1,721,234 research outputs found
Inflammation, coagulation, vascular permeability and thrombosis
No full textAmple evidence exists on the close link among the immune response, inflammation and coagulation [1, 2]. Proinflammatory cytokines such as interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α) induce the expression of tissue factor (TF) the main initiator of blood coagulation [2]. TF activates the coagulation cascade generating thrombin which leads to the formation of fibrin clot from fibrinogen. At the cellular level, the coagulant mediators act on protease-activated receptors (PARs) inducing the expression of proinflammatory cytokines [3]. In turn, the two systems - coagulation and inflammation - activate each other, thus increasing the response. This self-refuelling loop may be amplified by the dysfunction of the major natural anticoagulant pathways (i.e. antithrombin, protein C system, and tissue factor pathway inhibitor) occurring in several inflammatory conditions [4]. Inflammation affects the coagulation system as observed in sepsis [5], rheumatoid arthritis [6, 7], autoimmune skin diseases [8, 9], inflammatory bowel diseases [10], and hypereosinophilic syndromes [11] which show an increased risk of thrombosis. Moreover, inflammatory mediators, acting synergistically with coagulation factors, may contribute to increase vascular permeability in conditions like urticaria and other cutaneous disorders [12, 13]. In this issue we will focus on several aspects of the complex interplay between inflammation and coagulation in different human diseases: sepsis (Chapter 1), rhematoid arthritis (Chapter 2), autoimmune and immune-mediated skin diseases (Chapter 3), urticaria and angioedema (Chapter 4), inflammatory bowel diseases (Chapter 5), and hypereosinophilic conditions (Chapter 6). The final aim is to identify new targets for therapies that can modify the dysregulation of coagulation and inflammation pathways, acting both locally, by preventing tissue damage and vascular hyperpermeability, and systemically, by reducing thrombotic ris
Bradykinin involvement in angioedema
No full textIn recent years, several lines of evidence indicate that the kinin system is involved in the pathogenesis of angioedema due to C1-inhibitor deficiency as well as that related to treatment with angiotensin-converting enzyme (ACE) inhibitors. C1-inhibitor is the main inhibiting protein of the contact system; therefore, when C-1 inhibitor is deficient, the contact system should be more active and the generation of bradykinin increased. On the other hand, ACE is the main enzyme that catabolizes bradykinin; thus when ACE is inhibited, bradykinin should be increased because less is catabolized. In order to demonstrate these views, we have studied patients with angioedema due to C1-inhibitor deficiency and ACE-inhibitor treatment. We measured bradykinin directly in plasma with a radioimmunoassay after liquid phase extraction and high-performance liquid chromatography, then indirectly studied the generation of bradykinin by evaluating with western blot analysis the cleavage of high-molecular-weight kininogen, the progenitor molecule of bradykinin. Plasma levels of bradykinin were high in both groups of angioedema patients, whereas high-molecular-weight kininogen was cleaved in patients with angioedema due to C1-inhibitor deficiency but normal in those with ACE-inhibitor–related angioedema. This indicates an increased bradykinin production in angioedema due to C1-inhibitor deficiency and a reduced bradykinin catabolism in ACE-inhibitor–related angioedema. Whatever the reason for the increased plasma levels of bradykinin (increased production or decreased catabolism), these data provide the rationale for the use of the recently developed bradykinin receptor antagonists in these two types of angioedema
Cardiovascular events and survival in rheumatoid arthritis : effects of anti-tumor necrosis factor-alpha treatment
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The complex differential diagnosis between thrombotic thrombocytopenic purpura and the atypical hemolytic uremic syndrome : laboratory weapons and their impact on treatment choice and monitoring
No full textThrombocytopenia and microangiopathic hemolytic anemia are the hallmark of the thrombotic microangiopathies (TMAs) thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS). TTP, inherited or autoimmune, is mainly caused by the plasma deficiency of the von Willebrand factor cleaving protease ADAMTS13, owing to gene mutations or autoantibodies. Typical HUS is often caused by infections with Shiga-Toxin-producing Escherichia coli and thus is called STEC-HUS. The rarer atypical form of HUS is often associated with complement dysregulation, owing to the inherited deficiency or dysfunction of factor H or other complement proteins. In the past the distinction between these TMAs was almost exclusively based on clinical grounds, the term TTP being used for cases with predominant neurological involvement, STEC HUS for cases presenting with bloody diarrhea and atypical HUS identifying patients with severe renal damage. However the clinical presentation may not easily distinguish TTP from atypical HUS. A more accurate differential diagnosis has clinical implications, because plasma exchange (the treatment of choice in TTP) is much less effective in atypical HUS, which shows dramatic short- and long-term therapeutic benefits from eculizumab, a monoclonal antibody that inhibits complement activation. This article will point out that the measurement of ADAMTS13 is able to diagnose accurately the majority of TTP cases, and that very simple tests such as the platelet count and serum creatinine can predict the deficiency of the protease with a good degree of accuracy. In atypical HUS, new methods were recently developed that not only demonstrate the activation of the complement system, i.e., the main disease mechanism, but also help to tailor the short- and long-term treatment with eculizumab
[The kinin system: biological mechanisms and clinical implications]
No full textThe discovery of the kinin system is not recent, but its study in clinical field has been done only in the last years. This system is composed by substrates (kininogens) and plasma and tissue kallikreins are the specific activators of these substrates producing two vasoactive peptides called bradykinin and kallidin. The biologic effects of kinins are mediated by specific receptors called B1 and B2. The activation of this system is particularly important in blood pressure regulation and in inflammatory reactions. The kinin system is involved in many clinical situations including respiratory allergic reactions, septic shock, hypertension and its treatment, hypotensive transfusion reactions, heart diseases, pancreatitis, hereditary and acquired angioedema, Alzheimer's disease and liver cirrhosis with ascites. The study of the kinin system in clinical field, which had been limited by methodological difficulties, has now received an important stimulus by the recent availability of specific and sensitive methods of dosage
Activation of blood coagulation in plasma from chronic urticaria patients with negative autologous plasma skin test
No full textSkin reactivity to the intradermal injection of autologous serum (autologous serum skin test - ASST) and/or plasma (autologous plasma skin test - APST) is thought to identify chronic urticaria (CU) patients with an autoimmune/autoreactive disease. Immune-mediated inflammation and coagulation are strictly linked, and coagulation activation has been described in CU patients as shown by the elevation of plasma prothrombin fragment F1+2 and, in severe cases, of d-dimer as wel
Reply : activation of the blood coagulation cascade is involved in patients with chronic urticaria
No full textActivation of the contact system and fibrinolysis in autoimmune acquired angioedema : a rationale for prophylactic use of tranexamic acid
No full textC1-inhibitor deficiency results in bouts of mucocutaneous edema and may be inherited (hereditary angioedema) or acquired (acquired angioedema [AAE]). The two forms have the same clinical picture but differ in the response to treatment. Prophylaxis with antifibrinolytic agents produces better results in the acquired form than in the inherited form, in which androgen derivatives are more effective. It is hypothesized that activation of the contact and fibrinolytic systems is involved in the pathogenesis of attacks. We evaluated these two systems in plasma from eight patients with AAE and anti-C1-inhibitor autoantibodies (autoimmune AAE) by measuring the cleavage of high molecular weight kininogen and the complexes formed by plasmin and its inhibitor alpha 2-antiplasmin. We also measured complement parameters, autoantibody titer, and cleaved C1-inhibitor (relative molecular mass = 96,000), because autoantibodies to C1-inhibitor are known to facilitate its cleavage by proteases. Plasma was obtained from patients in remission, during prophylactic treatment with the antifibrinolytic agent tranexamic acid (2 to 4.5 gm/day) and also from two patients during acute attacks of edema. Levels of cleaved high molecular weight kininogen and antiplasmin-plasmin complexes in patients with AAE were both higher in basal conditions, during treatment, and during acute attacks than those in normal subjects (p < 0.001). The cleaved inactive form of C1-inhibitor was also present in all patients in all three conditions. Therapy with antifibrinolytic agents reduced the frequency and intensity of symptoms without significantly changing any of the biochemical parameter
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