Thrombosis

Thrombi are solid masses or plugs formed in the circulation from blood constituents. Platelets and fibrin form the basic structure. Their clinical significance results from ischaemia from local vascular Obstruction or distant embolization.

Hereditary disorders of haemostasis The prevalence of inherited disorders associated with increased risk of thrombosis is at least as high as that of hereditary bleeding disorders. A hereditary thrombophilia' should be particularly suspected in young patients who suffer from spontaneous thrombosis, recurrent deep vein thromboses an unusual site of thrombosis (e.g. axillary, splanchnic veins, sagittal sinus).

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 4% of Caucasian factor V alleles Patients who are heterozygous for factor V Leiden are at an approximately 5-8-fold increased risk of thrombosis compared to the general population. Individuals who are homozygous have a 30-140 fold risk. Following venous thrombosis they have a higher risk of re-thrombosis compared to individuals with deep vein thrombosis (DVT) but normal factor V.

the underlying reason 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 activated protein C * screening :polymerase chain reaction (PCR) screening for the mutation is relatively simple and the test is widely performed.

Anti-thrombin deficiency Inheritance is autosomal dominant. There are recurrent venous thromboses usually starting in early adult life. Arterial thrombi occur occasionally. Anti-thrombin concentrates are available and are used to prevent thrombosis during surgery or childbirth.

Protein C deficiency Inheritance is autosomal dominant with variable 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, Rarely, infants may be born with homozygous deficiency and characteristically present with severe disseminated intravascular coagulation (DIC) or purpura fulminans in infancy.

Protein S deficiency The inheritance is autosomal dominant. 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.

Prothrombin allele G20210A Prothrombin allele G20210A is a variant (prevalence2-3% in the population) that leads to increased plasma prothrombin levels and increases thrombotic risk by at least twofold

Hyperhomocysteinaemia Higher levels of plasma homocysteine may be genetic or acquired and are associated with increased risk for both venous and arterial thrombosis. homocystinuria is a rare autosomal recessive disorder Vascular disease and thrombosis are major features of the disease. Heterozygous present in approximately 0.5% of the population and leads to a moderate increase in homocysteine.

Acquired risk factors for hyperhomocysteinaemia include deficiencies of folate, vitamin BI2 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

Hereditary or acquired disorders of haemostasis High factor VIII or fibrinogen levels are also associated arterial thrombosis. The combination of multiple risk factors is associated with increased risk of thrombosis.

Acquired risk factors 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 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

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 pro-coagulant 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, Behcet's disease, systemic tuberculosis, systemic lupus erythematosus

Blood disorders *in patients with polycythaemia vera and essential thrombocythaemia, the high incidence of thrombosis is due to : Increased viscosity, thrombocytosis, altered platelet membrane receptors and responses *There is a high incidence of venous thrombosis in patients with sickle cell disease and patients with post splenectomy thrombocytosis

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 antiphospholipid syndrome This may be defined as the occurrence of thrombosis or recurrent miscarriage in association with laboratory evidence of persistent antiphospholipid antibody. One antiphospholipid antibody is the 'lupus anticoagulant' (LA) which was initially detected in patients with SLE, and also found in other autoimmune disorders particularly of connective tissues, lymphoproliferative diseases, post-viral infections, with certain drugs including phenothiazines and as an 'idiopathic' phenomenon in otherwise healthy subjects. it is associated with venous and arterial thrombosis.

Factor IX concentrates Venous thrombosis may complicate the use of factor IX concentrates which contain trace amounts of activated coagulation factors. Patients with liver disease who are unable to clear these activated factors are especially at risk.