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Chapter 27 Thrombosis and antithrombotic therapy / 367

adult life. Arterial thrombi occur occasionally. longed down - regulation of fibrinolysis through acti-
Antithrombin concentrates are available and are vation of thrombin - activated fi brinolysis inhibitor
used to prevent thrombosis during surgery or child- (see p. 325 ).
birth. Many molecular variants of antithrombin
have been categorized and are associated with
varying degrees of risk of thrombosis. Hyperhomocysteinaemia
Higher levels of plasma homocysteine may be
genetic or acquired and are associated with increased
Protein C d efi ciency
risk for both venous and arterial thrombosis.
Inheritance is autosomal dominant with variable However, recent large trials show little evidence that
penetrance. Protein C levels in heterozygotes are lowering the levels reduces these risks.
approximately 50% of normal. Characteristically, Homocysteine is derived from dietary methio-
many patients develop skin necrosis as a result of nine and is removed by either remethylation to
dermal vessel occlusion when treated with warfarin, methionine or conversion to cysteine via a trans -
thought to be caused by reduction of protein C sulphuration pathway (Fig. 27.5 ). Classic homo-

levels even further in the first day or two of warfarin cystinuria is a rare autosomal recessive disorder
therapy before reduction in the levels of the vitamin caused by deficiency of cystathione β - synthase,

K - dependent clotting factors, especially factors II the enzyme responsible for trans - sulphuration.
and X. Rarely, infants may be born with homozygous Vascular disease and thrombosis are major features
deficiency and characteristically present with severe of the disease. Heterozygous cystathione β - synthase

disseminated intravascular coagulation (DIC) or deficiency is present in approximately 0.5% of

purpura fulminans in infancy. APC concentrates are the population and leads to a moderate increase
available and are used in selected acquired cases of in homocysteine. Methylene tetrahydrofolate
severe sepsis with DIC as well as in genetic protein reductase is involved in the remethylation

C deficiency. APC is also used in selected patients pathway and a common thermolabile variant of
with multiorgan failure and sepsis for its anti - the enzyme may be responsible for mild homo-

inflammitory, anticoagulant and pro - fi brinolytic cysteinaemia (above 15 μ mol/L) although this
eff ects. may only be seen in the presence of folate or vitamin
B 12 defi ciency. Acquired risk factors for hyperhomo-
cysteinaemia include deficiencies of folate, vitamin

Protein S d efi ciency
B 12 or vitamin B 6 , drugs (e.g. ciclosporin), renal

Protein S deficiency has been found in a number of damage and smoking. The levels also increase with
families with a thrombotic tendency. It is a cofactor age and are higher in men and post - menopausal
for protein C and the clinical features are similar to females.
protein C deficiency, including a tendency to skin

necrosis with warfarin therapy. The inheritance is

Defects of fi brinogen

autosomal dominant.
Defects of fibrinogen are usually clinically silent

or cause excess bleeding. Thrombosis is a rare
Prothrombin a llele G 20210 A association.
Prothrombin allele G20210A is a variant (preva-
lence 2 – 3% in the population) that leads to ABO b lood g roup
increased plasma prothrombin levels and increases
thrombotic risk by fivefold. It is probable that the Non - O blood group carriers have a higher risk of

cause of venous thrombosis with this mutation and venous thrombosis or embolism than O carriers.

with high levels of factors VIII, IX and XI is that This is related to their higher plasma levels of von
sustained generation of thrombin results in pro- Willebrand factor and factor VIII.