Inhibition of Factor XI: A New Era in the Treatment of Venous Thromboembolism in Cancer Patients?

Direct oral anticoagulants against activated factor X and thrombin were the last milestone in thrombosis treatment. Step by step, they replaced antivitamin K and heparins in most of their therapeutic indications. As effective as the previous anticoagulant, the decreased but persistent risk of bleeding while using direct oral anticoagulants has created space for new therapeutics aiming to provide the same efficacy with better safety. On this basis, drug targeting factor XI emerged as an option. In particular, cancer patients might be one of the populations that will most benefit from this technical advance. In this review, after a brief presentation of the different factor IX inhibitors, we explore the potential benefit of this new treatment for cancer patients.

[Management of superficial vein thrombosis]. / Prise en charge des thromboses veineuses superficielles.

Recent epidemiological studies have highlighted the potential severity of superficial vein thrombosis of the lower limbs (SVT). Diagnosis is based on clinical and Doppler ultrasonography evaluation, and define its therapeutic management. If SVT is associated with objectively confirmed deep vein thrombosis or pulmonary embolism, curative anticoagulation is indicated. If SVT is isolated and measured over 5 cm long, prophylactic dosage of fondaparinux may be provided for 45 days.

[Epidemiologic and therapeutic advances in superficial venous thrombosis of the legs]. / Epidémiologie et traitement des thromboses veineuses superficielles des membres inférieurs.

Thromboses affecting venous superficial system have been considered as benign diseases. Recent studies demonstrate that they might be associated with more severe venous events (as deep venous thrombosis [DVT] or pulmonary embolism [PE]), initially or during 3-month followup. The POST study presents clinical evolution of 844 patients with superficial venous thrombosis (SVT) of lower limbs. Of note, concomitant DVT and/or symptomatic PE were initially found in one quarter of them. Among the 586 patients with isolated SVT (i. e. without DVT or symptomatic PE, and at more than 3 cm of the saphenofemoral junction), 10% presented with DVT, PE, recurrent or extensive SVT during the 3-month follow-up. These results, as the heterogeneous therapeutic management, were confirmed by another cohort study (OPTIMEV). In the CALISTO study, Fondaparinux, at a dose of 2.5 mg once a day for 45 days was effective in the treatment of patients with isolated SVT of the legs and did not have serious side effects. In absence of contra-indication, this treatment may be preferred in patients with confirmed isolated SVT of lower limb.

Splice variant-specific stabilization of JNKs by IB1/JIP1.

Islet-Brain 1 (IB1) (also called JNK-interacting protein 1; JIP1) is a scaffold protein that tethers components of the JNK mitogen-activated protein kinase pathway inducing a modulation of the activity and the target specificity of the JNK kinases. Dysfunctions in IB1 have been associated with diseases such as early type II diabetes. To gain more insight in the functions of IB1, its ability to modulate the expression levels of the various JNK proteins was assessed. Each of the three JNK genes gives rise to several splice variants encoding short or long proteins. The expression levels of the short JNK proteins, but not of the long variants, were systematically higher in rat tissues and in transformed cell lines expressing high IB1 levels compared to tissues and cells with no or low IB1 expression. HEK293 cells bearing a tetracycline-inducible IB1 construct showed a specific increase of the short JNK endogenous splice variants in the presence of tetracycline. The augmented expression level of the short JNK splice variants induced by IB1 resulted from an increased stability towards degradation. Modulation of the stability of specific JNK splice variants represents therefore a newly identified mechanism used by IB1 to regulate the JNK MAPK pathway.

Screening cancer after venous thromboembolism: How many abnormal tests before diagnosing cancer? An analysis of practice.

INTRODUCTION: Since Trousseau, we knows that venous thrombemboembolism (VTE) can reveal occult cancer. Different strategies of cancer screening have been evaluated: they are often time-consuming, cause stress and anxiety, and frequently require second-look examinations (due to the risk of false positives), with ultimately a very low yield (about 5%). We evaluated the number of suspect cancer tests before reporting them to the number of cancers finally diagnosed, after a VTE, in the setting of practice's analysis. METHODS: We studied retrospectively patients hospitalized for a VTE and with a cancer screening, between 2011 and 2012. Screening cancer was defined by performing at least one of the following tests: PSA, fecal occult blood test, mammography, abdominopelvic iconography (abdominal ultrasound and/or abdominal CT scan). We recorded the suspected cancer tests, the cancers diagnosed, their stage and the survival. These results were expressed as a percentage with a 95% confidence interval. RESULTS: Out of the 491 patients treated for a VTE, screening cancer was performed on 295 patients (median age 66.2 years). Nineteen PSA (16.7%, 95% CI [10.3-25]) were abnormal, with 2 localized prostate cancers. Nineteen fecal occult blood tests (15.3%, 95% CI [9.5-23]) were positive, with 2 local cancers. Five mammograms suspected cancer (4.7% 95% CI [1.6-10.8]) for one confirmed. Thirty-eight abdomino-pelvic iconographies (14.4% 95% CI [10.4-19.2]) were suspect, with 7 confirmed cancers, 6 being metastatic at times of diagnostic. CONCLUSION: Among the 607 tests performed, 81 were suspected of cancer (13.3%) for only 12 cancers confirmed (2.0%). Screening cancer exposes patients to several false positive tests.

Thrombophilia and risk of venous thrombosis in patients with cancer.

Venous thrombosis is a common and severe complication in patients with cancer. We reviewed studies assessing whether a state of acquired or congenital thrombophilia influenced the risk of thrombosis in patients with cancer. The results are equivocal. However, the majority of studies were of limited size. The influence of thrombophilia in patients with cancer may be more difficult to demonstrate than in the general population, the risk of thrombosis due to cancer per se possibly outweighing the contribution of thrombophilic factors. Moreover, the results may depend on the genetic background of the population, the type of cancer, the type of thrombosis, and the chemotherapeutic treatment. Nevertheless, it appears that factor V Leiden or G20210A prothrombin gene mutation increases the risk of venous thromboembolism about 2- to 4-fold, compared with patients with cancer without either of these mutations. Similar results were observed for the occurrence of central venous catheter-associated thrombosis. Antiphospholipid antibodies and acquired resistance to activated protein C were frequently observed in patients with cancer and appeared to favor the occurrence of thrombosis. The role of hyperhomocysteinemia deserves further investigation. Since the clinical implications of these findings remain to be clarified, routine screening of cancer patients for thrombophilia cannot yet be recommended on the basis of these studies. Studies designed to assess the value of thromboprophylaxis in high-risk patients, including thrombophilic patients, with long-term central venous catheters may be valuable.

[Initial treatment of venous thromboembolic events]. / Traitement initial de la maladie thrombo-embolique veineuse.

Initial treatment of venous thromboembolic events is currently based on antithrombotics. This treatment is validated and identical for deep vein thrombosis (DVT) and pulmonary embolism. For distal DVT, this treatment has still to be validated. This reference therapeutic strategy is firstly parenteral and based on low-molecular-weight heparins (LMWH) or fondaparinux, subcutaneously prescribed at fixed dosage based on body weight without any systematic dose adjustment on hemostasis tests. Unfractionated heparin is steel the reference treatment in case of severe renal insufficiency. This parenteral treatment has to be relieved by vitamin K antagonists (VKA). VKA has to be co-administrated for at least 3 days, without any loading dose and can be early initiated. VKA dose needs to be adjusted in order to maintain INR between 2 and 3. However, in case of cancer, LMWH have to be carried on for 6 months. A part this antithrombotic treatment, thrombolytics are recommended in case of massive PE and vena cava filter should be used in case of recurrence despite adequate antithrombotic treatment or in case of contraindication to antithrombotic.

Intravenous thrombolytic therapy in patients with phlegmasia caerulea dolens.

In a prospective study, nine patients with phlegmasia caerulea dolens (PCD) related to iliac occlusive thrombosis were treated with intravenous thrombolysis. After thrombolysis, despite no significant improvement in the Marder score value, progression to venous gangrene, major hemorrhage or death was not observed and no amputation was needed. Intravenous thrombolysis should be seriously considered in patients with PCD.

Islet-brain (IB)/JNK-interacting proteins (JIPs): future targets for the treatment of neurodegenerative diseases?

Islet-Brain (IB) proteins [also called JNK-interacting proteins (JIPs)] are scaffold proteins that are mainly expressed in the pancreatic islets and in the brain. Functionally, the IB family is composed of IB1, IB2, IB3, and IB4 each with distinct splice variants. The IB family of proteins regulates several mitogen-activated protein kinase (MAPK) pathways by tethering their components and modifying the spectrum of substrates targeted by the MAPKs. The expression of these proteins is developmentally regulated, indicating that they play important functions during brain formation. While it is currently unclear what the precise physiological functions of the IB proteins are, there are indications that they participate in subcellular targeting of signalling proteins and modulate cell survival. Synthetic derivatives of these proteins can efficiently counteract apoptotic signalling in cells and tissues and represent therefore promising protective agents against traumatic insults, including stroke and hypoxia. This review will focus on the molecular functions of the IB proteins and their potential implications in the development of several human pathologies.

[New oral anticoagulants in the treatment of venous thromboembolism]. / Nouveaux anticoagulants oraux dans le traitement curatif de la maladie thromboembolique veineuse.

Rivaroxaban (with initial increased dosage) may be used as a stand-alone therapy in patients with venous thrombo-embolism. The development of new anticoagulant drugs opened several options in the management of venous thrombo-embolism. The efficacy and safety of these new oral anticoagulants in specific population as elderly and those with renal impairment deserve future research. At that time, only rivaroxaban is licensed in France, in the treatment of deep venous thrombosis.

Recent findings in the epidemiology, diagnosis and treatment of superficial-vein thrombosis.

Recent data on lower-limb superficial-vein thrombosis (SVT) may substantially impact its clinical management. Thus, the clear confirmation that SVT is closely linked to deep-vein thrombosis (DVT) or pulmonary embolism (PE) highlights the potential severity of the disease. DVT or PE are diagnosed in 20-30% of SVT patients. Moreover, clinically relevant symptomatic thromboembolic events complicate isolated SVT (without concomitant DVT or PE at diagnosis) in 4-8% of patients. For the first time, an anticoagulant treatment, once-daily 2.5 mg fondaparinux for 45 days, was demonstrated to be effective and safe for preventing these symptomatic thromboembolic events in patients with lower-limb isolated SVT in the randomized placebo-controlled CALISTO study. Based on these recent findings, new recommendations on the management of SVT patients, including complete ultrasonography examination of the legs, and in patients with isolated SVT, prescription of once-daily 2.5 mg fondaparinux subcutaneously for 45 days on top of symptomatic treatments, may be proposed.

Clinical efficacy and safety of fondaparinux in the prevention and treatment of venous and arterial thrombosis.

Fondaparinux (Arixtra) is a synthetic, selective Factor Xa inhibitor. Its pharmacokinetic profile allows once-daily subcutaneous administration of the drug without any laboratory monitoring. The benefit-to-risk ratio of fondaparinux in the prevention of venous thromboembolism has been extensively studied in both surgical and acutely ill medical patients at risk of thrombosis. Its efficacy and safety have also been investigated in the initial treatment of symptomatic deep-vein thrombosis and pulmonary embolism. Finally, a number of Phase II trials investigated the safety and efficacy of fondaparinux in patients with acute coronary syndromes, and a large Phase III program is ongoing in this setting. This review focuses on the use of fondaparinux in the prevention and treatment of thromboembolic disorders.