Peripheral nerve changes assessed by conduction velocity distribution in patients with primary Raynaud's phenomenon and dysautonomia.

AIM: Different mechanisms (neural and intravascular) are thought to be important in the pathogenesis of Raynaud's phenomenon (RP). In a previous study we confirmed autonomic nervous system impairment in patients with primary RP, but the pathogenic role of peripheral nerves remained unclear. The aim of the current study was an electrophysiological analysis of peripheral nerves using both standard conduction velocity and the conduction velocity distribution (CVD) in patients with primary RP in order to investigate the causes of dysautonomia. METHODS: We examined 34 patients with primary RP and dysautonomia and 31 sex- and age-matched controls. Standard motor and sensory conduction tests in ulnar and peroneal (sural) nerves and a CVD test in the same nerves were performed. RESULTS: Clinically, none of the patients had motor symptoms, while 35.3% of them presented sensory neuropathy. Standard neurographic tests were within the normal limits except for the significant prolongation of mean sensory latency in both examined nerves. CVD revealed significant slowing of motor conduction velocity in all the conduction values, e.g. in the 10th, 50th, and 90th percentiles of velocity. There were no differences in the width of the velocity distribution in the patient group and controls. CONCLUSION: The results of CVD indicated the presence of generalized subclinical peripheral motor nerve impairment (subclinical polyneuropathy) in patients with primary RP and dysautonomia. Based on the present and previous studies, we conclude that the mechanism of autonomic dysfunction in primary RP is mixed, resulting from both central and peripheral neural abnormalities.

Intermittent pneumatic compression in stable claudicants: effect on hemostasis and endothelial function.

AIM: Intermittent pneumatic compression (IPC) increases systemic fibrinolytic activity but may also injure endothelial cells and thereby induce coagulation. The safety and utility of IPC in patients with peripheral arterial disease (PAD) therefore remains uncertain. The aim of this study was to determine whether IPC is associated with coagulation activation and endothelial cell damage, platelet factor 4 (PF4), thrombin-antithrombin complex (TAT), total nitrate and nitrite level and von Willebrand factor (VWF) concentration. METHODS: PF4, TAT, total nitrate, nitrite level and VWF were analyzed before and after first, 5th, 15th session (1 hour/day) of IPC and then 3 weeks after completion of therapy in 25 claudicants and compared to 11 healthy volunteers of similar age and sex. RESULTS: PF4, a measure of platelet activation/secretion, was significantly higher in claudicants (55+/-50 IU/mL) compared to healthy controls (22+/-14 IU/mL) (P<0.05). In PAD patients PF4 has decreased steadily and significantly throughout the time of compressive therapy (to 33+/-42 IU/mL) and further more at the end of the follow-up period (23+/-26 IU/mL). TAT concentration was low in PAD patients but further decreased during IPC therapy. There was a tendency of nitrite and nitrate concentration to increase during the course of IPC therapy, but in PAD patients it did not reached statistical significance (P=0.2), while in healthy controls this increase was significant (up to 79+/-14 mmol/L, P<0.05) and persisted 3 weeks after completion of IPC (up to 82+/-7 mmol/L, P<0.05). VWF antigen concentration remained stable in claudicants during IPC therapy and 3 weeks later but significantly decreased during IPC therapy (after fifth and fifteenth IPC session, P=0.04) and stayed decreased 3 weeks after treatment termination in control group. Pain-free walking distance (PWD) had increased continuously during treatment period from 55+/-23 to 63+/-32 meters after fifth IPC treatment, to 81+/-43 (P<0.05) after the last session of therapy, and slightly decreased to 77+/-28 meters 3 weeks after completion of IPC. CONCLUSIONS: IPC is safe for PAD patients, does not activate coagulation, but decreases platelet activation and improves endothelial health; this coincides with significant prolongation of walking distance.

Autonomic dysfunction in primary Raynaud's phenomenon.

AIM: The pathogenesis of Raynaud's phenomenon is still unclear. Neural and intravascular mechanisms are thought to be involved in the pathological process. The role of the autonomic nervous system is continually discussed, with particular attention to over-reactivity of the sympathetic part. The aim of this study was the clinical and electrophysiological analysis of autonomic nervous system function in patients with primary Raynaud's phenomenon. METHODS: Thirty four patients with primary Raynaud's phenomenon and 31 sex and age-matched controls were examined. Neurological examination, modified Low's Questionnaire, orthostatic and sustained handgrip tests, conduction velocity study in three nerves, sympathetic skin response (SSR), and heart rate variability (HRV) during deep breathing and at rest with the fast Fourier transform were performed. RESULTS: In the clinical examinations, 35.3% of the primary Raynaud's patients presented sensory neuropathy, but this was not confirmed in the standard conduction velocity tests. The modified Low's Questionnaire revealed dysautonomy in 82% of the patients. Autonomic regulation during the orthostatic and handgrip tests were within the normal limits. HRV at rest and the E/I ratio were significantly lower in the patient group than in the controls, while HRV spectrum analysis revealed the predominance of the low-frequency band in the patients. CONCLUSIONS: These results indicate the presence of sympathetic dysregulation and impairment of parasympathetic modulation of heart function in primary Raynaud's patients. The different cardiovascular and sudomotor functions are not affected to the same degree. These observations might support the theory of a central impairment of autonomic function in primary Raynaud's phenomenon. Peripheral nerve lesion as a coexisting cause of the observed dysautonomy remains uncertain.

Tissue factor, tissue pathway factor inhibitor and risk factors of atherosclerosis in patients with chronic limbs ischemia: preliminary study.

AIM: Thrombus formation plays a critical role in pathogenesis of cardiovascular complications in atherosclerotic peripheral arterial occlusive disease (PAOD). Tissue factor (TF) initiates the clotting cascade and is considered an important regulator of hemostasis and thrombosis. TF activity is regulated by TF pathway inhibitor (TFPI). The aim of our study was to evaluate plasma levels of the TF, TFPI and their relation to coagulation system and various other risk factors of atherosclerosis in patients with chronic limbs ischemia. METHODS: Plasma TF, total TFPI, truncated TFPI, full-length TFPI were assessed by ELISA using commercially available kits (IMUBIND Tissue Factor; Total TFPI; Truncated TFPI ELISA Kit; American Diagnostica Inc. Stamford) in 62 claudicant patients with PAOD and 20 healthy controls. RESULTS: We observed statistically higher levels of TF (94+/-52 pg/mL), total TFPI (43+/-8 ng/mL), and truncated TFPI (22+/-7 ng/mL) in patients with PAOD compared to healthy individuals (TF: 66+/-15 pg/mL; total TFPI: 36+/-4 ng/mL; truncated TFPI: 14+/-5 ng/mL). Full-length TFPI (20+/-4 ng/mL) is lower in patients with PAOD than in controls (23+/-5 ng/mL). The study indicated a positive correlation between TF and truncated TFPI (r=0.34), total TFPI and full TFPI (r=0.5), total TFPI and truncated TFPI (r=0.83) in patients with PAOD, and negative correlation between full TFPI and truncated TFPI (r=-0.65) in the control. CONCLUSION: Elevated levels of TF, disorders of balance between full-length TFPI and truncated TFPI as well as significantly increased truncated TFPI level in patients with PAOD can be independent risk factors of atherosclerotic complications.

Prevalence of lower extremity venous disease in inflammatory bowel disease.

AIM: Inflammatory bowel disease (IBD) has long been considered a risk factor for venous thromboembolism (VTE). Whereas most patients have persistent venous valvular dysfunction following lower extremity deep venous thrombosis (DVT), we hypothesized that patients with IBD would have an increased prevalence of valvular incompetence and changes of chronic DVT (reduced venous caliber with thickened walls) relative to patients with irritable bowel syndrome (IBS) or normal volunteers. METHODS: Subjects with confirmed IBD, clinical features of IBS or normal volunteers underwent complete, prospective duplex ultrasound assessment of their lower extremity venous vascular system. The sonographer performing the venous study was blinded to the clinical diagnosis of the patients. Valvular incompetence was graded as mild, moderate or severe based on accepted criteria. RESULTS: Eighty patients with IBD (ulcerative colitis, UC: 66; Crohn's disease: 14), 80 patients with IBS, and 80 healthy volunteers agreed to participate. One patient with UC was found to have non-occlusive chronic DVT within the left superficial femoral vein. Mild and moderate valvular incompetence was evenly distributed between the 3 groups. No patients met criteria for either acute DVT or severe venous incompetence. CONCLUSION: In patients with IBD, neither valvular incompetence nor chronic venous obstruction are over-represented compared to patients with IBS or normal volunteers. In this prospective assessment of venous physiology by duplex ultrasound, we were not able to confirm prior reports that IBD is a major risk factor for VTE.

Cerebral venous sinus thrombosis: Incidence of venous thrombosis recurrence and survival.

OBJECTIVE: To determine whether treatments guidelines for lower extremity venous thrombosis (DVT) could be applied to patients with cerebral venous sinus thrombosis (CVST), the rates of recurrent venous thrombosis and survival for these two diseases were compared. METHODS: The authors studied all patients diagnosed with CVST at the Mayo Clinic between 1978 and 2001. Survival and recurrent venous thrombosis rates (cerebral or noncerebral) were compared with those from patients with DVT. Survival rates were also compared with white US residents. RESULTS: One hundred fifty-four patients (age 40 +/- 19 years) were included (58% women). Warfarin, prescribed in 50% of patients, was continued for an average of 9 months. During a mean of follow up of 36 +/- 47 months (464 patient-years), 20 patients experienced 23 recurrent venous thrombi for an event rate of 5.0/100 patient-years. This recurrence rate was similar to patients with lower extremity DVT (3.8/100 patient-years). Mortality rates were lower for CVST (2.8/100 patient-years) compared with DVT (6.2/100 patient-years; p = 0.001) patients but higher than expected for white US residents (p = 0.001). Increasing age and active malignancy were the only predictors of poor survival. Neither recurrent thrombosis nor survival was influenced by warfarin therapy. CONCLUSIONS: The likelihood of recurrent venous thrombosis is similar after cerebral venous sinus thrombosis (CVST) and lower extremity deep venous thrombosis (DVT). Compared with DVT, survival rates are higher following CVST but are adversely influenced by malignancy and older age.

Platelets' glycoproteins and their ligands in patients with intermittent claudication.

BACKGROUND: Platelet thrombi play critical role in pathogenesis of cardiovascular complications in atherosclerotic peripheral arterial disease (PAOD). The aim of this study was to evaluate the concentration of platelets GP IIb/IIIa, GP I b/IX and plasma levels of their ligands (fibrinogen and vWF) and their relation to other atherosclerotic risk factors in the patients with intermittent claudication secondary to PAOD. METHODS: Consecutive patients of the University Vascular Clinic were studied: 64 claudicants and 38 controls were enrolled. The concentration of platelets GPII b/IIIa and GP Ib/IX was estimated by ELISA method using monoclonal antibody against GPII b/IIIa (CD41a) and GPI b/IX (CD42a Immunotech). Plasma levels of vWF, fibrinogen, and platelets were measured by routine RESULTS: Plasma vWF (145+/-41%), fibrinogen (3.8+/-1 g/l) and platelet concentration of GP Ib/IX (121.1+/-23.39), GPIIb/IIIa (117.9 6 +/-32.7%), as well as plasma lipids and uric acid were statistically higher in claudicants than in controls (vWF: 103+/-42%, fibrinogen: 2.9+/-0.5 g/l, GP Ib/IX: 100+/-16.9%, GP IIb/IIIa: 100+/-29.4%). We have observed statistically higher concentration of GP IIb/IIIa and GP Ib/IX in smoking patients than in non-smoking patients with PAOD and significant correlation between the concentration of GP Ib/IX and GP IIb/IIIa and plasma fibrinogen in patients with PAOD and controls. CONCLUSIONS: Our results demonstrate higher platelet concentration of GP Ib/IX,GP IIb/IIIa and elevated plasma levels of ligands for platelets receptors-fibrinogen and vWF in patients with PAOD. This prothrombotic conditions may explain increased cardiovascular morbidity and mortality in this patient's group.

Coagulation in diabetic and non-diabetic claudicants.

BACKGROUND: In order to compare hemostasis in diabetic and non-diabetic claudicants we evaluated endothelial (von Willebrand factor, vWF), rheologic (fibrinogen, hematocrit), coagulation system (thrombin-antithrombin complex, TAT) and platelet (platelet factor 4, PF4, aggregation on thrombin, collagen and ADP stimulation) parameters in both groups and healthy controls. METHODS: Twenty-five diabetic, 34 non-diabetic patients with claudication and 26 healthy individuals were enrolled into the study. RESULTS: The severity of lower limbs ischemia was similar in two groups of claudicants but coronary heart disease and cerebral ischemia were significantly more common in diabetic than in non-diabetic claudicants. vWF level was significantly higher in diabetic than non-diabetic claudicants and healthy controls (184+/-43%, 147+/-43%, and 103+/-42%, respectively). Fibrinogen was significantly higher in diabetic and non-diabetic claudicants compared to controls (4.2+/-1.7, and 3.9+/-1.1, versus 2.9+/-0.5 g/l) and TAT plasma concentration was much higher in diabetic compare to non-diabetic patients and controls (9.8+/-4.4, 1.7+/-1.1, and 1.3+/-0.6 microg, respectively). PF4 concentration was significantly higher in non-diabetic patients with PAOD (34+/-29 UI/ml) when compare to healthy controls (14+/-9 UI/ml), but diabetic PAOD patients with the disease showed lower PF4 concentration (26+/-30 UI/ml). Platelet aggregation with all used activators was similar in all groups likewise hematocrit values, and platelet count. CONCLUSIONS: Complicated DM is linked with significant endothelial perturbation when compared with healthy, but also with PAOD individuals; rheologic parameters are not different from those found in PAOD patients; coagulation system activation but not platelet hyperactivity is associated with DM complicated by PAOD when compared to both control groups.

[Chronic peripheral arterial occlusive disease, platelet glycoproteins GPIIb-IIIa and GP Ib-IX, plasma von Willebrand factor and plasma fibrinogen concentrations in patients with type 2 diabetes mellitus]. / Przewlekla obwodowa niewydolnosc tetnicza a stezenie glikoprotein GPIIb-IIIa i GP Ib-IX w krwinkach plytkowych oraz czynnika von Willebranda i fibrynogenu w osoczu u chorych na cukrzyce typu 2.

Diabetes mellitus (DM) type 2 is a very strong risk factor for atherosclerosis. The final event of atherosclerosis is the vessels occlusion by platelet riche thrombus. Platelets adhesion and aggregation is mediated by interaction between platelets glycoproteins: GPIb-IX, GPIIb-IIIa and adhesive proteins: von Willebrand factor or fibrinogen. The expression of platelets GPIb-IX, GPIIb-IIIa, plasma vWF, fibrinogen concentrations were evaluated in 40 patients with diabetes type 2 (22 patients with PAOD stage II and IV according to Fontain, 18 diabetics without paod) and 32 healthy individuals. The expression of platelets glycoproteins GPIIb-IIIa and GPIb-IX was estimated by ELISA using monoclonal antibody against GPIIb-IIIa (CD41a) and GPIb-IX (CD 42a Immunotech). Plasma vWf (189.7 +/- 53.6%), fibrinogen (4.5 +/- +/- 1.3 g/l) level and expression of platelets GPIb-IX (63.2 +/- 19.6% in platelets concentration 125,000/mm3, 104.5 +/- 28.1% in platelets concentrations 250,000/mm3) and GPIIb-IIIa 50.8 +/- 10.1% in platelets concentrations 125,000/mm3, 95.3 +/- 21.3% in platelets concentrations 250,000/mm3 were statistically higher in patients with diabetes type 2 than in controls (vWf: 94.9 +/- 27.1%, fibrinogen: 2.8 +/- 0.4 g/l, GPIb-IX in platelets concentration 125,000/mm3: 43.8 +/- 9.3%, in concentration 250,000/mm3: 83.9 +/- 18.3%, GPIIb-IIIa in platelets concentration 125,000/mm3: 33.7 +/- 10.1%, in platelets concentration 250,000/mm3: 63.2 +/- 15.4%). We found significant correlation between the expression of GPIIb-IIIa, GPIb-IIIa, GPIb-IX and plasma adhesive proteins: vWF, fibrinogen in controls and both subgroups of diabetic patients. The correlation between plasma vWF and fibrinogen level and degree of arterial insufficiency in diabetic patients was also found. We can assume that higher vWf, fibrinogen plasma level in diabetic patients with and without PAOD could account for high expression of platelets GPIIb-IIIa and GPIb-IX.