Coagulopathy, thromboembolic complications, and the use of heparin in COVID-19 pneumonia.

The SARS-CoV-2 (COVID-19) is causing a pandemic and potentially fatal disease of global public health concern. Viral infections are known to be associated with coagulation impairment; thus, thrombosis, hemorrhage, or both may occur. Understanding the pathophysiologic mechanisms underlying the development of coagulation disorders during viral infection is essential for the development of therapeutic strategies. Coagulopathy in COVID-19 infection is emerging as a precipitant factor for severe respiratory complications and death. An increase in coagulation markers, such as fibrinogen and D-dimer, has been found in severe COVID-19 cases. Heparin, clinically used as an anticoagulant, also has anti-inflammatory properties, including binding of inflammatory cytokines, inhibition of neutrophil chemotaxis, and protection of endothelial cells, and a potential antiviral effect. We hypothesized that low-molecular-weight heparin may attenuate cytokine storm in COVID-19 patients; therefore, low-molecular-weight heparin could be a valid adjunctive therapeutic drug for the treatment of COVID-19 pneumopathy. In this paper, we review potential mechanisms involved in coagulation impairment after viral infection and the possible role of heparin in the treatment of COVID-19 patients.

Gamma Knife Radiosurgery for Short Unilateral Neuralgiform Headache Attacks with Conjunctival Injection and Tearing (SUNCT) Syndrome: Targeting the Trigeminal Nerve and the Sphenopalatine Ganglion. Case Report and Literature Review.

BACKGROUND: Short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) is a primary headache syndrome with an unclear pathogenesis, and only in very few cases, SUNCT is secondary to known lesions (secondary SUNCT). Several pharmacological as well as interventional and invasive treatments have been used to treat SUNT cases, with no definitive results. We describe a patient with idiopathic SUNCT syndrome, successfully treated with gamma knife radiosurgery and we report a review of the cases of the literature treated with radiosurgery. CASE REPORT: A 63-year-old woman complained of episodes of intense and regular paroxysmal facial pain in the territory of the maxillary branch of the trigeminal nerve accompanied by inflammation of conjunctiva and involuntary lacrimation from 2006. During the following years, she received several treatments: combination of drugs, acupuncture, and endonasal infiltration of the sphenopalatine ganglion. The frequency of the painful attacks increased progressively and it was impossible for her to have a normal active life. Combined gamma knife radiosurgery treatment, targeting the trigeminal nerve (80 Gy maximum dose) and the sphenopalatine ganglion (80 Gy maximum dose) was performed in April 2016 (visual analog score before treatment = 6). Pain gradually reduced in the following months, as well as frequency and severity of the attacks. No sensory deficit developed. The follow-up length of our patient is 37 months: she is nearly pain free (visual analog score = 2) and has resumed a normal life. CONCLUSIONS: Patients with idiopathic SUNCT have few therapeutic options. Our case demonstrates that gamma knife radiosurgery is a feasible and effective noninvasive option to treat patients with medically refractory idiopathic SUNCT.

[Late recovery of renal function in a patient with acute on chronic renal failure treated with peritoneal dialysis]. / Tardivo recupero della funzione renale in un paziente con insufficienza renale acuta su cronica trattato con dialisi peritoneale.

Contrast-induced nephropathy has become a significant source of hospital morbidity and mortality particularly in patients with multi-organs defects. No current treatment can reverse or ameliorate contrast induced nephropathy once it occurs, but prophylaxis is possible. We present the case of a 61-year-old male patient with concomitant chronic kidney disease (CKD stage III K/DOQI) and diabetes complicated by severe multi-vascular disease, who developed acute kidney damage probably due to the simultaneously exposure to intravascular contrast media and cholesterol crystal embolism. In addition, owing to rapid deterioration of renal function, this patient started renal replacement therapy. No renal biopsy was performed due to the poor clinical condition of the patient. After a month of hemodialysis, he switched to a peritoneal dialysis procedure to which specific treatment for vascular lesions, including antibiotics, prostanoids, hyperbaric oxygen therapy, antiaggregants/anticoagulants and physiotherapy, was associated. After 7 months, the dialysis treatment was stopped and he began intensive clinical follow-up. At present, the patient is in conservative medical treatment (the Tenckhoff catheter has been removed), he is in good condition and severe vascular lesions are absent. Our conclusion is that contrast-induced nephropathy in vasculopathic diabetic patients requires a multidisciplinary approach. In particular, good cooperation between nephrologists and angiologists is useful to avoid rapid and chronic deterioration of renal failure and to prevent the onset and development of severe vascular damage.

Effect on walking distance and atherosclerosis progression of a nitric oxide-donating agent in intermittent claudication.

BACKGROUND: Peripheral arterial disease (PAD) is almost invariably associated with a generalized atherosclerotic involvement of the arterial tree and endothelial dysfunction. Previous short-term studies showed improvement of vascular reactivity and walking capacity in PAD patients by measures aimed at restoring nitric oxide (NO) production. NO is also known to prevent the progression of atherosclerosis. We wished to assess whether the prolonged administration of an NO-donating agent (NCX 4016) improves the functional capacity of PAD patients and affects the progression of atherosclerosis as assessed by carotid intima-media thickness (IMT). METHODS: This prospective, double-blind, placebo-controlled study enrolled 442 patients with stable intermittent claudication who were randomized to NCX 4016 (800 mg, twice daily) or its placebo for 6 months. The primary study outcome was the absolute claudication distance on a constant treadmill test (10% incline, 3 km/h). The main secondary end point was the change of the mean far-wall right common carotid artery IMT. RESULTS: The increase of absolute claudication distance at 6 months compared with baseline was 126±140 meters in the placebo-treated group and 117±137 meters in the NCX 4016-treated group, with no significant differences. Carotid IMT increased in the placebo-treated group (+0.01±0.01 mm; P=.55) and decreased in the NCX 4016-treated group (-0.03±0.01 mm; P=.0306). Other secondary end points did not differ between the two treatments. CONCLUSIONS: Long-term NO donation does not improve the claudication distance but does reduce progression of atherosclerosis in patients with PAD. Further studies aimed at assessing whether long-term NO donation may prevent ischemic cardiovascular events are warranted.

Ascorbic acid prevents vascular dysfunction induced by oral glucose load in healthy subjects.

OBJECTIVES: To examine the effects of oral glucose load on forearm circulatory regulation before and after ascorbic acid administration in healthy subjects. DESIGN: Microcirculation study with laser Doppler was performed at the hand in basal conditions, after ischemia and after acetylcholine and nitroprusside; strain gauge plethysmography was performed at basal and after ischemia. The tests were repeated in the same sequence 2 hour after oral administration of glucose (75 g). The subjects were randomised for administration of ascorbic acid (1 g bid) or placebo (sodium bicarbonate 1 g bid) for 10 days. After that, the tests were repeated before and after a new oral glucose load. Blood pressure and heart rate were monitored. RESULTS: Macrocirculatory flux, pressure values and heart rate were unvaried throughout the study. The glucose load caused a reduction in the hyperemic peak flow with laser Doppler and plethysmography; it reduced flux recovery time and hyperemic curve area after ischemia; acetylcholine elicited a minor increase in flux with laser Doppler. The response to nitroprusside was unvaried after glucose load as compared to basal conditions. Treatment with ascorbic acid prevented the decrease in hyperemia after glucose, detected with laser Doppler and plethysmography. Ascorbic acid prevented the decreased response to acetylcholine after glucose, the response to nitroprusside was unaffected by ascorbic acid. Results after placebo were unvaried. CONCLUSIONS: Oral glucose load impairs endothelium dependent dilation and hyperaemia at microcirculation, probably via oxidative stress; ascorbic acid can prevent it.

Endothelial progenitor cells in patients with severe peripheral arterial disease.

The aims of this study were to investigate the interrelationships between endothelial progenitor cells (EPCs), peripheral arterial disease (PAD), and atherosclerotic risk factors, as only limited data are available regarding the EPCs in patients with PAD. The authors studied the number of EPCs by different methods in a carefully selected group of 45 patients with PAD along with 24 healthy subjects (HS). In patients with PAD, by utilizing the dual-binding method, the number of EPCs was significantly increased compared to HS (M +/- SD, PAD: 73 +/- 33, HS: 52 +/- 20 EPCs/high power field; p < .001). On the contrary, both CD34(+) cell count and CD133(+) cell count were significantly decreased compared to HS. Colony-forming units were significantly increased in PAD compared to HS (median and 25th and 75th percentiles, PAD: 7, 1, 9; HS: 1, 1, 4 CFU/well, respectively; Mann-Whitney, p = .006). In patients with PAD, the number and proliferative activity of circulating EPCs are increased with respect to HS even though EPC count by flourecence-activated cell sorting (FACS) analysis provided different results and this may explain the discrepancy in data collected using different methods. The regulation of the number and biological activity of EPCs in PAD remains unclear.

Forearm haemodynamics, arterial stiffness and microcirculatory reactivity in rheumatoid arthritis.

OBJECTIVES: Cardiovascular disease is the major cause of mortality in patients with rheumatoid arthritis. This work studied the presence of impaired forearm haemodynamics, arterial stiffness and microcirculatory reactivity in young women with rheumatoid arthritis. METHODS: Sixty-five women aged 41-52 years, with rheumatoid arthritis, were screened for the absence of common cardiovascular risk factors. They underwent laser Doppler study on the hand at rest and after ischaemia, endothelium-dependent dilation with colour Doppler ultrasound and pulsewave velocity (PWV). Forty healthy subjects were also examined. RESULTS: Microcirculatory flux at rest with laser Doppler was reduced in rheumatoid arthritis patients (112 +/- 45 versus 220 +/- 65 perfusion units (PU, arbitrary units); P < 0.005), post-ischaemic peak flow was lower in rheumatoid arthritis patients (235 +/- 65 versus 329 +/- 76 PU; P < 0.05); percentage increase in peak flow was higher in rheumatoid arthritis patients compared with healthy subjects (153 +/- 12 versus 65 +/- 18%; P < 0.005). Time to peak flow was longer in rheumatoid arthritis patients (12.7 +/- 8 versus 6.2 +/- 2 s; P < 0.005). Higher microcirculatory resistance was detected in rheumatoid arthritis patients (0.656 +/- 0.011 versus 0.358 +/- 0.009 mmHg/PU; P < 0.05). Endothelium-dependent dilation was impaired in rheumatoid arthritis patients (increase in artery dilation 8.2 +/- 2 versus 11.5 +/- 3%; P < 0.05) and correlated directly with actual C-reactive protein. PWV was higher in rheumatoid arthritis patients (9.3 +/- 0.2 versus 8.4 +/- 0.4 m/s; P < 0.05) and correlated directly with the duration of disease. District resistance by the arm was higher in rheumatoid arthritis patients (1098 +/- 190 versus 661 +/- 55 mmHg/l per minute; P < 0.005). CONCLUSION: Female rheumatoid arthritis patients present with impaired microcirculatory reactivity, endothelial dysfunction and increased arterial stiffness. Alterations in the vascular bed are extended and may explain the increased incidence of cardiovascular events in these patients.

Endothelial progenitor cells in patients with essential hypertension.

OBJECTIVE(S): The eventual role of blood pressure on the endothelial progenitor cell (EPC) has rarely been evaluated and data collected so far relate to patients with co-existing coronary heart disease. METHODS: We have studied the number and functional activity of EPC as well as the number of EPC endothelial colony-forming units (CFU) in a carefully selected group of 36 patients with essential hypertension and 24 normotensive control subjects. RESULTS: In patients with essential hypertension, the EPC number was not statistically different from that found in control subjects (mean +/- SD, essential hypertension 58 +/- 29, controls 53 +/- 20; EPC/high power field). CFU per well were not statistically different in patients with essential hypertension compared with normotensive controls (mean +/- SD, patients with essential hypertension 2.4 +/- 2.6, normotensive controls 3 +/- 3.3 CFU/well). In essential hypertension patients, the EPC number was inversely correlated with both total (R=0.635, P < 0.0001) and low-density lipoprotein (LDL)-cholesterol (R=0.486, P < 0.05). Neither the EPC number nor the EPC CFU were correlated with age, systolic blood pressure, diastolic blood pressure, body mass index, lipoprotein(a), high-sensitivity C-reactive protein or homocysteine. CONCLUSIONS: The present study shows that essential hypertension is not characterized by the altered number or functional activity of EPC. Plasma total and LDL-cholesterol are independent predictors of reduced numbers of circulating EPC in essential hypertension patients. The absence of any correlation between the characteristics of EPC and several markers predictive of cardiovascular damage merits further investigation.

Inflammation and platelet activation in peripheral arterial occlusive disease.

OBJECTIVES: Epidemiological evidence indicates that inflammation accompanies the progression of atherosclerosis. The aim of the present cross-sectional study was to define relationships between platelet activation and inflammation in patients with mild to severe (stages II to IV) peripheral arterial occlusive disease (PAOD) and matched controls. The effect of chronic administration of low-dose acetylsalicylic acid was investigated. METHODS: Subjects were studied on a single occasion. C-reactive protein (CRP) and two indexes of in vivo platelet activation were measured - the urinary excretion of 11-dehydrothromboxane (TX) B(2) by immunoassay and circulating platelet-monocyte aggregates (PMAs) by flow cytometry. RESULTS: Plasma PMAs and urinary 11-dehydro-TXB(2) were significantly increased in PAOD patients compared with controls (P<0.01 for all). A positive correlation between 11-dehydro-TXB(2) and CRP was found in the study population (r(s)=0.63, P<0.001). Using logistic regression analysis, CRP was the only independent correlate of 11-dehydro-TXB(2) (ß(CRP)=11.9, P<0.01), whereas only the presence of PAOD was an independent predictor of high PMA levels (ß(PAOD)=13.7, P=0.001). Chronic administration of acetylsalicylic acid reduced 11-dehydro-TXB(2), but not PMA and CRP. CONCLUSIONS: There is evidence that platelet activation in patients with PAOD is related to the vascular disease and is dependent on the severity of inflammation.

Ischemia-modified albumin and NT-prohormone-brain natriuretic peptide in peripheral arterial disease.

Cardiovascular disease is the leading cause of mortality and morbidity in Western countries. Despite its remarkable medical and social consequences, the prevalence of peripheral arterial disease (PAD) is often underestimated among atherosclerotic disorders. So far, little is known about the behavior of traditional and emerging markers of ischemic heart disease that should allow the reliable identification of PAD patients at increased risk of developing myocardial ischemia and heart failure or dysfunction. To investigate this topic, we measured cardiac troponin T (cTnT), ischemia-modified albumin (IMA) and NT-prohormone-brain natriuretic peptide (NT-proBNP) in 35 consecutive patients with clinically ascertained PAD (stage 2-4, according to Lériche-Fontaine) asymptomatic for chest pain and current heart failure, and 20 controls displaying moderate to high cardiovascular risk factors (hypertension, diabetes, hyperlipidemia), but with no clinical evidence of PAD. Although the concentrations of cTnT and IMA were not statistically increased in PAD patients, NT-pro-BNP values were substantially higher in PAD patients than in controls (62.6 vs. 7.4 pmol/L, p<0.0001). The percentage of subjects displaying values exceeding the specific NT-proBNP diagnostic threshold (>14.8 pmol/L) was also significantly different between PAD patients and controls (74% vs. 10%, p<0.001). After excluding PAD patients exceeding the 0.01 ng/mL cTnT cutoff value indicative of current ischemic cardiac involvement, the median concentration of NT-proBNP remained statistically increased (28.0 vs. 5.8 pmol/L, p<0.0001). Taken together, these results indicate that NT-proBNP, but not IMA, is substantially increased in PAD patients. This finding suggests that such patients, even though asymptomatic, might develop myocardial dysfunction, and thus warrant further investigation.

Haemodynamic effects of eprosartan and valsartan in hypertensive patients during isometric and mental stress.

OBJECTIVE: To assess the effects of eprosartan and valsartan on the haemodynamics of forearm circulation in hypertensives undergoing isometric and mental stress. DESIGN AND METHODS: Thirty-six patients with essential stable hypertension underwent haemodynamic evaluations on the left arm: humeral flux and calibre by means of colour Doppler ultrasound, microcirculatory flux on the third finger of left hand by means of laser Doppler flowmetry, blood pressure and heart rate monitor. District resistance was calculated as the ratio between mean arterial pressure and blood flow, and microcirculatory conductance was calculated as the ratio between flux and the mean pressure. The evaluations were performed at rest, during handgrip and during mental stress. Patients were randomized to receive eprosartan (600 mg) or valsartan (160 mg); tests were repeated after 15 days of therapy. RESULTS: Both treatments reduced blood pressure (P<0.05) and peripheral resistance during tests. Eprosartan obtained a greater reduction in resistance during handgrip than valsartan. Laser Doppler flowmetry showed a significant decrease of flux only with mental stress. Laser Doppler flowmetry showed a reduction in conductance during both tests--this reduction was smaller with eprosartan during handgrip. None of the molecules affected the conductance during mental stress. While both were able to reduce microcirculatory decrease in conductance; in particular, eprosartan controlled this drop during handgrip better than valsartan. CONCLUSIONS: Angiotensin II receptor type 1 inhibition exerts protective effects during adrenergic and noradrenergic stress in hypertensives. Eprosartan is more efficacious than valsartan in controlling noradrenergic effects.

Determinants of platelet activation in human essential hypertension.

Experimental data suggest that oxidative stress might be enhanced in hypertension and contribute to platelet activation. We hypothesized that both oxidative stress and platelet activation could be related to the clinical characteristics of hypertensive patients. The urinary excretion of 11-dehydrothromboxane (TX) B2, reflecting in vivo platelet activation, was measured in 75 patients with mild to severe essential hypertension and 75 pair-matched, healthy controls. The urinary excretion of 8-iso-prostaglandin (PG) F2alpha was determined as an index of in vivo lipid peroxidation. Urinary 11-dehydro-TXB2 was significantly higher in essential hypertensives compared with controls. Although no statistically significant difference in urinary 8-iso-PGF2alpha was observed between patients and controls, plasma vitamin C was lower and plasma homocysteine higher in hypertensive patients than in controls. Both urinary 11-dehydro-TXB2 and 8-iso-PGF2alpha were higher in patients with advanced hypertensive retinopathy compared with patients without retinopathy. Multivariate linear regression analysis identified urinary 8-iso-PGF2alpha, plasma fibrinogen, homocysteine, and vitamin E as the only variables independently correlated with urinary 11-dehydro-TXB2. Logistic regression analysis showed that high urinary 8-iso-PGF2alpha, plasma fibrinogen, and homocysteine, as well as low plasma vitamin E, advanced retinopathy, elevated diastolic blood pressure, and the absence of antihypertensive treatment, were predictors of high urinary 11-dehydro-TXB2. We demonstrated increased oxidative stress and persistent platelet activation in essential hypertensives with advanced vascular lesions. These findings might help identify hypertensive patients who are at increased risk of cardiovascular events and who might benefit from long-term antiplatelet therapy.

Increased oxidative stress and platelet activation in patients with hypertension and renovascular disease.

BACKGROUND: Hypertensive patients with renovascular disease (RVD) may be exposed to increased oxidative stress, possibly related to activation of the renin-angiotensin system. METHODS AND RESULTS: We measured the urinary excretion of 8-iso-prostaglandin (PG) F2alpha and 11-dehydro-thromboxane (TX) B2 as indexes of in vivo lipid peroxidation and platelet activation, respectively, in 25 patients with RVD, 25 patients with essential hypertension, and 25 healthy subjects. Plasma renin activity in peripheral and renal veins, angiotensin II in renal veins, cholesterol, glucose, triglycerides, homocysteine, and antioxidant vitamins A, C, and E were also determined. Patients were also studied 6 months after a technically successful angioplasty of the stenotic renal arteries. Urinary 8-iso-PGF2alpha was significantly higher in patients with RVD (median, 305 pg/mg creatinine; range, 124 to 1224 pg/mg creatinine) than in patients with essential hypertension (median, 176 pg/mg creatinine; range, 48 to 384 pg/mg creatinine) or in healthy subjects (median, 123 pg/mg creatinine; range, 58 to 385 pg/mg creatinine). Urinary 11-dehydro-TXB2 was also significantly higher in RVD patients compared with healthy subjects. In RVD patients, urinary 8-iso-PGF2alpha correlated with 11-dehydro-TXB2 (r(s)=0.48; P<0.05) and renal vein renin (r(s)=0.67; P<0.005) and angiotensin II (r(s)=0.65; P=0.005) ratios. A reduction in 8-iso-PGF2alpha after angioplasty was observed in RVD patients with high baseline levels of lipid peroxidation. Changes in 8-iso-PGF2alpha were related to baseline lipid peroxidation (r(s)=-0.73; P<0.001), renal vein angiotensin II (r(s)=-0.70; P<0.01) and renin (r(s)=-0.63; P<0.05) ratios. CONCLUSIONS: Lipid peroxidation is markedly enhanced in hypertensive patients with RVD and is related to activation of the renin-angiotensin system. Moreover, persistent platelet activation triggered or amplified by bioactive isoprostanes may contribute to the progression of cardiovascular and renal damage in this setting.

Effects of nebivolol and atenolol on small arteries and microcirculatory endothelium-dependent dilation in hypertensive patients undergoing isometric stress.

OBJECTIVE: To examine the effects on small arteries and on the cutaneous microcirculatory system of nebivolol and atenolol in hypertensive patients. DESIGN: Twenty hypertensive patients were randomly assigned to receive nebivolol or atenolol in a single-blind, placebo-controlled cross-over study. Piezoelectric plethysmography on the third finger, laser Doppler on the third finger at rest and after iontophoretic administration of acetylcholine, and pressure-heart rate monitoring, were carried out both at rest and during handgrip. The tests were performed 45 min after 5 mg nebivolol or 100 mg atenolol administration, then repeated 2 days later with a placebo and, after a further 2 days, with atenolol or nebivolol again. RESULTS: Both atenolol and nebivolol reduced diastolic blood pressure values and heart rate, as well the increase of blood pressure and heart rate during handgrip. No change was recorded after placebo. Piezoelectric plethysmography showed a significant increase in the ratio between time to peak and total time (PT/TT), calculated on the sphygmic wave, during handgrip (0.295 0.005 versus 0.231 0.015, P<0.005). After nebivolol, a decrease was recorded in rest conditions (0.185 0.008 versus 0.231 0.015, P<0.005) with no statistically significant increase during handgrip, whereas atenolol showed an increase in the PT/TT ratio at rest, with a sustained response during handgrip. Laser Doppler showed an increased response to acetylcholine only after nebivolol. CONCLUSIONS: Nebivolol and atenolol significantly reduced diastolic blood pressure and heart rate, favourably modulating response to handgrip. Nebivolol improved small artery distensibility index. Endothelium-dependent cutaneous vasodilation after acetylcholine demonstrated a lack of response with atenolol whereas nebivolol favourably acts on endothelial function.

Effect of glutathione infusion on leg arterial circulation, cutaneous microcirculation, and pain-free walking distance in patients with peripheral obstructive arterial disease: a randomized, double-blind, placebo-controlled trial.

OBJECTIVE: To assess the effects of glutathione on pain-free walking distance (PFWD) and hemodynamic parameters in patients with peripheral artery disease. PATIENTS AND METHODS: Forty patients with Fontaine stage II peripheral artery disease who were seen between September 2000 and March 2001 at the vascular laboratory and ward of the Division of Vascular Medicine and Rehabilitation at Verona University were studied in a double-blind, placebo-controlled trial. The patients were randomly assigned (20 per group) to treatment with intravenous glutathione twice a day or saline solution twice a day for 5 days. Treatments were administered in a double-blind manner. The 2 groups of patients underwent measurement of PFWD by strain-gauge plethysmography and laser Doppler flowmetry (with postischemic test) of the symptomatic leg at rest and after treadmill test. All measurements and tests were repeated 12 hours after the last infusion. RESULTS: Between the 2 groups, hemodynamic tests showed no differences in baseline values and at rest after treatment. At rest, no differences were observed between basal and posttreatment values; findings in the saline group were similar during tests before and after the infusion period. In the glutathione group, we observed increases in PFWD (196+/-15 vs 143+/-11 m; P<.04), macrocirculatory flow after treadmill test with plethysmography at the end of treatment (9.3+/-2 vs 2.8+/-0.5 mL per 100 mL/min; P<.002), and postischemic hyperemia with laser Doppler flowmetry, registered as perfusion units (PU), at the end of infusions (14.4+/-3.2 vs 6.18+/-1.5 PU; P<.005), with a greater area under the curve after treatment (705+/-103 vs 508+/-45 PU/s; P<.001) and reduced time to flow motion (32+/-4 vs 48+/-11 seconds; P<.05). CONCLUSION: In patients with peripheral artery disease, glutathione prolongs PFWD and shows an improvement of macrocirculatory and microcirculatory parameters.