Summary Hemophilia is a rare disorder that is complex to diagnose and to manage. These evidence‐based guidelines offer practical recommendations on the diagnosis and general management of hemophilia, as well as the management of complications including musculoskeletal issues, inhibitors, and transfusion‐transmitted infections. By compiling these guidelines, the World Federation of Hemophilia aims to assist healthcare providers seeking to initiate and/or maintain hemophilia care programs, encourage practice harmonization around the world and, where recommendations lack adequate evidence, stimulate appropriate studies.

PURPOSE To provide updated recommendations about prophylaxis and treatment of venous thromboembolism (VTE) in patients with cancer. METHODS PubMed and the Cochrane Library were searched for randomized controlled trials (RCTs) and meta-analyses of RCTs published from August 1, 2014, through December 4, 2018. ASCO convened an Expert Panel to review the evidence and revise previous recommendations as needed. RESULTS The systematic review included 35 publications on VTE prophylaxis and treatment and 18 publications on VTE risk assessment. Two RCTs of direct oral anticoagulants (DOACs) for the treatment of VTE in patients with cancer reported that edoxaban and rivaroxaban are effective but are linked with a higher risk of bleeding compared with low-molecular-weight heparin (LMWH) in patients with GI and potentially genitourinary cancers. Two additional RCTs reported on DOACs for thromboprophylaxis in ambulatory patients with cancer at increased risk of VTE. RECOMMENDATIONS Changes to previous recommendations: Clinicians may offer thromboprophylaxis with apixaban, rivaroxaban, or LMWH to selected high-risk outpatients with cancer; rivaroxaban and edoxaban have been added as options for VTE treatment; patients with brain metastases are now addressed in the VTE treatment section; and the recommendation regarding long-term postoperative LMWH has been expanded. Re-affirmed recommendations: Most hospitalized patients with cancer and an acute medical condition require thromboprophylaxis throughout hospitalization. Thromboprophylaxis is not routinely recommended for all outpatients with cancer. Patients undergoing major cancer surgery should receive prophylaxis starting before surgery and continuing for at least 7 to 10 days. Patients with cancer should be periodically assessed for VTE risk, and oncology professionals should provide patient education about the signs and symptoms of VTE. Additional information is available at www.asco.org/supportive-care-guidelines .

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Blood microparticles (MPs) in sickle cell disease (SCD) are reportedly derived only from erythrocytes and platelets. Yet in SCD, endothelial cells and monocytes are activated and abnormally express tissue factor (TF). Thus, sickle blood might contain TF-positive MPs derived from these cells. With the use of flow cytometry to enumerate and characterize MPs, we found total MPs to be elevated in crisis (P ‫؍‬ .0001) and steady state (P ‫؍‬ .02) in subjects with sickle cell disease versus control subjects. These MPs were derived from erythrocytes, platelets, monocytes, and endothelial cells. Erythrocytederived MPs were elevated in sickle crisis (P ‫؍‬ .0001) and steady state (P ‫؍‬ .02) versus control subjects, as were monocytederived MPs (P ‫؍‬ .0004 and P ‫؍‬ .009, respectively). Endothelial and plateletderived MPs were elevated in sickle crisis versus control subjects. Total TF-positive MPs were elevated in sickle crisis versus steady state (P ‫؍‬ .004) and control subjects (P < .0001) and were derived from both monocytes and endothelial cells. Sickle MPs shortened plasma-clotting time compared with control MPs, and a TF antibody partially inhibited this procoagulant activity. Markers of coagulation were elevated in patients with sickle cell disease versus control subjects and correlated with total MPs and TF-positive MPs (P < .01 for both). These data support the concept that SCD is an inflammatory state with monocyte and endothelial activation and abnormal TF activity.

The D-dimer antigen is a unique marker of fibrin degradation that is formed by the sequential action of 3 enzymes: thrombin, factor XIIIa, and plasmin. First, thrombin cleaves fibrinogen producing fibrin monomers, which polymerize and serve as a template for factor XIIIa and plasmin formation. Second, thrombin activates plasma factor XIII bound to fibrin polymers to produce the active transglutaminase, factor XIIIa. Factor XIIIa catalyzes the formation of covalent bonds between D-domains in the polymerized fibrin. Finally, plasmin degrades the crosslinked fibrin to release fibrin degradation products and expose the D-dimer antigen. D-dimer antigen can exist on fibrin degradation products derived from soluble fibrin before its incorporation into a fibrin gel, or after the fibrin clot has IntroductionFibrinogen is a soluble plasma glycoprotein that is transformed into highly self-adhesive fibrin monomers after thrombin cleavage. 1 A detailed overview of the process of fibrin formation was recently published. 2 In brief, in the first step of D-dimer formation, thrombin cleavage exposes a previously cryptic polymerization site on fibrinogen that promotes the binding of either another fibrinogen or a monomeric fibrin molecule. 3 Fibrin monomers then bind to one another in an overlapping manner to form 2 molecule thick protofibrils ( Figure 1). 4,5 Plasma remains fluid until 25% to 30% of plasma fibrinogen is cleaved by thrombin, 6 allowing time for fibrin to polymerize while simultaneously promoting thrombin activation of plasma factor XIII. 7 Thrombin remains associated with fibrin, 8 and as additional fibrin molecules polymerize, it activates plasma factor XIII bound to fibrinogen. 9 The complex between soluble fibrin polymers, thrombin, and plasma factor XIII promotes the formation of factor XIIIa before a fibrin gel is detected. 6 In the second step of D-dimer formation, factor XIIIa covalently cross links fibrin monomers via intermolecular isopeptide bonds formed between lysine and glutamine residues within the soluble protofibrils and the insoluble fibrin gel. 10 D-dimer antigen remains undetectable until it is released from crosslinked fibrin by the action of plasmin. In the final step of D-dimer formation, plasmin formed on the fibrin surface by plasminogen activation cleaves substrate fibrin at specific sites ( Figure 1). 11 Fibrin degradation products are produced in a wide variety of molecular weights, including the terminal degradation products of crosslinked fibrin containing D-dimer and fragment E complex (Figure 1). 12,13 It is uncommon to detect circulating terminal fibrin degradation products (D-dimer-E complex) in human plasma, whereas soluble high-molecular-weight fragments that contain the "D-dimer antigen" are present in patients with DIC and other thrombotic disorders. 14 These fragments may be derived from soluble fibrin before it has been incorporated into a fibrin gel, or alternatively may be derived from high-molecular-weight complexes released from an insoluble clot (Figure 2). 15,16 "D-...

Abstract-Hemostasis requires both platelets and the coagulation system. At sites of vessel injury, bleeding is minimized by the formation of a hemostatic plug consisting of platelets and fibrin. The traditional view of the regulation of blood coagulation is that the initiation phase is triggered by the extrinsic pathway, whereas amplification requires the intrinsic pathway. The extrinsic pathway consists of the transmembrane receptor tissue factor (TF) and plasma factor VII/VIIa (FVII/FVIIa), and the intrinsic pathway consists of plasma FXI, FIX, and FVIII. Under physiological conditions, TF is constitutively expressed by adventitial cells surrounding blood vessels and initiates clotting. In addition so-called blood-borne TF in the form of cell-derived microparticles (MPs) and TF expression within platelets suggests that TF may play a role in the amplification phase of the coagulation cascade. Under pathologic conditions, TF is expressed by monocytes, neutrophils, endothelial cells, and platelets, which results in an elevation of the levels of circulating TF-positive MPs. TF expression within the vasculature likely contributes to thrombosis in a variety of diseases. Understanding how the extrinsic pathway of blood coagulation contributes to hemostasis and thrombosis may lead to the development of safe and effective hemostatic agents and antithrombotic drugs. Key Words: coagulation Ⅲ arterial thrombosis Ⅲ deep vein thrombosis T he hemostatic system maintains blood in a fluid state under normal conditions and responds to vessel injury by the rapid formation of a clot. Disruption of the endothelium exposes platelets to collagen in the vessel wall and plasma factor VII/VIIa (FVII/FVIIa) to extravascular tissue factor (TF; Figure 1). Other proteins, such as von Willebrand factor (vWF), facilitate the binding of platelets to the injured vessel wall. The TF:FVIIa complex is traditionally referred to as the extrinsic pathway and is proposed to be the primary activator of the coagulation protease cascade in vivo. Subsequently, propagation of the thrombus involves recruitment of additional platelets and amplification of the coagulation cascade by the intrinsic pathway of blood coagulation, which includes the hemophilia factors FVIII and FIX (Figure 1). Importantly, platelets play a critical role in the amplification of the coagulation cascade by providing a thrombogenic surface. Finally, fibrin stabilizes the platelet-rich thrombus (Figure 1). This review focuses on the role of the extrinsic pathway (TF and FVIIa) in hemostasis and thrombosis. See cover TF and FVII in HemostasisHemostasis is the protective physiological response to vascular injury that results in exposure of blood components to the subendothelial layers of the vessel wall. TF is constitutively expressed by certain cells within the vessel wall and cells surrounding blood vessels, such as vascular smooth muscle cells, pericytes, and adventitial fibroblasts. 1-5 TF is also expressed in a tissue-specific pattern with high levels in the brain, lung, kidney, he...

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