Warfarin therapy for livedoid vasculopathy associated with cryofibrinogenemia and hyperhomocysteinemia

BACKGROUND: Livedoid vasculopathy is an idiopathic, chronic disorder manifested by painful, purpuric macules on the lower extremities that superficially ulcerate, resulting in atrophic, stellate scars with peripheral telangiectasias and hyperpigmentation. OBSERVATIONS: A 50-year-old man presented with recurrent, painful ulcerations on the medial aspect of his malleoli and calves. The clinical presentation, histologic findings, and results of laboratory evaluation confirmed the diagnosis of livedoid vasculopathy in this case. Despite being refractory to treatment with multiple other medications, the lesions responded dramatically to oral warfarin sodium therapy. CONCLUSION: Treatment with warfarin may be a beneficial therapy for patients with livedoid vasculopathy.     

Ulcerations caused by livedoid vasculopathy associated with a prothrombotic state: Response to warfarin

A 50-year-old woman had a lifelong history of painful ulcerations as a result of livedoid vasculopathy. She was a heterozygous carrier of factor V Leiden and prothrombin gene mutations and was receiving hormone replacement therapy. The ulcers healed after warfarin therapy, which has been reported to be effective in only one previous patient with this condition.     

Intractable livedoid vasculopathy successfully treated with hyperbaric oxygen

We describe a new method for treating livedoid vasculopathy. The typical presentation of livedoid vasculopathy includes chronic, recurrent painful ulcers, satellite scar-like atrophy and telangiectasia involving the lower extremities. Histologically, these lesions show areas of ulceration and dermal vessel occlusion without frank inflammatory cell infiltration. There is currently no satisfactory therapy available for this disease. Hyperbaric oxygen (HBO) has recently established itself as one of the most effective methods of treating ischaemic wounds, including diabetic ulcers. We used this therapy in two patients whose lesions were resistant to multiple therapeutic modalities. Not only did their ulcers respond rapidly to the HBO therapy, but the disturbing wound pain also resolved at the same time. To our knowledge, this is the first successful trial of HBO therapy in livedoid vasculopathy. We believe this to be a very promising new therapy for livedoid vasculopathy and to be worth further investigation.     

A case of livedoid vasculopathy associated with factor V Leiden mutation: successful treatment with oral warfarin

Livedoid vasculopathy is characterized by painful purpuric lesions on the extremities which frequently ulcerate and heal with atrophic scarring. It has been considered to be a vasculitic process but now there has been increasing evidence that abnormal coagulation plays a major role in the pathogenesis of this rare disorder. We report the case of a 19-year-old male who had been suffering from recurrent painful ulcerations on both lower legs with atrophic scars for 4 years. A biopsy specimen revealed vasculopathy, and laboratory studies showed resistance to activated protein C with factor V Leiden mutation. Treatment with oral warfarin led to rapid improvement of the lesions.     

Livedoid vasculopathy. Pathogenesis, diagnosis and treatment of cutaneous infarction

Livedo vasculopathy is a chronic recurrent disease of the cutaneous circulation and is characterized by episodic occurrence of painful ulcerations of the lower leg. These heal slowly leaving small porcelain-white scars called atrophie blanche. Recent research has shown that livedoid vasculopathy is a coagulation disorder classified as a vasculopathy different from inflammatory vasculitis. Distinguishing between the disorders enhances the pathophysiologic understanding and supports the therapeutic rationale. The prevention of irreversible residual scarring is the main goal in treating cutaneous infarction; prompt treatment is required.     

Livedovaskulopathie

Livedo vasculopathy is a chronic recurrent disease of the cutaneous circulation and is characterized by episodic occurrence of painful ulcerations of the lower leg. These heal slowly leaving small porcelain-white scars called atrophie blanche. Recent research has shown that livedoid vasculopathy is a coagulation disorder classified as a vasculopathy different from inflammatory vasculitis. Distinguishing between the disorders enhances the pathophysiologic understanding and supports the therapeutic rationale. The prevention of irreversible residual scarring is the main goal in treating cutaneous infarction; prompt treatment is required.     

Livedoid vasculopathy associated with heterozygous protein C deficiency

Livedoid vasculopathy is characterized by recurrent painful ulceration of the feet, ankles and legs that heals with residual white atrophic scars. For many years, livedoid vasculopathy has been considered to be a primary vasculitic process. Recently, however, there has been a trend towards considering livedoid vasculopathy as an occlusive vasculopathy due to a hypercoagulable state. Livedoid vasculopathy (under the designation livedo vasculitis) was first reported to be associated with protein C deficiency in 1992. We describe an additional patient with livedoid vasculopathy associated with heterozygous protein C deficiency. This second reported case suggests that protein C deficiency may be one cause of the hypercoagulable condition in these patients and demonstrates the necessity for further investigation of thrombogenic factors underlying the disease.     

23例青斑样血管病临床分析

目的：提高对青斑样血管病的临床认识及诊断能力，探讨有效的治疗方法。方法：回顾性分析2010-2017年诊断的青斑样血管病患者的临床资料，包括临床及组织病理特点、治疗方法及疗效。结果：诊断了23例青斑样血管病患者，其中男6例，女17例，发病年龄(24.86±7.63)岁；皮损主要发生于踝周（21/23），皮损表现为疼痛性紫癜、溃疡及象牙色萎缩；组织病理改变主要表现为真皮浅中层小血管壁纤维素样变性及管腔内透明血栓形成；治疗上以抗凝、抗血小板聚集及促纤溶为主，己酮可可碱、达那唑、阿司匹林治疗效果好。结论：青斑样血管病具有特征性临床及组织病理学改变，但早期容易误诊误治，己酮可可碱有助于本病的治疗及预防复发。     

Livedovaskulopathie bei heterozygoter Faktor-V-Leiden-Mutation und Sticky-Platelet-Syndrom

A 64-year-old male patient presented with painful ulcerations and livedo racemosa of both lower limbs. He had a history of cerebral and myocardial infarctions. Dermatohistologic findings and laboratory tests of the patient's coagulation system revealed the diagnosis of livedoid vasculopathy with heterozygous factor V Leiden mutation and sticky platelet syndrome type II. Systemic treatment with acetylsalicylic acid and heparin as well as topical therapy with disinfectant and granulation-inducing agents resulted in improvement of the skin lesions.     

Livedoid vasculopathy – current aspects of diagnosis and treatment of cutaneous infarction

Livedoid vasculopathy is a rare, chronic, recurrent disease of the cutaneous microcirculation. Its typical clinical manifestation is a triad which consists of livedo racemosa of the skin, episodic painful ulcerations of the distal aspects of the legs and a healing process leaving small porcelain‐white scars called atrophie blanche. As an important result of recent research, livedoid vasculopathy has been defined as a coagulation disorder classified as a vasculopathy different from inflammatory vasculitis. This differentiation adds to the current pathophysiologic understanding and supports the therapeutic rationale with respect to the use of new systemic anticoagulants. The prevention of irreversible residual scarring and the improvement of patientsí quality of life are the main goals in treating cutaneous infarction and require early and consequent treatment. This article presents current knowledge on diagnosing this rare disease and offers practical guidance on its therapy.     

Livedoid vasculopathy in a patient with factor V mutation (Leiden)

BACKGROUND: Frequently, no underlying disease can be detected in patients with livedoid vasculopathy. For these forms, an unknown vaso-occlusive or thrombogenic process has been accused to play a role. Thus, a patient with livedoid vasculopathy was examined for different parameters which can be involved in coagulopathies. METHODS: Laboratory studies for different autoantigen reactive immunoglobulins, cryoglobulins, and circulating immune complexes were carried out. Besides dermatopathologic examination, a biopsy specimen was analyzed by direct immunofluorescence for immunoglobulin (Ig) and complement deposits. Furthermore, hemostaseological function tests including activated protein C (APC) resistance were undertaken. RESULTs: Positive only at very low titres were antinuclear antibodies and c-ANCA, all other parameters were within normal ranges or negative. Direct immunofluorescence revealed IgM, C3 and fibrogen deposits. Hemostaseological function tests demonstrated a pathologic activated protein c resistance and PCR analysis a heterozygous defect of the factor V (Leiden). CONCLUSIONS: The diagnosis of livedoid vasculopathy associated with factor V mutation (Leiden) was made. Since the underlying cause for livedoid vasculopathy often remains unknown, we suggest that hemostaseological function tests including APC resistance and factor V gene mutation analysis should be carried out. Further studies have to follow in order to elucidate the role of mutant factor V in livedoid vasculopathy and in cutaneous ulcerations.     

Livedoid vasculopathy: long-term follow-up results following hyperbaric oxygen therapy

BACKGROUND: Livedoid vasculopathy, also known as atrophie blanche, is a recurrent painful vasculopathy appearing mostly on the lower limbs. Treatment is challenging and relapses are frequent. OBJECTIVES: To analyse the long-term effect and safety of hyperbaric oxygen (HBO) therapy in treating livedoid vasculopathy. METHODS: Twelve patients with active livedoid vasculopathy were included in this study. All patients underwent HBO therapy five times a week. Each week photographs were taken and the total dose of analgesics was recorded. Side-effects were documented and assessed. Recurrence was defined as the presence of skin ulceration. RESULTS: Of the eight patients who completed the treatment, resumption of ambulation and reduction of analgesics were achieved at an average of 4.9 HBO therapy sessions. Leg ulcers in all eight patients healed completely at a mean of 3.4 weeks (range 2-5 weeks). Six patients suffered relapses of ulceration and responded to additional HBO therapy. No significant side-effects were found. CONCLUSIONS: HBO is a relatively safe, fast and effective method to treat patients with livedoid vasculopathy.     

青斑样血管病的诊疗进展

青斑样血管病是一种非炎性、真皮内血管阻塞性皮肤病,以双下肢远端反复出现疼痛性溃疡,网状青斑以及瓷白色萎缩性瘢痕为主要临床表现。本病病因及发病机制不明,可能与机体高凝状态,纤维蛋白溶解障碍和/或与免疫系统疾病相关。目前无特效疗法,主要以缓解疼痛、防止皮损进展为目的。     

Frequency of thrombophilia determinant factors in patients with livedoid vasculopathy and treatment with anticoagulant drugs – a prospective study

Background Livedoid vasculopathy (LV) is a chronic idiopathic disease characterized by painful purpuric macules on lower extremities. Its exact aetiology remains uncertain, but thrombotic and microcirculatory phenomena have been implicated as possible pathogenic factors. Objectives To assess prospectively the frequency of thrombophilia and to verify the effectiveness of anticoagulant therapy among LV patients. Methods Thirty‐four LV patients were tested for prothrombin time, activated partial thromboplastin time, antithrombin activity, protein C and S activity, anticardiolipin antibodies, lupus anticoagulant, prothrombin gene mutation, factor V Leiden mutation, methylenetetrahydrofolate reductase mutation, plasma homocysteine and fibrinogen. Thirteen of these patients were treated with anticoagulant drugs (either warfarin or heparin). Results Of 34 patients, 18 (52%) presented laboratory abnormalities of procoagulant conditions. Positive treatment response to anticoagulant therapy was observed in 11 patients. Improvement of pain was obtained in 1–3 weeks, an average of 1.8 week. Complete healing of the lesions was observed in about 2.3 months. Remission was sustained even after treatment interruption and lasted an average 7.8 months. No severe adverse effects were noticed. Conclusion The authors suggest all patients with diagnosis of LV to be investigated for thrombophilic status. Anticoagulant drugs were well tolerated and seemed to be effective in treating not only LV symptoms but also its ulcerations.     

Heterozygous prothrombin gene mutation associated with livedoid vasculopathy

A 53-year-old woman presented with a chronic history of recurrent, painful ulcers, predominantly involving her lower legs. Both her clinical picture and histopathological findings were consistent with a diagnosis of livedoid vasculopathy, although she did have unusual findings of deep tender nodules and the presence of lesions over her elbows. Multiple investigations were undertaken, the only abnormality being a heterozygous mutation of the prothrombin G2021A gene. Although various coagulopathic states have been associated with livedoid vasculopathy, the finding of an associated prothrombin gene mutation is quite rare. Warfarin has ameliorated the clinical course when anti-inflammatory drugs and other anticoagulants were unhelpful.     

青斑样血管病64例皮损特点分析

【摘要】 目的 分析青斑样血管病网状青斑和紫癜性皮损的特点、分布规律。方法 回顾中国医学科学院皮肤病医院2017年7月至2020年10月诊治的64例青斑样血管病患者的临床资料。结果 64例中男23例,女41例;年龄13 ~ 54岁,发病年龄7 ~ 51岁,48例25岁前发病;病程6个月至10年。49例夏季发病或病情加重,皮损基本表现为坏死性不规则紫癜、紫癜性皮病样红斑、不规则溃疡、网状青斑、毛细血管扩张、不规则的白色萎缩性瘢痕和色素沉着。64例溃疡和坏死性紫癜多为不规则形,发生于足背和踝关节周围。40例有紫癜性皮病样的皮损表现,其中32例表现为色素性紫癜,8例表现为毛细血管扩张性紫癜。4例出现麻木刺痛等神经末梢受损的症状。结论 青斑样血管病的皮损表现多样,对于出现广泛网状青斑、紫癜样皮病样皮损、麻木等症状的患者,需做好鉴别诊断。     

达那唑联合低分子肝素/雷公藤多甙治疗难治性青斑性血管病12例

目的评价达那唑片联合低分子肝素针/雷公藤多甙片治疗青斑性血管病的临床疗效和安全性。方法对常规治疗无效的12例青斑性血管病患者,予达那唑片联合低分子肝素针/雷公藤多甙片治疗。急性期予达那唑片100 mg口服,2次/d,低分子肝素针0.3 mL皮下注射,1次/d,雷公藤多甙片20 mg口服,3次/d。维持期予达那唑片100 mg口服,1次/d,低分子肝素针0.3 mL皮下注射,隔日1次,雷公藤多甙片20 mg口服,2次/d。随访0.5~3年。结果 2周后,10例溃疡开始结痂、变浅、面积缩小,疼痛减轻,无新发皮疹;治疗8~16周后,12例痊愈。疗程中不良反应少且轻微。结论达那唑片联合低分子肝素针/雷公藤多甙片对于常规治疗疗效差的青斑性血管病安全有效。     

From dermatological conditions to COVID‐19: Reasoning for anticoagulation,suppression of inflammation,and hyperbaric oxygen therapy

COVID‐19 generates a complex systemic inflammatory response that can lead to death due to wide macrophage activation, endothelial damage, and coagulation in critically ill patients. SARS‐CoV‐2‐induced lung injury due to inflammatory mediated thrombosis could be similar to the livedoid vasculopathy in the skin, supporting a translational comparison of these clinical settings. In this article, we discuss anticoagulation, suppression of inflammatory response, and hyperbaric oxygen therapy in the context of severe COVID‐19 and livedoid vasculopathy.     

联合或者单独使用利伐沙班治疗青斑样血管病三例

【摘要】 青斑样血管病是一种皮肤浅层血管丛微血管血栓导致的慢性皮肤缺血坏死性疾病,该病少见且缺乏有效的治疗手段。抗凝药物治疗该病的有效性得到公认,但广泛应用受到用药途径及不良反应的影响。Xa因子抑制剂利伐沙班可用于预防及治疗血栓及因此造成的溃疡,无需监测凝血功能,不良反应少,口服方便。我们联合或单独使用利伐沙班治疗3例青斑样血管病,取得满意效果。     

Livedoid vasculopathy associated with plasminogen activator inhibitor-1 promoter homozygosity (4G/4G) treated successfully with tissue plasminogen activator

BACKGROUND: Livedoid vasculopathy (LV) is an occlusive thrombotic disease that affects primarily the small blood vessels of the lower extremities and often is associated with recurrent painful ulcerations. The pathogenesis of LV is unclear, but the disease is largely attributed to a hypercoagulable state. Factor V Leiden mutation, heterozygous protein C deficiency, homozygous hyperhomocysteinemia, and other inherited thrombophilias have been associated with LV. Plasminogen activator inhibitor-1 (PAI-1) is an important inhibitor of the fibrinolytic system. Elevated levels of PAI-1 are found in some patients with thrombotic diseases. Some of these patients are homozygous for an allele of PAI-1 containing a stretch of 4 guanines at base -675 in the promoter region. This variant is associated with elevated PAI-1 protein levels, impaired fibrinolysis, and increased risk of thrombosis. OBSERVATIONS: A 33-year-old white woman had a 3-month history of painful enlarging ulcers on both ankles. Various therapies, including administration of oral antibiotic agents and prednisone up to 100 mg/d, to treat presumed vasculitis, were unsuccessful. Skin biopsy specimens revealed numerous thick-walled small blood vessels, many of which were filled with fibrin thrombi, in association with minimal perivascular inflammatory infiltrate, extensive epidermal necrosis, and focal ulceration. A diagnosis of thrombotic vasculopathy was made. Clinical workup revealed an elevated plasma level of PAI-1 (31 microM/mL; reference range, <25 microM/mL) and PAI-1 promoter 4G/4G homozygosity detected at DNA sequencing. Treatment with heparin sodium and tissue plasminogen activator dramatically improved the lesions, resulting in complete healing of the ulcerations. Continuation of anticoagulant therapy with warfarin sodium and episodic administration of tissue plasminogen activator was required for symptomatic control. CONCLUSIONS: Patients with LV may have elevated plasma PAI-1 levels. This may be associated with the PAI-1 promoter 4G/4G genotype, which has not previously been linked with LV. Further studies in patients with LV are warranted to determine how frequently this genotype is present because it may identify responsiveness to fibrinolytic therapy.