Inherited Thrombophilic Disorders

9 Inherited thrombophilic disorders

Dorit Blickstein

INTRODUCTION In contrast to the simple, reliable and inexpensive laboratory tests used to investigate Inherited thrombophilia is thought to increase bleeding disorders such as prothrombin time the risk of pregnancy related venous thrombo- (PT) and partial thromboplastin time (PTT), embolism (VTE), including deep vein throm- no such diagnostic means exist for testing/ bosis (DVT) and pulmonary embolism (PE). screening of hypercoagulable states. Moreover, Pregnancy is a hypercoagulable state due the literature holds that thrombophilia testing/ to the increased concentration of coagulation screening is expensive. For example, Wu and factors, decreased natural anticoagulants and colleagues2 calculated the incremental cost- fibrinolytic activity1. The pregnant woman is effectiveness ratio (ICER; the lower the ICER therefore at increased risk for VTE and this the more cost-effective the strategy to avoid a predisposition is much accentuated in patients major adverse clinical outcome) for universal with thrombophilia. Thus it is important to screening prior to prescribing combined con- identify this group of patients before or early traception, for example, is as high as £202,402 in pregnancy in order to tailor appropriate pre- (UK), whereas for hormone replacement it is ventive means. far less (£6824) (UK). Stated another way, it is not cost-effective to perform routine thrombophilia screening before prescribing hormonal THE APPROACH TO VENOUS therapy. Several authorities have maintained THROMBOEMBOLISM that screening the general population is not justified mainly because of the above men- The clinical approach to acute VTE is the tioned financial considerations3–5. Therefore, same in patients with or without inherited in order to avoid indiscriminate thrombophilia thrombophilia. However, most patients with screening and waste of health resources, one a confirmed episode of VTE will eventually must consider the indication, advantages and undergo thrombophilia screening if acquired pitfalls of such an investigation. Injudicious causes are excluded. Obviously, the clinical thrombophilia screening should therefore be utility of testing is the a priori assumption that discouraged. the test results are likely to improve health Every testing/screening should be based on outcome. In this context, one should remem- the prevalence of each inherited thrombophilic ber that screening is performed in the absence condition and the association of each with the of disease, whereas testing is performed in the risk of VTE. Several inherited thrombophilic presence of symptoms or signs. It follows that conditions predispose to venous thrombosis. in the case of thrombophilia the actual workup The most important are factor V Leiden muta- is for testing rather than for screening. tion, prothrombin gene mutation, protein C,

111 PRECONCEPTIONAL MEDICINE protein S and antithrombin deficiency, elevated purpura fulminans without sepsis. Because this factor VIIIc and hyperhomocysteinemia6. The circumstance is suspected to manifest a homo- frequency of the natural anticoagulant protein zygous state of protein C and S deficiencies, S, protein C and antithrombin deficiencies is first degree relatives should also be screened. low in the general population (<1% in total) Warfarin decreases the level of the natu- as well as in patients with VTE (5% in total), ral anticoagulant protein C and S, as well as but the frequency of gain of functional muta- vitamin K-dependent coagulation factors. In tions – factor V Leiden and prothrombin gene some patients receiving warfarin, the decrease mutation – is common in the general popula- in anticoagulants is faster than the decrease tion (3–7% and 3%, respectively) as well as in coagulation factors, and they develop skin in patients with VTE (25% and 10%, respec- necrosis. Accordingly, patients who sustained tively). The prevalence of factor V Leiden and warfarin skin necrosis are suspected to be het- prothrombin gene mutation is 10–15% in the erozygous for protein C and S deficiency and Caucasian population but increases to about should therefore be investigated. 50% in patients with recurrent thromboem- bolic phenomena. Because selection for thrombophilia test- Family history ing/screening is required, a rather long list of candidates has been created over the years. To Patients with first degree relatives who have simplify this list, these candidates have been had a VTE at a young age or as a pregnancy grouped under three subheadings7–21. complication are candidates for screening.

Venous thromboembolism Previous adverse pregnancy outcomes

Age is the single most important factor for The association of some adverse pregnancy VTE, and hence, young patients (defined as outcomes with inherited thrombophilia is con- <50 years) who experienced previous VTE troversial. Since placenta-mediated pregnancy after an event that is no longer present, such complications are thought to result from as minor surgery or bone fracture, should placental micro/macrothrombosis in blood undergo evaluation. However, even if there is vessels, one might assume that thrombo- no identifiable risk factor for VTE,patients with philia should increase thrombotic risk. How- unprovoked VTE at any age, should be screened ever, conflicting data exist for the link between for thrombophilia. Similarly, the association pregnancy complications and thrombophilic of VTE in the absence of any other risk factor risk factors. A recent meta-analysis of 25 except the use of exogenous estrogens (oral con- studies on 11,183 women found a significant traception and hormone replacement) or preg- association between pregnancy complications nancy, should lead to screening, as is the case and thrombophilia, especially for early and for patients with recurrent VTE at any age or early late recurrent pregnancy loss associated with age of onset. In addition to the common sites of antiphospholipid antibodies (APLA), factor V DVT, it has been suggested that patients with Leiden and the prothrombin gene mutation13. superficial thrombophlebitis without malignancy Data evaluation demonstrated a strong asso- and those with DVT at unusual sites (cerebral, ciation between factor V Leiden and recurrent mesenteric, portal or hepatic) under the age pregnancy loss, as well as severity of preg- of 50 years also should be evaluated. This cat- nancy complications in the second and third egory includes the rare event of a neonate with trimesters compared to first trimester. The

112 Inherited thrombophilic disorders evaluation, however, indicates that the rela- Clot based assays like protein S and factor tionship between thrombophilia and pregnan- VIII should not be performed during the acute cy complications is confounded by ethnicity, phase of VTE, during pregnancy, or during oral severity of illness and method of testing14. contraception and warfarin treatment. Tests In contrast, other recent studies failed to should be performed at least 2–3 months after demonstrate an association between throm- pregnancy and withdrawal of oral contracep- bophilia and adverse pregnancy outcome15–25. tion, and 1 month after warfarin treatment is While thrombophilias are associated with completed. placental-mediated pregnancy complications, Antithrombin levels may be determined their causal contribution is weak. The associa- during acute VTE before unfractionated hep- tion makes biological sense (consistent with arin (UFH) or low molecular weight heparin the pathophysiological theory of the devel- (LMWH) treatments are initiated, as both opment of pregnancy complications) but the interact with antithrombin. This is because association is inconsistent, non-specific, with- antithrombin concentrate replacement may be out biological gradient and with no convincing necessary for acute VTE, together with hepa- evidence from clinical studies for causal asso- rin or LMWH treatment for severe antithrombin deficiency. ciation18,21. Publication bias also plays a role Screening seems to be unnecessary in in the interpretation of findings in relevant patients on prolonged anticoagulant treatment studies. (malignancy or recurrent VTE) because the It is therefore not surprising that the lat- decision for treatment has already been made. est American College of Chest Physicians Likewise, in patients with a personal or famil- (ACCP) guidelines on VTE, thrombophilia ial VTE history, there is no need for routine and antithrombotic therapy recommend that preoperative screening, as the results will not only women who have had recurrent early loss change the recommended thromboprophylax- (three or more miscarriages), unexplained late is policy in most of them7. pregnancy loss, and severe or recurrent pre- eclampsia or intrauterine growth restriction 26 (IUGR) be screened for APLA . WHY PERFORM THROMBOPHILIC TESTS?

WHEN TO TEST FOR The rationale to perform thrombophilia test- THROMBOPHILIA? ing is mainly to establish the genetic basis of the VTE5,29. Once known, the etiologic factor Coagulation factors and natural anticoagula- or presence of combined defects may be com- tion levels change during acute VTE, under municated to the patients and may influence 7,27,28 specific medication and during pregnancy . the duration of treatment and establish the Biochemical evaluation can be postponed until potential risk for recurrence. This knowledge the treatment duration (3–6 months) for an also may help in providing thromboprophylax- acute VTE is over, whereas polymerase chain is to high-risk patients and their first-degree reaction (PCR) tests for factor V Leiden and relatives. factor II mutation can be performed at any One potential advantage of thrombophilia time. Similarly, lupus anticoagulant (LAC) and testing is for consulting women with a per- APLA levels do not change with acute VTE, sonal or significant family history of VTE who but should be re-confirmed after a 12-week may wish to use oral contraception, HRT, or interval. to become pregnant. Advantages of testing are

113 PRECONCEPTIONAL MEDICINE more pronounced among women considering in the absence of randomized controlled tri- HRT than oral contraception, because of the als that support treatment during pregnancy, much higher risk of VTE in middle-aged wom- one may question the wisdom of screening en. Ancillary advantages of family screening patients with adverse pregnancy outcomes. are to provide additional health benefits such Third, the arguments related to the cost- as controlling blood pressure, lipid disorders, effectiveness of routine universal screening are obesity and smoking. cogent. For example, one would need to screen From a scientific point of view, recognizing 2 million women for factor V Leiden before the prevalence of thrombophilia in minori- starting oral contraception in order to prevent ties30 or in certain disease conditions unre- one death from pulmonary embolism35. lated to VTE or pregnancy complications may Fourth, there is a definite psychological improve the true impact of such conditions in effect of screening stress which may affect terms of public health. quality of life in patients with a potential rather than with a real risk. For example, a positive thrombophilia test does not necessarily mean WHY NOT PERFORM VTE in the future, as 40% of women tested THROMBOPHILIA SCREENING? positive will never develop VTE36. Conversely, false reassurance is unjustified in a patient Numerous arguments exist against screening with negative testing merely because our for thrombophilia31–33. The arguments related understanding of the coagulation cascade is to the inaccuracy in establishing the correct incomplete, and the availability of commercial laboratory diagnosis are beyond the scope of laboratory kits is limited. For example, protein this chapter28,29. Nor is the problem related to Z deficiency or antibodies are known throm- websites promoting genetic testing for thrombophilic factors, but their assessment is vastly bophilia without physician supervision. How- limited because the laboratory methodology is ever, other relevant opinions should be heard. not widely available. First and foremost is the fact that in most Finally, as noted above, a patient with a posi- cases the decision about duration and inten- tive test may never have any health problem. sity of anticoagulant therapy can be made Yet, some insurance companies may be reluc- by clinical criteria without actually knowing tant to insure this patient or may increase the the underlying cause. In simple terms, VTE cost involved. patients with or without thrombophilia will be Preconception consulting for women with a managed in a similar way in most cases. history of pregnancy complications and docu- Second, controversy exists regarding the abil- mented thrombophilia should include the con- ity of a given defect to predict which patient is troversy of the association between the genetic likely to have a recurrent VTE32. Stated differ- defects and pregnancy outcome. It must be ently, the presence of a positive test of several emphasized, however, that at present the asso- thrombophilias does not necessarily mean an ciation between thrombophilia and adverse increased risk of recurrence34. Conversely, con- pregnancy outcome is unclear, as thrombo- cern has been voiced that unnecessary testing philias are only weakly associated with adverse may overestimate the risk with consequently pregnancy outcomes. It appears that thrombo- needless and potentially hazardous treatment. philias are but one of many factors involved in In this respect, it is important to note that poor obstetric outcome.

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WHAT IS THE MOST ECONOMICAL pregnancy loss39 and to identify patients at WAY TO SCREEN FOR INHERITED increased risk for VTE40. THROMBOPHILIA?

One way to reduce the costs of screening/test- ANTITHROMBOTIC THERAPY ing is to look for specific thrombophilia fac- DURING PREGNANCY tors rather than to test for every known factor for which a test is available. Table 1 shows the Anticoagulation is indicated during pregnancy list of tests according to priority, which is set for the prevention of VTE, treatment of acute by the likelihood of inherited thrombophilia VTE, prevention of emboli in patients with in a given case28. The highest diagnostic yield mechanical heart valves, and in prevention is expected with the high priority tests mainly of recurrent pregnancy loss in women with because they are also the most frequent. APLA. Other inexpensive and useful means for Available antithrombotic drugs include UFH screening patients with hypercoagulable and LMWH, and the antiaggregant agent com- states and pregnancy complications have been monly used is aspirin. LMWH is recommended reported recently. The ProC Global assay is over UFH for the prevention and treatment of one that globally evaluates the functionality of VTE during pregnancy26. UFH treatment has the protein C pathway37–40. The assay is based significant side-effects such as osteoporosis on the ability of endogenous activated protein and heparin-induced thrombocytopenia (HIT), C (APC), generated by a snake venom extract, and requires laboratory monitoring. These to prolong an activated partial thromboplas- side-effects are significantly less common tin time (APTT). This assay can distinguish with LMWH, and there is no need for routine patients with or without protein C pathway laboratory testing during treatment (except abnormalities. It has been reported that the for the infrequent need for dose-adjustments ProC Global assay can be used as the initial by measuring anti-Xa). LMWH has better step in screening for factor V Leiden-related bioavailability, longer plasma half-life and an APC resistance and protein C deficiency in improved safety profile over UFH according to patients who are not on oral anticoagulants. the 8th edition of ACCP guidelines26. This assay, however, has low sensitivity to UFH and LMWH do not cross the pla- protein S deficiency. The ProC Global test is centa and are not secreted in breast milk. A claimed to screen for women with idiopathic recent review showed a good safety profile of

Table 1 Testing according to high, intermediate and low priority of thrombophilia factors. Adapted from reference 28

High priority Intermediate priority Low priority APCR Protein C activity Dysfibrinogenemia Factor V Leiden Free protein S Elevated fibrinogen level Factor II mutation Decreased antithrombin activity Increased activity of factors IX and XI Elevated homocysteine level Increased anticardiolipin MTHFR Elevated factor VIII level antibodies Lupus anticoagulant

APCR, activated protein C resistance; MTHFR, methylenetetrahydrofolate reductase

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enoxaparin during pregnancy41. In particular, placenta-mediated pregnancy complications, the rates of bleeding complications and osteo- with or without genetic thrombophilia, should porosis were low, and there were no cases of not be treated routinely by anticoagulants, heparin-induced thrombocytopenia (HIT). unless in the context of randomized controlled Women with a history of VTE or thrombo- trials. philia have an increased risk for pregnancy To date, no clear criteria or guidelines exist associated recurrent VTE42, but no large clini- for the diagnosis and treatment of women cal trials have assessed the role of prophylaxis with thrombophilia in pregnancy. Physicians in pregnant women with previous VTE. Retro- may treat these women based on clinical judg- spective and prospective studies demonstrated ment and on their own experience. a good pregnancy outcome for women with The most recent guidelines on VTE, throm- previous VTE whether or not treated by hepa- bophilia, antithrombotic therapy and preg rin prophylaxis43,44. This, however, was not true nancy were published by the ACCP26 and the for women with APLA who are at high risk of Royal College of Obstetricians and Gynaecolo- VTE, pregnancy loss and pre-eclampsia45. Data gists in 200955. The recommended thrombo- demonstrate that women with APLA and prophylaxis in pregnancy can be divided into recurrent fetal loss have an improved preg- two subgroups. nancy outcome when treated with combined 1. Prevention of recurrent VTE in pregnancy: therapy consisting of low-dose aspirin and a. A previous VTE event associated with heparin prophylaxis46. In contrast, a random- a transient risk factor and no throm- ized trial failed to confirm an improved preg- bophilia: clinical surveillance antepar- nancy outcome by adding heparin to aspirin in tum and anticoagulant prophylaxis this specific population of women47. postpartum; Several meta-analyses have been performed to investigate the association between throm- b. A previous VTE event associated with bophilia and pre-eclampsia48–50. Factor V pregnancy or estrogen containing drug: Leiden, MTHFR 677C>T polymorphism and antepartum clinical surveillance or pro- other inherited thrombophilias were found to phylactic/intermediate-dose anticoagu- moderately increase the risk of pre-eclampsia, lant prophylaxis (LMWH/UFH) plus but the link is weak and routine screening for postpartum prophylaxis; thrombophilia is not recommended. The effect c. Single idiopathic VTE event without of aspirin on the recurrence of pre-eclampsia thrombophilia: prophylactic/intermedi- has been studied in large trials, but no such ate-dose anticoagulant (LMWH/UFH) trials have been performed with LMWH. or clinical surveillance antepartum plus Small and uncontrolled studies on treatment postpartum anticoagulant; with LMWH of women with inherited thrombophilia and pregnancy loss have suggested d. Single episode of VTE and laboratory that prophylaxis with enoxaparin is effective confirmed thrombophilia without long- (and safe) in improving pregnancy outome term anticoagulants: prophylactic/inter- and has a potential for reducing late pregnancy mediate-dose anticoagulant (LMWH/ complications51,52. Two recent randomized UFH) or clinical surveillance antepar- controlled trials53,54 demonstrated no reduc- tum plus postpartum anticoagulant; tion in pregnancy loss rate with antithrom- e. Single episode of VTE and high-risk botic intervention in pregnant women with thrombophilias (antithrombin defi- two or more unexplained recurrent pregnancy ciency, APLA, compound heterozygote losses. At present, women with a history of for factor V Leiden and prothrombin

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mutation, homozygosity for these muta- an obstetrician, hematologist and coagulation tions) not receiving long-term anticoag- expert. This team should counsel the woman ulants: prophylactic/intermediate-dose about the recommended diagnostic tests, sug- anticoagulant (LMWH/UFH) antepar- gest available treatment protocols and super- tum plus postpartum anticoagulation; vise the subsequent pregnancy. f. Multiple episodes of VTE not receiving long-term anticoagulants: prophylactic /intermediate/adjusted-dose anticoagu- SUMMARY lant (LMWH/UFH) antepartum plus postpartum anticoagulants; Until we find useful and inexpensive screening tools, it is not recommended to test every g. Long-term anticoagulants for prior patient or her/his relatives for thrombophilia. VTE: frequent pregnancy tests and Screening should be limited to patients at substitution of adjusted/intermediate- high-risk of VTE. Each index case should be dose UFH/LMWH when pregnancy is carefully evaluated by an expert physician who achieved. Postpartum, long-term anti- should tailor the laboratory testing as well as coagulants should be resumed; treatment modalities. h. All women with previous VTE are Thrombophilias are considered to be only advised to use graduated compression weakly associated with adverse pregnancy out- stockings; come and are but one of many factors involved i. Women with thrombophilia and no in such circumstances. At present, women prior VTE: individual risk assessment; with a history of placenta-mediated pregnancy complications, with or without genetic throm- j. Antithrombin deficiency and no his- bophilia, should not be treated routinely with tory of VTE: antepartum and postpar- anticoagulants, unless in the context of ran- tum prophylaxis. Other thrombophilias without prior VTE: clinical surveillance domized controlled trials. or prophylactic anticoagulants (LMWH/ In order to optimize the diagnosis and treat- UFH) antepartum plus postpartum ment of pregnant women with thrombophilia anticoagulants. and previous VTE or pregnancy complications, a team made up of an obstetrician, hematolo- 2. Prevention of recurrent pregnancy compli- gist and coagulation expert seems essential. cations in women with thrombophilia: a. APLA and three or more events of pregnancy loss, no VTE or arterial throm- References bosis: antepartum prophylactic/intermediate UFH/LMWH, combined with 1. Bremme K. Haemostasis In Normal Pregnancy. aspirin; Women’s Issues In Thrombosis And Hemostasis. London, UK: Martin Dunitz Ltd, 2002:151–65 b. High risk for pre-eclampsia: low-dose 2. Wu O, Robertson L, Twaddle S, et al. The aspirin throughout pregnancy; Thrombosis: Risk and Economic Assessment c. History of pre-eclampsia: UFH/LMWH of Thrombophilia Screening (TREATS) Study. is not recommended for subsequent Screening for thrombophilia in high-risk situ- pregnancies. ations: a meta-analysis and cost-effectiveness analysis. Br J Haematol 2005;131:80–90 A woman with previous VTE or pregnancy com- 3. Middeldorp S, Meinardi JR, Koopman MM, et al. plications, who wishes to get pregnant again, A prospective study of asymptomatic carriers needs the consultation and co-management of of the factor V Leiden mutation to determine

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