Anticoagulation therapy is common in the elderly. It is used in thrombotic disease for the secondary prevention of myocardial ischaemia (MI), thrombotic stroke and transient ischaemic attacks. It is also used in the acute treatment of MI, intermittent claudication, cardiac valve disease, atrial fibrilliation, deep vein thrombosis (DVT) and pulmonary embolism.

GPs commonly use aspirin, clopidogrel, heparin and warfarin or sinthrome, but there are now a number of new oral anticoagulants available and NICE is currently appraising many of them. These drugs exploit advances in the knowledge of coagulation and fibrinolytic physiology.

Patients may also present with bleeding disorders that are congenital or acquired. There are a number of chemicals in the body that act to cause thrombus and clot and a number of chemicals acting to limit the size of the clot, to cause fibrinolysis and to prevent clotting. The details of these are fascinating, not totally understood and can be confusing. Some basic explanation is provided in this article.

Thrombin, platelets, fibrin, von Willebrand Factor and coagulation factors produce clot, but plasmin inhibits clots and causes fibrinolysis. Mention of the underlying processes give a useful overview to act as a basis for understanding patient disease and therapy.

It has been estimated that 6.5% of all admissions to hospital are due to adverse drug reactions, the most common being gastrointestinal haemorrhage and leading drug problems were caused by aspirin, diuretics, warfarin, and non-steroidal anti-inflammatory drugs.1

Endothelial vascular cells

Endothelial vascular cells play an important role in haemostasis. They can stimulate coagulation by the synthesis of:

• Von Willebrand factor, which stimulates platelet adhesion to the vessel wall and aggregation

• Tissue factor, which triggers blood coagulation, activating the clotting cascade

• PAI-1 (plasminogen activator inhibitor), which inhibits plasminogen activator and so inhibits fibrinolysis.

They can inhibit coagulation by:

• T-PA (tissue plasminogen activator), which is found on the surface of fibrin and activates plasminogen to create plasmin which is a protease causing destruction of fibrin (fibrinolysis)

• PGI2 (a prostaglandin) and EDRF (endothelium derived relaxant factor = NO), which promote vasodilatation and limit the formation of platelet plugs

• Thrombomodulin, which with cofactor protein C inactivates thrombin.


Primary haemostasis is characterised by vascular contraction, platelet adhesion and formation of a soft aggregate plug. Platelets contain lots of chemicals to promote and inhibit clot formation and are produced by megakaryocytes in the bone marrow. Thrombopoietin, produced by the liver and kidneys, stimulates production. Platelets are budded off from megakaryocyte cytoplasm so have no nucleus but have granules, dense bodies and membrane receptors. They live about nine days and some are stored in the spleen where all are eventually destroyed. Platelets are activated when blood vessel injury exposes collagen.

Injury to the blood vessel causes temporary vasoconstriction, platelet activation and platelet aggregation by linking to von Willebrand factor (vWF) which acts like bolts to tether the platelet at the injured vessel wall. vWF is present at the site of injured endothelium released from platelets. Lack of vWF usually causes mild bleeding and bruising problems. It is the commonest inherited clotting problem and there are four types of von Willebrand disease.

Activated platelets release serotonin and thromboxane to promote vasoconstriction. There is also a factor which inhibits heparin. Platelets then produce pseudopods that stretch out to cover the injured surface and bridge collagen fibres. Platelet receptors change shape to bind fibrinogen and more platelets. Platelets release various growth factors, F5, F13, fibrinogen, PAI-1 (plasminogen activator inhibitor), a counter-control, ADP and calcium. Fibrinogen has lots of platelet binding sites. Activated platelets bind to the fibrinogen, which activates to fibrin and cross-links over the exposed collagen wound with the platelets. All this produces a soft plug, it takes about 20 seconds for platelet aggregation to occur.


The "extrinsic pathway" is an outdated term and is the major coagulation pathway starting with tissue factor exposure and via clotting factors ending with thrombin formation.

Tissue factor (TF/thromboplastin/F3) is membrane bound and exposed on tissue injury at the blood vessel. It acts to activate the circulating inactive clotting factors that then cause thrombin formation. The clotting factors have a cascade system of checks and counterchecks and at each stage the factor is amplified in amount, they are not numbered by order of action.

Blood and endothelial cells do not normally express TF. Coagulation is initiated by the binding of F7 to TF, resulting in the activation of F7 by F11a, 10a and 12a. The binding and activation of F7 needs calcium.

TF is present in macrophages and in atheroma where it is thought to initiate clot formation. F7a bound to TF activates F9 and 10 to promote coagulation. However tissue factor pathway inhibitor (TFPI) inhibits the F7a-TF complex to prevent clotting and provide a counter-control.

The "intrinsic system" is also an outdated term and relates to collagen binding kininogen, F12 and prekallikrein activating to kallikrein and eventually activating F8. F11a activates F9a, forms a complex with phospholipid and F8a which activates F10. However deficiency of some of these factors like kallikrein does not cause bleeding disorders but seems more to affect inflammatory mechanisms.

From these two routes the coagulation process continues through the "common pathway" to produce thrombin from prothrombin. Thrombin acts to cleave fibrinogen to form insoluble fibrin which causes a clot by interacting with activated platelets.

Prostaglandins (PGs), thromboxane and prostacyclin act to promote clotting by vasoconstriction, platelet aggregation and activation and are produced via an enzyme called cyclo-oxygenase (COX) after cell injury.

Inhibition of COX by NSAIDs like ibuprofen and aspirin prevents formation of these PGs, prostacyclin and thromboxane, which reduces platelet aggregation and activation and can promote bleeding.

Antiplasmin is liver-synthesized and is the body's most effective inhibitor of fibrinolysis, as the name suggests by inhibiting plasmin.

Another counter-control to plasmin is PAI-1. This is a plasminogen activator inhibitor and is synthesized in endothelial, liver and smooth muscle cells, and platelets. PAI-1 is released from endothelial cells to inhibit t-PA and u-PA (see under fibrinolysis) and so cause thrombus formation. Binding to vitronectin at the clot stabilises PAI-1 in its active form. Plasma concentrations of PAI-1 show marked diurnal variation and are highest in the early morning hours. PAI-1 is also an acute phase reactant. High levels have been found in patients with heart attacks or CHD and may be a risk factor for MI.


Plasminogen, formed by the liver, is converted to plasmin, a protease which breaks down fibrin and so dissolves clots-fibrinolytic. It is similar to the enzymes trypsin and chymotrypsin (pancreatic enzyme). Plasminogen needs t-PA (tissue plasminogen activator) or u-PA, to activate it by cleaving a peptide bond. t-PA is synthesized in the endothelium and interacts with plasmin on the fibrin surface. It has a short half life in plasma of 3-5 minutes, any unused plasmin is neutralised by antiplasmin and then metabolised by the liver. Deficiency of plasminogen is associated with thromboembolism.

Tissue Factor Path Inhibitor (TFPI) is liver synthesised and like antithrombin is found on endothelium. Heparin injection releases TFPI to the circulation. TFPI inhibits tissue factor and so inhibits the coagulation cascade.

Thrombomodulin (TM) is a glycoprotein of arterial and venous endothelium. It is absent from brain endothelium but present in the lymph system. TM binds thrombin and protein C which is activated with calcium to activated protein C, APC, and released to inhibit some clotting factors, especially F8a and F5a. Also, on binding to TM, thrombin is inactivated and so loses the capacity to split fibrinogen to fibrin. This too has a negative feedback on clotting. Protein C deficiency is one cause of hereditary thrombophilia. A more common cause is increased APC resistance, often resulting from a mutation (Lieden gene) in the F5 gene. Because of this mutation, APC cannot bind and inactivate F5a. APC is a potent anticoagulant usually.

Within this reaction is another cofactor, protein S, and a deficiency of this is also associated with an increased risk for thrombosis. Acquired deficiencies are seen with vitamin K deficiency, liver injury, anti-vitamin K therapy and pregnancy.

Antithrombin (occasionally called heparin co-factor) is liver synthesized and inhibits lots of clotting factors to promote bleeding. Hereditary deficiency of antithrombin increases the risk of thrombosis but can be asymptomatic and is quite common in the population. Heparin binds to antithrombin and magnifies its action 100 fold. Heparin is naturally occurring in mast cells in many tissues especially the liver and arises probably from mast cell progenitors in the bone marrow.

Prostacyclin PGI2 is released from the endothelium surrounding the platelet plug to limit the size of the thrombus also by inhibiting platelet aggregation and by vasodilation. EDRF (endothelium derived relaxant factor = NO) also promotes vasodilation.

The fibrinolytic system keeps the vascular system free of clots. It is the antagonist to the coagulation system, dissolving fibrin clots by the specific and powerful protease plasmin which breaks down fibrin. This causes release of fibrinogen degradation products (FDPs), into fragment X then D-dimers. D-dimer assay measures fibrin degradation, it informs the clinician that clots have occurred and the body is trying to break them down.


The prothrombin time or PT is the lab test used to measure coumarin-type anticoagulant drugs like warfarin. PT is measured in seconds or as an International Normalised Ratio (INR). The PT is how long it takes a plasma sample to clot after a mixture of thromboplastin (this is tissue factor and phospholipids) and calcium are added. If the patient's blood has less prothrombin or a decrease in some clotting factors than a control then the PT time will be prolonged. Normal values for PT time are 11-13 seconds.

To allow comparison of PT time the World Health Organization instituted INR in which PT is expressed as a ratio. Targets for INR vary, depending on the reason for anticoagulation, usually between 2.5 and 3.5.

Warfarin has a long onset of action, taking days to achieve a therapeutic level. Initially the patient requiring anticoagulation may be managed with heparin as well. Vitamin K is essential to a liver enzyme which adds a carboxyl group to factors 2,7,9 and 10, Protein S, Protein C and Protein Z. In this reaction Vitamin K is oxidised. Vitamin K epoxide reductase, (VKORC) reduces vitamin K back to its active form from the oxidised form. VKORC is important as warfarin blocks VKORC, causing a deficiency of vitamin K and inhibiting maturation of clotting factors.

Vitamin K deficiency can also occur in malabsorption eg. cystic fibrosis or in liver failure, leading to coagulation factors being unable to bind to phospholipid. If PT is too long on warfarin the antidote then is to give vitamin K. Many drugs affect the action of warfarin at the liver and so may affect the PT time. Warfarin must be stopped and PT must be normal in order to have surgery.

The activated partial thromboplastin time (aPTT) is a common screening test to evaluate the "intrinsic clotting system," monitor intravenous heparin therapy and screen for lupus anticoagulants.

The aPTT measures the clotting time of plasma from the activation of factor 12 by mixing blood with silica and a phospholipid. If a patient's aPTT is abnormal additional tests will be done to determine the exact cause of the coagulation problem. Normal aPTT is usually 25-38 seconds. The aPTT of a newborn is usually prolonged and may be up to 55 seconds, it decreases to the adult range by six months of age.

The aPTT is the most commonly used test to monitor intravenous heparin therapy. The aPTT is measured every six hours during the first day of IV heparin therapy and six hours after any dosage change. Protamine sulfate may be given as an antidote to IV heparin.

If low molecular weight heparin (LMW heparin) is given for anticoagulation a prolonged aPTT does not occur because this, like fondaparinux, targets F10a which is not affected by the "intrinsic coagulation system". F8a and F9a are part of this system and these are forms of haemophilia and so would have a prolonged aPTT.

A prolonged aPTT can occur with some drugs and conditions and in non-IV heparinised patients, this can occur due to: salicylates (aspirin), inherited or acquired intrinsic clotting factor deficiency or abnormality, massive blood replacement, lupus anticoagulant or excessive coumarin (warfarin) dosage through the faulty coagulation factor production.


Haemophilia is an X chromosome linked recessive trait that is the result of deficiency in the production of F8 or F9. It therefore occurs very largely in boys. There can be severe, moderate or mild forms. Haemophilia A is 4-5 times more common than haemophilia B. There is often excessive bleeding after trivial injuries. Haematoma, haemarthroses and haematuria are common.

Haemophilia A, classic haemophilia, is due to an abnormality in F8, either deficiency or due to the presence of inhibitors. Liver transplant corrects haemophilia. It occurs in one in 5,000 males.

Hemophilia B, or Christmas disease, is due to an abnormality involving Factor 9. Incidence is one in 25,000 boys. Stephen Christmas (1947-93) died from AIDS from contaminated blood samples required for his condition. He was British but lived in Toronto. This haemophilia affected many of the European royal families.

The aPTT is prolonged in haemophilia and is used as a screening test for the disease. The patient with haemophilia has a normal PT and a normal platelet count.

Von Willebrand's disease (vWF)

Von Willebrand disease is the most common hereditary coagulation disorder. It occurs in about 1% of the general population. Many cases go undiagnosed with only a mild bleeding tendency. Deficiency or defective vWF results in problems with platelet adhesion and activation. Haematoma, haematuria and epistaxis. may occur. In these patients prothrombin time (PT) is normal but activated partial thromboplastin (aPTT) time may be prolonged but can also be normal. The level of vWF can be measured by antigen but varies with blood group and level of F8.

Lupus anticoagulant (lupus antibody, LA, lupus inhibitors)

Lupus anticoagulant is an immunoglobulin that binds to phospholipids on the cell membrane increasing platelet aggregation and promotes thrombus formation. It can sometimes be called phospholipid syndrome for this reason. Patients may suffer recurrent miscarriages. It can be associated with other antibodies and occurs in 30% of systemic lupus erythematosus patients. It was first described in 1983. However in vitro the antibodies cause an increase in aPTT hence the name.

Bleeding time

Bleeding time measures the length of time that bleeding continues after a standardised wound is made on the forearm or ear lobe. Normal bleeding time depends on both the number and function of platelets. Bleeding time may be prolonged in von Willebrand's disease, thrombcytopenia, inherited platelet dysfunction, recent NSAID or antihistamine use. Using the ear lobe, a normal bleeding time is 1-4 minutes. Using the forearm method a normal bleeding time is 2-9 minutes.


Thrombocytopenia is the most common reason for bleeding. It may be due to decreased platelet production, bone marrow disease or increased platelet destruction, side effects from drugs like anticancer agents and some infections. Idiopathic thrombocytopenic purpura (ITP) is a condition in which antibodies form against platelets. Bleeding into skin and mucous membranes: ecchymosis, epistaxis, petechiae, gastrointestinal or genitourinary bleeding are suggestive of platelet disorders.


Disseminated intravascular coagulation (DIC) occurs as a result of obstetric problems like placental abruption, septic abortion, retained products of conception, amniotic fluid embolism or severe pre-eclampsia/eclampsia. Other causes are septicaemia, malignancies, liver cirrhosis, sickle cell disease, trauma, crush injuries, snake bites, incompatible blood transfusions.

DIC is a consumption coagulopathy; abnormal production of thrombin consumes the other clotting factors, leading to uncontrolled bleeding. DIC is always secondary to a disease process in which lots of tissue injury triggers blood clotting. Bleeding can occur anywhere. DIC produces lots of coagulation test abnormalities: prolonged PT and aPTT times, prolonged bleeding time, decreased fibrinogen and platelet count, positive fibrin split products, fibrin degradation products, raised D-dimer, decreased clotting factors. To reverse DIC, the underlying problem must be treated. In some situations the treatment for uncontrolled bleeding in DIC is heparin administration, which blocks thrombin formation and this then blocks consumption of the other clotting factors and results in haemostasis.


This overview of modern understanding of thrombosis, fibrinolysis and coagulation tests provides a platform for the next article in this series. Part two published this month in GM Heart and Diabetes explores anticoagulant and fibrinolytic medications that are currently available and also looks at their exploitation in providing clinical benefits to patients.


Further articles in this series will be published in GM Journal.

Conflict of interest: none declared




1. Munir Pirmohamed, Sally James, Shaun Meakin, et al. Adverse drug reactions as cause of admission to hospital: prospective analysis of 18 820 patients. BMJ 2004; 329: 15

2. accessed June 2013

3. Ganong's Review of Medical Physiology 2012. 24th Edition (Lange Basic Science).

4. Medical Sciences by Jeannette Naish, Patricia Revest and Denise Syndercombe Court 2009

5. NICE clinical guideline144 Venous thromboembolic disease. accessed June 2013

6. http://www. accessed June 2013

7. Wikipedia coagulation. accessed June 2013