There are 3 main types of lower extremity ulcers: venous, arterial, and neuropathic. Venous ulcers constitute the majority of all leg ulcers, whereas foot ulcers are more likely to be due to arterial insufficiency or neuropathy. Up to 80% of leg ulcers are caused by venous disease, and arterial disease accounts for another 10% to 25%, which may coexist with venous disease.
Venous ulcers may be painful though classically, they have been described as painless. They do not lead to amputation, and do not require surgical intervention as often as ulcers caused by arterial insufficiency. The exact pathogenic steps leading from venous hypertension to venous ulceration is still unclear.
Epidemiology Disease Associations Pathogenesis Laboratory/Radiologic/Other Diagnostic Testing Gross Appearance and Clinical Variants Histopathological Features and Variants Special Stains/
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EPIDEMIOLOGY CHARACTERIZATION INCIDENCE
More than half of lower extremity ulcerations
An overall prevalence ranging from 0.06% to 2%
In 1973, who found an extrapolated figure of 400,000 to 600,000 venous ulcers for the entire US population.
Venous leg ulcer: Incidence and prevalence in the elderly
David J. Margolis
Philadelphia, Pennsylvania, and Baltimore, Maryland
J Am Acad Dermatol 2002;46:381-6 Abstract quote
Background: Venous leg ulcer is a disease most common in those aged 65 years and older. However, the incidence and prevalence have not been well established.
Objective: Our purpose was to estimate the prevalence and incidence of venous leg ulcers in the elderly.
Methods: We studied the General Practice Research Database, validated our case ascertainment strategy, and estimated the annual prevalence and incidence of venous leg ulcer.
Results: The positive predictive value of our ascertainment strategy was 98.3% (95% confidence interval [CI], 90.0, 100.0). The annual prevalence of venous leg ulcer among the elderly was 1.69 (95% CI, 1.65, 1.74). The overall incidence rate was 0.76 (95% CI, 0.71, 0.83) for men and 1.42 (1.35, 1.48) per 100 person-years for women.
Conclusion: Venous leg ulcer is a significant problem in those aged 65 years and older. As compared with previous studies, because we used medical records from a population of known size, our results are precise and less biased.
More common with increasing age, with a peak prevalence between 60 and 80 years.
72% of persons have their first ulcer by 60 years
Twenty-two percent of patients have their first ulcer by age 40 and 13% before 30 years of age
After adjustment for age, a slight female predominance has been observed, with a female-to-male ratio of 1.6:1
Job Requires long hours of standing tends to slow the healing of the wounds Trauma History of significant leg injury such as a broken leg, stab or gunshot wound, or a crush injury as well as phlebitis Socioeconomic Lack of medical insurance
DISEASE ASSOCIATIONS CHARACTERIZATION Insufficiency of the superficial and perforating veins In combination carries a greater risk than insufficiency of the superficial veins alone Obesity Heart disease Deep venous thrombosis
Well-recognized association between deep venous thrombosis and venous ulceration, known as the postphlebitic syndrome, however, the attributable risk of deep venous thrombosis for chronic venous insufficiency is unknown
Congenital Defects Congenital absence of valves, previous surgery of varicose veins, primary valve or venous wall degeneration, and arteriovenous shunts
Factor V Leiden Mutation in Postthrombotic and Non-postthrombotic Venous Ulcers
Jürg Hafner, etal.
Arch Dermatol. 2001;137:599-603 Abstract quote
To determine the prevalence of the factor V Leiden mutation in patients with postthrombotic and non-postthrombotic venous ulcers.
Department of Dermatology, University Hospital of Zurich, Zurich, Switzerland.
Seventy-three consecutive outpatients and inpatients with venous ulcers and 45 age- and sex-matched control subjects (matched to the 42 patients with postthrombotic syndrome).
Main Outcome Measures
Frequency of postthrombotic and non-postthrombotic findings in patients with venous ulcers. Prevalence of the factor V Leiden mutation in these different subgroups.
Postthrombotic syndrome was identified as the cause of 42 (58%; 95% confidence interval [CI], 45%-69%) of 73 venous ulcers, and the remainder were caused by primary valvular insufficiency. In postthrombotic ulcers, the prevalence of the factor V Leiden mutation was 38% (95% CI, 24%-54%) (16/42), which corresponds to an odds ratio of 13.2 (95% CI, 2.8-62.3; P<.001). In non-postthrombotic venous ulcers, the prevalence was 16% (95% CI, 5%-34%) (5/31), which corresponds to an odds ratio of 3.2 (95% CI, 1.0-10.0; P = .07).
The factor V Leiden mutation is highly prevalent in patients with postthrombotic venous ulcers. Even patients with non-postthrombotic venous ulcers show a moderately elevated prevalence of the factor V Leiden mutation. Some of the latter might be misclassified because of near-to-perfect revascularization after asymptomatic deep venous thrombosis. However, as long as the therapeutic consequences of the factor V Leiden mutation are not established, systematic screening cannot be recommended in patients with venous ulcers.
PATHOGENESIS CHARACTERIZATION Venous Hypertension is Chronic venous insufficiency In a diseased venous system or failure of the calf muscle pump, venous pressure in the deep system upon ambulation may either fall minimally or not at all
This sustained ambulatory pressure has been termed venous hypertension which ultimately, this venous hypertension in the deep veins may be transmitted to the superficial system
Occurs by 1 of 4 pathophysiologic mechanisms:
(1) Dysfunction of valves in the superficial and/or communicating veins because of congenital or acquired incompetence
(2) Dysfunction of valves in the deep system because of congenital absence, inherent weakness, or thrombotic damage
(3) Deep venous outflow obstruction rather than valvular incompetence
(4) Muscle dysfunction and calf muscle pump failure from inflammatory conditions of the joints or muscles, fibrosis, or neuropathies
Pericapillary fibrin cuffs and fibrinolytic abnormalities hypotheses
Fibrin and fibrinogen have a direct down-regulatory effect on procollagen type I synthesis by dermal fibroblast cultures and fibroblasts on fibrin gels synthesize less collagen
Hypothesized that persistence and continued deposition of fibrin and certain fibrinogen fragments may inhibit the capacity of fibroblasts to produce collagen and thus retard repair
Alternatively, fibrin and fibrinogen receptor breakdown products are chemotactic for fibroblasts
Fibrin leads to fibrosis in vivo
Co-localization of fibrin with collagen in certain fibrotic conditions has been established
The growth factor “trap” hypothesis
Fibrinogen, 2-macroglobulin, and other macromolecules that leak into the dermis as a result of venous hypertension or capillary damage “trap” growth factors and other stimulatory or homeostatic substances
Trapped molecules may be unavailable for the maintenance of tissue integrity and the repair process
2-Macroglobulin is a scavenger of growth factors such as transforming growth factor (TGF-)
There are markedly increased levels of TGF-1, 2-macroglobulin, and collagen-producing fibroblasts abnormally distributed within the fibrin cuffs surrounding the capillaries of the ulcer bed
An inappropriate interaction between these molecules and others may result in unavailability to repair minor traumatic wounds in the area and a propensity to actual ulcerations
White cell trapping hypothesis
Br J Surg 1991;78:210-1
Reduced pressure gradient between the arterial and venous systems with a postulated consequent reduced flow in the capillary bed between the systems
Leads to erythrocyte aggregation in the capillaries and leukocyte plugging of the capillaries
Between 5% and 20% of leukocytes have been shown to accumulate in dependent extremities of healthy subjects
Acute changes are reversible when the leg is elevated
This “trapping phenomenon” occurred to a greater degree (30%) when legs of patients with venous disease were held in a dependent position
Hypothesized that white blood cell plugging in the capillaries of lipodermatosclerotic limbs during dependency accounts for the capillary closure noted on microscopic sections, causing local ischemia
Aggregation of leukocytes not only contributes to the physical barrier, but also causes the release of certain mediators (including proteolytic enzymes such as collagenase and elastase, cytokines, free radicals, and chemotactic factors), which can cause further vascular permeability and release of large molecules such as fibrinogen into the pericapillary tissues
CHARACTERIZATION Radiographs Ultrasound
Color duplex ultrasound scanning is currently the gold standard in evaluation of venous anatomy and physiology because of its accuracy, reproducibility, and noninvasive nature
Advantage of visualizing other anatomic structures in the leg that can produce pain or swelling and mimic venous disease (eg, soft tissue masses, arterial aneurysms)
Br J Surg 1994;81:182-7.
Majority located over the medial malleolus, with the remainder located elsewhere on the leg or foot
Termed the gaiter area corresponding to the gaiter region of the boots of British soldiers (the medial malleolus)
Either or both legs may be affected:
Left leg involved in 44%
Right leg in 35%
Both legs in 21%
Venous ulcers are large, often larger (up to 550 cm2 or circumferential) than ulcers of nonvenous origin (2.6 vs 1.2 cm2)
VARIANTS Chronic venous leg ulcer
Br Med J 1986;294:1389-91.
A subset of patients (up to 34%) have ulcers of extremely long duration, defined as more than 5 years
Lipodermatosclerosis (Sclerosing panniculitis)
J Am Acad Dermatol 1993;28:623-7.
Highly associated with venous insufficiency or restricted to the legs of patients with venous insufficiency
Acute inflammatory stage:
Variable severity can precede the chronic phase of lipodermatosclerosis
Involves the leg above the malleolus (usually medially based) and is characterized by a more diffuse, not well-demarcated, extremely tender, erythematous, warm induration
May develop without obvious clinical signs of venous disease and frequently leads to misdiagnosis as other clinical entities such as morphea, persistent cellulitis, erythema nodosum, and other panniculitides
Frequently precedes the development of venous ulcers. However, lipodermatosclerotic skin is not invariably present, suggesting other or different mechanisms are likely involved in the pathogenesis of venous ulcers
Degree of induration of lipodermatosclerosis may correlate directly with delayed healing of the ulcer
Atrophie blanche can surround the venous ulcer in the presence or absence of lipodermatosclerotic skin
PROGNOSIS AND TREATMENT CHARACTERIZATION Prognostic Factors Survival Recurrence
Br Med J 1986;294:1389-91.
Once treated, many patients have a recurrence, which is reported to be as high as 72% of treated subjects
This high recurrence rate coupled with long ulcer duration of more than 1 year in more than half of patients helps explain the high prevalence of venous disease
A subset of patients (up to 34%) have ulcers of extremely long duration, defined as more than 5 years
Treatment goals for patients with chronic venous insufficiency include: Reduction of edema
Alleviation of pain
Improvement of lipodermatosclerosis
Healing of ulcers
Prevention of recurrence
Compression remains the cornerstone of therapy
Organotypic cultures of autologous hair follicle keratinocytes for the treatment of recurrent leg ulcers.
Limat A, French LE, Blal L, Saurat JH, Hunziker T, Salomon D.
Clinic of Dermatology, University Hospital Geneva, HUG et DHURDV, and Inselspital-Berne.
J Am Acad Dermatol 2003 Feb;48(2):207-14 Abstract quote
Our purpose was to evaluate, in an open study, the efficacy of epidermal equivalents (EEs), a tissue-engineered epidermis prepared from autologous hair follicle keratinocytes, for the treatment of recurrent leg ulcers (n = 50).
To generate EEs, keratinocytes expanded from the outer root sheaths of plucked anagen hair follicles were seeded on cell culture inserts at air-liquid interface. The total culture time was 5 to 6 weeks. Three days after the procedure, 95% of EEs adhered to the wound bed. After 8 weeks, 70% of the total wound surface was re-epithelialized and 32% of the ulcers were healed. After applying the EEs, a major relief of wound pain was noticed by the patients. EEs were applied in ambulatory patients without surgical facilities.
Because 92% of the cases included in this study presented a recurrence of their ulcers after a split-thickness skin graft, we consider these ulcers as difficult to treat and propose the EEs as an alternative effective treatment of recurrent leg ulcers.
Apligraf-Tissue engineered skin
Arch Dermatol 1998;134:293-300.
231 patients with venous ulcers were randomized to receive compression therapy with or without Apligraf
Two hundred seventy-five patients were evaluated in this prospective, multicenter, controlled study
Significantly more patients healed at 6 months when treated with Apligraf plus compression therapy than with compression alone (63% vs 49%; P = .02)
Median time to complete wound closure was significantly shorter with Apligraf (61 vs 181 days)
Apligraf was particularly effective in difficult-to-heal ulcers—ulcers of more than 6 months' duration and larger and deeper ulcers
The longevity of a bilayered skin substitute after application to venous ulcers.
Phillips TJ, Manzoor J, Rojas A, Isaacs C, Carson P, Sabolinski M, Young J, Falanga V.
Department of Dermatology, Boston University School of Medicine, 609 Albany St, Boston, MA 02118.
Arch Dermatol 2002 Aug;138(8):1079-81 Abstract quote
BACKGROUND: A bilayered skin substitute composed of allogeneic keratinocytes and fibroblasts in a collagen gel has been approved by the US Food and Drug Administration for the treatment of venous and diabetic ulcers. Its mechanism of action has not been fully determined.
OBJECTIVE: To determine the longevity of allogeneic fibroblasts and keratinocytes in a bilayered skin substitute in patients with venous leg ulcers.
METHODS: Ten patients with venous leg ulcers were treated with a bilayered skin substitute on day 0, days 3 to 5, and weeks 1 through 3. Biopsy specimens of the grafted wound were taken. We used polymerase chain reaction analysis to determine whether allogeneic DNA was present in the biopsy specimens.
RESULTS: We detected allogeneic DNA in 2 of 8 specimens at 1 month after initial grafting. Neither of the 2 patients showed persistence of allogeneic DNA at 2 months after initial grafting.
CONCLUSIONS: Allogeneic cells from a bilayered skin substitute do not appear to survive permanently after grafting for treatment of venous leg ulcers. Other mechanisms of action might include cytokine release, structural support, or provision of a moist wound environment.
GMCSF Granulocyte-macrophage colony-stimulating factor
Int J Dermatol 1999;38:380-6.
Complete healing in 90.4% of 52 venous ulcers treated with granulocyte-macrophage colony-stimulating factor and compression therapy, with an average healing time of 19 weeks and a 6% relapse rate 1 year after healing
HORMONE REPLACEMENT THERAPY
Hormone replacement therapy and prevention of pressure ulcers and venous leg ulcers.
Margolis DJ, Knauss J, Bilker W.
Lancet 2002 Feb 23;359(9307):675-7 Abstract quote
Pressure ulcers and venous leg ulcers are common chronic wounds. Oestrogens in the form of hormone replacement therapy (HRT) might have an effect on wound healing, but this possibility has not been studied in detail.
Using a case-cohort study including elderly patients in the UK General Practice Research Database, we showed that patients who received HRT were less likely to develop a venous leg ulcer (age-adjusted relative risk 0.65 [95% CI 0.61-0.69]) or a pressure ulcer (0.68 [0.62-0.76]) than those who did not use HRT.
Therefore, we believe that HRT could be beneficial for the prevention of these wounds.
Noncontact radiant heat bandage (Warm-up Active Wound Therapy)
Adv Wound Care 1999;12:89-93.
Safe and efficacious for the inpatient treatment of recalcitrant chronic venous ulcers in 17 patients
Monochromatic infrared energy Effective in healing leg ulcers of different origins XIMELAGATRAN
- Ximelagatran vs low-molecular-weight heparin and warfarin for the treatment of deep vein thrombosis: a randomized trial.
Fiessinger JN, Huisman MV, Davidson BL, Bounameaux H, Francis CW, Eriksson H, Lundstrom T, Berkowitz SD, Nystrom P, Thorsen M, Ginsberg JS; THRIVE Treatment Study Investigators.
Department of Vascular Medicine, Hopital Europeen Georges Pompidou, Paris, France.
JAMA. 2005 Feb 9;293(6):681-9. Abstract quote
CONTEXT: Ximelagatran, an oral direct thrombin inhibitor with a rapid onset of action and predictable antithrombotic effect, has the potential to be a simple therapeutic alternative to current standard treatment of acute venous thromboembolism.
OBJECTIVE: To compare the efficacy and safety of ximelagatran with standard enoxaparin/warfarin treatment for the prevention of recurrent venous thromboembolism.
DESIGN, SETTING, AND PATIENTS: Randomized, double-blind, noninferiority trial (Thrombin Inhibitor in Venous Thromboembolism [THRIVE] Treatment Study) of 2489 patients with acute deep vein thrombosis, of whom approximately one third had concomitant pulmonary embolism. The study was conducted at 279 centers in 28 countries from September 2000 through December 2002.
INTERVENTIONS: Patients were randomized to receive 6 months of treatment with either oral ximelagatran, 36 mg twice daily, or subcutaneous enoxaparin, 1 mg/kg twice daily, for 5 to 20 days followed by warfarin adjusted to maintain an international normalized ratio of 2.0 to 3.0.
MAIN OUTCOME MEASURES: Recurrent venous thromboembolism, bleeding, and mortality.
RESULTS: Venous thromboembolism recurred in 26 of the 1240 patients assigned to receive ximelagatran (estimated cumulative risk, 2.1%) and in 24 of the 1249 patients assigned to receive enoxaparin/warfarin (2.0%). The absolute difference between ximelagatran and enoxaparin/warfarin was 0.2% (95% confidence interval [CI], -1.0% to 1.3%). This met the prespecified criterion for noninferiority. Corresponding values for major bleeding were 1.3% and 2.2% (difference, -1.0%; 95% CI, -2.1% to 0.1%), and for mortality were 2.3% and 3.4% (difference, -1.1%; 95% CI, -2.4% to 0.2%). Alanine aminotransferase levels increased to more than 3 times the upper limit of normal in 119 patients (9.6%) and 25 patients (2.0%) receiving ximelagatran and enoxaparin/warfarin, respectively. Increased enzyme levels were mainly asymptomatic. Retrospective analysis of locally reported adverse events showed a higher rate of serious coronary events with ximelagatran (10/1240 patients) compared with enoxaparin/warfarin (1/1249 patients).
CONCLUSIONS: Oral ximelagatran administered in a fixed dose without coagulation monitoring, was as effective as enoxaparin/warfarin for treatment of deep vein thrombosis with or without pulmonary embolism and showed similar, low rates of bleeding. Increased levels of liver enzymes in 9.6% of ximelagatran-treated patients require regular monitoring; the mechanism requires further evaluation. Prospective assessment of coronary events in future studies is warranted.
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