Clinical relevance of hypercoagulability and possible hypofibrinolysis associated with estrone and estriol

Estrone (E₁) and Estriol (E₃) are endogenous female hormones, present in increased concentrations during female specific physiological processes (menopause and pregnancy respectively) that are associated with increased venous thrombotic risk. These hormones are also used as hormone therapies that are also associated with increased thromboembolism risk. Viscoelastic analysis revealed no significant difference to clot formation after hormone addition, however morphological analysis showed that the addition of both E₁ and E₃ result in fibrin clots composed of thinner fibrin fibers arranged in dense matted networks. These changes to the fibrin network ultrastructure are indicative of a prothrombotic state but may also indicate hypofibrinolysis. We therefore conclude that the increased risk of venous thrombosis during pregnancy and menopause may originate from a combination of hypercoagulation and a possible hypofibrinolytic mechanism of these hormones. Therefore females with a hypercoagulable tendency that fall pregnant or enter menopause need to be monitored to prevent venous thrombotic events. The decision to use hormone therapies during and after menopause should not be taken lightly and the risk‐reward scale should be closely examined to ensure it does not tip towards thrombosis and subsequent thrombotic events that ultimately could have been prevented.     

A Combined Activity of Thrombin and P-Selectin Is Essential for Platelet Activation by Pancreatic Cancer Cells

Pancreatic cancer patients have an elevated risk of suffering from venous thrombosis. Among several risk factors that contribute to hypercoagulability of this malignancy, platelets possess a key role in the initiation of clot formation. Although single mechanisms of platelet activation are well-known in principle, combinations thereof and their potential synergy to mediate platelet activation is, in the case of pancreatic cancer, far from being clear. Applying an inhibitor screening approach using light transmission aggregometry, dense granule release, and thrombin formation assays, we provide evidence that a combination of tissue factor-induced thrombin formation by cancer cells and their platelet P-selectin binding is responsible for AsPC-1 and Capan-2 pancreatic cancer cell-mediated platelet activation. While the blockade of one of these pathways leads to a pronounced inhibition of platelet aggregation and dense granule release, the simultaneous blockade of both pathways is inevitable to prevent platelet aggregation completely and minimize ATP release. In contrast, MIA PaCa-2 pancreatic cancer cells express reduced levels of tissue factor and P-selectin ligands and thus turn out to be poor platelet activators. Consequently, a simultaneous blockade of thrombin and P-selectin binding seems to be a powerful approach, as mediated by heparin to crucially reduce the hypercoagulable state of pancreatic cancer patients.     

Albumin Infusion in Critically Ill COVID-19 Patients: Hemodilution and Anticoagulation

Hypercoagulation is one of the major risk factors for ICU treatment, mechanical ventilation, and death in critically ill patients infected with SARS-CoV-2. At the same time, hypoalbuminemia is one risk factor in such patients, independent of age and comorbidities. Especially in patients with severe SARS-CoV-2-infection, albumin infusion may be essential to improve hemodynamics and to reduce the plasma level of the main marker of thromboembolism, namely, the D-dimer plasma level, as suggested by a recent report. Albumin is responsible for 80% of the oncotic pressure in the vessels. This is necessary to keep enough water within the systemic circulatory system and for the maintenance of sufficient blood pressure, as well as for sufficient blood supply for vital organs like the brain, lungs, heart, and kidney. The liver reacts to a decrease in oncotic pressure with an increase in albumin synthesis. This is normally possible through the use of amino acids from the proteins introduced with the nutrients reaching the portal blood. If these are not sufficiently provided with the diet, amino acids are delivered to the liver from muscular proteins by systemic circulation. The liver is also the source of coagulation proteins, such as fibrinogen, fibronectin, and most of the v WF VIII, which are physiological components of the extracellular matrix of the vessel wall. While albumin is the main negative acute-phase protein, fibrinogen, fibronectin, and v WF VIII are positive acute-phase proteins. Acute illnesses cause the activation of defense mechanisms (acute-phase reaction) that may lead to an increase of fibrinolysis and an increase of plasma level of fibrinogen breakdown products, mainly fibrin and D-dimer. The measurement of the plasma level of the D-dimer has been used as a marker for venous thromboembolism, where a fourfold increase of the D-dimer plasma level was used as a negative prognostic marker in critically ill SARS-CoV-2 hospitalized patients. Increased fibrinolysis can take place in ischemic peripheral sites, where the mentioned coagulation proteins can become part of the provisional clot (e.g., in the lungs). Although critically ill SARS-CoV-2-infected patients are considered septic shock patients, albumin infusions have not been considered for hemodynamic resuscitation and as anticoagulants. The role of coagulation factors as provisional components of the extracellular matrix in case of generalized peripheral ischemia due to hypoalbuminemia and hypovolemia is discussed in this review.     

青钱柳水提物对糖尿病肾病大鼠血脂、血凝和脂质过氧化的影响

本文研究了青钱柳水提物(ACP)对糖尿病肾病(DN)大鼠脂代谢、血凝、纤溶和脂质过氧化的影响。以高脂高糖饮食加小剂量STZ诱导DN大鼠模型,随机分为模型组、二甲双胍组(0.20 g/kg/day)和低、中、高ACP给药组(0.05,0.10,0.15g/kg/day)。药物干预8周,观察大鼠一般状态,记录血糖、尿蛋白变化,试验结束后,测定血清血脂指标、血浆血凝和纤溶指标以及肝脏脂质过氧化指标。实验表明:ACP给药组能显著降低DN大鼠血糖、尿蛋白以及TC、TG、LDL-C、FFA,D-Dimer、PTA和MDA含量(p0.05),其中TG最高降幅58.03%;显著提高HDL-C,PT、APTT、TT、FIB、INR、PT-R、APTT-R、T-AOC、SOD、GSH-Px和CAT水平(p0.05),其中PT最高升幅74.60%;且各指标与血糖值相关,FFA与血糖显著相关(r=0.9990)。提示ACP对试验性DN模型大鼠具有降血脂、抗脂质过氧化、抑制高凝状态、活化纤溶系统从而保护肾功能的作用。     

Accelerated Spatial Fibrin Growth and Impaired Contraction of Blood Clots in Patients with Rheumatoid Arthritis

Rheumatoid arthritis (RA) is an autoimmune disease associated with thrombotic complications. To elucidate pathogenic mechanisms, hemostatic disorders in RA were correlated with other laboratory and clinical manifestations. Hemostasis was assessed using relatively new complementary tests, the spatial growth of a plasma clot (Thrombodynamics assay), and contraction of whole blood clots. Platelet functionality was assessed with flow cytometry that quantified the expression of P-selectin and the fibrinogen-binding capacity of platelets before and after activation with a thrombin receptor-activating peptide. Parameters of fibrin clot growth and the kinetics of contraction of blood clots were significantly altered in patients with RA compared to the control group. In Thrombodynamics measurements, an increase in the clot growth rate, size, and optical density of plasma clots altogether indicated chronic hypercoagulability. The rate and extent of blood clot contraction in patients with RA was significantly reduced and associated with platelet dysfunction revealed by an impaired response to activation. Changes in the parameters of clot growth and contraction correlated with the laboratory signs of systemic inflammation, including hyperfibrinogenemia. These results confirm the pathogenic role of hemostatic disorders in RA and support the validity of fibrin clot growth and the blood clot contraction assay as indicators of a (pro)thrombotic state.