case-by-case basis. Patients may be considered candidates for chronic treatment with antiplatelet agents. The best and most cost-effective screening method for thrombophilia in women who are planning to conceive is selective screening based on the presence of previous personal or family history of either prior extracerebral or cerebral venous thromboembolism events.     

Treatment of established thrombotic events in patients with cancer

Acutely ill medical patients with cancer and cancer patients requiring Anticoagulants remain the cornerstone of therapy for venous thromboembolism. In patients with cancer, monotherapy with low molecular weight heparin (LMWH) is preferred over initial therapy with heparin followed by long-term treatment with vitamin K antagonists (VKA) because it is more efficacious and does not interfere with chemotherapy. The shorter duration of action of LMWHs compared with VKAs also offers greater flexibility to accommodate invasive procedures and thrombocytopenia. Newer oral antithrombotic agents may further simplify treatment of cancer-associated thrombosis because they are given at fixed doses and do not require laboratory monitoring of their anticoagulant effect. However, there are very limited data and experience with these agents in patients with cancer and some of these drugs do interact with a number of chemotherapeutic agents. Other unanswered clinical questions include the optimal duration of anticoagulant therapy, which anticoagulant to use after 6 months of treatment, how to treat patients with recurrent thrombosis or patients with a high risk for bleeding. Formal studies are needed to address these unmet clinical needs.     

Role of fibrinolysis and interventional therapy for acute venous thromboembolism

The initial goals of treatment for venous thromboembolism (VTE) are usually achieved with anticoagulation. This review focuses on fibrinolysis and interventional therapy in VTE, treatments whose indications are much more controversial. The benefit-to-risk ratio of fibrinolysis in deep vein thrombosis (DVT) is dubious. Thrombolytic treatment is recommended for unstable patients with pulmonary embolism (PE), although these patients represent less than 5% of all patients hospitalized for PE. The use of thrombolytic treatment in patients with sub-massive PE remains controversial. Two indications are widely recognized for inferior vena cava filters: the first is a permanent or temporary contraindication to anticoagulation, in patients with proximal DVT or PE. The second is the occurrence of PE or propagation of the thrombus in patients treated for DVT or recurrence in patients with PE. The PREPIC study demonstrated that in acute VTE, vena cava filters reduced the risk of PE but increased that of DVT and had no effect on survival. The fact that prevention of PE is mainly observed during the short initial period following the diagnosis of an acute VTE event justifies a new randomized study with the use of retrievable filters as an adjuvant to anticoagulation in high risk patients with PE.