The design and synthesis of new synthetic low-molecular-weight heparins

Low molecular weight heparins (LMWH) have remained the most favorable form of heparin in clinics since 1990s’ owing to its predictable pharmacokinetic properties. However, LMWH is mainly eliminated through kidney, thus limits its use in renal-impaired patients. In addition, the anticoagulant activity of LMWH is only partially neutralized by protamine. LMWH is obtained from a full-length, highly sulfated polysaccharide harvested from porcine mucosal tissue. The depolymerization involved in LMWH production generates a broad size distribution of LMWH fragments (6-22 sugar residues). This, combined with the various methods used to produce commercial LMWHs, result in variable pharmacological and pharmacokinetic properties. An alternative, chemoenzymatic approach offers a method for the synthesis of LMWH that has the potential to overcome the limitations of current LMWHs. This review summarizes the application of a chemoenzymatic approach to generate LMWH and the rationale for development of a synthetic LMWH

Use of Mouse Models to Study the Role of Tissue Factor in Tumor Biology

Tissue factor (TF) is the primary initiator of the coagulation cascade and plays an essential role in hemostasis. TF also contributes to many diseases, including cancer. The correlation between thrombosis and cancer has been recognized for more than a century. However, it is only in the past two decades that we have begun to understand the role of TF in tumor biology. TF expression is upregulated on both tumor and host cells in cancer patients as well as in the circulation. Clinical observations indicate a direct correlation between the levels of tumor cell TF expression and poor prognosis for cancer patients. The role of TF in tumor biology has been extensively studied using various mouse tumor models. It has been demonstrated that tumor cell TF contributes to tumor metastasis, growth, and angiogenesis. The role of host TF in tumor progression is less clear. Recently developed mouse models with altered levels of TF may be useful in further analysis of the role of host cell TF in cancer

Tissue factor and thrombin in sickle cell anemia

Sickle cell anemia is an inherited hematologic disorder associated with hemolytic and vaso-occlusive complications. An activation of coagulation is also a prominent feature of sickle cell anemia. Growing evidence indicates that coagulation may contribute to the inflammation and vascular injury in sickle cell anemia. This review focuses on tissue factor expression and its contribution to the activation of coagulation, thrombosis and vascular inflammation in sickle cell anemia

Cellular sources of tissue factor in endotoxemia and sepsis

Sepsis is a systemic host response to infection by pathogenic microorganisms. Activation of the coagulation cascade during endotoxemia and sepsis leads to disseminated intravascular coagulation. This review focuses on tissue factor expression by hematopoietic and non-hematopoietic cells and its contribution to the activation of coagulation during endotoxemia and sepsis

Interplay between coagulation and vascular inflammation in sickle cell disease

Sickle cell disease is the most common inherited hematologic disorder that leads to the irreversible damage of multiple organs. Although sickling of red blood cells and vaso-occlusion are central to the pathophysiology of sickle cell disease the importance of hemolytic anemia and vasculopathy has been recently recognized. Hypercoagulation state is another prominent feature of sickle cell disease and is mediated by activation of both intrinsic and extrinsic coagulation pathways. Growing evidence demonstrates that coagulation may not only contribute to the thrombotic complications, but also to vascular inflammation associated with this disease. This article summarizes the role of vascular inflammation and coagulation activation, discusses potential mechanisms responsible for activation of coagulation and reviews recent data demonstrating the crosstalk between coagulation and vascular inflammation in sickle cell disease

Tissue factor, protease activated receptors and pathologic heart remodelling

Tissue factor is the primary initiator of coagulation cascade and plays an essential role in haemostasis and thrombosis. In addition, tissue factor and coagulation proteases contribute to many cellular responses via activation of protease activated receptors. The heart is an organ with high levels of constitutive tissue factor expression. This review focuses on the role of tissue factor, coagulation proteases and protease activated receptors in heart haemostasis and the pathological heart remodelling associated with myocardial infarction, viral myocarditis and hypertension

Arteriovenous oscillations of the redox potential: Is the redox state influencing blood flow?

OBJECTIVE Studies on the regulation of human blood flow revealed several modes of oscillations with frequencies ranging from 0.005 to 1 Hz. Several mechanisms were proposed that might influence these oscillations, such as the activity of vascular endothelium, the neurogenic activity of vessel wall, the intrinsic activity of vascular smooth muscle, respiration, and heartbeat. These studies relied typically on non-invasive techniques, for example, laser Doppler flowmetry. Oscillations of biochemical markers were rarely coupled to blood flow. METHODS The redox potential difference between the artery and the vein was measured by platinum electrodes placed in the parallel homonymous femoral artery and the femoral vein of ventilated anesthetized pigs. RESULTS Continuous measurement at 5 Hz sampling rate using a digital nanovoltmeter revealed fluctuating signals with three basic modes of oscillations: ∼ 1, ∼ 0.1 and ∼ 0.01 Hz. These signals clearly overlap with reported modes of oscillations in blood flow, suggesting coupling of the redox potential and blood flow. DISCUSSION The amplitude of the oscillations associated with heart action was significantly smaller than for the other two modes, despite the fact that heart action has the greatest influence on blood flow. This finding suggests that redox potential in blood might be not a derivative but either a mediator or an effector of the blood flow control system

In vitro and in vivo characterization of a reversible synthetic heparin analog

The global supply of unfractionated heparin (UFH) and all commercially available low molecular weight heparins (LMWH) remain dependent on animal sources, such as porcine intestine or bovine lung. Recent experience has shown that contamination of the supply chain (with over-sulfated chondroitin sulfates) can result in lethal toxicity. Fondaparinux is currently the only commercially available synthetic analogue of heparin. We recently described a new class of chemoenzymatically synthesized heparin analogues. One of these compounds (S12-mer) is a dodecasaccharide consisting of an antithrombin-binding moiety with repeating units of IdoA2S-GlcNS6S and two 3-O-sulfate groups that confer the ability to bind protamine

Protease-activated receptors and myocardial infarction

Protease activated receptors (PARs) are widely expressed within the heart. They are activated by a myriad of proteases, including coagulation proteases. In vitro studies showed that activation of PAR-1 and PAR-2 on cardiomyocytes induced hypertrophy. In addition, PAR-1 stimulation on cardiac fibroblasts induced proliferation. Genetic and pharmacologic approaches have been used to investigate the role of the different PARs in cardiac ischemia/reperfusion (I/R) injury. In mice and rats PAR-1 is reported to play a role in inflammation, infarct size and remodeling after cardiac I/R injury. However, there are notable differences between the effect of a deficiency in PAR-1 and inhibition of PAR-1. For instance, inhibition of PAR-1 reduced infarct size whereas there was no effect of a deficiency of PAR-1. These differences maybe due to off-target effects of the inhibitor or PAR-4 compensation of PAR-1 deficiency. Similarly, a deficiency of PAR-2 was associated with reduced cardiac inflammation and improved heart function after I/R injury, whereas pharmacologic activation of PAR-2 was found to be protective due to increased vasodilatation. These differences maybe due to different signaling responses induced by an endogenous proteases versus an exogenous agonist peptide. Surprisingly, PAR-4 deficiency resulted in increased cardiac injury and increased mortality after I/R injury. In contrast, a pharmacological study indicated that inhibition of PAR-4 was cardioprotective. It is possible that the major cellular target of the PAR-4 inhibitor is platelets, which have been shown to contribute to inflammation in the injured heart, whereas PAR-4 signaling in cardiomyocytes may be protective. These discrepant results between genetic and pharmacological approaches indicate that further studies are needed to determine the role of different PARs in the injured heart