Practical Hemostasis and Thrombosis

Nigel S. Key, Michael Makris, David Lillicrap, Nigel S. Key, Michael Makris, David Lillicrap

• Publisher: Wiley-Blackwell
• Year: 2016
• ISBN:
  9781118344750
• Edition: 3
• Topic: Medicine
• Subtopic: Hematology

Designed as a practical, succinct guide, for quick reference by clinicians with everyday questions, this title guides the reader through the range of approaches available for diagnosis, management, or prevention of hemorrhagic and thrombotic diseases or disorders.

• Provides essential practical management for all those working in the field of hemostasis and thrombosis
• Includes new chapters on direct oral anticoagulants, acquired inhibitors of coagulation, and expanded discussion of thrombotic microangiopathies
• Covers in a clear and succinct format, the diagnosis, treatment and prevention of thrombotic and haemostatic disorders
• Follows templated chapter formats for rapid referral, including key points and summary boxes, and further reading
• Highlights controversial issues and provides advice for everyday questions encountered in the clinic

Chapter 1
Basic Principles Underlying Coagulation

Dougald M. Monroe

Key Points

• This model of hemostasis views the process as having three overlapping phases: initiation, amplification, and propagation.
• Initiation takes place on cells that contain tissue factor when factor VIIa/TF activates factors IX and X; the factor Xa generates a small amount of thrombin.
• Thrombin from the initiation phase contributes to platelet activation and activates factors V and VIII.
• Propagation takes place on the activated platelet when factor IXa from the initiation phase binds to platelet factor VIIIa leading to platelet surface factor Xa, which complexes with factor Va giving a burst of thrombin.
• In clinical assays, the PT assess the initiation phase and the APTT assesses the propagation phase.

This chapter will discuss coagulation in the context of a hemostatic response to a break in the vasculature. Coagulation is the process that leads to fibrin formation; this process involves controlled interactions between protein coagulation factors. Hemostasis is coagulation that occurs in a physiological (as opposed to pathological) setting and results in sealing a break in the vasculature. This process has a number of components, including adhesion and activation of platelets coupled with ordered reactions of the protein coagulation factors. Hemostasis is essential to protect the integrity of the vasculature. Thrombosis is coagulation in a pathological (as opposed to physiological) setting that leads to localized intravascular clotting and potentially occlusion of a vessel. There is an overlap between the components involved in hemostasis and thrombosis, but there is also evidence to suggest that the processes of hemostasis and thrombosis have significant differences. There are also data to suggest that different vascular settings (arterial, venous, tumor microcirculation) may proceed to thrombosis by different mechanisms. Exploitation of these differences could lead to therapeutic agents that selectively target thrombosis without interfering significantly with hemostasis. Other chapters of this book will discuss some of the mechanisms behind thrombosis.

Healthy Vasculature

Intact vasculature has a number of active mechanisms to maintain coagulation in a quiescent state. Healthy endothelium expresses ecto-ADPase (CD39) and produces prostacyclin (PGI₂) and nitric oxide (NO); all of these tend to block platelet adhesion to and activation by healthy endothelium [1]. Platelets in turn support a quiescent endothelium, in part through release of platelet granule components [2]. Healthy endothelium also has active anticoagulant mechanisms, some of which will be discussed below. There is evidence that the vasculature is not identical through all parts of the body [3]. Further, it appears that there can be alterations in the vasculature in response to changes in the extracellular environment. These changes can locally alter the ability of endothelium to maintain a quiescent state.

Even though healthy vasculature maintains a quiescent state, there is evidence to support the idea that there is ongoing, low-level activation of coagulation factors [4]. This ongoing activation of coagulation factors is sometimes termed “idling” and may play a role in preparing for a rapid coagulation response to injury. Part of the evidence for idling comes from the observation that the activation peptides of factors IX and X can be detected in the plasma of healthy individuals. Because levels of the factor X activation peptide are significantly reduced in factor VII deficiency but unchanged in hemophilia, the factor VIIa complex with tissue factor is implicated as the key player in this idling process.

Tissue factor is present in a number of tissues throughout the body [5]. Immunohistochemical studies show that tissue factor is present at high levels in the brain, lung, and heart. Only low levels of tissue factor are detected in skeletal muscle, joints, spleen, and liver. In addition to being distributed in tissues, tissue factor is expressed on vascular smooth muscle cells and on the pericytes that surround blood vessels. This concentration of tissue factor around the vasculature has been referred to as a hemostatic envelope [5]. Endothelial cells in vivo do not express tissue factor, except possibly during invasion by cancer cells. Also, there is evidence to suggest that tissue factor may be present on microparticles in the circulation. The information to date suggests that this tissue factor accumulates in pathological thrombi [6]. Further, there is general agreement in these studies that circulating tissue factor levels are extremely low in healthy individuals [7]. Limited data suggest that tissue factor does not incorporate into hemostatic plugs [8], unlike the accumulation of tissue factor seen in thrombosis, and so the model of hemostasis described in this chapter does not include a role for circulating tissue factor in hemostasis.

Given the location of tissue factor, it seems plausible that the processes associated with idling may not be intravascular but may rather occur in the extravascular space. At least two mechanisms are known that can concentrate plasma coagulation factors around the vasculature (Figure 1.1). Coagulation proteins enter the extravascular space in proportion to their size; small proteins readily get into the extravascular space, whereas large proteins do not seem to reach the extravasculature [9]. Because tissue factor binds factor VII so tightly, it can trap factor VII that moves into the extravascular space. This means that blood vessels already have factor VII(a) bound [10]. Also, factor IX binds tightly and specifically to the extracellular matrix protein collagen IV; this results in factor IX being concentrated around blood vessels [11]. A role for this collagen IV-bound factor IX in hemostasis is suggested by the observation that mice expressing a factor IX that cannot bind collagen IV have a mild bleeding tendency [12].

Figure 1.1 Vessel. An intact blood vessels is pictured with the endothelial cells (tan) and surrounding pericytes (dark brown). Within the vessel are red blood cells and platelets (blue). Associated with the pericytes, tissue factor complexed with factor VII(a) is shown in green. Factor IX, shown in blue, is associated with collagen IV in the extravascular space.

Initiation

A break in the vasculature exposes extracellular matrix to blood and initiates the coagulation process (Figure 1.2). Platelets adhere at the site of injury through a number of specific interactions [13]. The plasma protein von Willebrand factor (VWF) can bind to exposed collagen and, under flow, undergoes a conformational change such that it binds tightly to the abundant platelet receptor glycoprotein Ib. This localization of platelets to the extracellular matrix promotes collagen interaction with platelet glycoprotein VI. Binding of collagen to glycoprotein VI triggers a signaling cascade that results in activation of platelet integrins [14]. Activated integrins mediate tight binding of platelets to extracellular matrix. This process adheres platelets to the site of injury.

Figure 1.2 Initiation. A break in the vasculature brings plasma coagulation factors and platelets into contact with the extravascular space. Unactivated platelets within the vessel are shown as blue disks. Platelets adhering to collagen in the extravascular space are activated and are represented as blue star shapes to indicate cytoskeletal-induced shape change. The expanded view shows the protein reactions in the initiation phase. Factor VIIa–tissue factor activates both factor IX and factor X. Factor Xa, in complex with factor Va released from platelets, can activate a small amount of thrombin (IIa).

In addition to platelet processes, plasma concentrations of factors IX and X are brought to the preformed factor VIIa/tissue factor complexes at the site of injury. Factor VIIa/tissue factor activates both factor IX and factor X; the activated proteins play distinct roles in the ensuing reactions. Factor IXa moves into association with platelets, where it plays a role in the later stages of hemostasis. Factor Xa forms a complex with factor Va to convert a small amount of prothrombin to thrombin. The source of factor Va for this reaction is likely protein released from the alpha granules of collagen adherent platelets [15]. Platelet factor V is released in a partially active form and does not require further activation to promote thrombin generation [15]. Thrombin formed on ...