Thrombophilia: the dermatological clinical spectrum

The aim of this article is to review the hypercoagulable states (thrombophilia) most commonly encountered by dermatologists, as well as their cutaneous signs, including livedo racemosa, cutaneous necrosis, digital ischemia and ulcerations, reticulated purpura, leg ulcers, and other skin conditions. Recognizing these cutaneous signs is the first step to proper treatment. Our aim is to describe which tests are indicated, and when, in these clinical settings. Introduction The possible causes of vascular occlusion can be divided into three large groups: (i) abnormalities of the vascular wall, (ii) changes in blood flow, and (iii) hypercoagulation of the blood [1]. The term thrombophilia was introduced in 1965 by Egeberg [2] and is currently used to describe conditions resulting from hereditary (or primary) and/or acquired hyper-coagulation of the blood that increase the predisposition to thromboembolic events [3]. Various risk factors, whether genetic or acquired, make up the pathogenesis of thrombosis in both arteries and veins [3]. Some individuals develop recurring thromboses despite preventative measures or develop thromboses in unusual locations [46] and can exhibit a state of hidden hypercoagulability [4]. With regard to acquired thrombophilia, the following conditions are observed: cryoglobulinemia, thrombotic thrombocytopenic purpura, myeloproliferative syndromes, nephrotic syndrome, hypercoagulability associated with cancer, and antiphospholipid syndrome [1]. Table 1 shows the hereditary and acquired risk factors most related to venous thrombosis [3]. Risk factors for venous thromboembolism (VTE) (advanced age, prolonged immobilization, surgery, fractures, use of hormonal contraceptives, pregnancy, puerperium, neoplasms, and antiphospholipid syndrome [5]) differ from those for arterial thrombotic disease (arterial hypertension, smoking, dyslipidemia, and diabetes mellitus) [5]. In Western countries, the incidence of VTE per year is approximately 1 in every 1,000 individuals [7,8]. Screening for states of hypercoagulability in the general population is not practical from either a clinical or economic point of view [4]. The scope of this article is to review the states of hypercoagulability (thrombophilia) most likely to be encountered by the dermatologist, their clinical manifestations, which exams are indicated in these situations, and when such exams are indicated. Hereditary thrombophilia Since the 1950s, the description of states of “hypercoagulability” – a group of abnormalities associated with hyperactivity of the clotting system and/or the occurrence of thrombotic phenomena – changed the view of VTE [9]. Hereditary thrombophilia can be classified into three large groups according to the pathogenic mechanism [1]: (i) Reduction of anticoagulant capacity: There are two systems capable of blocking the clotting cascade and preventing the development of a massive and uncontrollable thrombosis: natural anticoagulants (antithrombin III, protein C, and protein S) and fibrinolysis (plasminogen-plasmin system). A congenital deficit in any one of these components constitutes a possible cause of primary thrombophilia. (ii) Increase in coagulant capacity: Within this group is included the following: a. Resistance to activated protein C. In approximately 90 to 95% of cases, resistance to activated protein C is due to a unique mutation in clotting factor V known as factor V Leiden. There are other causes of resistance to activated protein C that are not due to factor V Leiden such as antiphospholipid syndrome and other, rarer mutations. b. Mutation of the prothrombin G20210A gene. c. Elevated levels of clotting factors VIII, IX, and XI. d. Dysfibrinogenemia. (iii) Other conditions: This group primarily includes hyperhomocysteinemia. Levels of homocysteine can be elevated due to acquired causes (chronic renal insufficiency, hypothyroidism, and deficiencies in folic acid or vitamin B12) and to genetic factors. Among the causes of hyper-homocysteinemia, the most frequent is mutation of the methylenetetrahydrofolate reductase gene (MTHFR) (mutation C677T). Inherited deficiencies in antithrombin (AT), protein C (PC), and its co-factor protein S (PS) were the first identified causes of thrombophilia [10]. Over the last decade, two common genetic polymorphisms were Correspondence to: Paulo Ricardo Criado, Rua Carneiro Leão 33, Vila Scarpelli Santo André São Paulo – Brazil, CEP: 09050-430, E-mail: [email protected]