Fibrin subunits in venous and arterial thromboembolism.

The subunit fibrin composition of thrombi of both venous and arterial origin was examined by sodium dodecyl sulphate gel electrophoresis. The thrombi were recovered by surgical intervention and all had the same fibrin subunit composition. The alpha chains were cross-linked as alpha-chain polymers alpha (p), the gamma chains as gamma-chain dimers (gamma-gamma) while the beta chains were not crosslinked; a further subunit of molecular weight 33 000 was shown to be present in all the fibrins examined and was a degradation fragment of the beta or gamma chains. This data suggests that the crosslinked alpha chains are rate limiting to the lysis of thrombi in vivo. The digestion of pulmonary emboli by plasmin yielded soluble degradation products which were identified as D dimer and E, the latter fragments being the major products obtained by the lysis of in-vitro made plasma clots. The similarity of the composition and lysis of thrombus fibrin to that formed in vitro augurs well for the justification of in-vitro research on mechanisms in thrombolysis.     

Fibrin clot formation and lysis: basic mechanisms

The hemostatic balance, introduced more than 40 years ago, addresses the components and reactions involved in fibrin turnover. Fibrin is placed in the core of this delicate balance. Defects in the mechanisms responsible for fibrin turnover might lead to thrombosis or bleeding, and fibrin consequently is an important substrate in the physiology of hemostasis. This review describes the components and processes involved in fibrin formation and fibrin degradation. Particular emphasis is put on the reactions involved in the conversion of fibrinogen to fibrin, the polymerization of fibrin molecules induced by coagulation factor XIII (FXIII), and the degradation of fibrinogen and fibrin mediated by plasmin and elastase. Furthermore, factors influencing fibrin structure and fibrin breakdown are addressed; in particular polymorphisms in the genes coding for fibrinogen and FXIII, but also the physical and biochemical conditions in which fibrin is formed. The past decades have produced a bulk of biochemical publications reviewing fibrin turnover and fibrin structure, and it has been shown that alterations in fibrin structure are important for the development of various disease conditions, whereas, the architecture of fibrin can be modified by certain drugs and chemical compounds. However, these topics deserve increased attention in clinical settings. Of particular importance might be more detailed clinical studies that review the influence of polymorphisms in the genes coding for the key factors involved in fibrin metabolism on the development of hemostatic diseases, but also the role of elastase-induced fibrin degradation deserves increased attention.     

EDTA-induced changes in platelet structure and function: clot retraction

Ethylenediamine tetracetic acid (EDTA) is known to cause structural, biochemical and functional injury to blood platelets, including irreversible dissociation of the fibrinogen receptor, glycoprotein alpha IIb beta 3 (GPIIb/IIIa). Despite inability to adhere to glass, spread, and to aggregate in response to adenosine diphosphate (ADP) and other agonists, EDTA-treated platelets support clot retraction as well as untreated cells. The present study has used clot retraction under isometric tension and electron microscopy to determine if there are any differences in platelet-fibrin interactions of clots formed from blood collected in EDTA or platelets from blood drawn into citrate (CCD) anticoagulants. No physical differences could be identified. Polymerizing fibrin bound intimately to aggregates developing from EDTA platelets undergoing shape change, internal transformation, adhesion and spreading on fibrin strands oriented in the long axis of contraction. The results suggest that reassociation of irreversibly dissociated GPIIb/IIIa takes place immediately after initiation of clot retraction, or that a significant proportion of GPIIb/IIIa receptors on resting platelets are inaccessible to EDTA and become available after activation by thrombin.     

EDTA-induced changes in platelet structure and function: clot retraction

Ethylenediamine tetracetic acid (EDTA) is known to cause structural, biochemical and functional injury to blood platelets, including irreversible dissociation of the fibrinogen receptor, glycoprotein alpha IIb beta 3 (GPIIb/IIIa). Despite inability to adhere to glass, spread, and to aggregate in response to adenosine diphosphate (ADP) and other agonists, EDTA-treated platelets support clot retraction as well as untreated cells. The present study has used clot retraction under isometric tension and electron microscopy to determine if there are any differences in platelet-fibrin interactions of clots formed from blood collected in EDTA or platelets from blood drawn into citrate (CCD) anticoagulants. No physical differences could be identified. Polymerizing fibrin bound intimately to aggregates developing from EDTA platelets undergoing shape change, internal transformation, adhesion and spreading on fibrin strands oriented in the long axis of contraction. The results suggest that reassociation of irreversibly dissociated GPIIb/IIIa takes place immediately after initiation of clot retraction, or that a significant proportion of GPIIb/IIIa receptors on resting platelets are inaccessible to EDTA and become available after activation by thrombin.     

Diagnosis of venous and arterial thromboembolic events in COVID-19 virus-infected patients

Journal of Thrombosis and Thrombolysis -     

Statins and risk of venous thromboembolic diseases: A two-sample mendelian randomization study

Background and aimsIn observational studies, statins have been suggested to have protective effects on venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE). To this aim, we performed a two-sample mendelian randomization (MR) analysis to determine whether these associations were causal.Methods and resultsData on the single nucleotide polymorphisms (SNPs) related to statin medication were obtained from the FinnGen study, and data for VTE, PE and DVT of lower extremities (LEDVT) were from the UK Biobank study, respectively. Inverse variance weighted (IVW) method was used as the principal analysis of MR, and sensitivity analysis was performed to detect horizontal pleiotropy and heterogeneity. MR estimates showed an inverse causal association between statin medication and the risk of VTE (odds ratio [OR]: 0.999, 95% CI: 0.998–1.000, P = 0.004), PE (OR: 0.999, 95% CI: 0.999–1.000, P = 0.011) and LEDVT (OR: 0.999, 95% CI: 0.999–1.000, P = 0.008).ConclusionOur findings provide direct evidence that statins might decrease the risk of VTE, PE and LEDVT in agreement with observational studies. The specific mechanism of statin therapy for venous thromboembolism needs to be further studied.     

Long-term arterial blockade and retrograde venous perfusion in peripheral arterial occlusive diseases

The method of longterm artificial arterial blockade in patients with peripheral arterial occlusive disease (PAOD) opens new therapeutic possibilities. However, it is yet not clear if and how the suspected dilation of collateral arteries can be therapeutically used. The retrograde venous perfusion permits the transport of active substances in high concentrations into ischemic areas. The resulting temporary local damping or even blockade of sympathetic innervation can under certain conditions achieve therapeutic effects. A longterm arterial blockade can be performed even in case of trophic lesions. This permits treatment in stage IV of PAOD. It has been proved that antibiotics reach a lesion by retrograde venous perfusion faster and better than by systemic application, especially in badly compensated cases. However, sufficient experience on the therapeutic effect and possible side effects in stage IV is still lacking.     

The role of hemorheology in the pathophysiology and treatment of arterial occlusive disease

Hemorheological types of treatment are more and more used in the field of clinical angiology. On the other hand a good portion of criticism is necessary not to go the wrong way. In spite of really attractive pathophysiological ideas the bed side situation is quite a different affair. Up to now it is not clear under which conditions and to what extent pathological hemorheological values are causative or at least aggravating factors of arterial occlusive diseases and the resultant functional impairment. So the essential points of what is called "clinical hemorheology" are not yet solved. Direct observation and documentation of hemorheological induced clinically interesting effects in humans as well as the serious trial to give definitions of clinical conditions in which the effects obtained are of clinical relevance are extremely necessary to enlighten an attractive and exciting component of clinical angiology.     

MicroRNAs在胃肠道疾病发生中的调控作用及其机制

MicroRNAs(miRNAs)是一类广泛存在于动、植物中的内源性非编码小RNA,通过影响mRNAs的翻译或稳定性来发挥重要的调节作用。miRNAs的表达差异不仅可能与胃肠道肿瘤的发生、复发转移及预后有关,其在一些胃肠道良性疾病如萎缩性胃炎、溃疡性结肠炎及肠易激综合征等的发生机制中也可能起着重要的作用。     

Microscopic structure of disturbed flows in the arterial and venous systems, and its implication in the localization of vascular diseases

A novel technique to prepare isolated transparent natural blood vessels was developed and used to investigate the connection between blood flow and the localization of vascular diseases in man. Transparent segments of arteries and veins were prepared from dogs and humans postmortem, and the flow patterns in various regions of the circulation were studied in detail by means of flow visualization and cinemicrographic techniques. It was found that under normal physiological conditions, complex spiral secondary flows and recirculation zones form in various regions of the arterial and venous systems such as the aortic arch, aortic T-junctions, carotid artery bifurcations, the major branching sites of the intracranial cerebral arteries and venous valve pockets. Incipient saccular aneurysms were found at the flow divider of the anterior communicating-anterior cerebral artery junction where the flow directly impinged on the vessel wall. In human cerebral arteries, atherosclerotic thickenings of the vessel wall were found to be localized on the outer wall (hip) of one or both daughter vessels at bifurcations and T-junctions, and at the inner wall of arterial bends, at the very places where secondary and recirculation flows were dominant and wall shear stress was low. The results clearly indicate that there is a strong correlation between the sites of flow disturbance and the preferred sites for the genesis and development of vascular diseases clinically found in man.     

The role of inflammation in venous thromboembolism and the link between arterial and venous thrombosis.

During the last decade, the role of inflammation in the etiopathogenesis of arterial thrombosis has been elucidated. However, little is known about the relationship between inflammation and venous thrombosis. Recently, inflammation has been accepted as a possible mechanism through which different risk factors trigger thrombus formation in veins. The data indicate that inflammation of the vessel wall initiates thrombus formation in an intact vein and that inflammation and coagulation systems are coupled by a common activation pathway. The first event in thrombus formation is most probably activation of endothelial cells, platelets and leucocytes, with initiation of inflammation and formation of microparticles that trigger the coagulation system through the induction of a tissue factor. Therefore, the key event in the initiation of venous thrombus formation is most probably vein wall inflammation. However, expected relationship between inflammatory markers as indicators of inflammatory process and clinical venous thromboembolism (VTE) has not yet been elucidated. C-reactive protein does not appear to be useful in predicting future venous thrombosis or to be useful in the diagnosis of VTE. Recently, it was demonstrated that probable association between VTE and several other markers of inflammation such as: interleukin (IL)-6, IL-8 and tumor necrosis factor-a exists. While these markers of inflammation were studied during or after acute venous thrombosis, further prospective studies are needed to determine the predictive value of inflammatory markers for VTE. The identification and elucidation of inflammatory markers relevant to venous thrombosis could provide targets for future therapy. That inflammation is the basic etiopathogenetic process of VTE is also supported by the relation of some risk factors to both arterial and venous thrombosis: age, increased body mass index, hypercholesterolemia, hypertension, lupus anticoagulant and hyperhomocysteinemia. A relation was also found between preclinical and clinical atherosclerotic disease and VTE. Also in line with these arguments are the preventive effects of aspirin and statins in both arterial and venous disease.     

Ventricular arterial stiffening: integrating the pathophysiology

Vascular stiffening of the large arteries is a common feature of aging and is exacerbated by many common disorders such as hypertension, diabetes, and renal disease. This change influences the phasic mechanical stresses imposed on the blood vessels that in turn is important to regulating smooth muscle tone, endothelial function, and vascular health. In addition, the heart typically adapts to confront higher and later systolic loads by both hypertrophy and ventricular systolic stiffening. This creates altered coupling between heart and vessel that importantly affects cardiovascular reserve function. In this overview, I discuss the notion of a coupling disease in which stiffness of both heart and arteries interact to limit performance and generate clinical symptoms. This involves changes in the mechanical interaction of both systems, changes in signaling within the arteries themselves, and alterations in coronary flow regulation. Lastly, I briefly review recent development in de-stiffening strategies that may pave the way to treat this syndrome and its clinical manifestations.