[Human immunodeficiency virus and venous thromboembolism: Role of direct oral anticoagulants]. / Modalités du traitement de la maladie veineuse thromboembolique du patient VIH par les anticoagulants oraux directs.

Nowadays, thanks to highly active antiretroviral therapy (HAART), human immunodeficiency virus (HIV) infection is transforming into a chronic disease. The life expectancy of people living with HIV (PWH) has increased, as well as their risk of developing several co-morbidities, in particular cardiovascular diseases. In addition, the incidence of venous thromboembolism (VTE) is increased in PWH with a 2 to 10 times higher incidence when compared to the general population. Over the last decade, direct oral anticoagulants (DOACs) have been widely used in the treatment and prevention of VTE and non-valvular atrial fibrillation. DOACs are characterized by a rapid onset of activity, a predictable response and a relatively wide therapeutic window. Nevertheless, drug interactions exist between HAART and DOACs, exposing PWH to a theoretically increased bleeding or thrombotic risk. DOACs are substrates of the transport protein P-glycoprotein and/or of isoforms of cytochromes P450 pathway, which can be affected by some antiretroviral drugs. Limited guidelines are available to assist physicians with the complexity of those drug-drug interactions. The aim of this paper is to provide an updated review on the evidence of the high risk of VTE in PWH and the place of DOAC therapy in this population.

Relationship between kalemia and intensive care unit admission or death in hospitalized COVID-19 patients: A cohort study.

BACKGROUND: SARS-CoV-2 uses Angiotensin-Converting Enzyme 2 as a viral gateway to the cell and could interact with the renin-angiotensin-aldosterone system. Other studies have shown kalemia abnormalities in patients with severe forms of coronavirus disease 2019. Our goal was to assess the prognosis value of kalemia within ten days of symptom offset in the COVID-19 hospitalized population. METHODS: We analyzed data from a prospective cohort that included 65 patients with COVID-19, admitted between March 15, 2020, and March 21, 2020. The study aimed at determining the relationship between baseline kalemia and the admission to an intensive care unit (ICU) or death. RESULTS: The median age of the patients was 65 [54-79] years old, and 66.2% of the patients were men. Baseline kalemia under 3.8mmol/l occurred in 31 patients (48%), including 11 patients (35.5%) who were admitted to an ICU and one patient (3.2%) who died before ICU admission. In the primary end-point analysis, the adjusted hazard ratios for admission to an ICU or death were 3.52 [95% confidence interval (CI), 1.12 to 11.04] among patients with low baseline kalemia. CONCLUSION: Our study suggests that low kalemia levels within ten days of the first symptom onset might be associated with an increased risk of intensive care unit admission or death. The future perspective should be to better understand this relationship.

Safety and efficacy of low-dose PI3K inhibitor taselisib in adult patients with CLOVES and Klippel-Trenaunay syndrome (KTS): the TOTEM trial, a phase 1/2 multicenter, open-label, single-arm study.

PURPOSE: PIK3CA pathogenic variants in the PIK3CA-related overgrowth spectrum (PROS) activate phosphoinositide 3-kinase signaling, providing a rationale for targeted therapy, but no drug has proven efficacy and safety in this population. Our aim was to establish the six-month tolerability and efficacy of low-dose taselisib, a selective class I PI3K inhibitor, in PROS patients. METHODS: Patients over 16 years with PROS and PIK3CA pathogenic variants were included in a phase IB/IIA multicenter, open-label single-arm trial (six patients at 1 mg/day of taselisib, then 24 at 2 mg/day). The primary outcome was the occurrence of dose limiting toxicity (DLT). Efficacy outcomes were the relative changes after treatment of (1) tissue volume at affected and unaffected sites, both clinically and on imaging; (2) cutaneous vascular outcomes when relevant; (3) biologic parameters; (4) quality of life; and (5) patient-reported outcomes. RESULTS: Among 19 enrolled patients, 2 experienced a DLT (enteritis and pachymeningitis) leading to early trial termination (17 treated, 10 completed the study). No serious adverse reaction occurred in the 1 mg cohort (n = 6). No significant reduction in affected tissue volume was observed (mean -4.2%; p = 0.81; SD 14.01). Thirteen (76.4%) participants reported clinical improvement (pain reduction, chronic bleeding resolution, functional improvement). CONCLUSION: Despite functional improvement, the safety profile of low-dose taselisib precludes its long-term use.

Ergotism with acute limb ischemia, provoked by HIV protease inhibitors interaction with ergotamine, rescued by multisite transluminal balloon angioplasty.

Acute limb ischemia induced by arterial vasospasm remains an exceptional situation, favoured by the use of arterial vasoconstrictors. The risk of these substances is largely underestimated in the general population, especially with the co-administration of strong cytochrome inhibitors like human immunodeficiency virus (HIV) protease inhibitors. A 33-year-old woman, who used to take dihydroergotamine for orthostatic hypotension, was prescribed a post-exposure HIV prophylaxis including lopinavir and ritonavir. One day later, she presented an acute bilateral limb ischemia with a sudden pain in both calves, initially while walking and then at rest with bilateral ischemic toes. Angiography confirmed diffuse arterial vasospasm of the lower limb arteries. A first-line therapy with isosorbide dinitrate and amlodipine was ineffective, with rapid clinical worsening. A combination of intra-arterial injections and intra-venous infusions of vasodilators, transluminal balloon angioplasty and bilateral 4-Compartment fasciotomies permitted rapid improvement and finally resulted in both lower limbs rescue. This case and literature review illustrate ergotism due to ergotamine overdose after taking HIV protease inhibitors. It also demonstrates the benefit of an interventional procedure besides medical therapy with vasodilators in severe arterial vasospasm. All along the lower limb arterial tree, transluminal balloon angioplasty restored the blood flow, without vasospasm recurrence. CONCLUSION: In case of ergotism with acute lower limbs ischemia, combining medical vasodilator therapy with interventional procedure can restore the arterial blood flow, thus allowing to save lower limbs.

Respiratory mechanics and gas exchanges in the early course of COVID-19 ARDS: a hypothesis-generating study.

RATIONALE: COVID-19 ARDS could differ from typical forms of the syndrome. OBJECTIVE: Pulmonary microvascular injury and thrombosis are increasingly reported as constitutive features of COVID-19 respiratory failure. Our aim was to study pulmonary mechanics and gas exchanges in COVID-2019 ARDS patients studied early after initiating protective invasive mechanical ventilation, seeking after corresponding pathophysiological and biological characteristics. METHODS: Between March 22 and March 30, 2020 respiratory mechanics, gas exchanges, circulating endothelial cells (CEC) as markers of endothelial damage, and D-dimers were studied in 22 moderate-to-severe COVID-19 ARDS patients, 1 [1-4] day after intubation (median [IQR]). MEASUREMENTS AND MAIN RESULTS: Thirteen moderate and 9 severe COVID-19 ARDS patients were studied after initiation of high PEEP protective mechanical ventilation. We observed moderately decreased respiratory system compliance: 39.5 [33.1-44.7] mL/cmH2O and end-expiratory lung volume: 2100 [1721-2434] mL. Gas exchanges were characterized by hypercapnia 55 [44-62] mmHg, high physiological dead-space (VD/VT): 75 [69-85.5] % and ventilatory ratio (VR): 2.9 [2.2-3.4]. VD/VT and VR were significantly correlated: r2 = 0.24, p = 0.014. No pulmonary embolism was suspected at the time of measurements. CECs and D-dimers were elevated as compared to normal values: 24 [12-46] cells per mL and 1483 [999-2217] ng/mL, respectively. CONCLUSIONS: We observed early in the course of COVID-19 ARDS high VD/VT in association with biological markers of endothelial damage and thrombosis. High VD/VT can be explained by high PEEP settings and added instrumental dead space, with a possible associated role of COVID-19-triggered pulmonary microvascular endothelial damage and microthrombotic process.

Correction to: Percutaneous Deep Venous Arterialization for Severe Critical Limb Ischemia in Patients With No Option of Revascularization: Early Experience From Two European Centers.

The fifth author's name was incorrectly published as "M. Messas". The correct name is "E. Messas". The original article has been corrected.

Efficacy of anti-TNF alpha in severe and refractory major vessel involvement of Behcet's disease: A multicenter observational study of 18 patients.

OBJECTIVE: To describe the outcome and tolerance in patients treated with anti-TNFα in severe and refractory major vessel disease in Behçet's disease (BD). METHODS: A multicenter study evaluating 18 refractory BD patients with major vessel involvement [pulmonary artery (n = 4), aorta (n = 4) or peripheral artery aneurysm (n = 1) and/or pulmonary artery (n = 7), inferior vena cava (n = 5), or intra-cardiac (n = 3) thrombosis or Budd Chiari Syndrome (n = 2)] treated with anti-TNFα agents. RESULTS: Vascular remission was achieved in 16 (89%) patients. The 9 months risk of relapse was significantly higher with conventional immunosuppressants used prior anti-TNFα agents as compared to anti-TNFα therapy [OR = 8.7 (1.42-62.6), p = 0.03]. The median daily dose of corticosteroids significantly decreased at 12 months. Side effects included infection (n = 4) and pulmonary edema (n = 1). CONCLUSION: TNFα-antagonists are safe and might be associated with a decreased risk of relapse at 9 months compared to conventional immunosuppressants in BD patients with major vessels disease.

Percutaneous Deep Venous Arterialization for Severe Critical Limb Ischemia in Patients With No Option of Revascularization: Early Experience From Two European Centers.

PURPOSE: To report our initial experience of fully percutaneous deep venous arterialization (pDVA) for the treatment of chronic critical limb ischemia (cCLI) after failed distal angioplasty. MATERIALS AND METHODS: pDVA was performed in five consecutive patients by creating an arteriovenous fistula (AVF) between a below the knee artery and its satellite deep vein. In this early experience, only patients with failed prior interventional attempts at establishing flow with no distal targets for an arterial bypass were selected. Early technical success was defined as successful AVF creation and retrograde venous perfusion of the wound site. Patient demographics, procedural details, morbidity/mortality and wound healing outcomes were assessed prospectively. Patients were followed up in wound care centers, and graft patency was documented on duplex ultrasound. RESULTS: All five consecutive patients (mean age 58 years) underwent successful pDVA without any procedural complications. There were neither 30-day major adverse limb events nor major cardiovascular complications. Three out of the five patients (60%) had clinical improvement as observed by resolution of rest pain and complete wound healing. At the 1-month FU, one patient died and one patient received a major amputation. The median wound healing time was 39 weeks. CONCLUSION: pDVA is a safe and feasible vascularization alternative in patients with end-stage/no-option CLI. The early experience highlights the need for a multidisciplinary approach including a dedicated wound care service.

Pulsed cavitational therapy using high-frequency ultrasound for the treatment of deep vein thrombosis in an in vitro model of human blood clot.

Post-thrombotic syndrome, a frequent complication of deep venous thrombosis, can be reduced with early vein recanalization. Pulsed cavitational therapy (PCT) using ultrasound is a recent non-invasive approach. We propose to test the efficacy and safety of high-frequency focused PCT for drug-free thrombolysis (thrombotripsy) in a realistic in vitro model of venous thrombosis. To reproduce venous thrombosis conditions, human whole blood was allowed to clot by stasis in silicone tubes (6 mm internal diameter) at a 30 cm H2O pressure, maintained during the whole experiment. We engineered an ultrasound device composed of dual 2.25 MHz transducers centered around a 6 MHz imaging probe. A therapeutic focus was generated at a 3.2 cm depth from the probe. Thrombotripsy was performed by longitudinally scanning the thrombus at three different speeds: 1 mm s-1 (n = 6); 2 mm s-1 (n = 6); 3 mm s-1 (n = 12). Restored outflow was measured every three passages. Filters were placed to evaluate the debris size. Twenty-four occlusive thrombi, of 2.5 cm mean length and 4.4 kPa mean stiffness, were studied. Flow restoration was systematically obtained by nine subsequent passages (4.5 min maximum). By varying the device's speed, we found an optimal speed of 1 mm s-1 to be efficient for effective recanalization with 90 s (three passages). Within 90 s, flow restoration was of 80, 62 and 74% at respectively 1, 2 and 3 mm s-1. For all groups, cavitation cloud drilled a 1.7 mm mean diameter channel throughout the clot. Debris analysis showed 92% of debris <10 µm, with no fragment > 200 µm.

[Recanalization procedure of the common femoral vein following iatrogenic femoral chronic occlusion: 3 cases]. / Recanalisation veineuse des membres inférieurs sur occlusion fémorale chronique iatrogène : à propos de 3 cas.

Common femoral vein occlusion (CFVO) is frequently found in patients with chronic venous insufficiency. The iatrogenic form, secondary to either central catheter or surgery, is very rare but highly symptomatic. Classical compression therapy barely improves the clinical status of these patients, making them suitable candidates for an interventional procedure for venous recanalization. METHODS: We report here three consecutive cases of iatrogenic CFVO referred to our outpatient clinic because the disease had an impact on daily life activities. We detail the recanalization procedure, the Doppler control and the short-term outcome. RESULTS: In each case, endovascular recanalization required rigid material (rigid guide or Colapinto needle) to cross the fibrous adhesions before angioplasty could be performed with stenting. The procedure required two attempts in each case, underlining its complexity, but eventually enabled effective recanalization. No major complication occurred per- or post-procedure. One month later, a duplex Doppler control confirmed the permeability of the common femoral vein. The patients had experienced rapid and significant symptom improvement. CONCLUSION: Patients suffering from severe chronic venous insufficiency caused by iatrogenic CFVO can benefit from endovascular recanalization. Although these procedures may be complex due to the extensive fibrosis at the Scarpa and require specialized equipment, no major complications were observed. Patency of the recanalization persisted at least one month after the procedure. Symptom relief was good.

Factors predictive of leg-ulcer healing in sickle cell disease: a multicentre, prospective cohort study.

BACKGROUND: Leg ulcers (LUs) are a chronic and severe complication of sickle cell disease (SCD). A prospective study in patients with SCD to identify factors associated with complete healing and recurrence of LUs is lacking. OBJECTIVES: To determine clinical and biological factors associated with SCD-LU complete healing and recurrence. METHODS: This prospective, observational cohort study was conducted at two adult SCD referral-centre sites (2009-2015) and included 98 consecutive patients with at least one LU lasting ≥ 2 weeks. The primary end points compared patients with healed vs. nonhealed LUs at week 24, and patients with vs. without recurrence during follow-up. RESULTS: The median (interquartile range) LU area, duration and follow-up were, respectively, 6·2 cm2 (3-12·8), 9 weeks (4-26) and 65·8 weeks (23·8-122·1). At week 24, LUs were healed in 47% of patients, while 49% of LUs recurred. Univariate analyses identified inclusion LU area < 8 cm2 (82% vs. 35%; P < 0·001), inclusion LU duration < 9 weeks (65% vs. 35%; P = 0·0013) and high median fetal haemoglobin level (P = 0·008) as being significantly associated with complete healing at week 24, and low lactate dehydrogenase level (P = 0·038) as being associated with recurrence. Multivariate analyses retained LU area < 8 cm2 (odds ratio 6·73, 95% confidence interval 2·35-19. 31; P < 0·001) and < 9 weeks' duration (OR 3·19, 95% confidence interval 1·16-8·76; P = 0·024) as being independently associated with healing at week 24. Factors independently associated with recurrence could not be identified. CONCLUSIONS: SCD-LU complete healing is independently associated with the clinical characteristics of LUs rather than the clinical or biological characteristics of SCD.

Biotherapies in large vessel vasculitis.

Giant cell arteritis (GCA) and Takayasu's arteritis (TA) are large vessel vasculitis (LVV) and aortic involvement is not uncommon in Behcet's disease (BD) and relapsing polychondritis (RP). Glucocorticosteroids are the mainstay of therapy in LVV. However, a significant proportion of patients have glucocorticoid dependance, serious side effects or refractory disease to steroids and other immunosuppressive treatments such as cyclophosphamide, azathioprine, mycophenolate mofetil and methotrexate. Recent advances in the understanding of the pathogenesis have resulted in the use of biological agents in patients with LVV. Anti-tumor necrosis factor-α drugs seem effective in patients with refractory Takayasu arteritis and vascular BD but have failed to do so in giant cell arteritis. Preliminary reports on the use of the anti-IL6-receptor antibody (tocilizumab), in LVV have been encouraging. The development of new biologic targeted therapies will probably open a promising future for patients with LVV.

[Takayasu arteritis]. / La maladie de Takayasu.

Takayasu arteritis is a chronic inflammatory vasculitis of unknown origin affecting large vessels, predominantly the aorta and its main branches. Vessel inflammation leads to wall thickening, fibrosis, and stenosis. The lesions are often asymptomatic leading to limb numbness, transient ischemic attack, cardiovascular event and renovascular hypertension. Treatment is based on corticosteroids, immunosuppressant and biologics if necessary. Endovascular treatment and open-surgery can be useful for end-organ ischemia relief.

Takayasu Arteritis and Pregnancy.

OBJECTIVE: To assess the relationship between Takayasu arteritis (TAK) and pregnancy outcome. METHODS: This study included 240 pregnancies in 96 patients fulfilling the American College of Rheumatology 1990 criteria for the classification of TAK and/or the 1994 Chapel Hill Consensus Conference nomenclature/criteria for vasculitis. We analyzed obstetric and maternal outcomes in women who were pregnant before and/or at the same time as or after TAK diagnosis. We assessed factors associated with complicated pregnancy. RESULTS: One hundred forty-two pregnancies occurred in 52 patients before TAK diagnosis (median age at pregnancy 26 years [interquartile range 23-30 years]), and 98 pregnancies occurred in 52 patients concomitant with or after TAK diagnosis (median age at pregnancy 28 years [interquartile range 26-31 years]). Pregnancies concomitant with or after TAK diagnosis had a 13-fold higher rate of obstetric complications compared to pregnancies before TAK diagnosis (odds ratio 13 [95% confidence interval 5-33], P < 0.0001). TAK was associated with a 40% frequency of obstetric complications, including preeclampsia/eclampsia (24 pregnancies [24%]), premature delivery (8 pregnancies [8%]), and intrauterine fetal growth restriction or death (5 pregnancies [5%]). Maternal complications of TAK occurred during 39% of pregnancies and included mainly new-onset or worsening hypertension (26 pregnancies [27%]). In multivariate analysis, smoking (odds ratio 6.15 [95% confidence interval 1.31-28.8]) and disease activity of TAK (a National Institutes of Health score of >1) (odds ratio 28.7 [95% confidence interval 7.89-104.7]) were independently associated with obstetric and maternal complications. CONCLUSION: TAK negatively affects pregnancy outcomes. Disease activity increases the risk of obstetric and maternal complications, mainly due to arterial hypertension.

[Peripheral artery occlusive disease of the lower limbs: Rapid aggravation in a patient taking nilotinib for chronic myeloid leukemia]. / Artériopathie des membres inférieurs d'aggravation rapide chez un patient traité par nilotinib pour leucémie myéloïde chronique.

The development of tyrosine kinase inhibitors (TKI) has revolutionized management of patients with chronic myeloid leukemia (CML), transforming this fatal disease into a chronic disease with nearly normal life expectancy. Nilotinib is a second generation TKI targeting the oncoprotein BCR-ABL used in patients in the chronic phase of CML. Several research teams have suggested over recent years that nilotinib might be the causal agent in the development or aggravation of vascular disease, particularly in patients with cardiovascular risk factors or an established cardiovascular disease. We report here the case of a patient who developed severe peripheral arterial disease of the lower limbs that worsened despite optimal medical and surgical care, presenting recurrent re-stenoses after different revascularization techniques (bypass, angioplasty…) associated with aggravation of severe trophic disorders to the point of potentially requiring amputation. Discontinuation of nilotinib enabled a stabilization of the arterial lesions and complete healing of the trophic lesions. This case illustrates the importance of recognizing co-morbid conditions in patients with severe vascular disease and to examine the possibility of drug interactions leading to rapid aggravation of arterial disease with no other cause. Studying the pathophysiological impact of TKIs on the vascular system may open new avenues of research for the investigation of factors triggering arteriosclerosis.

[Distal revascularization in diabetic patients with chronic limb ischemia]. / La revascularisation distale des diabétiques en ischémie critique.

Diabetes mellitus is an independent risk factor for peripheral artery disease. Life expectancy is 41 months for diabetic patients with an ischemic ulcer. The characteristics of diabetic arteriopathy make its treatment more difficult than in non-diabetic patients. Few data are available about the surgical treatment of arteriopathy in diabetic patients (including angioplasty or bypass), especially in case of distal arteriopathy. The choice of the procedure depends on multiple factors such as the disease localization, its extent, distal blood flow and vascular disease-related surgical risk. The principal aim of revascularisation is to restore direct flow to the foot in order to ensure wound healing and limb salvage. With percutaneous endoluminal angioplasty, limb salvage can be achieved in more than 80% of patients at 1-3 years. The percutaneous procedure is less invasive than open surgery, there are fewer complications, and morbidity and mortality rates are reduced; moreover, a second procedure remains possible in the future. With bypass surgery, the rate of limb salvage exceeds 80% at five years. Nevertheless, peri-operative mortality reaches 3% and arterial anatomy, patient-related risks factors or venous graft availability may be limitations. New endovascular techniques especially designed for the distal arteries of the lower limbs enable very distal revascularization with morbidity and mortality rates lower than with surgery.