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Initial Phase of Hemostasis
Published in Hau C. Kwaan, Meyer M. Samama, Clinical Thrombosis, 2019
When the blood vessel wall is injured, there are multiple mechanisms that can directly cause platelet aggregation and secretion of its granules. These processes serve to form the primary hemostatic plug, while the fibrin clot formation will provide a definitive and final hemostatic plug. The process is self-limiting so that a continuous thrombi formation would not occur under normal circumstances. When platelets are exposed to the subendothelium on the injured intima, the collagen microfibriles can directly activate platelets and produce a strong aggregation and secretion phase bypassing the ADP pathway. Thrombin generated from the activation of the blood coagulation process can also directly induce platelet aggregation. The antithrombotic mechanism includes the generation of prostacyclin, the activation of the fibrinolytic system and protein C, and the formation of the thrombin-antithrombin complex. (These processes are discussed in other chapters of this book.)
The Coagulopathy in Acute Promyelocytic Leukemia: DIC?
Published in László Muszbek, Hemostasis and Cancer, 2019
Giuseppe Avvisati, Jan Wouter ten Cate, Franco Mandelli
This mechanism was first suggested by Quigley,44 who demonstrated that the promyelocytes in APL patients contain a thromboplastin-like clot-promoting activity. These data were confirmed in a subsequent study revealing that the leukemic promyelocytes contain procoagulant activity (PCA).45 The PCA present in the granules of APL cells shortened the clotting time of normal plasma and of plasma deficient in FVIII or FIX. This potency was absent in plasma deficient in FV, FVII, or FX.45 Moreover, the PCA present in APL cells had immunological cross reactivity with human brain thromboplastin.46 These data suggest that intravascular thrombin generation and DIC may occur in APL. Indeed, increased FpA levels were described.47 FpA is cleaved from the fibrinogen molecule by thrombin, and increased FpA levels are therefore a reflection of intravascular thrombin generation. This study was corroborated very recently by Bauer and Rosenberg.31 These investigators further demonstrated increased levels of prothrombin activation fragment (F1 + 2) and thrombin-antithrombin complex (TAT), as well as high FpA levels. However, in one patient heparin lowered the FpA level without concomitant reduction in the concentration of F1 + 2 or TAT.
The Coagulation-Cancer Interaction in Situ
Published in Róza Ádány, Tumor Matrix Biology, 2017
Leo R. Zacharski, Vincent A. Memoli
We have applied immunohistochemical techniques systematically to several common adult tumor types.17,18 These efforts were rewarded by detection of specific cell-associated generation of enzymatically active thrombin within intact tissue. Criteria for generation of thrombin included: (1) colocalization of coagulation factor intermediates that was consistent with their participation in a chemically defined, thrombin-generating enzymatic cascade; (2) binding of hirudin, a chemically defined protease inhibitor that reacts specifically with thrombin; (3) detection of thrombin-antithrombin complex neoantigen; and (4) detection of exposed thrombin-specific cleavage sites on fibrinogen in the connective tissue matrix adjacent to the cells. However, the pattern of such reactivity varied between tumor types. Tumor cells exhibited thrombin generation in SCCL,30,31 renal cell carcinoma,32,33 malignant melanoma,34 and ovarian carcinoma.35 By contrast, tumor-associated macrophages exhibited thrombin generation in N-SCLC36 and lymphomas,37 while vascular endothelial cells showed thrombin generation in prostate cancer.38 Results obtained in malignant melanoma are illustrated in Figure 1.
Current and emerging pharmacotherapy for chronic spontaneous Urticaria: a focus on non-biological therapeutics
Published in Expert Opinion on Pharmacotherapy, 2021
Kam Lun Hon, Joyce T. S. Li, Alexander K.C. Leung, Vivian W. Y. Lee
Different biological processes such as autoimmunity, inflammation, coagulation, and auto-allergy are involved in basophil and mast cell degranulation [63]. Some CSU patients showed eosinophil-associated activation of the tissue factor pathway of coagulation cascade [63]. Studies also found marked increase of plasmatic markers of thrombin generation, such as prothrombin fragment 1 + 2 (F1 + 2), activated blood coagulation factor VII (FVIIa), and thrombin-antithrombin complex, especially during severe exacerbations in CSU patients [64–67]. Fibrinolysis causes an increase in D-dimer, which correlates with CSU severity [68]. A study detected elevated levels of fibrinogen/fibrin degradation products and D-dimer from fibrinolysis in CSU patients [69]. Plasma C-reactive protein levels parallel the increase in plasma markers of thrombin generation and fibrinolysis, suggesting an association between inflammation and coagulation activation in the pathogenesis of CSU [64,68].
New anticoagulants for venous thromboembolism and atrial fibrillation: what the future holds
Published in Expert Opinion on Investigational Drugs, 2018
Gerasimos Dimitropoulos, S. M. Zubair Rahim, Alexandra Sophie Moss, Gregory Y. H. Lip
Crowther et al. undertook the first-in-man, randomized, double-blind, placebo-controlled, single-ascending-dose, pharmacokinetic, and pharmacodynamic study of andexanet alfa in 32 healthy volunteers [128]. Anti-FXa activity was assayed in vitro through adding rivaroxaban to subject plasma samples. Thrombin generation and anti-FXa activity of rivaroxaban were reversed with andexanet alfa in a dose-dependent manner. There were no reported thrombotic adverse events or deaths. Prothrombin fragment 1 and 2, thrombin–antithrombin complex, and D-dimer were shown to transiently increase with andexanet alfa dose.
Trenonacog alfa for prophylaxis, on-demand and perioperative management of hemophilia B
Published in Expert Opinion on Biological Therapy, 2018
Yvonne Brennan, Jennifer Curnow, Emmanuel J. Favaloro
No clinically evident thrombotic events were reported during the clinical studies [24]. Thrombogenicity markers were evaluated in the 32 subjects who underwent PK assessment, adding evidence to support the safety of trenonacog alfa. D-dimer, prothrombin fragments 1 + 2, and thrombin–antithrombin complex levels were measured pre-infusion, 30 min, 3 and 24 h post-infusion. There was significant variability in the results of the thrombogenic markers; however, there were no clinically relevant increases in the concentration of the thrombogenic markers over time [26].