Mechanochemistry of von Willebrand factor

AbstractVon Willebrand factor (VWF), a blood multimeric protein with a very high molecular weight, plays a crucial role in the primary haemostasis, the physiological process characterized by the adhesion of blood platelets to the injured vessel wall. Hydrodynamic forces are responsible for extensive conformational transitions in the VWF multimers that change their structure from a globular form to a stretched linear conformation. This feature makes this protein particularly prone to be investigated by mechanochemistry, the branch of the biophysical chemistry devoted to investigating the effects of shear forces on protein conformation. This review describes the structural elements of the VWF molecule involved in the biochemical response to shear forces. The stretched VWF conformation favors the interaction with the platelet GpIb and at the same time with ADAMTS-13, the zinc-protease that cleaves VWF in the A2 domain, limiting its prothrombotic capacity. The shear-induced conformational transitions favor also a process of self-aggregation, responsible for the formation of a spider-web like network, particularly efficient in the trapping process of flowing platelets. The investigation of the biophysical effects of shear forces on VWF conformation contributes to unraveling the molecular mechanisms of many types of thrombotic and haemorrhagic syndromes

Immune and Hereditary Thrombotic Thrombocytopenic Purpura: Can ADAMTS13 Deficiency Alone Explain the Different Clinical Phenotypes?

: Thrombotic thrombocytopenic purpura (TTP) is a thrombotic microangiopathy caused by a hereditary or immune-mediated deficiency of the enzyme ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13). TTPs are caused by the following pathophysiological mechanisms: (1) the presence of inhibitory autoantibodies against ADAMTS13; and (2) hereditary mutations of the ADAMTS13 gene, which is present on chromosome 9. In both syndromes, TTP results from a severe deficiency of ADAMTS13, which is responsible for the impaired proteolytic processing of high-molecular-weight von Willebrand factor (HMW-VWF) multimers, which avidly interact with platelets and subendothelial collagen and promote tissue and multiorgan ischemia. Although the acute presentation of the occurring symptoms in acquired and hereditary TTPs is similar (microangiopathic hemolytic anemia, thrombocytopenia, and variable ischemic end-organ injury), their intensity, incidence, and precipitating factors are different, although, in both forms, a severe ADAMTS13 deficiency characterizes their physiopathology. This review is aimed at exploring the possible factors responsible for the different clinical and pathological features occurring in hereditary and immune-mediated TTPs

Severe intestinal bleeding due to left-sided portal hypertension after pancreatoduodenectomy with portal resection and splenic vein ligation

Pancreatoduodenectomy (PD) with portal vein (PV)/superior mesenteric vein (SMV) resection is well accepted for pancreatic head cancer because of the improvement in margin-negative resection and survival rates, without increasing postoperative morbidity and mortality in high volume centers. There is controversy in the surgical literature regarding the safety of splenic vein (SV) ligation during a PD with PV-SMV resection. Simple SV ligation has been associated with the development of left-sided portal hypertension, gastrointestinal bleeding and hypersplenism over the long term. We report a rare case of severe intestinal bleeding due to left-sided portal hypertension in patient who underwent a PD with PV-SMV confluence segmental resection and splenic ligation, preserving left gastric vein and inferior mesenteric vein, for cephalic pancreatic adenocarcinomas, seven months previously

Fertilization Management of Paddy Fields in Piedmont (NW Italy)

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Os dilemas do desenvolvimento: um olhar para o rural

A definição e a aplicação do desenvolvimento não é um consenso no meio acadêmico e político, ao contrário, é um tema muito amplo e polêmico. O objetivo deste artigo foi o de abordar essas diferentes concepções, atreladas ao meio rural brasileiro, buscando vincular as abordagens a alguns exemplos práticos. Para tanto, discutiu-se sobre alguns dos principais enfoques do desenvolvimento lançando mão de referenciais teóricos. Percebe-se que apesar de ser um tema bastante discutido há décadas no meio acadêmico, ainda não há uma aplicação prática efetiva, com algumas poucas exceções, de políticas que realmente favoreçam o desenvolvimento rural, territorial e sustentável

The Von Willebrand factor-ADAMTS-13 axis: a two-faced Janus in bleeding and thrombosis

Von Willebrand factor (VWF), a blood multimeric protein with a very high molecular weight, plays a crucial role in the primary hemostasis, the physiological process characterized by the adhesion of blood platelets to the injured vessel wall. Hydrodynamic forces are responsible for the VWF multimers conformational transitions from a globular to a stretched linear conformation. These characteristics render this protein a valuable object to be investigated by mechanochemistry, the biophysical chemistry branch that studies the effects of shear forces on protein conformation. This review will focus on the structural elements of the VWF molecule involved in the biochemical response to shear forces. The stretched VWF conformation favors the interaction with the platelet GpIb and at the same time with ADAMTS-13, the zinc-protease that cleaves VWF in the A2 domain, limiting its prothrombotic capacity. It is important to consider the level or the function of VWF or ADAMTS-13 always in relation each other, keeping in mind that in many thrombotic forms of microangiopathies the reduction of the ratio between the ADAMTS-13 activity and the VWF level (lower than 0.5) can be a valuable parameter to predict a real thrombotic risk. Hence, a significant increase in VWF level alone, even without any reduction of ADAMTS-13 concentration, would still be responsible for a significant reduction of the ADAMTS-13/VWF ratio, which ultimately could reflect or predict a prothrombotic risk. Future studies will have to validate the concept whether ADAMTS-13/VWF ratio could a valuable and reliable biomarker to predict or confirm the presence of thrombotic risk in several morbid conditions

Os dilemas do desenvolvimento: um olhar para o rural

A definição e a aplicação do desenvolvimento não é um consenso no meio acadêmico e político, ao contrário, é um tema muito amplo e polêmico. O objetivo deste artigo foi o de abordar essas diferentes concepções, atreladas ao meio rural brasileiro, buscando vincular as abordagens a alguns exemplos práticos. Para tanto, discutiu-se sobre alguns dos principais enfoques do desenvolvimento lançando mão de referenciais teóricos. Percebe-se que apesar de ser um tema bastante discutido há décadas no meio acadêmico, ainda não há uma aplicação prática efetiva, com algumas poucas exceções, de políticas que realmente favoreçam o desenvolvimento rural, territorial e sustentável

Um novo espaço em disputa: o produtor de arroz irrigado e as novas instituições reguladoras do uso e propriedade da água no extremo meridional brasileiro

The 1988 Constitution brought about significant changes in the Brazilian legislation, particularly those related to the property rights on rural estates. Besides that, substantial changes were introduced in relation to the usage of natural resources, as it is the case of water, raised to the common welfare category, as having a finite character and provided with economic value. For this account, important limitations were imposed to the private property, which only now begin to be embodied into the imaginary of social actors involved in productive processes which act in the sector of production systems. These changes have engendered a necessity for new institutional ties as well as invariable adaptations considered as a resistance on the part of the gaucho agrarian bourgeoisie. This is precisely the case of rice producers, who are considered as one of the sectors imposing a new dynamics on the socio-productive relationships from the process of modernization since the second half of the XX century, achieving an expressive expansion of the cultivated areas, rice production and productivity, as well as of the hydric consumption required for this culture. This paper analyzes these questions based on a case study performed in the municipality of Santa Vitoria do Palmar, the extreme gaucho south.A constituição de 1988 trouxe consigo alterações significativas na legislação brasileira, particularmente com relação ao direito de propriedade de imóveis rurais. Além disso, mudanças substanciais foram introduzidas com relação ao uso dos recursos naturais, como é o caso da água, elevada à categoria de bem comum, de caráter finito e dotada de valor econômico. Com isso se impôs à propriedade privada importantes limitações que só agora começam a ser incorporadas ao imaginário dos atores sociais implicados em processos produtivos e de agentes que operam no âmbito dos sistemas de produção. Essas mudanças engendram a necessidade de novas institucionalidades e de adequações invariavelmente recebidas com resistência por parte de setores da burguesia agrária gaúcha. Esse é precisamente o caso dos produtores de arroz, considerados como um dos setores que impuseram uma nova dinâmica nas relações sócio-produtivas a partir do processo de modernização desencadeado desde a segunda metade do século XX e que culminou com uma expansão impressionante na área cultivada, produção e produtividade orizícola, bem como no consumo hídrico requerido para essa cultura. A dissertação analisa essas questões com base em estudo de caso realizado no município de Santa Vitória do Palmar, no extremo sul gaúcho