Physicians' Academy for Cardiovascular Education

The coagulation process and anticoagulant therapy in heart disease

Literature - De Caterina R, Husted S, Wallentin L et al., - Thromb Haemost. 2013 Feb 28;109(4).

General mechanisms of coagulation and targets of anticoagulants (Section I). Position Paper of the ESC Working Group on Thrombosis - Task Force on Anticoagulants in Heart Disease.

De Caterina R, Husted S, Wallentin L et al.,
Thromb Haemost. 2013 Feb 28;109(4).


Despite the widespread use of anticoagulants, many needs remain unmet, prompting the development of many new agents. A Task Force of coagulation experts and clinical cardiologists has been appointed by the European Society of Cardiology (ESC) Working Group on Thrombosis. The Taskforce reviews the entire topic of anticoagulants in heart disease in multiple articles. We summarise the current overview of coagulation processes, targets of anticoagulants and touch on epidemiological data on the use of anticoagulants in heart disease.

The coagulation cascade and associated factors

Under physiological circumstances, the concerted action of platelets, the coagulation system, fibrinolysis and the vasomotor response maintains haemostasis. Platelets and fibrin rapidly form the haemostatic thrombus at a site of vessel damage. Fibrin within the thrombus induces its own degradation by plasmin-mediated fibrinolysis, to prevent thrombus propagation. When the delicate haemostatic balance is disturbed, too little or enhanced fibrin formation and deposition can ultimately cause either bleeding or thrombosis.
Tissue factor (TF) is constitutively expressed in the cells that surround the vessel wall and large organs. When TF comes into contact with plasma, it binds coagulation factor (F) VII/VIIa. Formation of this complex on cellular surfaces triggers the coagulation cascade. Expression of TF can also be induced in response to various stimuli, including inflammatory cytokines, endotoxins, growth factors and oxidised/modified LDL, thereby contributing to thrombosis in certain pathological conditions.
TF is present in the bloodstream at very low concentrations in healthy individuals. It can be found on circulating membrane-derived fragments, called microparticles (MPs), which still bear surface antigens of the parent cell. MPs can therefore initiate and propagate coagulation. Increased numbers of TF-bearing MPs have been detected in persons with established cardiovascular (CV) disease and CV risk factors.
Tissue factor pathway inhibitor (TFPI) is another regulator of TF/FVIIa-induced coagulation, by inhibiting the TF/FVIIa-complex. TFPI is rapidly released into the circulation by thrombin, shear forces or heparin administration. The effect of recombinant TFPI has been tested in patients with severe sepsis. All-cause mortality was not affected but risk of bleeding was increased. It may still have potential in subgroups of patients.

Initiation, amplification and propagation during the coagulation process

Current views on coagulation describe it as a series of tightly regulated reactions in three consecutive but overlapping phases (described in detail in the article).
Briefly, the initiation phase takes place at TF-bearing cells that are exposed after endothelial injury. The proteolytic TF/FVIIa-complex activates different factors that cause formation of the prothrombinase complex. Prothrombin is subsequently cleaved to thrombin, the enzyme responsible for fibrin formation. Next, in the amplification phase, thrombin activates platelets that adhere to the injury site. Multiple coagulation factors are released, contributing to thrombin generation. This is continued in the propagation phase. Thrombin converts fibrinogen to fibrin. Fibrin functions to form a network that stabilises platelet aggregates into a thrombus.
Due to the involvement of several enzymes, thrombin generation is an amplifying cascade, making upstream inhibition of coagulation attractive for therapeutic intervention.

Natural anticoagulant mechanisms

Inhibitory mechanisms control and localise thrombin generation and fibrin formation to the site of vascular injury. Patients with familial deficiencies of one of the inhibitory components tend to develop thromboembolic complications. Understanding of natural coagulation inhibitors can provide new strategies to develop anticoagulants. A few examples are discussed in the article.

Coagulation and inflammation

Coagulation and inflammation are tightly linked processes. Some of the routes via which coagulation influences inflammation, run via protease activated receptors (PARs). PAR inhibitors are currently being developed and PAR-1-targeted therapies have already been tested in phase III trials.

Mechanisms of thrombosis in heart disease

Different mechanisms can lead to excess activation of platelets and coagulation, allowing for different targeted antithrombotic strategies. Different thrombotic situations are discussed.

Targets for anticoagulation

Unfractionated heparin (UFH), low-molecular-weight heparins (LMWH) and vitamin K-antagonists (VKA) are widely used in the clinic as anticoagulants. Heparin consists of a family of highly sulphated polysaccharide chains, some of which can bind to the natural coagulation inhibitor antithrombin (AT). Through the binding of AT other coagulation factors and processes can also be inhibited, although the clinical relevance is unknown. VKA interfere with vitamin-K-dependent coagulation factors, as well as with activation of some natural anticoagulants.
Novel drugs that target the initiation phase of coagulation by inhibiting the TF/FVIIa-complex are being evaluated. Although promising in animal or in vitro studies, these TF/FVIIa-inhibitors have not reached clinical testing in heart disease.
Direct thrombin-inhibitors and direct coagulation factor inhibitors are touched upon and will be described in detail in a future section of the series of reviews by this Task Force.

Epidemiological data on anticoagulant therapy

Anticoagulant therapies are a core element of management of acute coronary syndrome (ACS). A vast majority of people presenting with ACS receive aspirin during hospital admission (90%), as well as UFH/LMWH (~80%). European surveys show variation in the use of anticoagulation therapy between countries.
Oral anticoagulation (OAC) therapy remains the best treatment option to prevent cardioembolism in atrial fibrillation (AF).VKA-treated AF patients suffered less often from ischaemic stroke in a systematic review of ‘real-world’ data than patients who received no or antiplatelet-therapy, while major bleeding rates were similar in all groups. Another systematic review revealed that many AF patients at high risk for stroke did not receive OACs, thus are undertreated according to guidelines.
A review of data on risk of AOC-related bleeding in AF has recently been published by the European Heart Rhythm Association, endorsed by the ESC working Group on Thrombosis. The risk of OAC-related bleeding is multi-factorial, with the highest risk after initiation of OAC treatment. The balance between the risk of bleeding and the risk of stroke needs to be estimated for each patient, based on patients’ values and preferences, as well as awareness of the prognostic implications of bleeding.
Heart failure (HF) is also associated with an increased risk of venous thromboembolism, cardio-embolic stroke and sudden death, sometimes caused by coronary occlusions. Although a systematic review showed a lower mortality and CV events rate in HF patients treated with anticoagulants as compared to control patients, current evidence does not support their routine use in HF patients.
The coagulation cascade offers many opportunities for therapies to interfere. New OACs are under development that target only a single step in the coagulation process. If these novel OACs are more convenient to administer, they may solve the undertreatment seen with regard to current treatment guidelines.
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