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Thrombophilia: Clinical–Practical Aspects

Thrombophilia: Clinical–Practical Aspects

J Thromb Thrombolysis (2015) 39:367–378 DOI 10.1007/s11239-015-1197-3

Thrombophilia: clinical–practical aspects

Stephan Moll

Published online: 28 February 2015 Springer Science+Business Media New York 2015

Abstract No consensus exists as to who should be tested Keywords Thrombophilia Á Testing Á Venous for thrombophilia, mainly due to the lack of good quality thromboembolism Á Deep vein Á DVT Á clinical outcome data in relationship to presence or absence Pulmonary of a given thrombophilia. Testing may be considered if (a) finding a thrombophilia predicts recurrent thrombosis Abbreviations and, thus, influences length of anticoagulation treatment ACCP American College of Chest Physicians decisions; (b) identifying a thrombophilia has implications APC-R Activated resistance on management of asymptomatic family members who are APLA Antiphospholipid carriers of the detected thrombophilia; (c) a patient wishes DVT to better understand why a thrombotic event occurred. EGAPP Evaluation of Genomic Applications in Testing may be helpful in patients with venous throm- Practice and Prevention boembolism at intermediate risk of recurrence in whom the FVL Leiden (R506Q) finding of a strong thrombophilia can be one of the argu- DOAC Direct oral (i.e. apixaban, ments for long-term anticoagulation - the ‘‘risk-of-recur- dabigatran, edoxaban, rivaroxaban) rence-triangle’’ may be a useful aid in this decision PAI-1 Plasminogen activator inhibitor-1 process. Patients whose venous thromboembolism was PE provoked by a major transient risk factor should not be tPA Tissue plasminogen activator tested for thrombophilia. Thrombophilia tests should only VTE Venous thromboembolism be ordered by health care professionals who can provide II G20210A the ‘‘4P’’: (a) appropriately select which patient to test, (b) provide pre-test counseling, (c) properly interpret the test results, and (d) provide education and advice to the patient. If testing is embarked on in patients with venous Introduction thromboembolism, it is advisable to be done at the time of decision making whether to stop or continue anticoagula- Thrombophilias can be inherited or acquired. Thrombosis— tion, i.e. typically after 3 months of anticoagulant therapy. either venous or arterial—is typically multifactorial, with Thrombophilia testing is best not done at the time of an individual risk factors potentiating each other, often in more acute thrombotic event and while a patient is on an than just additive fashion. When evaluating a patient with anticoagulant. thrombosis and making treatment decisions, particularly on the length of anticoagulation treatment in patients with ve- nous thromboembolism (VTE), it is, therefore, appropriate S. Moll (&) to consider all thrombosis risk factors and not focus exclu- Division of -Oncology, Department of Medicine, sively or too majorly on biochemical or genetic throm- University of North Carolina School of Medicine, CB 7035, Chapel Hill, NC 27599, USA bophilias. This manuscript discusses clinical–practical e-mail: [email protected] aspects of thrombophilias, with focus on why to test, whom 123 368 S. Moll to test, what to test, what not to test, test interpretation, and on the risk of recurrence (Table 1) and, thus, length of anti- clinical management consequences for individuals having therapy or (b) influences management of family been identified with a thrombophilia. members for the primary prevention of VTE. Acknowledging that limited scientific data exist on the uncommon throm- bophilias, I view the following as ‘‘strong thrombophilias’’ at Patient selection this point: (1) Homozygous FVL, (2) Homozygous pro- G20210A mutation, (3) the double heterozygous Reasons to test state of FVL plus II20210 mutation, (4) protein C deficiency, (5) deficiency, (6) deficiency, and (7) Three legitimate reasons exist to consider thrombophilia antiphospholipid syndrome. testing in clinical practice in a patient who has had a Elevated Factor VIII activity (FVIII) levels appear to thrombotic event: increase the risk for recurrent VTE if levels are more ex- tremely elevated ([230 IU/dL [1] or exceed the 90th per- a) A patient’s wish to understand why a thrombotic centile [2, 3]), but an effect is not present or less impressive event happened, and statistically not significant in studies of mildly to b) Predicting recurrent thrombosis and, thus, obtaining moderately elevated levels, such as values [155 IU/dL [4] information that helps influence length of antico- or[166 IU/dL [5]. It is difficult to know how to clinically agulation treatment decisions, use a FVIII value obtained for an assessment of risk of c) Family implications for asymptomatic carriers of the recurrent VTE in an individual patient. This is because detected thrombophilia. differences between published studies in respect to when A variety of thrombophilias are risk factor for a first VTE after an acute VTE event FVIII levels were measured, (Table 1) and, thus, if detected in a patient with VTE, can be methodologies for FVIII measurements, normal range listed as risk factors for and contributors to the first VTE definition and variable correlations between percentiles and event. However, the common and mild thrombophilias [e.g. absolute FVIII levels make it impossible to interpret the heterozygous prothrombin G20210A, heterozygous Factor V FVIII value obtained for its clinical significance. Leiden (FVL)] are not or only mild risk factors for VTE recurrence (Table 1) and, thus, their presence typically has no The ‘‘4P Approach’’ major impact on the decision how long to treat with antico- agulation. The purpose of thrombophilia testing is to detect a Whatever patient is selected for testing, four components strong thrombophilia that (a) has an impact in a VTE patient need to be fulfilled to assist with medical decision-making,

Table 1 Risk of venous thromboembolism associated with various thrombophilias Thrombophilia Risk relative to persons without the respective thrombophilia First VTE Recurrent VTE

Thrombophilia not present Reference group Reference group Heterozygous II G20210A 3.8 (95 % CI 3.0–4.9) [34] 1.45 (95 % CI 0.96–2.21) [31] Heterozygous FVL 4.9 (95 % CI 4.1–5.9) [34] 1.56 (95 % CI 1.14–2.12) [31] Homozygous II G20210A Insufficient data Insufficient data Heterozygous FVL 20 (95 % CI 11.1–36.1) [34] 1.0 (95 % CI 0.6–1.9) [32] or 4.81 (95 % CI 0.50–46.3) [31] ? heterozygous II G20210Aa Homozygous FVLa 18 (95 % CI 4.1–41) [33] 1.2 (95 % CI 0.5–2.6) [32] or 2.65 (95 % CI 1.18–5.97) [31] Protein S deficiency 30.6 (95 % CI 26.9–55.3) [30] Increased, but insufficient data for accurate risk assessment Protein C deficiency 24.1 (95 % CI 13.7–42.4) [30] Antithrombin deficiency 28.2 (95 % CI 13.5–58.6) [30] APLA Increased, but data insufficient and too Available evidence is of very low quality: Any APLA positive: heterogenous for accurate risk 1.41 assessment (95 % CI 0.99–2.00) [35] Anticardiolipin positive: 1.53 (95 % CI 0.76–3.11) [35] anticoagulant positive: 2.83 (95 % CI 0.83–9.64) [35] APLA antiphospholipid antibody, FVL , II G20210A prothrombin G20210A mutation, VTE venous thromboembolism a Due to discrepant data in the literature it is unclear what the risk for recurrent VTE is in patients with these thrombophilias

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Table 2 In whom to consider thrombophilia testing (author’s approach) 1. DVT or PE Patient with DVT or PE who is in the intermediate risk for recurrence zone (‘‘unclear how long to treat’’ category) in the ‘‘recurrence triangle (see also Fig. 2a) a. VTE associated with a mild trigger (minor , minor immobility or short-distance travel, birth-control pill, patch or ring) b. VTE that is unprovoked but patient is (a) at increased risk for or (b) has a strong preference not to be on anticoagulation. 2. VTE in unusual location Patient with unexplained VTE in unusual location (splanchnic, renal or cerebral and sinus vein thrombosis) 3. Family members Asymptomatic individual who has a first-degree relative with strong thrombophilia (see Table 4) 4. Arterial thrombosis Unexplained arterial thrombosis in a young person (see Table 3) 5. complications a. C3 unexplained pregnancy losses before week 10, or C1 loss after week 10 b. unexplained pregnancy complications (preeclampsia, intrauterine growth restriction, ) 6. Patient requests testing Patient with unprovoked VTE or minor risk factor-associated VTE who requests testing to understand why he/she developed a VTE. referred to in the literature as ‘‘The 4 P’s Approach’’ and to be comprehensive as to who should be tested, as (which, for simplification, is referred to here as the ‘‘4P there is a lack of scientific data for a number of clinical Approach’’): (1) Patient selection, (2) Pre-test counseling, scenarios. Table 2 summarizes the patient groups in which (3) Proper laboratory test interpretation, and (4) Provision I consider, but not inevitably recommend, thrombophilia of education and advice [6]. The health care professional testing. ordering thrombophilia tests should be able to provide all 4 components. Venous thromboembolism

Whom to test In the patient with VTE, the decision to treat with antico- agulation for only 3 months or long-term (indefinite, ‘‘life- No full agreement exists between guidelines, societies and long’’, for extended duration) depends on 3 factors: (1) the medical experts who should be tested for thrombophilia. It risk of recurrent VTE, (2) the risk for major bleeding, and is easier to conclude who should NOT be tested than to (3) the patient’s preference (Fig. 1). Patient-individualized identify patients in whom testing should be considered. assessment of all 3 components needs to take place in the Most experts agree that testing unselected patients with process of decision-making. The ‘‘risk of recurrence tri- thrombosis has no clinical value [7]. In addition, the angle’’ (Fig. 2a) is a visual aid that helps explain the Choosing Wisely campaign appropriately recommends to complex ‘‘length of anticoagulation’’ decision issues [9]: not test for thrombophilia patients with VTE associated with a major transient risk factor, such as major surgery • VTE associated with a major transient risk factor A [8]. Beyond that, it remains difficult to give clear guidance patient with VTE associated with a major transient risk

Fig. 1 The components influencing the decision ‘‘How long to anticoagulate’’ a patient with VTE

1. Risk factors for recurrent VTE 2. Risk factors for bleeding (a)…., (b)…., (c) ….. (a)…., (b)…., (c) …..

3. Patient preference “ hate factor” or “DOAC dislike factor”

VTE = venous thromboembolism; DOAC = direct oral anticoagulant

123 370 S. Moll

factor, such as major surgery, immobility or trauma, has does not or only slightly, respectively, push the a low risk of recurrent VTE and 3 months of antico- position of the patient downward in the triangle. agulation is the appropriate and recommended length of treatment [8]. Such a patient is in the top of the Arterial thrombosis ‘‘recurrence triangle’’ (Fig. 2a). Thrombophilia work- up in such a patient is not helpful and not recommended Thrombophilias play less of a role in arterial thrombosis than in [10]. The patient’s risk of recurrent VTE is low even if VTE, as arteriosclerosis is usually the predominant cause of a thrombophilia is detected. arterial occlusive events. However, in the younger person with • Unprovoked VTE These patients have a higher risk of an unexplained arterial event, thrombophilia enters into the recurrence and are in the lower (broad-based) part of differential diagnosis. A systematic approach to the evaluation the ‘‘recurrence triangle’’ (Fig. 2a): men with unpro- of such patients is advisable (Table 3). Heterozygous FVL and voked VTE have the highest risk for recurrence and, heterozygous prothrombin G20210A mutation are not, or only thus, are in the lowest part; women with unprovoked, minimal, respectively, contributors to arterial thrombosis [14]. non-hormone associated VTE are also in the lower It is not known whether the uncommon thrombophilias ho- part of the triangle, but above where men are. These mozygous FVL, homozygous prothrombin G20210A muta- patients’ high risk of recurrent VTE is the reason tion, or the double heterozygous (FVL ? prothrombin behind guidelines’ recommendations to treat patients G20210A) state increase the risk for arterial thrombosis. A large with unprovoked VTE with long-term anticoagulation, family study showed no association of arterial thrombosis with if they tolerate it well and find it acceptable [11]. antithrombin deficiency, but a clear association with protein C Presence or absence of a thrombophilia does not and protein S deficiency [15]. Antiphospholipid antibodies change that recommendation, as finding a throm- (APLA) are known risk factors for arterial thrombosis. I discuss bophilia would only push a patient lower in the thrombophilia work-up with the younger patient with unex- triangle, but absence would not move the patient plained arterial thrombosis, with the goal of identifying one of higher up in the triangle. Thrombophilia testing in the stronger thrombophilias.However, it is not known whether these patients is, therefore, not helpful for their patients with non-arteriosclerotic arterial thrombosis and a management. strong thrombophilia are more effectively treated with anti- • However, if a patient with unprovoked VTE is either at or anticoagulant therapy. This lack of knowledge, ob- higher risk for bleeding or finds long-term anticoagula- viously, needs to be discussed with the patient. From a patho- tion fairly unacceptable, further testing might be physiology point of view it makes sense to hypothesize that helpful: a positive D-dimer or finding a strong throm- anticoagulant therapy might be effective for the prevention of bophilia would move the patient down in the triangle recurrent arterial thrombotic events prophylaxis, as the pro- and would be reasons to consider long-term antico- thrombotic defect with these non-APLA thrombophilias is in agulation in spite of the higher bleeding risk or degree the plasmatic coagulation pathway (i.e. the coagulation cas- of a patient’s dislike of being on long-term cade). Alternatively, it also makes sense to postulate that anti- anticoagulation. platelet therapy might be effective, as arterial thrombosis, in • VTE associated with a minor transient risk factor A general, is predominantly a platelet-driven process. And, fi- patient with VTE associated with a minor transient nally, it is also reasonable to postulate that the combination of risk factor (-containing contraceptives, estro- anticoagulant and anti-platelet agent might be most effective. gen replacement therapy, minor surgery, minor im- Of course, a patient’s risk for bleeding needs to be factored into mobility) appear to have an intermediate risk of the decision-making, but this is typically low, as the patient is recurrent VTE and are in the middle of the ‘‘recur- young. In summary, in this area of absence of evidence I have a rence triangle’’ [12, 13] (Fig. 2a). However, for preference to treat young patients with unexplained arterial several conditions, such as VTE associated with thrombosis and strong thrombophilia with anticoagula- longer or shorter airline travel, minor , tion ± an anti-platelet agent, with re-evaluation after several estrogen-containing contraceptives, the risk of recur- months and periodically thereafter. However, the patient’s rence is not well known. It is in these patients that I preference should also strongly factor into the decision-making. consider D-dimer and thrombophilia testing (Table 2): a positive D-dimer or the finding of a strong thrombophilia moves the patient downward in the Pregnancy complications recurrence triangle and are reasons to consider long- term anticoagulation. However, presence of a mild Women with thrombophilia are at increased risk for VTE thrombophilia, i.e. the heterozygous prothrombin ante- and post-partum and with assisted reproduction. They G20210A or heterozygous Factor V Leiden, mutation, also have a higher rate of placenta-mediated pregnancy 123 Thrombophilia 371

a

VTE, major transient risk factor 3 months

VTE due to minor transient risk, Thrombophilia

woman with VTE on hormones - D-dimer + Strong

Woman, unprovoked VTE •DVT • PE Man, unprovoked VTE Long-term •DVT • PE

VTE = venous thromboembolism; DVT = deep vein thrombosis; PE = pulmonary embolism

bc

1a 1a 3 months 4b 3 months 4b C 1b 4a A 4a 3b 3b

4c 4c 2b B 2b 3a 3a Long-term Long-term

2a 3c 2a 3c

Fig. 2 a–c ‘‘Risk of recurrence triangle’’—how long to anticoagulate? associated VTE (position 4a); thrombophilia and D-dimer testing help a Position in the lower part of the triangle indicates a higher risk of decide on length of anticoagulation: a positive D-dimer (on and off recurrence; position in the tip of the triangle a low risk. Position above anticoagulation) and finding of a strong thrombophilia push the patient dotted red line is the area where the risk from major bleeding on down in the triangle (position 4c), below the red line. A negative D-dimer anticoagulation is higher than the risk of a recurrent VTE (case-fatality) and absence of a strong thrombophilia push the patient above the red line and, thus, discontinuation of anticoagulation is indicated. A position (position 4c) where anticoagulation can be discontinued. c Length of below the red line indicates that the case-fatality from a recurrent VTE is anticoagulation based on bleeding risk and ‘‘Anticoagulant hate factor’’. higher than that of a bleed. The position of the red line varies from patient High bleeding risk, high ‘‘anticoagulant hate factor (line ‘‘B’’).Thered to patient, depending on bleeding risk, as well as patient preference to be line is moved down in the patient with bleeding risk factors (such as old on an anticoagulant or not (‘‘anticoagulant hate factor’’). b Patient age, renal impairment, liver synthetic function, concomitant anti-platelet examples how the ‘‘recurrence triangle’’ can be used in the decision- therapy, history of bleed, widely fluctuating INRs on warfarin etc.). The making and discussion with the patient: Patient #1: VTE associated with threshold to take a patient off anticoagulation is lowered for fear of major risk factor; low risk for recurrent VTE (position 1a); no benefit bleeding. The same downward move of the red line occurs in the patient form thrombophilia or D-dimer testing; while a positive D-dimer or whose preference is not to be on anticoagulation. A positive D-dimer or presence of a strong thrombophilia would push the patient down in the the finding of a strong thrombophilia, which both indicate a higher risk for triangle (to position 1b) the patient would still be above the red line, recurrence, would be arguments to keep the patient on anticoagulation, where discontinuation of anticoagulation is indicated. Patient #2: Man accepting the higher risk for bleeding. Example: the woman with with unprovoked VTE; high risk of recurrence (position 2a); no benefit unprovoked VTE (position 3a) at increased risk for bleeding or with a from thrombophilia or D-dimer testing: while a negative D-dimer moves high ‘‘anticoagulant hate factor’’ may now decide to come off antico- the patient somewhat up to a lower risk of recurrence, he is still below the agulation, particularly if she has a negative D-dimer and no strong red line and long-term anticoagulation is indicated. Patient #3: Woman thrombophilia (position 3b). However, finding a positive D-dimer or a with unprovoked VTE; risk of recurrence is on the high side (position 3a); strong thrombophilia (position 3c) may argue for continued anticoagula- no benefit from thrombophilia or D-dimer testing; while a negative tion. Low bleeding risk, low ‘‘anticoagulant hate factor (line ‘‘C’’):The D-dimer moves the patient up some to a lower risk of recurrence (position red line is moved up in the patient at low risk for bleeding risk or a low 3b), it is still below the red line where long-term anticoagulation is ‘‘anticoagulant hate factor’’. The threshold to keep a patient on indicated. Patient #4: Man or woman with minor risk factor (short anticoagulation is lowered. Example: the woman with unprovoked distance travel; minor surgery, such as arthroscopic surgery, outpatient VTE (position 3a) may more comfortably decide to stay on anticoagula- surgery, etc.; cast or boot immobilizer) or woman with hormone- tion, even if her D-dimer is negative (position 3b)

123 372 S. Moll complications (recurrent early pregnancy losses, late pregnant women with thrombophilia is beneficial to pregnancy loss, preeclampsia, intrauterine growth restric- prevent recurrent early or late pregnancy loss. Clinical tion (IUGR), and placental abruption), even though these studies have not clearly and unequivocally shown associations are somewhat controversial. These topics have benefit of anticoagulation. An ongoing study (ALIFE2) recently been discussed in detail elsewhere [16–18]. is trying to address this issue further [22]. While my practice is to offer (but not inevitably recommend) • Increased VTE risk Women with or without throm- thrombophilia testing to women with unexplained bophilia and at increased VTE risk ante- and post- pregnancy loss (C3 before week 10 or C1 after week partum should be treated per existing evidence-based 10) and women with unexplained placenta-mediated guidelines. [19–21] pregnancy complications, my recommendations for • Pregnancy loss and placenta-mediated pregnancy management of future pregnancy, if a thrombophilia complications It is unclear whether anticoagulation in

Table 3 Structured approach when evaluating a patient with ‘‘unexplained’’ arterial thromboembolism A. Is arteriosclerosis the underlying problem? Arteriosclerotic changes demonstrated on imaging studies (on CT, contrast arteriogram or other radiologic imaging studies, on pathology specimens)? Arteriosclerosis risk factors present? Cigarette smoking High blood pressure High low density lipoprotein (LDL) cholesterol Low high density lipoprotein (HDL) cholesterol High lipoprotein (a) Diabetes mellitus Family history of arterial problems in young relatives (\50 years of age) B. Has the heart been thoroughly evaluated as an embolic source? Atrial fibrillation—EKG, Holter or event monitor Patent foramen ovale (PFO)—cardiac echo (TTE = transthoracic echo) with bubble study and Valsalva maneuver C. Other causes Is the patient on estrogen therapy (contraceptive pill, ring or patch; hormone replacement therapy)? Does the patient use cocaine or anabolic steroids? Is there evidence for Buerger’s disease (does patient smoke cigarettes or use cannabis)? Does patient have symptoms suggestive of a vasospastic disorder (Raynaud’s)? Were anatomic abnormalities seen in artery leading to the ischemic area (web, fibromuscular dysplasia, dissection, vasculitis, external compression)? Does patient have evidence of a rheumatologic or (arthritis, , or vasculitis) – consider laboratory work-up for vasculitis and immune disorder Is there a suggestion of an infectious arteritis? Could the patient have hyperviscosity or cryoglobulins? D. Thrombophilia work-up (author’s approach) and platelet count Antiphospholipid antibodies Anticardiolipin IgG and IgM antibodies Anti-b2-glycoprotein-I IgG and IgM antibodies Protein C activity Protein S activity and free protein S antigen Antithrombin activity Factor V Leiden and prothrombin G20210A mutation (purpose of testing is to detect the homozygous or double heterozygous state) Do not test for MTHFR polymorphisms, PAI-1 or tPA levels or polymorphisms, fibrinogen or Factor VIII activities.

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is found, are often more of a discussion of the ‘‘indiscriminate’’ approach to thrombophilia testing that limitations of our current knowledge than a true was promoted in earlier guidelines is not supported by recommendation. clinical evidence. Thus, it does NOT seem appropriate to recommend that whole patient populations be tested, such as all patients (a) with unprovoked VTE, (b) who are young Family testing (\50 years old) and have an unprovoked VTE, (c) with VTE in unusual locations, (d) with VTE of unusual extent, Table 4 summarizes my approach to thrombophilia testing or (e) with VTE recurrence in spite of anticoagulation. in family members of patients with known thrombophilia. Instead, a rather more selective approach to testing seems It is worth noting that a family history of VTE by itself— most appropriate, as discussed above and summarized in independent of the identification of a thrombophilia—in- Table 2. creases an asymptomatic person’s VTE risk two- to threefold, and even more so when several family members Existing guidelines have had VTE, independent of the presence of a throm- bophilia [23, 24]. And, to no surprise, the VTE risk for the Various guidelines have incorporated statements on asymptomatic individual increases further, the more VTE thrombophilia, but given the broadness of the topic and the risk factors the person has, such as obesity, estrogen-con- limited knowledge of some of the clinical aspects, the taining contraceptive use, underlying thrombophilia [23– guidelines have significant limitations, tend to generalize, 25]. Thus, individualized recommendations need to be and are of limited helpfulness in a number of patient si- given on what impact the presence of these various risk tuations that clinicians encounter in clinical practice. factors has on a person in respect to the absolute risk of • The British Society for Haematology in 2010 in its VTE. That absolute risk then determines what recom- ‘‘Clinical guidelines for testing for heritable throm- mendation to give regarding choice of contraceptives, bophilia’’ gives the most comprehensive recommenda- pregnancy management, and VTE prophylaxis in risk si- tions—summarized in 30 bulleted points—as to tuation. Unfortunately, for many of these risk factors it is (a) who should be tested, (b) who should not be tested, not known how they interact (additive, multiplicative, etc.). and (c) in which individuals no validated recommen- Figure 3 depicts a summary of contraceptives for discus- dations can be made about benefit of testing given a sion with the woman at risk for VTE, with the safest lack of evidence base [7]. Many of the recommenda- methods listed in green at the bottom of the triangle and the tions and suggestions are weak recommendations, re- ones with the highest risk of VTE shown at the tip of the flecting that for many clinical scenarios there is only triangle. Broadening of the triangle while moving up re- moderate or low quality evidence as to who should and flects increased VTE risk. should not be tested. • The ACCP 2012 guideline Whom NOT to test (a) In regard to VTE, the guideline concludes that In the last few years it has become clear that the presence while hereditary thrombophilias and antiphos- of a thrombophilia often does not influence clinical man- pholipid antibodies predict recurrence of VTE, agement. Therefore, a more wide-spread, ‘‘unselected’’, or they do not do so ‘‘strongly or consistently

Table 4 Which asymptomatic family members of a proband with thrombophilia to consider for thrombophilia testing (author’s approach) Proband’s thrombophilia Male family member Female family member Sons Brothers Daughters Sisters

Hetero FVL or hetero prothrombin G20210A No No No No Homo FVL or homo prothrombin G20210A No Reasonable No Yes Double hetero Reasonable Reasonable Yes Yes C, S, AT Reasonable Reasonable Yes Yes No indicates: do not suggest testing, because management of the asymptomatic family would not be different if a mild thrombophilia was detected Reasonable indicates: consider offering testing, because pharmacologic VTE prophylaxis could be considered with airline travel, cast, non-major surgery, or prolonged prophylaxis after major surgeries if the strong thrombophilia was detected Yes indicates: recommend testing, as finding of the strong thrombophilia would lead to the recommendation against estrogen contraceptives/ hormone therapy; give ante- and postpartum anticoagulation

123 374 S. Moll

• Ring (Etonogestrel & ) Estrogen combination pill • Patch • 3rd generation (Norelgestromin & ethinyl estradiol) •4th generation pills (Drospirenone & ethinyl estradiol) • 2nd generation

Progestin-only • Depo-Provera® • Nexplanon® rod • “Minipill” Mirena® IUD; Skyla® IUD Non-hormonal methods

1. Weiss G. Am J Obstet Gynecol. 1999;180:S295-S301. 3. Conard J, et al. Contraception. 2004;70:437-441. 2. Rosendaal FR, et al. Thromb Haemost. 2001;6:112-23. 4. Bergendal A, et al. Acta Obstet Gynecol Scand. 2009;88:261-266. 5. Barsoum M et al. Thromb Res 2010;126:373-8. 6. Van Hylkama-Vlieg A et al. Arterioscler Thromb Vasc Biol 2010;30:2297-300. 7. Mantha S et al. BMJ 2012;Aug 7;345:34944.

Fig. 3 Contraceptives and VTE risk

enough to influence recommendations on dura- (a) Do not offer testing to tion of anticoagulant therapy’’, once the ‘‘prima- • Patients with provoked VTE (due to transient ry [provoked versus unprovoked event] and major risk factor, such as trauma, surgery, secondary factors [(a) distal DVT versus prox- prolonged immobility, pregnancy, postpar- imal DVT or PE; (b) first versus recurrent VTE] tum state) or VTE due to hormonal therapy have been considered’’ [11]. (oral contraceptive pill, hormone replacement (b) In respect to arterial thrombosis, the ACCP 2012 therapy), as these patients need short-term guideline takes only reference to APLA, and anticoagulation no matter whether a throm- states that ‘‘subgroup analyses of secondary bophilia is present or not. prevention studies have not identified effects • Patients with VTE who are going to be on that warrant separate treatment recommendations long-term anticoagulation anyway. for any specific subset of patients with non- cardioembolic ’’ and that ‘‘recommenda- (b) Do not routinely offer testing to first degree tions for all subgroups, therefore, follow the relatives of patients with VTE and throm- general recommendations regarding patients with bophilia, as thrombophilia results would usually non-cardioembolic stroke’’ [26]. not—except for rare circumstances—alter the (c) In respect to women and pregnancy, the ACCP decision-making regarding thrombo-prophylaxis. 2012 guideline gives detailed management sug- (c) Consider testing in patients with unprovoked gestions for women with and without VTE, and VTE in whom discontinuation of anticoagulant for women with and without thrombophilia [20]. therapy is planned, for They also suggest that women with a history of • APLA, as finding APLA may be a reason to pregnancy complications not be screened for continue long-term anticoagulation. inherited thrombophilias [20]. • Hereditary thrombophilia if the patient also • The 2012 NICE Guideline is a guideline from the has a family history of VTE in a first degree British National Institute for Health and Clinical relative, as finding a deficiency of protein C, Excellence (NICE), published by the National Clinical protein S or antithrombin may be a reason to Guideline Centre (NCGC) and others [27, 28]. The continue long-term anticoagulation. Homozy- expert panel’s conclusions and recommendations are: gous FVL, homozygous prothrombin

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G20210A, and double heterozygous state are could well argue to NOT do thrombophilia testing in the not mentioned in this statement. setting of an acute VTE or while a patient is on an anti- coagulant given that (a) acute thrombosis and being on an • EGAPP (Evaluation of Genomic Applications in Prac- anticoagulant influence many of the test results and (b) the tice and Prevention) Working Group in 2011 limits its management of acute VTE in the first 3 months is the same testing recommendations to patients with unprovoked no matter whether a thrombophilia is present or not. VTE and recommends against ROUTINE testing of such patients for FVL and prothrombin G20210A When to test mutation. However, this recommendation does not extend to ‘‘patients with other risk factors for throm- It seems like a reasonable clinical management approach to bosis, such as contraceptive use’’ [29]. treat a patient with VTE with anticoagulation for 3 months • The Choosing Wisely 2013 campaign from the and then, in the patient in whom one concludes that American Society of Hematology made a very focused thrombophilia testing will contribute to the length of an- recommendation to ‘‘not test for thrombophilia in adult ticoagulation management decision, to obtain a D-dimer patients with VTE occurring in the setting of major and those thrombophilia tests that can be reliably done on transient risk factors (surgery, trauma, or prolonged anticoagulation (FVL, prothrombin G20210A, anticardi- immobility). [10] olipin and anti-b -glycoprotein-I antibodies). If these tests • The ACOG (American College of Gyne- 2 are negative/normal, then one can discontinue antico- cology) 2013 Practice Bulletin on inherited throm- agulation and 4 weeks later obtain a repeat D-dimer and bophilias in pregnancy gives detailed guidance on the residual thrombophilia laboratory test (lupus antico- management of pregnant women with and without agulant, activities of protein C, S and antithrombin, free thrombophilia [19]. protein S antigen). If any of these tests are clearly abnor- mal, moving the patient down in the ‘‘recurrence triangle’’, then one can resume anticoagulation. If anticoagulation Thromobphilia testing resumption with warfarin occurs, then bridging with a fast- acting anticoagulant for five days may be safest, par- What to test ticularly if the patient is found to have protein C or S deficiency; alternatively, a direct oral anticoagulant Table 5 lists the thrombophilia tests that seem reasonable (DOAC) could be started without a bridging parenteral to the author to consider when testing is indicated. anticoagulant. Additional comments: Testing caveats • It could be argued that blood testing done to determine length of anticoagulation could be limited to D-dimer Tables 6 and 7 summarize the most important points to testing (on and off anticoagulation) and that individual consider when interpreting thrombophilia test results. One

Table 5 Thrombophilia tests to consider when testing is indicated (author’s approach) CBC Factor V Leiden Prothrombin G20210A mutation Protein C activity Protein S activity, free protein S Antithrombin activity Antiphospholipid antibodies Anticardiolipin IgG and IgM antibodies Anti-ß2-glycoprotein-I IgG and IgM antibodies Lupus anticoagulant In selected subgroups of patients: Flow cytometry for PNH if unexplained cytopenias present, as well as in unexplained splanchnic vein thrombosis JAK2 V617F if CBC abnormalities suggestive of myeloproliferative neoplasm, as well as in splanchnic vein thrombosis Homocysteine in the young person with unexplained arterial or (to look for homocysteinuria) NOT to test: MTHFR polymorphisms, Factor VIII activity or antigen, tPA and PAI-1 levels and polymorphisms

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Table 6 Conditions associated with decreased coagulation factor levels Coagulation Factor Condition

Protein C Acute thrombosis Vitamin K antagonist (VKA) therapy Liver disease Protein-losing enteropathy Protein S Acute thrombosis Vitamin K antagonist (VKA) therapy Liver disease Inflammatory states Estrogens (contraceptives, pregnancy, postpartum state, hormone replacement therapy) Protein-losing enteropathy Antithrombin Acute thrombosis therapy Liver disease Protein-losing enteropathy Data in the literature on the effect of estrogens on protein C and antithrombin levels are inconsistent: Either no effect has been reported [36], or a slight decrease in AT and mild increase in protein C [37]

thrombophilia testing is not needed, as a D-dimer result • www.natfonline.org: The North American Thrombosis would be expected to capture the presence of a strong Forum is a non-profit health organization with, in re- thrombophilia by being positive. At present, evidence spect to patients, a focus on creating VTE patient for this assumption does not exist. support groups. • When discontinuing anticoagulation for 4 weeks to obtain reliable results for protein C and protein S activities and an off-anticoagulation D-dimer, the Summary points author does not bridge the patient with low molecular weight heparin or another anticoagulant, as that would • Only a physician who is able to provide the ‘‘4P’’ defeat the goal of getting a D-dimer test with the patient should order thrombophilia tests: having been off anticoagulation for 4 weeks. • Patients likely have to be off DOACs, low molecular 1: Appropriately select which patient should be weight heparin and fondaparinux for ca. 48 h (and for tested longer if renal function is impaired) for valid functional 2: Provide pre-test counseling coagulation test results for protein C, protein S and 3: Properly interpret the lab tests antithrombin activities, and lupus anticoagulant. War- 4: Provide education and advice to the patient. farin should have been discontinued for 3 or more • Do not do thrombophilia testing at the time of an acute weeks before protein C and S testing is done. thrombotic event. If testing is needed, test at 3 months, together with a D-dimer.

Patient education and support resources • Do not do thrombophilia testing while a patient is on an anticoagulant. • www.clotconnect.org: Clot Connect, a non-profit in- formation/education resource of the University of North Carolina (UNC) at Chapel Hill, has information • Do not test for thrombophilia in patients whose VTE for patients on DVT, PE, thrombophilia and was provoked by a major transient risk factor, such as anticoagulation. surgery. • stoptheclot.org: The National Blood Clot Alliance (NBCA) is a non-profit patient-led advocacy organi- zation for patients with blood clots, with a focus on • Be aware of the influences of on national VTE advocacy and patient information. thrombophilia test results (Table 7).

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Table 7 Influence of acute thrombosis and anticoagulants on thrombophilia test results Test Acute Unfractionated Low molecular weight Vitamin K DOACs thrombosis heparin heparin antagonists

Factor V Leiden genetic test Reliable Reliable Reliable Reliable Reliable APC resistance assay Reliablea ???a ???b Reliablea Unreliableh Prothrombin G20210A genetic Reliable Reliable Reliable Reliable Reliable test Protein C activity ???c Reliable Reliable Low Elevatedf Protein C antigen ???c Reliable Reliable Low Reliable Protein S activity May be low Reliable Reliable Low Elevatedf Protein S antigen May be low Reliable Reliable Low Reliable Antithrombin activity May be low May be low May be low May be elevatedh Elevatedg Lupus anticoagulant Accurated ???e ???e ???e False positivei Anticardiolipin antibodies Accurated Reliable Reliable Reliable Reliable d Anti-ß2-glycoprotein-I Accurate Reliable Reliable Reliable Reliable antibodies Homocysteine Reliable Reliable Reliable Reliable Reliable DOAC new oral anticoagulant (i.e. apixaban, dabigatran, edoxaban, rivaroxaban), APC activated protein C resistance a Reliable if the assay is performed with Factor V depleted plasma; thus: clinician needs to inquire how the individual laboratory performs the assay b Depending on the way the assay is performed results may be unreliable; health care provider needs to contact the laboratory and ask how the specific test performs on heparin c Probably reliable, but limited data in literature d Test result is accurate, but often temporarily positive or elevated at time of acute thrombosis, yet subsequently negative e While many test kits used for lupus anticoagulant testing contain a heparin neutralizer making these tests reliable on unfractionated heparin (UF) and possibly low molecular weight heparin (LMWH), clinicians needs to inquire with their laboratory how their individual test kit performs in samples with UF and LMWH f Activities of protein C, protein S activity and anti-thrombin may appear normal, even though a patient has a deficiency of protein C or S [38] g A few case reports show that VKA can lead to an increase in antithrombin levels in selected families h APC resistance assay may be falsely normal (i.e. false negative) [39] i Lupus anticoagulant tests can be false positive on the NOACs [40]

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