Inflammation
George Feuer, Felix A. de la Iglesia in Molecular Biochemistry of Human Disease, 2020
Fibrin in the blood clot is comparatively stable; under certain circumstances, however, it is lysed rapidly. The rapid lysis is not associated with increased proteolytic activity of the tissues or leukocytes, but it is the result of the activation of a proenzyme, the plasminogen activator in the blood itself. Plasminogen is converted to a proteolytic enzyme called plasmin or fibrinolysin. Plasminogen is present in the blood, in lymph, in some other body fluids and tissues, and in exudates in certain conditions. Plasminogen is a protein constituted as a single polypeptide chain with a molecular weight of 81,000 to 92,000 Da. Plasmin contains two chains connected by a disulfide bond, with a molecular weight of about 73,000 to 84,000. The conversion of plasminogen to plasmin due to the cleavage of a single bond resulting in the active molecule and the release of a peptide from the NH2-terminus of the molecule, weighing 8000 Da.379,382
Medications for endovascular therapy
Peter A. Schneider in Endovascular Skills: Guidewire and Catheter Skills for Endovascular Surgery, 2019
The primary pharmacologic agent for thrombolysis is tissue plasminogen activator (tPA). tPA is a protease found on endothelial cells. It catalyzes the conversion of plasminogen to plasmin, the major enzyme responsible for a clot breakdown. This can be produced using recombinant technology. Pharmacologic thrombolysis is typically performed by using a pulse-spray of several mg of tPA directly into the thrombus during the initial procedure. This permits a lacing of the clot with thrombolytic agent. A direct infusion at 1 mg/hour is then usually performed for the first 4 hours, followed by 0.5 mg/hour for subsequent hours. The patient is typically returned for interval arteriography in 8–12 hours, unless there is a substantial clinical change. The fibrinogen level must be monitored and if it drops to less than 2.94 µmol/L (100 mg/dL) or the patient develops signs of hemorrhage, the infusion is stopped. There are numerous potential contraindications for the use of tPA that must be carefully considered.
The Inflammatory Response: A Bridge Between The Constitutive and Inducible Systems
Julius P. Kreier in Infection, Resistance, and Immunity, 2022
As noted above, plasmin is a proteolytic enzyme, one function of which is to lyse clots. Plasmin slowly degrades the fibrin network that is the result of the clotting reaction and thus allows access of phagocytic cells to the microbes trapped in the dot and paves the way for replacement of the dot by scar tissue or cells. Some of the products of plasmin digestion of fibrin are short polypeptides called fibrinopeptides. These are vasodilators and thus bring more plasma and leukocytes into the area while the clot is being resolved. When plasmin acts on Hageman Factor, it converts it to a prekallikrein activator. The latter protease converts prekallikrein into kallikrein, which in turn converts the precursor protein kininogen into bradykinin. Bradykinin is an extremely potent vasodilator and also is chemotactic for phagocytic cells and thus further amplifies the reaction. Various kininases are also produced as the inflammatory reaction progresses. These break bradykinin down to inactive peptides and thus control the extent of activation by this pathway (Figure 4.4).
The potential association between metabolic syndrome and risk of post-surgical adhesion
Published in Archives of Physiology and Biochemistry, 2023
Gordon A Ferns, Milad Shahini Shams Abadi, Mohammad-Hassan Arjmand
Adhesion formation is a part of the wound healing process in tissues after trauma and surgeries. Both inflammation and fibrin clot deposition are the main mechanisms during the early phase of the normal or pathological healing process. Briefly, a rapid immune response begins with local and circulating immune cells, secretion of pro-inflammatory cytokines, and the formation of a fibrin matrix are an important mechanism in normal healing (diZerega & Campeau 2001). The balance between fibrin matrix deposition and degradation, or fibrinolytic activity, is important. The coagulation cascade is activated in response to injury to blood vessels and inflammation in the traumatised area with increases the permeability of vessels to increase exudate fluid and flow more inflammatory cells to the site. Fibrin matrix gel is lysed within a few days by the fibrinolytic system (Buckman et al. 1976). Plasmin is responsible for a physiological fibrinolytic sequence that result from plasminogen activation by tissue plasminogen activator (tPA) (Holmdahl et al. 1996). After surgery, a decrease of tPA activity is associated with an increased susceptibility to adhesions (Sulaiman et al. 2002).
Factors affecting the dynamics and heterogeneity of the EPR effect: pathophysiological and pathoanatomic features, drug formulations and physicochemical factors
Published in Expert Opinion on Drug Delivery, 2022
Rayhanul Islam, Hiroshi Maeda, Jun Fang
Plasminogen activators secreted by tumor cells are important in cancer metastasis, but they can serve as EPR effect enhancers, a strategy that Zhang et al. [61] reported. Plasminogen is responsible in fibrinolysis to break down fibrin gel or fibrin clots after activation to plasmin in tumor blood vessels, or in the vicinity of tumor or stromal tissues, thereby restoring and improving tumor blood flow and opening endothelial gaps. Thus, barriers are removed and drug penetration and accumulation in tumors are facilitated. Mei et al. [62] also developed a novel approach with plasminogen activator incorporated into a redox-responsive nanoparticle; they found marked drug accumulation in tumors by virtue of the EPR effect and at the same time observed tumor suppression via reactive oxygen species and cytokine modulation.
Pharmacological management of cerebral ischemia in the elderly
Published in Expert Opinion on Pharmacotherapy, 2021
Adithya Kannan, Mychael Delgardo, William Pennington-FitzGerald, Enoch X. Jiang, Brandon R. Christophe, E Sander Connolly
Ischemic stroke occurs when a cerebral blood vessel is occluded by a clot, which consists of activated platelets bound by a fibrin mesh. tPA is a serine protease that cleaves the zymogen plasminogen to plasmin, a broad-spectrum protease. Plasmin can break down fibrin, thereby degrading the clot and restoring blood flow [9]. Treatment with intravenous tPA within 4.5 hours of symptom onset is well established as the standard of care for ischemic stroke [10]. A recent pooled analysis of nine randomized controlled trials comparing treatment with alteplase to placebo or open control found that treatment initiated within this time window benefited patients across the spectrum of stroke severity of all ages, including those over 80 years old. The analysis also found earlier treatment to be associated with better outcomes [11]. Additionally, there is no evidence that the risk of intracerebral hemorrhage (ICH) associated with alteplase treatment increases in the elderly, even for those over 81 years old [12]. Despite this evidence, a retrospective study showed that the rate of tPA administration declines with patient age [13].