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Home , Haemophilia, Protein C deficiency, Protein S deficiency, Thrombocytopenia

Postgrad Med J 1996; 72: 87-94 CThe Fellowship of Postgraduate , 1996 Clinical guidelines Postgrad Med J: first published as 10.1136/pgmj.72.844.87 on 1 February 1996. Downloaded from Guidelines for the management of

Summary JD Cavenagh, BT Colvin Although there are numerous risk factors for venous thrombo- embolic disease, the term 'throm- Thromboembolic disease, which can affect both arterial and venous vascular bophilia' refers only to those systems, represents one of the major worldwide causes of morbidity and familial or acquired disorders of mortality. Although any assessment is fraught with inaccuracies, the best the haemostatic system that population-based studies of incidence estimate that approximately 70 000 cases result in an increased risk of of venous thromboembolic disease will be admitted to hospital in the UK each . The inherited throm- year. The in-hospital mortality is 12% and the three-year mortality reaches bophilias include antithrombin 30% .1 Venous thromboembolic disease is therefore an important medical III deficiency, resistance to acti- problem. In recent years several inherited and acquired predisposing conditions vated C ( Leiden), for thromboembolic disease have been identified and the recognition of these and entities presents challenges with respect to their appropriate management. This deficiencies as well as some rare paper is largely restricted to venous thromboembolic disease because abnor- forms ofdysfibrinogenaemia. It is malities of are better understood in this context. Arterial throm- possible that other inherited con- boembolism contributes to an even greater extent to mortality in the indust- ditions might also predispose to ralised world and risk factors within the haemostatic system are increasingly thrombosis. In contrast, when recognised as contributing significantly to the development of atheromatous using the above definition, the arterial disease. antiphospholipid syndrome is the only genuine acquired throm- Risk factors for bophilic state. Patients who have thromboembolic disease at a Numerous factors, both inherited and acquired, may predispose an individual to young age with no provoking venous thromboembolic disease (box 1). Acquired factors may take the form of event or who have a positive physiological processes, provoking events or specific . These distinc- family history or whose throm- tions are arbitrary and some factors may fall into more than one category. For bosis involves an unusual site instance, obesity has a genetic determinant and may well be considered a should be investigated for throm- pathological process in its own right. Also, it is becoming increasingly clear that bophilia. The management of a factors interact, often in a synergistic manner. Thus, individuals are much more patient identified as having a likely to experience a post-surgical if they already possess laboratory abnormality associ- an inherited predisposition to thrombosis. http://pmj.bmj.com/ ated with thrombophilia will The term thrombophilia' is probably best used to refer to those familial or depend on a variety of factors acquired disorders of the haemostatic system that result in an increased risk of such as the patient's individual thrombosis.2 A large number of inherited abnormalities of the haemostatic and family thrombotic history, system have been proposed as potential causes of thrombophilia, with varying the site of the thrombosis and the degrees of credibility. However, care must be taken to establish a genuine presence of other prothrombotic relationship between an inherited in vitro abnormality and thrombotic risk, since

risk factors. The use of pro- reporting bias is likely to overestimate any prothrombotic tendency. Familial on September 28, 2021 by guest. Protected copyright. phylactic anticoagulation during thrombophilia can only be said to exist if an identified laboratory abnormality and the puerperium cosegregates with increased thrombotic risk within affected families after the requires particularly careful con- propositi have been excluded. Such analysis has ruled out a variety of putative sideration in thrombophilic inherited such as factor XII deficiency, factor VII excess, women. As more becomes known cofactor II deficiency, plasminogen deficiency, tissue plasminogen about the thrombophilias it will activator (tPA) deficiency and plasminogen activator inhibitor-i (PAI-1) excess. become possible to formulate The excess risks associated with particular thrombophilic states are similarly more exact guidelines as to the hard to quantitate and the large prospective cohort studies which would be management of these conditions. required to do so have not been performed. Estimates of risk can vary wildly depending on the exact group of individuals studied. Much higher estimates of Keywords: guidelines, thrombophilia, thrombotic risk result if the families of affected patients rather than normal, thromboembolism prophylaxis randomly selected, individuals are analysed. This discrepancy may well result from distinct with greater pathological potential being present in affected families or indeed from the coexistence of a second prothrombotic within such families. Another important factor is the method by which the Department ofHaematology, The incidence of thromboembolic disease is determined. A clinical, non-objective, Royal London Hospital, Whitechapel, diagnosis of venous thrombosis is accurate in only 50% of cases. London El 1BB, UK JD Cavenagh The inherited thrombophilias BT Colvin

Correspondence to Dr JD Cavenagh The inherited thrombophilias that have so far been identified tend to result from defects in the naturally occurring systems that normally control and limit the Accepted 15 July 1995 haemostatic process. 88 Cavenagh, Colvin

ANTITHROMBIN III (AT-III) DEFICIENCY Risk factors for venous AT-III is the most important member of the serine inhibitor (serpin) thrombosis family involved in the control of haemostasis. It circulates in the plasma and binds to and inactivates a variety of activated serine involved in Postgrad Med J: first published as 10.1136/pgmj.72.844.87 on 1 February 1996. Downloaded from Inherited riskfactors * antithrombin III deficiency haemostasis (thrombin or factor IIa, factors Xa, IXa, XIa, and XIIa). Its active * resistance to activated protein C site consists ofa peptide sequence that is a 'dummy' substrate for activated serine () proteases which therefore bind to but fail to cleave it, instead forming a stable * complex that is rapidly removed from the circulation by the . The binding of * heparin or heparin sulphate to a distinct domain within AT-III results in the * dysfibrinogenaemias molecule acquiring a much higher affinity for thrombin, factor Xa and the other * possible risk factors: raised factor VIII level, raised fibrinogen level, serine proteases. As with deficiencies of any functional protein, AT-III hyperhomocysteinaemia deficiency is classified as Type I when subnormal quantities of a normal protein are present or as Type II when a functionally abnormal protein is produced.3 Acquired riskfactors Mutations which result in Type II deficiency can involve the active site, the * physiological factors: advancing heparin-binding site or both. AT-III molecules with mutant heparin-binding age, pregnancy and childbirth, sites result in a significantly lower risk of thrombosis than do the other abnormal obesity * provoking events: and forms. AT-III deficiency is transmitted as an autosomal dominant trait and trauma, immobility homozygotes, except for those homozygous for mutations at the heparin-binding * pathological factors: damage or site, die in utero. Approximately 70% ofpatients with familial AT-III deficiency obstruction to the veins (including will experience venous thromboembolic disease during their lifetime.4 Throm- previous thrombosis), boses tend to start at puberty, perhaps because of declining levels of aE- antiphospholipid syndrome, macroglobulin, an alternative thrombin inhibitor, which is relatively abundant malignancy (Trousseau's syndrome), , during the first two decades of life.5 Women with familial AT-III deficiency are oestrogen (including particularly susceptible to thrombosis during pregnancy (18% risk) and the contraceptive pills), nephrotic postpartum period (33% risk).6 syndrome, paroxysmal nocturnal haemoglobinuria, thrombotic thrombocytopenic , RESISTANCE TO ACTIVATED PROTEIN C (FACTOR V LEIDEN) heparin-induced The thrombomodulin-protein C mechanism is of fundamental and thrombosis syndrome, importance in regulating normal haemostasis. Stimulation of the coagulation myeloproliferative syndromes, cascades results in the generation ofthrombin which cleaves fibrinogen to form a hyperviscosity syndromes clot. Thrombin has multiple actions and, when it is bound to the endothelial cell membrane molecule thrombomodulin, it cleaves the vitamin Box 1 K-dependent serine protease protein C to form activated protein C which, in turn, cleaves factors Va and VIIIa into inactive molecules and so inhibits coagulation. Protein S, another -dependent protein, is an important co-factor for activated protein C which probably acts by enhancing its ability to bind to the phospholipid membranes of and endothelial cells where the factor Va- and VIIIa-containing complexes perform their enyzmatic functions. The underlying defect responsible for familial resistance to activated protein C is a point resulting in a single substitution at one of the two activated protein C-cleavage sites in factor Va (factor V Leiden).79 Thus, in http://pmj.bmj.com/ affected individuals, the coagulation system is rendered insensitive to the anticoagulant effects of activated protein C. Approximately 5% of the general population is heterozygous for this mutation and approximately 40% ofpatients with otherwise unexplained thrombosis possess it.'0"' Thus it is by far the most common known cause of inherited thrombophilia. Heterozygotes have a sevenfold increased risk of thromboembolic disease'2 and 30% of such patients

will have developed a thrombosis by 60 years of age. However, unlike other on September 28, 2021 by guest. Protected copyright. homozygous deficiencies, patients with homozygous factor V Leiden do not necessarily develop thromboembolic disease. Indeed, at 60 years of age, 40% of such individuals will still be thrombosis-free.'3 It is becoming clear that this common variant frequently results in thromboembolic disease in the context of additional provoking factors or when another inherited risk factor is also present, such as protein C deficiency.

PROTEIN C DEFICIENCY A large number of mutations result in protein C deficiency. In particular, Type II deficiency can result from mutations affecting the thrombomodulin cleavage site, the serine protease domain or the glutamate-rich domain that is y- carboxylated by vitamin K-dependent enzymes. It is not surprising, therefore, that the clinical phenotype of 'protein C deficiency' can vary widely. In some severely affected kindreds, protein C deficiency results in a 7500 chance of thromboembolic disease by the age of 60 years.'4 In contrast, a study of normal donors revealed a 0.500O prevalence ofprotein C deficiency with a negligible incidence of thromboembolic disease.'5 Different mutations clearly result in widely different clinical phenotypes which are not necessarily distinguishable by the results of in vitro assays. Indeed, an autosomal recessive form of the disease has been described, which results from the inheritance of two individually clinically silent mutations. Guidelines for management of thrombophilia 89

Patients from affected families typically develop thromboembolic disease from Case history the age of 20 years onwards. The half-life ofprotein C is shorter than those ofall the other vitamin than K-dependent (other factor VII). Therefore, Postgrad Med J: first published as 10.1136/pgmj.72.844.87 on 1 February 1996. Downloaded from A 22-year-old woman presented with when , disorientation and therapy is commenced, there is a period of dramatically increased weakness ofthe right side ofthe face. thrombotic risk which may be manifest as coumarin-induced skin necrosis. Papilloedema was found on Concurrent heparin therapy is required to prevent this complication. examination. A computed Homozygous neonates are likely to develop neonatal .'6"7 tomography (CT) scan showed Superficial is a characteristic feature of both protein C and in the superior sagittal protein S deficiencies. sinus. All other initial investigations were normal. She was treated with dexamethasone and acetazolamide PROTEIN S DEFICIENCY and her neurological status slowly Protein S circulates in an active, free form (40QO) and as an inactive form bound improved. Two weeks after hospital to C4b-binding protein (C4b-BP) (60%). Only free protein S can act as a discharge she developed pleuritic co-factor for activated protein C and so any increase in C4b-BP will reduce chest pain and protein S activity. Since C4b-BP is an acute phase reactant, any inflammatory was diagnosed by ventilation- process will in perfusion scanning. She was treated result a reduction in protein S activity. Indeed, 20% of all with intravenous heparin and hospitalised patients have low free protein S levels. Deficiency has proved subsequently started on oral difficult to define at the molecular level because ofthe presence of a homologous anticoagulation. pseudogene. In vitro, functional protein S deficiency can be confused with the As treatment for acne, she had been much more common factor V Leiden defect. Patients from affected families have taking a contraceptive pill with a high up to a 70% risk ofthrombosis by the age of60 years and affected oestrogen content. Her father had homozygously developed a spontaneous deep-vein neonates develop neonatal purpura fulminans. thrombosis at the age of22 years but there was no other family history of DYSFIBRINOGENAEMIA thromboembolic disease. Most mutations within the fibrinogen gene are clinically silent, some result in a Thrombophilia investigations were all tendency whilst others predispose to thromboembolic disease. There negative and she was maintained on are a variety ofmolecular mechanisms which result in increased thrombotic risk, warfarin for the next seven years until including abnormal she wished to become pregnant and thrombin binding and resistance to plasmin-mediated lysis. the drug was stopped. She soon Although there are well-described families with inherited thrombophilia due to became pregnant and prophylaxis dysfibrinogenaemias, they are rare and the actuarial risk of thromboembolic with adjusted dose heparin was disease is significantly lower than with the more well-recognised forms of initiated. inherited thrombophilia. Repeated thrombophilia testing prior to commencing heparin revealed OTHER POTENTIAL an AT-III level of64% (borderline INHERITED THROMBOPHILIAS low). Genetic analyses revealed a Raised levels of fibrinogen are well known to be a risk factor for arterial point mutation in exon 4 resulting in thrombosis and indeed a large population-based case-control study has demon- Type I deficiency. Labour was strated that a fibrinogen concentration > 5 g/l results in a four-fold increased induced at 38 weeks and the heparin relative risk of thromboembolic disease.'8 The level of fibrinogen may well be reduced to standard prophylactic partly genetically determined. Similarly, raised levels of factor VIII are dosage. Just prior to delivery, AT-IlI with (40 IU/kg) was infused and, after a associated thromboembolic disease and there is likely to be polymorphic, normal vaginal delivery, warfarin was genetically determined regulation offactor VIII expression.'9 Certainly, patients http://pmj.bmj.com/ recommended. A cord sample from with A are most unlikely to develop thromboembolic disease. The the baby girl had an equivocal AT-III inborn error of metabolism homocystinuria has long been recognised as being level but genetic analysis revealed that associated with an increased risk of thromboembolic disease. More recently, she had not inherited the mutant hyperhomocysteinaemia (which is due to gene. genetic variation in levels of gene This case highlights two points. expression) has been implicated as a risk factor for thrombosis.20 It is proposed Firstly, repeated testing is sometimes that raised levels of this amino acid result in endothelial dysfunction and

required in order to detect disturbed protein C activation by the thrombin-thrombomodulin pathway. on September 28, 2021 by guest. Protected copyright. abnormalities ofthe haemostatic These recently identified risk factors confer a relatively low probability of system since there is considerable thromboembolic disease on 'affected' individuals. However, they appear to be physiological and pathological important in population terms and may well be variability in the levels ofthese examples of those second factors proteins. Secondly, the value of that are required for the development ofthrombosis in patients with other, better genetic analysis is demonstrated described, inherited thrombophilias. which, in this case, clinched a difficult diagnosis and also confirmed normality in the offspring.

Table 1 Initial investigations Investigation Potential diagnoses Laboratory abnormality Full blood count polycythaemia rubra vera raised haematocrit and blood film essential thrombocythaemia raised count paroxysmal nocturnal anaemia and polychromasia haemoglobinaemia hyperviscosity rouleaux Activated partial thrombo- anticoagulant prolonged APTT (in some plastin time (APTT) cases) (TT) dysfibrinogenaemias shortened/prolonged TT 90 Cavenagh, Colvin

Acquired thrombophilia Situations when patients should be investigated for Although there are many important acquired risk factors for thrombosis, few are thrombophilia genuine thrombophilias as defined above, except for the antiphospholipid Postgrad Med J: first published as 10.1136/pgmj.72.844.87 on 1 February 1996. Downloaded from * venous thromboembolism before syndrome. This entity is defined by the presence of antiphospholipid the age of40-45 years (a lupus anticoagulant or anticardiolipin antibodies) in conjunction with certain * recurrent venous thrombosis or clinical events such as recurrent arterial and venous thrombosis, throm- thrombophlebitis bocytopenia or recurrent fetal loss.21,22 This syndrome can be primary, or * thrombosis in an unusual site, eg, secondary to systemic lupus erythematosus and other autoimmune mesenteric vein, cerebral sinus diseases, * unexplained neonatal thrombosis drugs or various infections including HIV. The pathogenesis of thrombophilia * skin necrosis, particularly ifon may vary between individuals and may involve reduced endothelial prostacyclin coumarins production or impaired protein C activation. * arterial thrombosis before the age of 30 years Which patients to investigate for thrombophilia? * relatives ofpatients with thrombophilic abnormality * patients with clear family history of Venous thrombosis is an extremely common problem and extensive investigation venous thrombosis for thrombophilia should only be undertaken in patients with features which * unexplained prolonged activated suggest a prothrombotic tendency. This is important not only because expensive partial thromboplastin time laboratory work is to be avoided when it is unnecessary, but also because (suggests lupus anticoagulant) universal screening ofpatients with thromboembolic disease will result in a large * recurrent fetal loss, immune number of 'false positive' results. For instance, up to 3% of a normal population or may have laboratory evidence of protein C deficiency but these individuals are systemic lupus erythematosus unlikely to have a significant thrombophilia.'5 Box 2 The British Committee for Standards in Haematology has published guidelines2 as to which patients should be investigated for thrombophilia (box 2). Illustrative cases (case histories) highlight some of the important issues about which patients should be selected for investigation. Investigations Case history The initial assessment of any patient with thrombosis should be directed at A 25-year-old man presented with determining if there is any overt risk factor for thromboembolic disease. The occipital headache and neck pain and history and physical examination may highlight evidence suggestive ofunderly- rapidly developed diplopia. ing malignant disease, , nephrotic syndrome or myelo- Examination revealed papilloedema, bilateral VIth nerve palsies and proliferative disorder. An initial screen will suggest further diagnoses (table 1). If pyramidal weakness ofthe left arm. no diagnosis has been made and thrombophilia is still suspected, then more Sagittal sinus thrombosis was elaborate haemostatic investigations are indicated (table 2). A large number of confirmed by digital subtraction diagnostic pitfalls exist, and these must be considered before a diagnosis of an angiography. Initial screening tests inherited thrombophilia is made (table 3). As can be seen, a large number of were all normal as were thrombophilia conditions can result in acquired deficiencies of natural investigations. He was treated with . Since intravenous heparin followed by reduced levels are found at the time of an acute thromboembolic event and since http://pmj.bmj.com/ warfarin and he slowly improved, heparin can reduce AT-III and warfarin can reduce protein C and protein S although there was a residual left VIth levels, thrombophilia investigations should ideally be performed when the nerve palsy. patient is off all anticoagulants and at a time remote from the thrombotic event. Six months later, whilst still on Normal ranges vary according to age and sex (as is well recognised with protein warfarin, he was found to be protein C C), and neonates have particularly low levels ofprotein C, protein S and deficient. His mother was also found AT-III. to have low protein C and had had Protein S levels are reduced in normal pregnant women and can reach levels that

three deep-vein thromboses. She are usually associated with inherited protein S deficiency.23 on September 28, 2021 by guest. Protected copyright. declined oral anticoagulation because Any positive investigation must be repeated at least once before a firm she had experienced a serious psoas diagnosis can be made in order to rule out technical error or biological variability. haematoma whilst previously on For instance, a lupus anticoagulant can develop transiently after certain viral warfarin. infections. Finally, if a potentially inheritable This case again demonstrates the defect is detected, then thought frequent necessity for repeated testing should be given to the testing and counselling of family members. in order to diagnose thrombophilic states. Also, it shows that protein C deficiency can be detected when patients are taking warfarin. Although thrombophilia testing is ideally Table 2 Investigations for thrombophilia performed when patients are offall anticoagulants, in some cases it is Investigation Comment deemed imprudent to stop warfarin. So long as the patient is tested when Resistance to activated protein C oral anticoagulation is stable, a Genetic analysis for factor V Leiden disproportionately low level of AT-III (functional assay) will detect Type I & II deficiencies protein C compared to the other Protein C (functional assay) will detect Type I & II deficiencies vitamin K-dependent coagulation Protein S (antigenic assay) functional assays give false positive results in the proteins suggests protein C presence of factor V Leiden.3" Free protein S deficiency. It is important to attempt level is what is functionally important to make the diagnosis in these Lupus anticoagulant circumstances so that family members Anticardiolipin antibodies the antiphospholipid syndrome may be can be investigated when appropriate. associated with a lupus anticoagulant, anticardiolipin antibodies or both Guidelines for management of thrombophilia 91

Table 3 Causes of acquired deficiencies of AT-Ill, protein C and protein S The investigation of potential thrombophilia Factor Decreasedproduction Increased destruction Postgrad Med J: first published as 10.1136/pgmj.72.844.87 on 1 February 1996. Downloaded from All patients with venous thrombosis AT-III DIC * treat with anticoagulants in the oestrogens acute thrombosis standard manner heparin therapy * assess the patient for the presence nephrotic syndrome ofany risk factors and, ifpresent, drugs (asparaginase) manage accordingly Protein C liver disease DIC warfarin acute thrombosis Does the patientfall into any ofthe drugs (asparaginase) categories listed in box 2? Protein S liver disease DIC * No: no further investigation warfarin acute thrombosis required pregnancy drugs (asparaginase) * Yes: does the nature or extent ofthe oestrogens raised C4b-BP (inflammation) thrombosis warrant life-long anticoagulation in its own right (eg, DIC = disseminated intravascular coagulation sagittal sinus thrombosis)? Ifso, attempts can be made to diagnose thrombophilia whilst the patient is on warfarin and family members can be tested. Ifnot, then: The management of thrombophilia Perform thrombophilia testing at least 3 If all with thromboembolic disease less than 45 of with no weeks after cessation ofwarfarin patients years age * initial screening tests (full blood readily identifiable cause for thrombosis are fully investigated as above, then count, blood film, platelets, approximately 5% will be found to be deficient in AT-III, protein C and protein activated partial thromboplastin S, respectively. A further 40% will have resistance to activated protein C. time, thrombin time) Therefore, approximately halfofthe patients suspected ofhaving thrombophilia * thrombophilia tests (resistance to will have no detectable haemostatic defect, and it is important to appreciate that activated protein C, factor V not mean are not or indeed that do not Leiden, AT-III, protein C, protein this does that they thrombophilic, they S, lupus anticoagulant, have familial thrombophilia. In these cases only an individual assessment of the anticardiolipin antibodies) patient's and his or her family's thrombotic history will enable one to propose a * ifa positive result is obtained, the rational management plan. It seems highly probable that further genetic test must be repeated at least once abnormalities resulting in thrombophilia will be discovered in the future. before the laboratory abnormality is confirmed * antiphospholipid antibodies may be THE ACUTE THROMBOEMBOLIC EVENT transient In virtually all cases, the management of a first thrombotic event in a * consider the potential causes of thrombophilic patient will be identical to that of all other patients since the acquired deficiencies ofAT-III, diagnosis of thrombophilia is not usually made until after warfarin has been protein C and protein S (table 3) stopped. The observation of heparin resistance should alert the clinician to the * in certain circumstances, attempt to possibility of AT-III deficiency. If a thrombosis occurs in an individual who is define the precise molecular defect (eg, factor V Leiden, Type II known to come from a protein C or protein S deficient kindred, then extra care AT-III deficiences involving the must be taken to ensure that warfarin is introduced under heparin cover to http://pmj.bmj.com/ heparin-binding site) prevent coumarin-induced skin necrosis. If neonatal purpura fulminans is * test the family members ofpatients suspected, then protein C and protein S assays should be performed urgently with positive results and, if profound protein C deficiency is confirmed (<1%), then protein C * remember that the failure to detect concentrates should be administered.'7 This unusual and very serious condition a laboratory abnormality (50% of patients who are included in box 2 has been treated successfully by regular protein C concentrate infusions, oral will have no such abnormality) does anticoagulation and also by liver transplantation.

not mean that thrombophilia does on September 28, 2021 by guest. Protected copyright. not exist LIFE-LONG ANTICOAGULATION An accepted strategy in general hospital practice is to manage a first thrombosis Box 3 with three months' and a second with twelve months' oral anticoagulation. A third thrombosis labels a patient as suffering from recurrent venous thrombosis and life-long anticoagulation is usually recommended. This is a reasonable basis on which to plan management for patients with thrombophilia. When a patient who is known to have a laboratory abnormality associated with thrombophilia suffers a second thromboembolic event, life-long anticoagulation should be considered. This recommendation takes into account the greatly increased risks ofrecurrent thromboembolic disease in this group. However, it is important to bear in mind that thrombophilic families exist who have no identifiable laboratory abnormality and the management of individuals from such families will be determined by each individual's and their family's thrombotic history. There are certain circumstances when life-long anticoagulation should be considered after only one thrombotic event. A very high risk of a second thrombosis in patients with the antiphospholipid syndrome has recently been highlighted, and for this group of patients life-long oral anticoagulation (INR 3-4.5) has been recommended after one thrombotic event.24 Various other factors are important in assessing any individual case. AT-Ill deficiency results in a greater thrombotic risk that protein C or protein S deficiency, although there is considerable variability within kindreds with AT-Ill deficiency, since some 92 Cavenagh, Colvin

have clinically mild mutations. Determination of the exact AT-III genetic The management of abnormality may be of help in this situation. The severity of the initial thrombophilia thrombotic event is clearly relevant and the management ofa patient after sagittal sinus thrombosis, for will tend to be more than after a Postgrad Med J: first published as 10.1136/pgmj.72.844.87 on 1 February 1996. Downloaded from 1 A first thrombosis in patients instance, aggressive included in box 2 femoral deep-vein thrombosis. Another important factor is whether the throm- bosis was spontaneous or provoked by one of many well known precipitants. Antiphospholipid syndrome Spontaneous events carry a higher risk of recurrence. The family history is of * advise life-long oral anticoagulation great relevance: if there has been a sequence of life-threatening events in a (INR 3-4.5) particular kindred, then there will be a low threshold for continuing anticoagula- tion in a affected member with it AT-III deficiency newly recognised thrombosis, although is * consider life-long oral important to remember that significant intra-family variation exists, presumably anticoagulation (INR 2-3) unless due to the presence or absence of coinherited predisposing abnormalities or Type II deficiency environmental differences. Ifthe patient has a sedentary, or perhaps wheelchair- * advise adjusted-dose heparin* bound, lifestyle, then again there will be a lower threshold for continued warfarin through and oral therapy. Finally, if a female patient wishes to conceive, this should be a major anticoagulation for at least 6 consideration in management since it is to avoid warfarin weeks** post-partum. Infuse important during AT-III concentrate just prior to pregnancy (see below). delivery whilst reducing heparin In summary, it would be foolish to state firm guidelines for long-term oral dosage to routine prophylactic anticoagulation in patients with a recognised haemostatic abnormality (or indeed levels*** for patients with thrombophilia with no such recognised abnormality). Wide * advise prophylactic anticoagulation variability in thrombotic risk exists within 'single' diagnostic categories as is for any subsequent high-risk clearly evident in AT-III and protein C deficiency. Furthermore, the situations coinheritance of secondary risk factors or the acquisition of disease or lifestyle- Protein C deficiency, protein S related risk factors make any generalisations unreliable. One must consider all deficiency and resistance to the relevant facts in each case and make a clinical judgement as to the relative activated protein C advantages and disadvantages of continued anticoagulation. * consider life-long oral anticoagulation (INR 2-3) only in PREGNANCY specific circumstances such as after a life-threatening thromboembolic Pregnancy and conception present particular problems for any woman on event, with an immobile life-style, long-term warfarin (whether because of a mechanical heart valve or throm- with a strong family history of bophilia). Warfarin possesses several unwanted potential side-effects which serious thromboembolic events or make it an unattractive drug for use during pregnancy.25 Firstly, it can result in coexistence ofmore than one coumarin-induced embryopathy (nasal hypoplasia and stippled epiphyses) with abnormality maximum risk from 6-12 of * initiation ofwarfarin therapy must weeks pregnancy. Secondly, it is associated with an be covered by heparin in protein C increased risk of various central nervous system abnormalities which can result or protein S deficiency from warfarin use at any time during pregnancy. Thirdly, its use carries the risk * if the thrombotic event was offetal bleeding, in particular ofintracranial bleeding during delivery. Although spontaneous, then advise the long-term use ofheparin has several unwanted effects for the mother (namely adjusted-dose heparin throughout the risk of thrombocytopenia and ), it is probably the safest pregnancy and oral anticoagulation to use for 6 weeks post-partum anticoagulant during pregnancy.26 Ideally, any conception should be * ifthe thrombotic event was during planned and a strategy formulated. A possible approach is to stop warfarin when http://pmj.bmj.com/ or after a previous pregnancy, then attempting to conceive and to continue on subcutaneous heparin until delivery. advise routine prophylactic Since it may take several months to conceive, this approach may result in quite anticoagulation during the first prolonged periods of heparinisation with its attendant problems. Another trimester followed by adjusted-dose approach is to remain on warfarin and to perform frequent pregnancy tests. As heparin until delivery when heparin should be reduced and substituted soon as pregnancy is detected, the woman can then switch to subcutaneous by warfarin for 6 weeks heparin.

post-partum For women without recognised thrombophilia27 it is generally recommended on September 28, 2021 by guest. Protected copyright. * advise prophylactic anticoagulation that, if a previous thrombotic event occurred during the puerperium, sub- during subsequent high-risk cutaneous heparin should start at delivery and warfarin should be used for six situations weeks post-partum. Conversely, if the thrombosis occurred during pregnancy * advise against the use ofthe itself, then heparin should start four to six weeks before the gestational stage at combined contraceptive pill which it occurred previously and warfarin should again be used for six weeks No laboratory abnormality post-partum. If a woman has had a thrombosis not related to pregnancy or any detected other recognised provocative event, then consideration should be given to the * management should be as for prophylactic use of heparin throughout pregnancy or restricted to the third protein C or protein S deficiencies trimester with subsequent warfarin for six weeks. These guidelines also provide a and resistance to activated protein reasonable basis for C although the risks ofrecurrent the management of pregnancies in women with recognised thromboembolic disease may well thrombophilic abnormalities. be lower in this group than for Women with AT-III deficiency appear to be at particularly high risk, even if those patients with defined they themselves have never experienced thromboembolic disease.6 Such women laboratory abnormalities may be offered adjusted-dose heparin prophylaxis throughout pregnancy, * be guided by any family history of followed by warfarin for a minimum of six weeks, in addition to infusion of thromboembolic disease AT-Ill concentrate2 just prior to delivery so that the heparin dosage can be continued/ reduced at the time of maximum haemostatic challenge. However, it is clear that the risks are much lower with deficiencies involving the heparin-binding site and these women probably do not require prophylaxis if they have never experienced venous thrombosis. Furthermore, if large analyses of normal populations are undertaken, AT-Ill deficiency is detectable in 1 in 600 people and virtually all of these have 'harmless' deficiencies.29 Therefore, it is clear that the management of Guidelines for management of thrombophilia 93

individuals who are found to have potentially thrombophilic deficiencies during /box 4 continued 'routine' screening should not be equated with that ofasymptomatic individuals who are identified from families with a thrombophilic history. 2 A second thrombosis in Women with protein C or protein S deficiency who have previously had a Postgrad Med J: first published as 10.1136/pgmj.72.844.87 on 1 February 1996. Downloaded from patients included in box 2 thrombosis should receive prophylaxis during pregnancy. Women who have had AT-III deficiency, protein C a thrombotic episode during late pregnancy or the puerperium may receive deficiency, protein S deficiency low-dose heparin until the third trimester when adjusted dose heparin should and resistance to activated commence. Women who have had a spontaneous thrombosis unrelated to protein C pregnancy should receive adjusted dose heparin throughout pregnancy as with * advise life-long oral anticoagulation AT-III deficiency. The final subset of women with protein C or protein S (INR 2-3) deficiency who require consideration are asymptomatic individuals who have * initiation ofwarfarin therapy must been detected an be covered by heparin in protein C following the identification of affected family member. In this and protein S deficiency case, a clinical judgement will have to be made in the light ofthe kindred's family history of thrombosis and after counselling the affected woman. The risk of No laboratory abnormality thromboembolic disease during pregnancy in women with resistance to activated detected protein C with no previous thrombosis is not clear at the present time and firm * Management must be based on guidelines cannot be given.30 individual and family history of thromboembolic disease Women with the anti-phospholipid syndrome and prior thromboembolic disease should receive adjusted doses of heparin throughout pregnancy. The 3 Asymptomatic family members problem ofrecurrent fetal loss is a distinct one and optimal management remains with laboratory abnormality unresolved. Trials are under way comparing the relative benefits of , heparin and . AT-III deficiency In summary, prescriptive guidelines are not possible. Each individual case * advise adjusted dose heparin throughout pregnancy and warfarin must be considered on its own merits and a management decision made after full for at least 6 weeks post-partum, discussion with the affected woman. Indeed, the decision-making process may except for the relatively benign become even more difficult as more women are found to have laboratory Type II defects 'abnormalities' that are known to be associated with thrombophilia in some * advise prophylaxis during high-risk kindreds, but which also have a relatively high frequency in the general situations population. * avoid the combined contraceptive pill PROPHYLAXIS DURING HIGH-RISK PERIODS Protein C deficiency and protein For individuals who are known to have a laboratory abnormality associated with S deficiency thrombophilia and who are not already receiving oral anticoagulation, there * advise prophylaxis during high-risk should be a very low threshold for recommending anticoagulant prophylaxis situations during periods ofhigh risk for * consider the family history when thromboembolism such as operations, immobility advising about subsequent and after trauma. Indeed, one of the main reasons for identifying affected pregnancies relatives of patients with thrombophilia is to be able to offer them advice about * the combined contraceptive pill is prophylaxis. probably safe with protein S deficiency but should be avoided in FURTHER COUNSELLING

protein C deficiency until more data Several issues should be with http://pmj.bmj.com/ are available discussed affected individuals and asymptomatic family members who are found to possess a thrombophilic laboratory abnor- Resistance to activated protein C mality. The advisability of prophylaxis during high-risk periods should be * the risks ofthrombosis are much discussed and the reversal ofpotentially avoidable risk factors encouraged, such lower than in the other identifiable as smoking and obesity. The use of the combined oral contraceptive pill should groups generally be discouraged if alternative methods of contraception are acceptable. * a low threshold for prophylaxis There is evidence that women with should exist, especially for those AT-III deficiency are at increased risk of individuals with a strong family thromboembolic disease whilst using the contraceptive pill although women on September 28, 2021 by guest. Protected copyright. history with protein S deficiency have no increased risk whilst taking a low-oestrogen pill * the combined contraceptive pill and there is currently not enough evidence available to comment on women with should be avoided ifother protein C deficiency.3' For all groups, the progesterone-only pill is probably safe. contraception is acceptable33 Hormone replacement therapy for post-menopausal women appears to be safe. The oestrogen component of hormone replacement therapy is lower than *Adjusted dose heparin: heparin 12 hourly most subcutaneously, dose adjusted to achieve an contraceptive pills and hormone replacement therapy confers considerable activated partial thromboplastin time advantages with respect to cardiovascular mortality and the development of which is just prolonged when tested 4-6 osteoporosis. hours after injection. There is limited experience of the use of low molecular weight heparin during pregnancy. Conclusion **Anticoagulation during the puerperium: warfarin (INR 2-3) for a minimum of six weeks Guidelines for the management ofthrombophilia are becoming clearer as more is ***Prophylactic anticoagulation during learnt about the molecular mechanisms and natural histories of the various pregnancy: heparin 5000-7500 IU 12 underlying disorders. Some suggested guidelines for testing and management of hourly subcutaneously thrombophilia are outlined in boxes 3 and 4. Although reasonably firm guidelines are possible in certain situations (eg, recurrent thrombosis in patients with a Box 4 recognised thrombophilic laboratory abnormality), it is not possible to give advice of proven validity in many other circumstances. For instance, there are many individuals with unexplained thrombosis with no apparent predisposition (see box 2) who do not have any laboratory abnormality. It seems probable that new molecular defects will be discovered that might explain the thrombotic predisposition in this group of individuals, as indeed occurred when resistance to 94 Cavenagh, Colvin

activated protein C was first described. Meanwhile, after due consideration of such a patient's personal and family thrombosis history, a clinical judgement has to be made on an individual basis as to any long-term anticoagulation or prophylaxis. All of the guidelines discussed above are based on risk analyses of Postgrad Med J: first published as 10.1136/pgmj.72.844.87 on 1 February 1996. Downloaded from individuals who have suffered a venous thrombosis or are the asymptomatic affected family members of such thrombotic individuals. In population terms this is a highly selected group and it is becoming clear that large-scale screening exercises ofthe general population will detect a very large number ofpeople who have detectable abnormalities of the haemostatic system but no personal or family history of thrombosis. At the present time counselling such individuals remains very difficult and will remain so until more is known about the natural histories associated with specific defects.

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