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This may be the very ﬁ rst illustration of a deep venous thrombosis at autopsy. It comes from ‘An essay on the proximate cause of the disease called Phlegmasia Dolens’ by David D Davis in Med.Chir.Trans. Lond. 1823, 12, 419-60. I found it in the Aberdeen Medical School Library when I was writing up my thesis in 1973. It is the case of Miss L who had had a swollen and painful leg during life. In fact, the clinical picture of deep venous thrombosis had been recognised much earlier, and even the forerunner of the so- called economy class syndrome. For example, in 1810 Ferriar described a patient ‘fatigued by a journey into the country, and lying in a bed afterwards not perfectly aired’ (Medical Histories and Reﬂ ections, Volume iii, Cadell and Davies, London). Charles Warlow http://pn.bmj.com/

T OUTSIDE NEUROLOGY Thrombophilia on September 30, 2021 by guest. Protected copyright.

Michael Greaves University of Aberdeen, UK; E-mail: [email protected] Practical Neurology, 2002, 3, 161–7

‘I call him a perfect physician who judges it better to abstain from treatment than pursue one which might perturb the course of the malady’ (Maimonedes, 1125–1204). This might well apply to long-term anticoagulation, with the inevitable risk of bleeding, in a patient with deep venous thrombosis who is found to have factor V Leiden. There is no evidence that the risk of recurrence is any higher than in a comparable patient with no evidence of inherited thrombophilia.

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Table 1 Systemic diseases and conditions and additional factors as- rial – there is no single ‘cause’. Furthermore, sociated with an increased risk of venous thrombosis the genetic, environmental and disease factors Diseases and conditions that contribute to venous thrombosis differ Obesity substantially from those that underlie arterial Cancer thromboembolism. In neurological practice, Haematological diseases the emphasis is on arterial thrombosis and its Haematological solid tumours consequences. However, deep venous throm- Myeloproliferative disease (essential thrombocythaemia, bosis of the legs and pulmonary embolism polycythaemia rubra vera) frequently complicate the clinical course of Paroxysmal nocturnal haemoglobinuria neurological disorders, and intracranial ve- Sickle cell disease nous thrombosis deserves special considera- Acute myocardial infarction tion. Acute stroke Systemic lupus erythematosus VENOUS THROMBOSIS Antiphospholipid syndrome Deep venous thrombosis occurs as a result of Behcet’s disease the interaction of multiple factors, both in- Inﬂ ammatory bowel disease herited and environmental. Out of Virchow’s Nephrotic syndrome triad of causes of thrombosis, stasis and blood Limb paralysis hypercoagulability predominate in relation to Surgery thrombosis in the deep veins of the lower limbs. Additional risk factors for venous thromboembolism Fibrin-rich thrombus forms in areas of sluggish Increasing age ﬂ ow. Vessel injury contributes in a minority of Hormone use cases, only. In visceral and intracranial venous Oral contraception thrombosis, hypercoagulability may play a lead- Hormone replacement therapy ing role, rather than stasis. Pregnancy and the puerperium Dehydration ARTERIAL THROMBOSIS Immobility Arterial thrombosis is also multifactorial but Due to illness here vessel wall pathology is central to the Due to splinting pathogenesis. Most frequently, platelet-rich During travel thrombus forms on a ruptured or ulcerated

Medications atheromatous plaque and vessel occlusion or http://pn.bmj.com/ Chemotherapy clot embolization leads to tissue infarction. Al- Tamoxifen ternatively, there is embolism of clot formed in Heparin (in heparin-induced thrombocytopenia) the ﬁ brillating left atrium, or on damaged heart Indwelling venous catheters and devices valves or left ventricular endocardium. Blood hypercoagulability may also contribute to the INTRODUCTION pathogenesis of arterial thrombosis. on September 30, 2021 by guest. Protected copyright. Advances in understanding the pathogenesis of Acquired situations and conditions that in- thrombosis have led to a massive increase in labo- crease the risk of venous thrombosis have long ratory investigations to identify causal factors in been recognized (Table 1). The diseases and affected individuals. However, this approach to lifestyle factors that increase the risk of athero- investigation, when employed indiscriminately, thrombosis are also familiar (Table 2). does not improve clinical management, may cause confusion, and is potentially wasteful of THROMBOPHILIA scarce resources. In this article I shall review the Recently, the term thrombophilia has been used inherited and environmental factors contribut- to describe the situation in someone who is at ing to thrombosis, and explore the clinical value increased risk of venous thromboembolism of laboratory investigation for prothrombotic through an inherited predisposition. This fol- states in patients with thrombosis. lowed the identiﬁ cation of some highly prevalent genetic risk factors for venous thrombosis, THE PATHOGENESIS OF which result in a life-long procoagulant state THROMBOSIS and which contribute substantially to the bur- The pathogenesis of thrombosis is multifacto- den of risk of venous thrombosis (Table 3). In

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Table 2 Common factors and diseases associated coagulants antithrombin, protein C and protein with increased risk of atherothrombosis S. In that year a common polymorphism in the Increasing age gene for factor V (factor V Leiden) was reported. Hypertension It is associated with relative insensitivity to the Male sex anticoagulant action of protein C – ‘protein C Diabetes mellitus resistance’ – and hence a procoagulant state Dyslipidaemia (Figs 1 and 2). In the laboratory it is detected Obesity by the coagulation assay for the protein C re- Smoking sistant phenotype, or alternatively and more Sedentary lifestyle specifi cally, by detection of the point mutation Positive family history using molecular genetic methods. Heterozy- gotes for factor V Leiden represent around 5% of the UK population and up to 10% in some Table 3 Thrombophilic conditions with a heritable northern European countries, and they have component a background risk of venous thrombosis that Activated protein C resistance/factor V Leiden is about fi vefold greater than noncarriers. The Prothrombin G20210A risk is higher still in homozygotes. Whilst defi - Antithrombin defi ciency ciency of antithrombin, protein C or protein S Protein C defi ciency is detected in fewer than 10% of cases of venous Protein S defi ciency thrombosis, factor V Leiden is present in up Raised factor VIII concentration to around 40%. The detection rate is highest Raised factor IX concentration when those with a positive family history and Raised factor XI concentration apparently ‘spontaneous’ (not associated with Raised fi brinogen concentration an obvious temporary major risk factor such as Hyperhomocysteinaemia surgery) thrombosis are tested. Although based on a limited number of cases, it seems that factor V Leiden also contributes to the occurrence of contrast, the more prevalent of these genetic intracranial venous thrombosis. factors, for example factor V Leiden, make a More recently, another prothrombotic point negligible contribution to arterial thrombosis. mutation, in the gene for the coagulation factor Furthermore, despite considerable research in prothrombin, has been reported. Prothrombin

the area, the search for other prothrombotic ge- G20210A has a prevalence of around 1% in the http://pn.bmj.com/ netic susceptibility markers for arterial throm- UK. Up to 10% of patients with deep venous bosis that make a major contribution to the thrombosis are heterozygous for the gene. burden of risk has not been fruitful. Most, such Predictably, it has been found in a similar pro- as polymorphisms in platelet receptor genes, portion of individuals with intracranial venous carry a small or no risk (Table 4). thrombosis. The heritability of thrombophilia also de- on September 30, 2021 by guest. Protected copyright. THE INHERITED pends on the genes that determine the plasma THROMBOPHILIAS concentrations of the clotting factors VIII, IX, Prior to 1994 the recognized genetic disorders XI and ﬁ brinogen. The risk of venous throm- known to carry increased risk of venous thrombosis rises with their plasma concentrations. bosis were deﬁ ciencies of the physiological anti- However, environmental factors also determine

Table 4 Candidate haemostatic markers and genetic risk factors for arterial thrombosis

Raised ﬁ brinogen concentration Raised factor VII concentration Raised factor VIII concentration Raised von Willebrand factor concentration Platelet receptor gene polymorphisms Thrombomodulin gene polymorphisms Plasminogen activator inhibitor-1 (PAI-1) gene polymorphisms

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the plasma levels. For example factor VIII and fi brinogen are acute phase proteins. Finally, increased plasma concentration of the amino acid homocysteine is determined in part by genetic variation in the enzymes responsible for its synthesis, cystathione syn- thetase and methylenetetrahydrofolate reduct- ase (MTHFR) as well as by the levels of vitamins B12, B6 and folic acid. Hyperhomocysteinaemia is accompanied by increased risk of both venous Figure 1 The principal physiological anticoagulant mechanisms. Thrombin, the enzyme and arterial thrombosis. Although a common responsible for conversion of soluble fi brinogen to insoluble fi brin, can also initiate an mutation in the gene for MTHFR, which is as- antithrombotic mechanism. When thrombin (generated through the coagulation cascade sociated with higher levels of homocysteine, is via the intrinsic or extrinsic pathway) binds to thrombomodulin on the surface of vascu- recognized, the mutation alone does not appear lar endothelium. It activates protein C. Activated protein C, with its cofactor protein S, to convey increased risk of venous thrombosis. inactivates clotting factors V and VIII. This acts as a brake on further thrombin generation. This suggests that other infl uences on homo- Therefore defi ciency of protein C or protein S, or of the inhibitor of thrombin itself (anti- cysteine metabolism may be more important, thrombin III), results in a prothrombotic state. aPC, activated protein C; S, protein S; ATIII, such as folate status. There is no proven value antithrombin. Inhibitors in blue; blue broken line indicates inhibition. in measuring homocysteine level in a patient with thrombosis at present because trials of the effect of suppression of plasma homocysteine on the risk of thrombotic events have not yet been completed. Because factor V Leiden and prothrombin G20210A are quite common, coinheritance with other thrombophilias occurs. The risk of venous thrombosis is increased further in such cases, for example

Figure 2 Factor V Leiden and prothrombin G20210A. when factor V Leiden and protein C defi ciency http://pn.bmj.com/ The point mutation in the factor V gene results in occur together in the same individual. synthesis of a variant of factor V that is insensi- tive to inhibition by activated protein C/protein S. COAGULATION RISK FACTORS Unimpeded activated factor V supports an increase FOR ARTERIAL THROMBOSIS in the background level of thrombin generation. The There is little evidence to implicate factor V Lei- point mutation in the prothrombin gene results in den, prothrombin G20210A and defi ciencies of on September 30, 2021 by guest. Protected copyright. enhanced synthesis and a higher plasma concentra- protein C, protein S and antithrombin in arte- tion of prothrombin, the zymogen for thrombin. aPC, rial thrombosis. Exceptions may be rare situa- activated protein C. tions, such as myocardial infarction in young women with other cardiovascular risk factors. A contribution to childhood stroke has been sug- gested, but is disputed. Although these genetic risk factors for venous thrombosis make little contribution to arterial disease, there are some associations between coronary and cerebrovas- cular thrombosis and coagulation factor levels. Fibrinogen is foremost among these. It is a likely candidate because it is the soluble substrate for thrombin in the generation of fi brin, it is an essential cofactor in platelet aggregation, and it makes a substantial contribution to the viscos- ity of blood. Plasma fi brinogen concentration

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has been independently associated with the ing factors are listed in Table 1. The use of the risk of stroke and myocardial infarction. Those combined oral contraceptive is worthy of spe- with the highest levels have around a twofold cial comment. In all users it induces a degree of increased risk. However, fi brinogen levels are resistance to the anticoagulant effect of protein highly-correlated with other cardiovascular C. This is comparable to the heterozygous state risk factors, such as age and smoking, and so for factor V Leiden and results in an increased far there is no evidence that lowering fi brinogen risk of venous thromboembolism of around concentration is protective and it is not easily four times background risk. However, as most achievable anyway. Furthermore, fi brinogen is users are young the absolute risk remains low. an acute phase reactant and an increased plasma In women who are also heterozygous for factor concentration could therefore merely refl ect the V Leiden there is a multiplicative, rather than presence of established atheromatous disease. additive, interaction with the oral contraceptive, Therefore, at present there is doubt about any resulting in a 30- to 40-fold increased risk over cause and effect relationship between fi brino- background. Despite this, most such women gen and arterial thrombosis. Similar consid- still do not suffer thrombosis. erations apply to a physiological inhibitor of This, often multifactorial, gene–environment fi brinolysis, plasminogen activator inhibitor interaction, must underlie most episodes of ve- (PAI-1). Although high levels are associated nous thromboembolism. There is a combined with atherothrombotic disease, PAI-1 is an acute effect of genetic predisposition (with some phase reactant, its plasma level correlates with common thrombophilic variants, some less other risk factors, and cause and effect have not common and some not yet identifi ed), inter- been demonstrated. Therefore, measurement of acting with increasing age and the infl uence of plasma fi brinogen and PAI-1 concentrations is transient environmental or disease risk factors, of no value in patient management. which fi nally triggers an acute episode. Other coagulation risk factors that have received attention as candidate markers for ANTIPHOSPHOLIPID SYNDROME arterial thrombotic disease are coagulation Systemic diseases contribute signifi cantly to the factor VIII and von Willebrand factor (vWF), occurrence of venous thrombosis. The antiphos- and factor VII. The best evidence is for factor pholipid syndrome and cancer, including occult VIII and vWF. The plasma concentrations are tumours, stand out because of their relatively highly correlated, because they form a complex, high prevalence and an especially high risk of

and high levels in patients with atherosclerotic recurrent thrombosis. In the antiphospholipid http://pn.bmj.com/ disease appear to predict increased risk of acute syndrome, the presence of persistent antiphos- thrombotic events. However, again, knowledge pholipid antibody is accompanied by thrombo- of the plasma concentrations of factor VIII and sis and/or recurrent pregnancy failure. There are vWF does not infl uence clinical management. other associations, including thrombocytopenia Although candidate genetic haemostatic risk and livedo reticularis. In contrast to inherited factors for arterial thrombosis have been assessed thrombophilia, both arterial and venous throm- on September 30, 2021 by guest. Protected copyright. (Table 4), in general the results are not conclusive. boembolism are common. Ischaemic stroke, In many cases, for example some platelet receptor often occurring at a young age and in the absence polymorphisms, there is no clear functional link of the usual risk factors, is an important feature. between genotype and thrombosis. At present, Venous thrombosis may affect unusual vessels, there is no clinical benefi t to the individual with including intracranial veins. Laboratory diagno- heart attack or stroke from seeking these suppos- sis requires the demonstration of persistent anti- edly prothrombotic genes. cardiolipin antibody or lupus anticoagulant. In some cases both types of antibody are present. GENE–ENVIRONMENT INTERACTION INTRACRANIAL VENOUS Patients with inherited thrombophilia, even THROMBOSIS those with combined defects, do not suffer In intracranial venous thrombosis, infection of from venous thrombosis most of the time. neighbouring structures such as the middle ear A trigger is usually necessary. Increasing age has long been recognized as a cause. Unsurpris- makes a signifi cant contribution, through as yet ingly, additional provoking factors are similar unrecognized mechanisms. Other precipitat- to those in limb deep venous thrombosis. Use

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of oral contraceptives, pregnancy, dehydration, given to the young, those with two or more fi rst polycythaemia, sickle cell disease, malignancy, degree relatives with venous thrombosis, and paroxysmal nocturnal haemoglobinuria, the patients in whom there is no clear environmen- antiphospholipid syndrome and infl ammatory tal factor or disease that has provoked the acute bowel disease have all been implicated. Inher- episode. Even then there is no evidence to guide ited thrombophilia is probably present in a therapeutic decisions based on the detection or similar proportion to that in patients with limb otherwise of inherited thrombophilia. deep venous thrombosis. Intracranial venous thrombosis and THE DIAGNOSIS OF ischaemic arterial stroke THROMBOPHILIA There is no evidence that any different consid- It has become commonplace to seek laboratory erations to venous thrombosis in the legs should confi rmation of inherited thrombophilia in al- apply to intracranial venous thrombosis. Fur- most everyone with acute venous thromboembo- thermore, because the inherited thrombophilias lism. Although laboratory tests for the inherited play little if any part in arterial thrombosis, there heterozygosity thrombophilias are readily available, their clini- is no value in routine testing for these conditions cal value is far from clear. Furthermore, testing in ischaemic arterial stroke. Indeed, such an ap- for factor V should not detract from the consideration of proach may lead to unjustifi able interventions important, often modifi able, environmental and because of the high prevalence of thrombophilic Leiden or disease risk factors, which may be contributing to genotypes in the general population: het- the pathogenesis of the thrombotic episode. erozygosity for factor V Leiden or prothrombin prothrombin G20210A will be detected by chance in around Thrombophilia testing at 6% of cases of ischaemic arterial stroke. G20210A will presentation of acute venous thrombosis of the limbs The diagnosis of inherited be detected by Identifi cation of inherited thrombophilia is thrombophilia and the prevention of seldom, if ever, of value in the management of venous thromboembolism chance in around the acute episode. This is because the genetic The likely impact of the increased knowledge of predisposition has no infl uence on the severity inherited thrombophilias is in the prevention 6% of cases of nor extent of thrombosis, nor on the response of venous thromboembolism in clinically- to anticoagulant therapy. Furthermore, even the unaffected carriers. However, this advance has

ischaemic arterial duration of anticoagulant therapy is not usually yet to be realized. Screening of populations at http://pn.bmj.com/ infl uenced by the results of tests for inherited risk has been advocated but the effectiveness stroke thrombophilia. This is because the recurrence of such a policy is open to doubt. For example, rates of limb deep venous thrombosis on discon- although there is a multiplicative effect between tinuing anticoagulant therapy are no different in factor V Leiden and oral contraceptive use, the factor IV Leiden heterozygotes from those in background rate of venous thrombosis in the whom inherited thrombophilia is not detected. young and fi t population in question is very on September 30, 2021 by guest. Protected copyright. Indeed, there is no reason why they should be. low. Thus it has been calculated that several The occurrence of venous thromboembolism million women must be screened to prevent a in an individual in circumstances when most do single fatal event. Furthermore, some women not suffer from an event identifi es that person as would avoid oral contraception as a result of a predisposed, whatever the results of the labora- positive test with the inevitable increased risk tory tests. An exception may be antithrombin de- of pregnancy. The situation is similar in screen- fi ciency, where clinical anecdote suggests higher ing women prior to hormone replacement use, recurrence rates. This may also be the case for ho- although the background rate of thrombosis is mozygotes for factor V Leiden and prothrombin higher in this older population. G20210A, double heterozygotes,and those with Case fi nding to permit family studies in order combined thrombophilic defects. However, these to identify relatives at increased risk is likely to individuals are encountered only rarely and tend be a more effective approach to thrombosis pre- to present with thrombosis at an early age, often vention. However, most heterozygotes for factor with a strong family history. For these reasons it V Leiden will never suffer venous thrombosis is appropriate to be selective in the investigation and the psychological and lifestyle risks associ- for inherited thrombophilia. Priority should be ated with the diagnosis of a genetic predisposi-

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tion should not be underestimated. Testing for inherited thrombophilia should not be used PUTTING CURRENT indiscriminately, and appropriate facilities for KNOWLEDGE INTO CLINICAL counselling before and after testing must be in PRACTICE place. Even then, benefi t is likely mainly from Based on the considerations presented in this testing in families where there is a history of article the conclusions are: venous thrombosis in more than one individ- • Thrombosis is a multihit condition – there ual, especially when events occur at a relatively is no single ‘cause’. young age, and are apparently unprovoked. • In venous thromboembolism in the legs and in the head the clinical history and The problem of diagnostic error physical examination will often reveal – pitfalls in the laboratory diagnosis important modifi able risk factors. of inherited thrombophilia • Inherited thrombophilia is not modifi - A further complication stems from the possibil- able and detecting it should rarely infl u- ity of diagnostic error. This is especially relevant ence clinical management; therefore its to defi ciencies of proteins C and S, because with detection can be regarded as of second- the commonly-employed assays there is overlap ary importance. between levels in heterozygotes and unaffected in- • If testing for inherited thrombophilia is dividuals. Also the plasma concentration of anti- pursued it is only likely to be of benefi t thrombin falls during acute thrombotic episodes if facilities are in place for testing at risk and with heparin therapy. Furthermore protein C relatives as well. The provision of expert and protein S are vitamin-K-dependent proteins counselling is essential. Usually this will and defi ciency cannot be diagnosed reliably dur- require liaison with haematologists and ing warfarin therapy. Their levels also change clinical geneticists. Whether this is a cost during normal pregnancy. Finally, if the protein C effective approach to thrombosis preven- resistance assay is used to test for factor V Leiden, tion has not been established. confusion may arise because protein C resistance • There is no indication for thrombophilia may be a consequence of atherothrombosis. testing during the acute presentation with Great care is required therefore in the choice and thrombosis because the results may be interpretation of tests and in the timing of blood misleading. sampling for testing for thrombophilia. • In arterial thrombosis, including is-

Particular issues arise in the performance of chaemic stroke, the clinical history and http://pn.bmj.com/ genetic tests for a generally late onset disorder physical examination, along with simple with a low fatality rate and incomplete pen- biochemical tests will often reveal impor- etrance. In investigating for thrombophilia it tant modifi able risk factors is essential to consider what can be achieved • In ischaemic stroke, routine testing for and whether harm can result. Harm includes inherited thrombophilia is not indicated generation of anxiety in asymptomatic relatives, because the common thrombophilic con- on September 30, 2021 by guest. Protected copyright. unwanted pregnancy due to avoidance of oral ditions do not contribute signifi cantly to contraception, unnecessary denial of the ben- the pathogenesis, and treatment would efi ts of hormone replacement therapy and inap- not be affected. propriate exposure to antithrombotic therapies. • There is no benefi t in seeking evidence of alterations in coagulation factors and ge- FURTHER READING netic susceptibility genes in an individual Greaves M (1999) Antiphospholipid antibodies and with stroke because management would thrombosis. Lancet, 353, 1348–53. not be affected. Greaves M, Baglin T (2000) Laboratory testing for heritable thrombophilia: impact on clinical management • In patients with arterial or venous throm- of thrombotic disease. British Journal of Haematology, bosis, antiphospholipid antibodies should 2000, 699–703. be sought as the thrombosis recurrence Reiner AP, Siscovick DS, Rosendaal FR (2001) Hemo- rate in the antiphospholipid syndrome is static risk factors and arterial thrombotic disease. particularly high. Longer term antithrom- Thrombosis and Haemostasis, 85, 584–95. botic therapy may be indicated, although Walker ID, Greaves M, Preston FE (2001) Investigation and management of heritable thrombophilia. Brit. J. the substantial bleeding risk from warfa- Haematol., 114, 512–28. rin should be carefully considered.

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