Arterial thrombosis

Pathogenesis

Atherosclerosis of the arterial wall, plaque rupture and endothelial injury expose blood to subendothelial collagen and tissue factor. This initiates the formation of a platelet nidus on which platelets adhere and aggregate.

Platelet deposition and thrombus formation are important in the pathogenesis of atherosclerosis. Platelet-derived growth factor stimulates the migration and proliferation of smooth muscle cells and fibroblasts in the arterial intima. Regrowth of endothelium and repair at the site of arterial damage and incorporated thrombus result in thickening of the vessel wall.

As well as blocking arteries locally, emboli of platelets and fibrin may break away from the primary thrombus to occlude distal arteries. Examples are carotid artery thrombi leading to cerebral thrombosis and transient ischaemic attacks and heart valve and chamber thrombi leading to systemic emboli and infarcts (Fig. 27.1).

Clinical risk factors

The risk factors for arterial thrombosis are related to the development of atherosclerosis and are listed in Table 27.1. The identification of patients at risk is largely based on clinical assessment. A number of epidemiological studies have resulted in the construction of coronary artery thrombosis risk profiles based on sex, age, elevated blood pressure, high levels of serum cholesterol, glucose intolerance, cigarette smoking and electrocardiogram abnormalities. These profiles have allowed pre-symptomatic assessment of young and apparently fit subjects and are valuable in counselling a change in lifestyle or for recommending medical therapy in individuals at risk. Epidemiological evidence implicates four inflammatory markers, fibrinogen, C-reactive protein, lipoprotein-associated phospholipase A₂ and interleukin-6 as predictive for coronary heart disease.

Table 27.1 Risk factors for arterial thrombosis (atherosclerosisis).

CRP, C-reactive protein; ECG, electrocardiogram.

Venous thrombosis

Table 27.2 lists a number of recognized risk factors.

Table 27.2 Hereditary and acquired risk factors for venous thrombosis.

HRT, hormone replacement therapy.

Hereditary disorders of haemostasis

The prevalence of inherited disorders associated with increased risk of thrombosis is higher than that of hereditary bleeding disorders. A hereditary ‘thrombophilia’ should be particularly suspected in young patients who develop spontaneous thrombosis, recurrent DVTs (Fig. 27.2) or an unusual site of thrombosis (e.g. axillary, splanchnic veins, sagittal sinus). Several abnormalities are now well characterized (Table 27.2).

Factor V Leiden gene mutation (activated protein C resistance)

This is the most common inherited cause of an increased risk of venous thrombosis. It occurs in approximately 3–7% of Caucasian factor V alleles. There is failure of activated protein C (APC) when added to plasma to prolong the activated partial thromboplastin time (APTT) test. Protein C, when activated, breaks down activated factor V so APC should slow the clotting reaction and prolong the APTT. APC resistance is caused by a genetic polymorphism in the factor V gene (replacement of arginine at position 506 with glutamine–Arg506Gln) which makes factor V less susceptible to cleavage by APC (Fig. 27.3). This is called the factor V Leiden mutation. The frequency of factor V Leiden in the general population in Western countries means that it cannot be regarded as a rare mutation but as a genetic polymorphism that is maintained in the population (Fig. 27.4). Presumably, individuals with this allele have been ‘selected’, probably because of a reduced bleeding tendency (e.g. post-partum). It does not increase the risk of arterial thrombosis.

Patients who are heterozygous for factor V Leiden are at an approximately five- to eight-fold increased risk of venous thrombosis compared to the general population but only 10% of carriers develop thrombosis during their lifetime. Individuals who are homozygous have a 30–140- fold risk. Following venous thrombosis they have a higher risk of re-thrombosis than individuals with DVT but normal factor V.

The incidence of factor V Leiden in patients with venous thrombosis is approximately 20–40%. Polymerase chain reaction (PCR) screening for the mutation is relatively simple and the test is widely performed. The absolute risk of thrombosis will depend on many other factors and it is difficult to advise individual patients of their risk. At present it is not recommended to start anticoagulation therapy in individuals with the Leiden mutation, even if homozygous, with no history of thrombosis. A small minority of patients with APC resistance do not have factor V Leiden but have other mutations of factor V.

Antithrombin deficiency

Inheritance is autosomal dominant. There are recurrent venous thromboses usually starting in early adult life. Arterial thrombi occur occasionally. Antithrombin concentrates are available and are used to prevent thrombosis during surgery or childbirth. Many molecular variants of antithrombin have been categorized and are associated with varying degrees of risk of thrombosis.

Protein C deficiency

Inheritance is autosomal dominant with variable penetrance. Protein C levels in heterozygotes are approximately 50% of normal. Characteristically, many patients develop skin necrosis as a result of dermal vessel occlusion when treated with warfarin, thought to be caused by reduction of protein C levels even further in the first day or two of warfarin therapy before reduction in the levels of the vitamin K-dependent clotting factors, especially factors II and X. Rarely, infants may be born with homozygous deficiency and characteristically present with severe disseminated intravascular coagulation (DIC) or purpura fulminans in infancy. APC concentrates are available and are used in selected acquired cases of severe sepsis with DIC as well as in genetic protein C deficiency. APC is also used in selected patients with multiorgan failure and sepsis for its anti-inflammitory, anticoagulant and pro-fibrinolytic effects.

Protein S deficiency

Protein S deficiency has been found in a number of families with a thrombotic tendency. It is a cofactor for protein C and the clinical features are similar to protein C deficiency, including a tendency to skin necrosis with warfarin therapy. The inheritance is autosomal dominant.

Prothrombin allele G20210A

Prothrombin allele G20210A is a variant (prevalence 2–3% in the population) that leads to increased plasma prothrombin levels and increases thrombotic risk by fivefold. It is probable that the cause of venous thrombosis with this mutation and with high levels of factors VIII, IX and XI is that sustained generation of thrombin results in pro longed down-regulation of fibrinolysis through activation of thrombin-activated fibrinolysis inhibitor (see p. 325).

Hyperhomocysteinaemia

Higher levels of plasma homocysteine may be genetic or acquired and are associated with increased risk for both venous and arterial thrombosis. However, recent large trials show little evidence that lowering the levels reduces these risks.

Homocysteine is derived from dietary methionine and is removed by either remethylation to methionine or conversion to cysteine via a trans-sulphuration pathway (Fig. 27.5). Classic homocystinuria is a rare autosomal recessive disorder caused by deficiency of cystathione β-synthase, the enzyme responsible for trans-sulphuration. Vascular disease and thrombosis are major features of the disease. Heterozygous cystathione β-synthase deficiency is present in approximately 0.5% of the population and leads to a moderate increase in homocysteine. Methylene tetrahydrofolate reductase is involved in the remethylation pathway and a common thermolabile variant of the enzyme may be responsible for mild homocysteinaemia (above 15μ mol/L) although this may only be seen in the presence of folate or vitamin B₁₂ deficiency. Acquired risk factors for hyperhomocysteinaemia include deficiencies of folate, vitamin B₁₂ or vitamin B₆, drugs (e.g. ciclosporin), renal damage and smoking. The levels also increase with age and are higher in men and post-menopausal females.

Defects of fibrinogen

Defects of fibrinogen are usually clinically silent or cause excess bleeding. Thrombosis is a rare association.

ABO blood group

Non-O blood group carriers have a higher risk of venous thrombosis or embolism than O carriers. This is related to their higher plasma levels of von Willebrand factor and factor VIII.

Hereditary or acquired disorders of haemostasis

High factor VIII or fibrinogen levels are also associated with venous thrombosis. The combination of multiple risk factors is associated with increased risk of thrombosis. If these are persistent they may represent a reason for extended anticoagulation.

Acquired risk factors

These may cause thrombosis in patients without another identifiable abnormality but are more likely to do so if an inherited predisposing abnormality (e.g. factor V Leiden) is also present.

Postoperative venous thrombosis

This is more likely to occur in the elderly, obese, those with a previous or family history of venous thrombosis, and in those in whom major abdominal or hip operations are performed. Elasticated stockings or mechanical methods (see p. 377) are used to reduce the risk of DVT.

Venous stasis and immobility

These factors are probably responsible for the high incidence of postoperative venous thrombosis and for venous thrombosis associated with congestive cardiac failure, myocardial infarction and varicose veins. In atrial fibrillation, thrombin generation from accumulation of activated clotting factors leads to a high risk clot formation in the atrial appendage and consequent systemic embolization. The use of muscle relaxants during anaesthesia may also contribute to venous stasis. Venous thrombosis also has a higher frequency after prolonged aeroplane journeys.

Malignancy

Patients with carcinoma of the ovary, brain and pancreas have a particularly increased risk of venous thrombosis but there is an increased risk with all cancers. The tumours produce tissue factor and a procoagulant that directly activates factor X. Mucin-secreting adenocarcinomas may be associated with DIC.

Inflammation

This up-regulates procoagulant factors, down-regulates anticoagulant pathways, particularly protein C. Thrombosis is particularly likely in inflammatory bowel disease, Behçet’s disease, systemic tuberculosis, systemic lupus erythematosus (SLE) and diabetes.

Blood disorders

Increased viscosity, thrombocytosis, altered platelet membrane receptors and responses are possible factors for the high incidence of thrombosis in patients with polycythaemia vera and essential thrombocythaemia. Testing for the JAK2 V617F mutation may indicate an otherwise unsuspected myeloproliferative disease in patients with hepatic or portal vein thrombosis. There is a high incidence of venous thrombosis, including thrombi in large veins (e.g. the hepatic vein) in patients with paroxysmal nocturnal haemoglobinuria. An increased tendency to venous thrombosis has been observed in patients with sickle cell disease, with post-splenectomy thrombocytosis and those with a paraprotein.

Oestrogen therapy

Oestrogen therapy, particularly high dose therapy, is associated with increased plasma levels of factors II, VII, VIII, IX and X and depressed levels of antithrombin and tissue plasminogen activator in the vessel wall. There is a high incidence of postoperative venous thrombosis in women on high dose oestrogen therapy and full dose oestrogen-containing oral contraceptives. The risk is much less with low dose oestrogen contraceptive preparations. Hormone replacement therapy also increases the risk of thrombosis, largely obviated by the use of low oestrogen preparations.

The antiphospholipid syndrome

The antiphospholipid syndrome (APS) can be defined as the occurrence of venous and arterial thrombosis and/or recurrent miscarriage in association with laboratory evidence of persistent antiphospholipid antibody. The predominant antibodies in this disorder are directed against protein antigens that bind to anionic phospholipids, such as β₂-glycoprotein 1 (β₂-GPI-1) and prothrombin.

One antiphospholipid antibody is the ‘lupus anticoagulant’ (LA) which was initially detected in patients with SLE, and is identified by a prolonged plasma APTT which does not correct with a 50: 50 mixture of normal plasma. Paradoxically, in view of its name, it is associated with venous and arterial thrombosis. A second test dependent on limiting quantities of phospholipid (e.g. the dilute Russell’s viper venom test) is also used in diagnosis. Whereas lupus anticoagulants are reactive in the fluid phase, other antiphospholipid antibodies, such as anticardiolipin antibodies and antibodies to β₂-GPI-1, are identified by solid phase immunoassay. Both solid phase assays and coagulation tests for LA should be used in the diagnosis of APS.

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10: The spleen 19: Hodgkin lymphoma 30: Pregnancy and neonatal haematology 25: Bleeding disorders caused by vascular and platelet abnormalities 24: Platelets, blood coagulation and haemostasis 7: Genetic disorders of haemoglobin

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