Haemostasis and fibrinolysis
Ken Myers, Paul Hannah, Marcus Cremonese, Lourens Bester, Phil Bekhor, Attilio Cavezzi, Marianne de Maeseneer, Greg Goodman, David Jenkins, Herman Lee, Adrian Lim, David Mitchell, Nick Morrison, Andrew Nicolaides, Hugo Partsch, Tony Penington, Neil Piller, Stefania Roberts, Greg Seeley, Paul Thibault, Steve Yelland in Manual of Venous and Lymphatic Diseases, 2017
Fibrinolysis is an enzymatic reaction that breaks down a fibrin clot to limit the extent of thrombosis (Figure 20.3). Tissue plasminogen activator (tPA) and urokinase plasminogen activator (u-PA) released from vascular endothelium act on fibrin-bound plasminogen to produce the enzyme plasmin. Plasmin breaks down the clot into fibrin degradation products (FDPs) that are cleared by other proteases or by the kidney and liver. Tissue plasminogen activator is ver y slowly released into the blood such that it takes several days after bleeding has stopped for the clot to be broken down, allowing time for wounds to initiate repair. Plasmin activity is regulated to prevent widespread fibrinolysis by plasminogen activator inhibitor, α 2 antiplasmin, α 2 macroglobulin and thrombin-activatable fibrinolysis inhibitor. D-dimer is a type of FDP that contains the cross-linkage that FXIII had applied to fibrin, and thus indicates the lysis of completed clot. It allows a very sensitive but not specific test which is only useful as a negative test to rule out clotting.
Hormonal control of the menstrual cycle and hormonal disorders
Helen Bickerstaff, Louise C Kenny in Gynaecology, 2017
Menstruation (day 1) is the shedding of the ‘dead’ endometrium and ceases as the endometrium regenerates (which normally happens by day 5–6 of the cycle). Immediately prior to menstruation, three distinct layers of endometrium can be seen. The basalis is the lower 25% of the endometrium, which will remain throughout menstruation and shows few changes during the menstrual cycle. The midportion is the stratum spongiosum with oedematous stroma and exhausted glands. The superficial portion (upper 25%) is the stratum compactum with prominent decidualized stromal cells. A fall in circulating levels of oestrogen and progesterone approximately 14 days after ovulation leads to loss of tissue fluid, vasoconstriction of spiral arterioles and distal ischaemia. This results in tissue breakdown and loss of the upper layers, along with bleeding from fragments of the remaining arterioles, seen as menstrual bleeding. Enhanced fibrinolysis reduces clotting.
Fibrinolytic System
Hau C. Kwaan, Meyer M. Samama in Clinical Thrombosis, 2019
While coagulation in hemostasis serves to control blood loss following vascular injury, several processes occur at the same time limiting the extension of the clot. These include the action of antithrombin III, and the activation of protein C and of the fibrinolytic system. Fibrinolysis removes the fibrin clot once it has achieved its hemostatic function. This is brought about by the conversion of plasminogen, a zymogen, into an active serine protease, plasmin. Though plasmin may cause proteolysis of other plasma proteins when it is present in high concentrations in plasma, physiologically its action is limited to the hydrolysis of fibrin. The conversion of plasminogen to plasmin can be achieved by a number of plasminogen activators. In vivo, they have been identified as tissue-type plasminogen activator (t-PA) and a urokinase-type plasminogen activator (u-PA).
Tranexamic acid for childbirth: why, when, and for whom
Published in Expert Review of Hematology, 2019
Loïc Sentilhes, Hugo Madar, Aurélien Mattuizzi, Alizée Froeliger, Benjamin Merlot, Benoit Elleboode, Catherine Deneux-Tharaux
Tranexamic acid is an antifibrinolytic agent that exerts its effect by blocking lysine binding sites on plasminogen and plasmin molecules and has the potential to enhance the effectiveness of the patient’s own haemostatic mechanisms [12]. Consequently, clot breakdown (fibrinolysis) is inhibited and bleeding is reduced [12]. The reported association between early fibrinogenemia decrease and the final severity in women with PPH [13,14] further supports the possibility that TXA might be an effective intervention in PPH [12]. Moreover, during the last decade, it has been demonstrated that TXA is effective to reduce morbidity and even bleeding-related mortality in various contexts outside obstetrics, both for prevention and treatment of excessive bleeding. In particular, TXA administration reduces the need for transfusion in elective surgery [15,16] and mortality in trauma patients (CRASH-2 trial) [17], without increasing vascular occlusion. In the gynecological setting, TXA is effective at decreasing blood loss in women with menorrhagia, a bleeding that comes from the uterus by definition [18].
Clinical changes of leptin/ghrelin and PAI-1 levels in adolescent girls with abnormal uterine bleeding-ovulatory dysfunction
Published in Gynecological Endocrinology, 2022
Zhao Wen, Zeng Qiaoqian, Sun Wen, Wang Yonghong, He Jingwei
Plasmin is the primary enzyme of fibrinolysis, released from plasminogen by tissue plasminogen activator (t-PA) and urine plasminogen activator (u-PA), and t-PA is regulated by PAI-1. Lack of PAI-1 may cause severe menorrhagia. For example, a case report showed that a 26-year-old woman with a family history of PAI-1 deficiency, bleeding more than 4 continuous months per period and used over 100 pads each period [34]. What is more, PAI-1 can restrain trophoblast invasion mediated by urokinase-type PA [35], and researchers also found the expression of the messenger ribonucleic acid (mRNA) of PAI-1 in endometrial tissue, and PAI-1 may contribute to the therapeutic effect of intrauterine levonorgestrel system (LNG–IUS) in treating menorrhagia [36]. These studies indicate that PAI-1 might play a role by acting on endometrium. As mentioned above, the expression of PAI-1 could be affected by progesterone [15], and AUB in adolescence is usually anovulatory with lower level of progesterone, which might explain the lower level of PAI-1 in AUB-O group. And the reduced PAI-1 activity, elevated fibrinolytic activity, disturbance of the fibrinolytic system, and low hemodynamic coagulation may also be one of the causes of clinical manifestations, such as dripping menstruation and increased menstruation. Therefore, plasma PAI-1 levels may be useful in assessing the severity and efficacy of adolescent menstrual bleeding.
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.