Michelangelo Sartori

Evolution of untreated calf deep-vein thrombosis in high risk symptomatic outpatients: the blind, prospective CALTHRO study.

The natural history of calf deep-vein thrombosis (DVT) is still uncertain and it is debated whether it warrants to be diagnosed and treated. We aimed to investigate the complication rate of untreated isolated calf DVT (ICDVT). Symptomatic outpatients were prospectively managed with serial compression ultrasonography (SCUS). Those without proximal DVT and with likely pre-test clinical probability (PCP) or altered D-dimer received immediate subsequent complete examination of calf deep veins (CCUS) by a different operator. The result of CCUS was kept blind both to the managing doctor and the patient and disclosed after three months. Primary outcome was the rate of venous thromboembolism at three months. We examined 431 subjects (196 males; median age 68.0 years) in whom five outcomes were recorded (1.2%; 95% confidence intervals [CI]: 0.4-2.7). If CCUS results had been available, outcomes would have been recorded in 3/424 patients (0.7%; 95% CI: 0.2-2.1) with two events in subjects negative at both serial and complete CUS. ICDVT was diagnosed in 65 subjects (15.3%; 95% CI: 12-19); of whom 59 remained uneventful (one was lost to follow-up). A significant higher rate of outcomes was recorded in subjects with than without ICDVT (5/64; 7.8%; 95% CI: 3-17 vs. 3/351; 0.8%; 95% CI: 0-2; p=0.003). However, after excluding two events picked at serial CUS in subjects with ICDVT, the difference became barely significant (3/64; 4.7%; 95% CI: 1-13; p=0.049). Thrombotic evolution of untreated ICDVT in high-risk subjects may be relevant. Larger studies are needed to address this issue.

The Wells rule and D-dimer for the diagnosis of isolated distal deep vein thrombosis

Summary.  Background:  Pretest clinical probability with the Wells rule and D‐dimer have been widely investigated for the diagnosis of symptomatic proximal deep vein thrombosis (DVT) of the lower limbs, but they have not been formally tested for symptomatic isolated distal DVT diagnosis.

Two years outcome of isolated distal deep vein thrombosis

BACKGROUND Isolated distal deep vein thrombosis (IDDVT) is frequently found in symptomatic outpatients, but its long term outcome is still uncertain. AIMS To assess IDDVT long term outcome and the impact of IDDVT characteristics on outcome. METHODS In a prospective, single center study we enrolled symptomatic outpatients in whom IDDVT was detected by whole-leg compression ultrasonography. Patients with provoked IDDVT were treated with low molecular weight heparins (LMWH) for 30 days while those with unprovoked IDDVT received with vitamin K antagonists (VKA) for three months. The primary end-point was the rate of the composite of pulmonary embolism (PE), proximal deep vein thrombosis (DVT), and IDDVT recurrence/extension during 24 month follow-up. RESULTS 90 patients (age 61 ± 18, male 48.9%) were enrolled. Risk factors for thrombosis were reduced mobility (34.4%), obesity (25.3%), surgery (15.6%), and previous DVT (15.6%) and cancer in 8 patients (8.9%). Eighty-eight patients were treated (56 with LMWH and 32 with VKA). During follow-up (median 24 ± 2 months), 17 events were recorded, which included 3 PE (two in cancer patients), 4 proximal DVTs (one in cancer patient) and 10 IDDVT. Male sex (HR 4.73 CI95%: 1.55-14.5; p=0.006) and cancer (HR 5.47 CI95%: 1.76-17.6; p=0.003) were associated with a higher risk of complications, whereas IDDVT anatomical characteristics, anticoagulant therapy type, and provoked IDDVT were not. CONCLUSIONS The risk of recurrent venous thromboembolism after IDDVT may be relevant in male patients or in patients with active cancer. Larger studies are needed to address this issue.

Thrombophilic risk factors and peripheral arterial disease severity

Few data are available on thrombophilic risk factors and progression of atherosclerotic peripheral arterial disease (PAD). Thrombophilic alterations can be an aggravating factor when arterial stenoses are present. In a cross-sectional study, we evaluated the presence of the thrombophilic factors fibrinogen, homocysteine, factor (F)VIII, lupus anticoagulant (LAC), FII G20210A, and FV R506Q mutations in 181 patients with PAD at Fontaines stage II (claudication), in 110 patients with critical limb ischaemia (CLI), and in 210 controls. Fibrinogen was higher in patients with CLI vs. those with claudication and controls (427.9 +/- 10.5 vs. 373.1 +/- 5.2 vs. 348.9 +/- 7.0 p=0.001, respectively). Homocysteine and FVIII were higher in patients with PAD than in controls, but were similar in patients with CLI and claudication. The prevalence of LAC increased in patients with CLI vs. those with claudication and controls (21.4% vs. 7.8% vs. 5.2% p<0.001, respectively). The prevalence of FII 20210A allele was higher in patients with CLI vs. those with claudication and controls. Using a logistic model, FII G20210A mutation (odds ratio [OR] 19.8, confidence interval [CI] 4.5-87.1, p=0.001), LAC (OR 2.7, CI1.1-6.5, p=0.032), and fibrinogen (OR 1.01, CI 1.00-1.01, p=0.001) were associated with CLI, whereas homocysteine, FVIII, and FV R506Q mutation were not. CLI risk increased according to the number of thrombophilic alterations. In conclusion, altered levels of some important thrombophilic risk factors are independently associated with PAD severity. These data suggest that the presence of two or more thrombophilic risk factors raise the likelihood of PAD being more severe, justifying the need for larger longitudinal studies.

D-dimer for the diagnosis of upper extremity deep and superficial venous thrombosis

BACKGROUND D-dimer role is well established in the diagnostic work-up for lower limb deep vein thrombosis (DVT), however it has not been formally tested for clinically suspected upper extremity DVT and/or superficial vein thrombosis (SVT). AIM To ascertain D-dimer diagnostic accuracy for upper extremity DVT and/or SVT. STUDY DESIGN We performed a single centre management study in outpatients referred by emergency or primary care physicians for clinically suspected upper extremity DVT. All patients underwent D-dimer testing (cut-off value: ≤500 ng/mL), and a B-mode and color Doppler ultrasonography examination. In case of either technical problems or anatomical barriers, ultrasonography was repeated after 5-7 days. All patients were followed up for three months for the occurrence of symptomatic DVT and/or SVT and/or pulmonary embolism. RESULTS We enrolled 239 patients (F: 63.6%; mean±SD age: 58.3±16.8). At the initial diagnostic work-up, DVT was detected in 24 (10%) patients while SVT in 35 (14.6%) patients. During follow-up, one upper extremity DVT was found. D-dimer levels were higher in patients with DVT than in those without. Sensitivity and specificity of D-dimer for DVT were 92% (95%CI: 73-99%) and 60% (95%CI: 52-67%) respectively, with a negative predictive value of 98% (95%CI: 93-100%), whereas for SVT they were 77% (95%CI: 59-89%) and 60% (95%CI: 52-67%) respectively, with a negative predictive value of 93% (95%CI: 86-97%). CONCLUSIONS D-dimer has a negative predictive value ≥93% for excluding DVT in symptomatic outpatients and it can be a useful test in the diagnostic work-up of suspected upper extremity DVT.

D-dimer, FVIII and thrombotic burden in the acute phase of deep vein thrombosis in relation to the risk of post-thrombotic syndrome

BACKGROUND Post-thrombotic syndrome (PTS) is the most common complication of deep vein thrombosis (DVT), but few data are available on the risk factors for PTS. AIMS To assess whether the time-course of D-dimer, FVIII, and thrombotic burden are related to PTS development. METHODS Patients (n=59) with proximal DVT of the lower limbs (age 64; range:20-88years; male 56%) were enrolled on the day of diagnosis (D0) and all received heparin for 5-7days, overlapped and followed by vitamin K antagonists (VKA) for 3months. Whole-leg compression ultrasound examination was conducted on D0 and 7 (D7), 30 (D30), and 90 (D90) days afterwards, when blood samples were also taken for D-dimer (STA Liatest) and FVIII (chromogenic assay) testing. Thrombotic burden was defined at each time point according to a score, which considered thrombosis extent and occlusion degree. Villalta score was evaluated at D30, D90, and D180. RESULTS At D90, 12 patients developed PTS (Villalta score ≥5) and the median Villalta score was 1 (IQR 0.3-3.0) and was not correlated with either D-dimer or FVIIII time course. At D180, 13 patients had PTS and they had similar thrombotic score at D0, D30 to those without PTS, but higher at D90 (7.6±5.1 vs. 3.2±3.6; p=0.011). Thrombotic score at D90 was correlated with Villalta score at D90 (rho=0.374, p=0.009) and at D180 (rho=0.436, p=0.006). CONCLUSIONS Thrombotic burden after 90days of VKA is correlated with PTS.

D-dimer use for deep venous thrombosis exclusion in elderly patients: a comparative analysis of three different approaches to establish cut-off values for an assay with results expressed in D-dimer units

The use of adapted cut‐off values in the elderly, combined with clinical probability (PTP), increases the proportion of patients in whom venous thromboembolism (VTE) can be safely excluded, compared with the conventional cut‐off value of 500 μg/L fibrinogen equivalent units (FEU). We evaluated the clinical performance of three different approaches to establish cut‐off values for a D‐dimer assay whose results are expressed in D‐dimer units (D‐DU).

G1691A factor V and G20210A FII mutations, acute ischemic stroke of unknown cause, and patent foramen ovale.

BACKGROUND Genetic polymorphisms of haemostatic factors such as G1691A factor V (FV Leiden) and G20210A prothrombin (FII) may be involved in the onset of patent foramen ovale (PFO)-related cerebral ischaemia. We assessed the possible association between such inherited thrombophilic alterations and right-to-left shunt in patients with stroke. METHODS We investigated the presence of G20210A FII and FV Leiden mutations in 340 Caucasian patients consecutively evaluated by our Angiology Unit for stroke of unknown cause. PFO was assessed in all patients with Transcranial Doppler with intravenous injection of agitated saline. Stroke patients were divided into two groups: patients with PFO (n=136), and patients without PFO (n=204). As control group, we studied 272 subjects with early venous insufficiency. RESULTS The prevalence of FII G20210A mutation was significantly higher in patients with PFO vs. controls (OR: 2.90; 95% CI: 1.19-7.07) and in patients without PFO vs. controls (OR: 2.88; 95% CI: 1.25-6.60) but was similar in patients with and without PFO (OR: 1.11; 95% CI: 0.51-2.44). The frequency of FV Leiden mutation was similar in the three groups. Across the population the presence of the FII G20210A mutation (OR: 2.97;95% CI: 1.32-6.69), a history of DVT (OR: 1.04; 95% CI: 1.02-1.06), and oestrogen-containing contraceptive therapy (OR: 1.14; 95% CI: 1.09-1.18) were all associated with stroke of unknown cause after adjustment for other risk factors, This was not the case with PFO. CONCLUSIONS Our data do not support the assumption that these inherited thrombophilic alterations are associated with PFO in patients with cryptogenic stroke. FII G20210A mutation may be associated with cryptogenic stroke irrespective of the presence of PFO.

Treatment of Isolated Below the Knee Deep Vein Thrombosis

The natural history of isolated distal deep-vein thrombosis (IDDVT) is still uncertain, as well as the real clinical risks associated with the disease and the need for its diagnosis and treatment. While more and more IDDVTs are diagnosed in everyday clinical practice, their appropriate therapeutic management is, unfortunately, far from straightforward, and different recommendations on how patients with diagnosed IDDVT should be treated are present between expert professionals and even among international guidelines. The present article aims at briefly reviewing the issue of IDDVT therapy in general, particularly focusing on the different approaches to the treatment of the disease that have been suggested by recent guidelines, those that are currently adopted in clinical practice, and necessary future directions.

The incidence of heparin-induced thrombocytopenia in patients treated with low molecular weight heparin for superficial vein thrombosis

BACKGROUND The risk of heparin induced thrombocytopenia (HIT) associated with low molecular weight heparin (LMWH) for treatment of superficial vein thrombosis (SVT) is uncertain. As a result the necessity of platelet count monitoring is unclear in this setting. AIMS To assess the risk of HIT in outpatients treated with LMWH for SVT. METHODS In a prospective single centre study we included all symptomatic outpatients in whom a real-time B-mode and color Doppler ultrasonography examination revealed SVT without DVT. Patients treated with vitamin K antagonists or fondaparinux were excluded. Patients received full dose enoxaparin for 1week followed by half therapeutic dose for 3weeks or parnaparin 8500UI aXa for 10days followed by 6400UI aXa once daily for 20days. Platelet count was performed on the day of diagnosis (D0) and 7 (D7), and 14 (D14) days afterward. Primary outcomes were the rate of thromboembolic events and of HIT during a 3-month follow-up. RESULTS 678 outpatients (age: 64.7±16.2years, male: 42.0%) were evaluated. During follow-up, 7 venous thrombo-embolic events were recorded (1.03% CI 95%: 0.50-2.11%), while no major bleeding was observed (0.0% CI 95%: 0.0-0.56%). Platelet count was 255±93×10(9)/L at D0, 245±93×10(9)/L at D7 (p=0.204 vs. D0) and 261±116×10(9)/L at D14 (p=0.405 vs. D0). No fall in platelet count>50% and no case of HIT were recorded (HR 0.0% CI 95%: 0-0.56%). CONCLUSIONS A 4-week LMWH treatment for SVT is associated with an incidence of HIT lower than 0.6% and platelet count monitoring may be omitted in this setting.