Correlation between vitamin D levels and hard-to-heal wounds: a systematic review.

OBJECTIVE: Hard-to-heal wounds are a major biological, psychological, social and financial burden on both individual patients and the broader health system. They are associated with a variety of comorbidities and have a complex aetiology, but are typically associated with nutritional deficiencies, such as low vitamin D levels. This systematic literature review evaluates the current research regarding the connection between inadequate vitamin D status and wound healing. METHOD: PubMed and EBSCO databases were searched following PRISMA guidelines for primary research studies relating to pressure ulcers, diabetic ulcers or venous ulcers and vitamin D status. RESULTS: A total of 10 studies, involving 2359 participants, met the inclusion criteria. There was a strong correlation between low levels of 25-hydroxyvitamin D and the presence of all three types of hard-to-heal wounds. CONCLUSION: Research suggests a correlation between low vitamin D levels and hard-to-heal wounds. However, it is not clear if the relationship is causal or only correlational. There is also emerging evidence on the use of vitamin D supplementation for the treatment of hard-to-heal wounds. More research is needed to understand the correlation between vitamin D and hard-to-heal wounds.

Potential markers of healing from near infrared spectroscopy imaging of venous leg ulcer. A randomized controlled clinical trial comparing conventional with hyperbaric oxygen treatment.

The aim of this study is to ascertain whether the simultaneous measurement of hemoglobin O2 saturation (StO2 ) and dimension of venous leg ulcers (VLU) by near infrared spectroscopy (NIRS) imaging can predict the healing course with protocols employing a conventional treatment alone or in combination with hyperbaric oxygen therapy (HBOT). NIRS 2D images of wound region were obtained in 81 patients with hard-to-heal VLU that had been assigned, in a randomized controlled clinical trial, to the following protocols: 30 HBOT sessions, adjunctive to the conventional therapy, either twice daily over 3 weeks (group A) or once daily over 6 weeks (group B), and conventional therapy without HBOT (group C). Seventy-three patients completed the study with a total of 511 NIRS images being analyzed. At the end of treatment, wound area was significantly smaller in all three groups. However, at the 3-week mark the wound area reduction tended to be less evident in group A than in the other groups. This trend continued up to the 6-week end-point when a significantly greater area reduction was found with group B (65.5%) and group C (56.8%) compared to group A (29.7%) (P < .01). Furthermore, a higher incidence of complete healing was noted with group B (20%) than with group A (4.5%) and group C (3.8%). When using a final wound reduction in excess of 40% to distinguish healing from nonhealing ulcers, it was found that only the former present NIRS StO2 values abating over the study period both at center and edge of lesions. In conclusion, NIRS analysis of StO2 and wound area can predict the healing course of VLU. Adjunctive HBOT significantly facilitates VLU healing compared to the conventional treatment alone. This positive action, however, becomes manifest only with a longer and less intensive treatment schedule.

Hyperhomocysteinaemia and chronic venous ulcers.

Chronic venous ulceration (CVU) is the major cause of chronic wounds of lower extremities, and is a part of the complex of chronic venous disease. Previous studies have hypothesised that several thrombophilic factors, such as hyperhomocysteinaemia (HHcy), may be associated with chronic venous ulcers. In this study, we evaluated the prevalence of HHcy in patients with venous leg ulcers and the effect of folic acid therapy on wound healing. Eighty-seven patients with venous leg ulcers were enrolled in this study to calculate the prevalence of HHcy in this population. All patients underwent basic treatment for venous ulcer (compression therapy ± surgical procedures). Patients with HHcy (group A) received basic treatment and administered folic acid (1·2 mg/day for 12 months) and patients without HHcy (group B) received only basic treatment. Healing was assessed by means of computerised planimetry analysis. The prevalence of HHcy among patients with chronic venous ulcer enrolled in this study was 62·06%. Healing rate was significantly higher (P < 0·05) in group A patients (78·75%) compared with group B patients (63·33%). This study suggests a close association, statistically significant, between HHcy and CVU. Homocysteine-lowering therapy with folic acid seems to expedite wound healing. Despite these aspects, the exact molecular mechanisms between homocysteine and CVU have not been clearly defined and further studies are needed.

[Algorithm of treatment postthrombotic disease of the lower extremities].

The results of application of pathogenetically substantiated diagnostic algorithm for determination of the treatment method in patients, suffering postthrombotic disease of the lower extremities, are adduced. Using algorithm proposed a clinical state was estimated, subfascial pressure on the shin was determined, ultrasound duplex scanning (USDS) of venous system was conducted, the stimulation electroneuromyography of the shins done, and a level of D-dimer (DD) with activity of antithrombin-III (AT--III) in general and regional blood flow with calculation of its ratio were established. In 33 (31.1%) patients a conservative therapy was conducted, in 34 (32.1%)--a postponed surgical intervention, in 39 (36.8%)--surgical correction of the venous blood flow, in 22 (20.8%)--preparation and closure of trophic ulcers in accordance to the clinic method. Determination of the DD level and the AT-III activity together with data of USDS have permitted to establish differentially the indications for performance of a vein-correcting operative interventions.

Increased Lipoprotein (a) concentrations in patients with chronic venous leg ulcers: a study on patients with or without postthrombotic syndrome.

Chronic venous leg ulcers are common and cause considerable burden of disease for affected patients with significant costs for health care systems worldwide. The complex pathophysiology of chronic venous leg ulcers is still not entirely understood. In addition, reliable pathogenic and/or prognostic parameters are not known. Published data suggest that patients with chronic venous leg ulcers reveal congenital or acquired thrombophilia. We examined the serum Lipoprotein (a) [Lp(a)] level, a proatherogenic and prothrombotic risk factor, in patients with chronic venous leg ulcers (n=210, stratified into patients with postthrombotic syndrome or without) and in a healthy control group (n=341). Forty-two percent of all patients, compared with 20% of healthy controls, revealed significantly increased Lp(a) serum concentrations above 0.3 g/L. Furthermore, 49% without postthrombotic syndrome but only 35% with postthrombotic syndrome showed increased Lp(a) levels. The increase of Lp(a) level was significantly different between all three groups (p<0.001). There was no correlation of Lp(a) levels and CRP values in all groups. Based on these data, it is conceivable that Lp(a) plasma level is a novel pathogenic parameter for chronic venous leg ulcers. Elevated concentrations may contribute to the pathogenesis through induction of thrombogenic microcirculatory dysregulations, impaired extravascular fibrinolysis, or other mechanisms like proinflammatory effects.

Investigating the humoral immune response in chronic venous leg ulcer patients colonised with Pseudomonas aeruginosa.

The ability to manage the bioburden in chronic wounds is most likely coupled to the humoral immune response of the patient. We analysed markers of systemic immune response in patients with chronic venous leg ulcers (CVLUs) colonised (no-systemic infection) with the opportunistic pathogen Pseudomonas aeruginosa. Sera from 44 clinically non infected patients with CVLUs were analysed for total IgM and IgG isotype 1-4, complement C3, mannose-binding lectin (MBL), interleukin (IL)-6, C-reactive protein (CRP) and specific anti-P. aeruginosa antibodies against exotoxin A, elastase and alkaline phosphatase. Concentrations of IL-6 versus CRP intercorrelated (ß = 2.43 95% CI (1.34-4.34)), but were independent of P. aeruginosa colonisation. MBL deficiency (MBL < 500 ng/ml) correlated to high serum levels of IgG(1) (P = 0.038) consistent with a compensatory mechanism, but not related to presence of P. aeruginosa in the ulcers. Twenty-four patients (54.5%) were culture positive for P. aeruginosa, also conferring significantly high serum levels of complement C3 (P = 0.014), but only two of these had positive titres for antibodies against exotoxin A. All patient sera were negative for antibodies against elastase and alkaline phosphatase. Fluorescent in situ hybridization analysis on randomly selected culture-positive patients could not establish unambiguous presence of P. aeruginosa biofilms in the ulcers. A multiple regression model showed P. aeruginosa and systemic CRP as significant factors in deterioration of ulcer healing rate.

[Hyperhomocysteinemia and leg ulcers: A prospective study of 68 patients]. / Hyperhomocystéinémie et ulcères de jambes : étude prospective de 68 observations.

BACKGROUND: Homocysteine is a sulphur-containing amino acid derived from methionine. Hyperhomocysteinaemia is now recognised as an independent risk factor for occlusive arterial disease and thrombotic venous disease. The aim of this study was to determine the prevalence of hyperhomocysteinemia in patients with leg ulcers. PATIENTS AND METHODS: We prospectively investigated hospitalised patients for vascular leg ulcers between March 2008 and June 2009 at two dermatology centres. We collected details of cardiovascular disease and determined nutritional status by means of the MNA score. Fasting blood samples were taken and analyzed for homocysteine, albumin, prealbumin, folic acid, vitamin B12, creatinine and a complete blood count. RESULTS: Sixty-eight patients were enrolled in the study: 48 women and 20 men. Fifty-three percent of patients had venous leg ulcers, 18% had arterial leg ulcers and 20% had leg ulcers of mixed origin. The prevalence of hyperhomocysteinemia was 56%, with no differences according to ulcer type or gender. DISCUSSION: While the prevalence of hyperhomocysteinemia in our population of leg ulcer patients was high, this descriptive study does not allow us to establish any causal link between hyperhomocysteinemia and leg ulcers. Moreover, since the literature indicates that homocysteine-lowering therapy does not reduce cardiovascular and thromboembolic risk, there appears to be little call for further trials on hyperhomocysteinaemia and leg ulcers.

Association between venous leg ulcers and sex chromosome anomalies in men.

We report here two cases of men, aged 46 and 23 years, with refractory chronic venous leg ulcers in association with sex chromosome aberrations: one with a 47,XXY/48,XXXY karyotype (Klinefelter syndrome) and the other with a 47,XYY karyotype (Jacob syndrome). In both patients, the occurrence of leg ulcers was the reason for seeking medical care; their medical history was other-wise unremarkable. Chromosomal analyses were performed due to the unusually young age for development of venous leg ulcers. The pathophysiology behind the occurrence of venous leg ulcers in patients with numerical aberrations of the sex chromosomes is incompletely understood. Involvement of elevated plasminogen activator inhibitor-1 levels in the pathogenesis of venous leg ulcers has been reported in patients with Klinefelter syndrome. Notably, our patient with 47,XXY/48,XXXY presented with androgen deficiency but normal plasminogen activator inhibitor-1 activity.

Higher prevalence of thrombophilia in patients with varicose veins and venous ulcers than controls.

BACKGROUND: Uncontrolled studies suggest that patients with chronic venous ulceration (CVU) have an increased prevalence of thrombophilia, similar to that observed in patients with deep vein thrombosis. This study compared the nature and prevalence of thrombophilia in patients with varicose veins (VV, CEAP clinical [C] grade C(2) to C(3)) and patients with CVU (C(5) to C(6)) with an age- and sex-matched population without clinical or duplex ultrasound evidence of venous disease. METHODS: Twenty-seven patients with VV, 27 patients with CVU, and 54 age- and sex-matched case controls with no clinical or duplex evidence of lower limb venous disease, underwent testing for factor V Leiden and prothrombin 20210A mutations, antithrombin deficiencies, and levels of antiphospholipid antibodies, homocysteine, protein C and S, and factor VIII, IX, and XI. RESULTS: The overall prevalences of single and multiple thrombophilias were significantly higher in cases than in controls. Specifically, in VV patients, the prevalences of no, single, and multiple thrombophilias were 33%, 52%, and 15%, respectively, compared with 63%, 26%, and 11% in VV controls. In CVU patients, the prevalences of no, single, and multiple thrombophilias was 26%, 30%, and 44%, respectively, compared with 66%, 22%, and 11% in CVU controls. Compared with controls, only factor XI levels were significantly higher in VV patients, and homocysteine and factor VIII, IX, and XI levels were all significantly higher in CVU patients. CONCLUSION: Patients with VV, and particularly CVU, have significantly higher prevalences of single and multiple thrombophilias than age- and sex-matched controls without clinical or duplex evidence of lower limb venous disease. These data support the hypothesis that thrombophilia predisposes to the development of superficial and deep lower limb venous reflux, and so VV and CVU, through the increased occurrence of clinical and subclinical thrombosis.

To what extent might deep venous thrombosis and chronic venous insufficiency share a common etiology?

According to the valve cusp hypoxia hypothesis (VCHH), deep venous thrombosis is caused by sustained non-pulsatile (streamline) venous blood flow. This leads to hypoxemia in the valve pockets; hypoxic injury to the inner (parietalis) endothelium of the cusp leaflets activates the elk-1/egr-1 pathway, leading to leukocyte and platelet swarming at the site of injury and, potentially, blood coagulation. Here, we propose an extension of the VCHH to account for chronic venous insufficiency. First, should the foregoing events not proceed to frank thrombogenesis, the valves may nevertheless be chronically injured and become incompetent. Serial incompetence in lower limb valves may then generate ''passive'' venous hypertension. Second, should ostial valve thrombosis obstruct venous return from muscles via tributaries draining into the femoral vein, as Virchow illustrated, ''active'' venous hypertension may supervene: muscle contraction would force the blood in the vessels behind the blocked ostial valves to re-route. Passive or active venous hypertension opposes return flow, leading to luminal hypoxemia and vein wall distension, which in turn may impair vasa venarum perfusion; the resulting mural endothelial hypoxia would lead to leukocyte invasion of the wall and remodelling of the media. We propose that varicose veins result if gross active hypertension stretches the valve ''rings'', rendering attached valves incompetent caudad to obstructed sites, replacing normal centripetal flow in perforating veins with centrifugal flow and over-distending those vessels. We also discuss how hypoxemia-related venous/capillary wall lesions may lead to accumulation of leukocytes, progressive blockage of capillary blood flow, lipodermosclerosis and skin ulceration.

Correlation between chronic venous ulcer exudate proteins and clinical profile: A cross-sectional study.

Chronic venous ulcers affect the quality of life of patients around the world. The aims of this study were to identify the proteins expressed in chronic venous ulcer exudates, to categorize them according to their roles and to correlate them with the clinical and epidemiological aspects of the disease. The study population consisted of 37 ulcers from 28 patients, and the inflammatory exudates of these thirty-seven ulcers were subjected to tryptic digestion and mass spectrometry analysis. Twenty-three patients were female (62.2%), and five (37.8%) were male. The patients had a mean age of 70 (±10.1) years. Of the patients, 73% adhered to compression and rest, 81.1% reported a history of primary varices, 54.1% reported a history of systemic arterial hypertension, 54.1% reported a history of devitalized tissue in the wound bed and 64.9% reported ulcers with more than ten years of evolution. Seventy-six proteins were identified, and they were grouped according to their primary role in the healing process. Eight correlations between clinical and epidemiological data and protein expression were noteworthy: diabetes mellitus vs. Ig gamma-2 and apolipoprotein-A1 and albumin; congestive heart failure vs. Ig lambda-2; colonization vs. actin; compressive therapy vs. Ig kappa; systemic arterial hypertension vs. alpha-2-macroglobulin and apolipoprotein-A1; area of ulcer vs. apolipoprotein-A1; race vs. heavy chain Ig and Ig γ-1 chain; age and race vs. Ig γ-1 chain. These associations may help to elucidate the prognosis and chronicity of chronic venous ulcers based on secreted proteins.

Sulodexide in venous disease.

Sulodexide is a glycosaminoglycan extracted from porcine intestinal mucosa. The purpose of this review is to discuss sulodexide's complex pharmacological profile and its clinical applications for venous disease. Sulodexide has wide-ranging biological effects on the vascular system, including antithrombotic, profibrinolytic, anti-inflammatory, endothelial protective and vasoregulatory effects. Sulodexide has emerged as a potential therapeutic option for the management of chronic venous insufficiency, including venous ulceration, and the prevention of recurrent venous thromboembolism, with a low rate of major bleeding complications. Sulodexide's pleiotropic vascular effects may facilitate the management of common venous disorders.

Supplementation with eicosapentaenoic acid and docosahexaenoic acid reduces high levels of circulating proinflammatory cytokines in aging adults: A randomized, controlled study.

BACKGROUND: High levels of circulating proinflammatory cytokines are characteristic of inflammaging, a term coined to describe age-related chronic systemic inflammation involved in the etiology of many age-related disorders including nonhealing wounds. Some studies have shown that supplementing diets with n-3 polyunsaturated fatty acids (eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]) lowers systemic levels of key proinflammatory cytokines associated with inflammaging. However, findings from the few studies that have focused exclusively on older adults are inconclusive. As such, the objective of this randomized controlled study was to test the effects of EPA+DHA therapy on circulating levels of proinflammatory cytokines in adults in middle to late adulthood. METHODS: Plasma levels of fatty acids and interleukin (IL)-6, IL-1ß and tumor necrosis factor-α (TNF-α) were measured in 35 participants with chronic venous leg ulcers (mean age: 60.6 years) randomnly assigned to 8 weeks of EPA+DHA therapy (2.5 g/d) or placebo therapy. RESULTS: EPA+DHA therapy had a significant lowering effect on levels of IL-6, IL-1ß and TNF-α after 4 weeks of therapy and an even greater lowering effect after 8 weeks of therapy. Further, after adjusting for baseline difference, the treatment group had significantly lower levels of IL-6 (p = 0.008), IL-1ß (p < 0.001), and TNF-α (p < 0.001) at Week 4 and at Week 8 [IL-6 (p = 0.007), IL-1ß (p < 0.001), and TNF-α (p < 0.001)] compared to the control group. CONCLUSION: Adults in middle to late adulthood receiving EPA+DHA therapy demonstrated significantly greater reductions in circulating levels of proinflammatory cytokines compared with those receiving placebo therapy. EPA+DHA therapy may be an effective low-risk dietary intervention for assuaging the harmful effects of inflammaging.

Improvement of microcirculation and healing of venous hypertension and ulcers with Crystacide: evaluation with a microcirculatory model, including free radicals, laser doppler flux, and PO2/PCO2 measurements.

In 32 patients with chronic venous insufficiency and venous hypertension associated with ulcerations, the effects of the local application of a hydrogen peroxide cream (Crystacide) applied onto the skin was evaluated using a complex, proportional, microcirculatory model to assess and quantify venous microangiopathy after local treatment. A comparative group treated without Crystacide was included. Laser Doppler flowmetry was used to assess skin perfusion (flux and venoarteriolar response) in association with transcutaneous PO2 and PCO2 measurements. Local plasma free radicals were evaluated in the area surrounding the venous ulcer using the D-Roms test. Crystacide was applied around and on the ulcer for 10 days. Crystacide was more effective than the control treatments. PO2 was increased (improved, P < .05), and plasma free radicals, PCO2, and laser Doppler flowmetry were decreased (improving toward normal values, P < .05). Also, the ulcerated area was significantly smaller at 10 days in the Crystacide group in comparison with controls (P < .05). In the proportional microcirculatory model, all parameters indicated an important level of improvement significantly larger than in controls. In conclusion, in chronic venous insufficiency and venous ulcerations, local treatment with Crystacide (10 days) improves the microcirculation and decreases skin free radicals, thus improving healing.

Serum oxidized low-density lipoprotein level as a marker of oxidative stress in patients undergoing hyperbaric oxygen therapy.

OBJECTIVE: Oxidative stress (OS) is involved in the pathogenesis of atherosclerosis. Hyperbaric oxygen therapy (HBOT), in which 100% oxygen is inhaled under hyperbaric pressure, may create OS. Therefore, the aim of this research was to measure the serum oxidized low-density lipoprotein (oxLDL) level in patients undergoing HBOT. METHODS: Twenty-nine patients who underwent HBOT to treat various diseases were enrolled in this study. The serum oxLDL level was measured at the beginning of the first and after the 10th therapy session. RESULTS: There was no significant difference between the oxLDL level of patients before and after HBOT (4.96±0.1 vs. 4.94±0.1 U/mL; p=0.36). CONCLUSION: HBOT seems to be safe in terms of oxLDL production up to 10 sessions. However, further large-scale studies investigating longer duration of HBOT treatment are required to understand the role of OS.

The soluble urokinase plasminogen activator receptor and its fragments in venous ulcers.

OBJECTIVE: Activation of proteolytic mechanisms at the cell surface through the activity of urokinase-type plasminogen activator (uPA) bound to its receptor, uPAR, is an important process in wound healing. The soluble forms of uPAR (suPAR and its fragments I, II, and III) have nonproteolytic functions that include chemotaxis, adhesion, and proliferation, which also have a role in wound healing. The aim of this study was to determine whether suPAR and its cleaved fragments are present in venous ulcers and whether their levels are associated with healing. METHODS: Ulcer exudates were collected from patients with venous leg ulcers (n = 30). Healing was defined as complete re-epithelialization within 6 months of compression therapy. Time-resolved fluorescence immunoassays were validated for quantification of suPAR and its fragments in ulcer exudates. The effect of exudates on keratinocyte migration was analyzed by an in vitro scratch assay. RESULTS: Ulcer exudates from patients who healed (n = 9) had approximately threefold higher levels of intact suPAR (P = .005), twofold higher levels of suPARI (P = .03), and approximately threefold higher levels suPARII-III (P < .0001) compared with nonhealers (n = 21). Exudate from healing ulcers stimulated keratinocyte migration (P = .02), whereas depletion of suPAR from exudates resulted in cell apoptosis. CONCLUSIONS: We conclude that suPAR and its fragments are present in the environs of venous ulcers and may act as indicators of the propensity of venous ulcers to heal, with suPARII-III being the best discriminator. We speculate that suPAR and its fragments may have a role in the maintenance of an optimal ulcer-healing environment.

Fibrin- and fibrinogen-related antigens in patients with venous disease and venous ulceration.

Abnormalities in systemic fibrinolysis have been implicated in the pathogenesis of venous ulceration. Patients with venous disease have a prolonged euglobulin lysis time and elevated plasma fibrinogen levels, yet little is known about the metabolism of fibrinogen and fibrin in such patients. In this study, we have used a technique that involves electrophoresis and densitometric analysis of captured fibrin-related antigens to measure the concentration and proportions of the individual fibrin and fibrinogen degradation products in patients with venous disease of the lower extremity. As a group, patients with venous disease had markedly elevated levels of total fibrin-related antigen and D-dimer, the terminal degradation product of cross-linked fibrin. Levels of D-monomer, the breakdown product of fibrinogen and non-cross-linked fibrin monomer, and a measure of fibrinogenolysis were normal in all patients. In patients with ulcers, the levels of D-dimer were disproportionately higher than expected from fibrin monomer levels. On an individual basis, significant elevations of D-dimer were present in six (55%) of the 11 patients with venous disease with ulcers and in three (43%) of the seven patients with venous disease without ulcers. We conclude that patients with venous disease have uniform evidence for enhanced fibrin formation, as evidenced by elevated levels of total fibrin-related antigen and D-dimer. This is regardless of whether the venous disease is accompanied by ulceration.

Protein C and protein S plasma levels in patients with lipodermatosclerosis and venous ulceration.

Lipodermatosclerosis of the lower extremity, with or without ulceration, is a common manifestation of severe venous disease and the result of sustained venous hypertension. The latter is generally a sequela of deep vein thrombosis. Factors that enhance clot formation or impair fibrinolysis contribute to the pathogenesis of venous disease. It is already established that faulty fibrinolysis may play a pathogenic role in patients with venous disease. We examined the possibility that patients with venous disease have abnormally low plasma levels of proteins C and S, two proteins whose deficiencies have been reported to cause an increased frequency of thromboembolic disease. Using immunologic and functional assays for plasma proteins C and S, we found that 4 (21%) of 19 patients with lipodermatosclerosis and leg ulcers had abnormally low levels of protein C or protein S. One of 7 patients with lipodermatosclerosis without ulceration had a profoundly depressed level of protein C and a history of cerebral stroke at a young age. Plasma levels of protein C were normal in five patients with arterial insufficiency severe enough to cause leg ulceration. We conclude that abnormally low plasma levels of proteins C and S may be found in patients with lipodermatosclerosis and venous ulceration. As with the abnormally low fibrinolytic activity in these patients, our findings indicate a possible propensity for increased thrombotic disease.

Elevated plasma levels of beta-thromboglobulin and platelet factor 4 in patients with rheumatic disorders and cutaneous vasculitis.

The efficacy of plasma levels of beta-thromboglobulin (beta-TG) and platelet factor 4 (PF4) as markers of the presence and activity of vasculiditic processes in rheumatic diseases were evaluated, first by serial measurement of their levels in a patient with rheumatoid arthritis and a chronic leg ulcer in the course of treatment, and second in 11 patients with rheumatoid arthritis without cutaneous vasculitis, and in nine patients with a variety of rheumatic diseases with cutaneous vasculitis. In the former, plasma levels of beta-TG and PF4 were elevated and slowly reduced in parallel with healing, raised again after relapse, and normalized after disappearance of the leg ulcer. In the latter, both plasma levels were elevated in all of the nine patients with cutaneous vascular lesions and in one of the 11 patients rheumatoid arthritis without skin lesions. Levels of beta-TG and PF4 may be useful to estimate the presence of vascular lesions in rheumatic disorders.