rel="nofollow" href="#ulink_844f4522-e83a-5619-99de-57be2b874b9a">Table 24.6). Deficiencies of antithrombin, protein C, and protein S are rare, but significant conditions do exist. They are autosomally dominantly inherited and only occur in the heterozygous form, the homozygous form being incompatible with life. These conditions usually present with venous thrombosis, which may be unusually widespread or occur at an unusual site, sometimes occurring spontaneously but often following a recognized predisposing factor. They may be recurrent, and there is often a positive family history of venous thrombosis. Although patients may present at a younger age, they can be diagnosed at any age, and certainly second or recurrent episodes of thrombosis will occur in old age. The diagnosis of these conditions can be somewhat problematic as the concentrations of all these proteins fall during active thrombosis, and antithrombin levels fall during heparin therapy, while protein C and S levels fall during warfarin therapy.
Table 24.5 INR ranges in various conditions.
| INR | Clinical state |
|---|---|
| 2.0–3.0 | Treatment of deep vein thrombosis Pulmonary embolism Systemic embolism Prevention of venous thromboembolism in myocardial infarction Mitral stenosis with embolism Transient ischaemic attacks Atrial fibrillation |
| 3.0–4.5 | Recurrent deep vein thrombosis and pulmonary embolism Arterial disease, including myocardial infarction Mechanical prosthetic heart valves |
Table 24.6 Thrombophilic conditions.
| Antithrombin – quantitative deficiency (type 1) or qualitative dysfunction (type 2) |
| Protein C – quantitative deficiency or qualitative dysfunction |
| Protein S – deficiency of total or free protein S |
| Factor V Leiden |
| Prothrombin 20210A allele |
| Antiphospholipid syndrome (lupus anticoagulant, anti‐beta 2 glycoprotein 1 Ab, ACA Ab) |
Consequently, patients should ideally be investigated when they neither have active thrombosis nor are on anticoagulants. The finding of a deficiency state should lead to family screening as other family members are at risk. In the absence of a first episode of thrombosis, management should consist of adequate thromboprophylaxis at times of increased risk, such as surgery and immobilization. After a first episode of thrombosis, reasonable management is to anticoagulate for three to six months with warfarin with a target range of 2–3 or a DOAC; after recurrent thrombosis, lifelong anticoagulation should be considered, initially with a target range of 2–3 but increasing to 3–4 should further episodes of thrombosis occur while patients are already anticoagulated.17 Patients with triple‐positive APS should not receive a DOAC and be anticoagulated with warfarin at the higher target range.
Factor V Leiden is the most common inherited prothrombotic genetic disorder. The basis of this defect is a single base substitution at position 1691 of the factor V heavy chain, resulting in a substitution of the amino acid glutamine for an arginine residue. This abolishes an activated protein C cleavage site and results in a factor V molecule that can be activated by thrombin but can no longer be inactivated by APCR; consequently, there is enhanced and prolonged activation of the coagulation cascade, increased thrombin generation, and hence a predisposition to thrombosis. This condition can therefore be diagnosed both by a plasma assay and by genetic analysis of the factor V gene. The condition is autosomally dominantly inherited and is extremely common, occurring at an incidence of between 2 and 10% in the Caucasian population, although it appears to be rare or absent in non‐Caucasian populations. Unlike the other thrombophilic conditions, individuals with both heterozygous and homozygous forms of this condition exist, and the lifelong incidence of thrombosis appears to be somewhat less than antithrombin, protein C, and S deficiency. Indeed, a significant proportion of patients with this condition may never have a thrombotic event. The frequency with which it occurs within the Caucasian population suggests that in evolutionary terms, it must have some as yet obscure evolutionary advantage, but with life expectancy increasing and surgery becoming more frequent nowadays, it is clear that this condition is a major predisposing factor contributing to venous thrombosis. Indeed, between 40 and 60% of patients having a first episode of thrombosis have this condition, a 12‐fold increase over the incidence within the background population.
Prothrombin 20210A allele is another genetic condition common in Caucasian populations at an incidence of 1–5% that increases thrombotic risk to a similar degree to Factor V Leiden. Again most patients do not have thrombosis, and population and family screening for Factor V Leiden and PT20210A is now no longer recommended.
Lupus anticoagulant
Lupus anticoagulant is a laboratory diagnosis based on the finding of a prolonged APTT that is not due to a deficiency of a specific coagulation factor or a specific inhibitor of any coagulation factor, but to an autoantibody apparently directed against phospholipids but in reality directed primarily against proteins that are intimately associated with phospholipids. Since the reactions of the coagulation cascade are phospholipid dependent, these antiphospholipid antibodies decrease the efficiency of the coagulation cascade and prolong the clotting time. The diagnosis can be confirmed using the dilute Russell viper venom test (DRVVT), in which the test is optimized so that phospholipid availability is rate‐limiting; this accentuates the effect of antiphospholipid antibody. Confirmation is achieved by showing that the clotting time returns to normal when excess phospholipid (in the form of freeze‐fractured platelets) is added to quench the antibodies and that the test is not corrected by the addition of normal plasma that contains only additional coagulation factors.
The name lupus anticoagulant is somewhat unfortunate. The lupus refers to systemic lupus erythematosus (SLE), and it was in patients with this condition that the phenomenon was first observed. However, it has subsequently become clear that the majority of patients do not have SLE. Likewise, although it appears to be anticoagulant in vitro by prolonging the activated partial thromboplastin time (APTT), in vivo some lupus anticoagulants are associated with an acquired predisposition to thrombosis, and bleeding does not occur. Consequently, the finding of a lupus anticoagulant may be an indication for thromboprophylaxis or even anticoagulation.
The significance of the finding of a lupus anticoagulant can be very variable. Transiently positive tests frequently occur after infections, and many drugs can precipitate these antibodies, as can chronic infection such as syphilis. In these circumstances, the antibody does not appear to be associated with an increased incidence of either arterial or venous thrombosis. In patients with an underlying collagen vascular disease or in whom a primary antiphospholipid syndrome (APS) is diagnosed, there is an association between the finding of a positive test and recurrent arterial or venous thrombosis. The primary antiphospholipid syndrome consists of a positive lupus anticoagulant test and an association with livedo reticularis, thrombocytopenia, and recurrent miscarriages in females. The lupus anticoagulant can precipitate both arterial and venous thrombosis, and within an individual, the site of second and subsequent thrombosis tends to occur in the same system; these patients may require long‐term anticoagulation. There is no evidence that the antibodies causing the prolongation of the APTT in vitro are those that cause thrombosis; indeed, they may be an epiphenomenon, as a wide range of autoantibodies are found in these conditions, including antibodies against cardiolipin, which can be IgG or IgM, and are detected by a solid‐phase enzyme‐linked immunosorbent assay (ELISA).19 Likewise, antibodies against the protein beta‐2 glycoprotein‐1 are also associated with APS. Thrombotic events are particularly prevalent in patients with so‐called triple positivity: LA, ACA, and anti‐beta‐2 glycoprotin‐1 antibodies. These patients have recurrent thrombosis and should not be treated