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 for thrombophilia, mainly due to the lack of good quality clinical outcome data in relationship to presence or absence of a given thrombophilia. Testing may be considered if (a) finding a thrombophilia predicts recurrent thrombosis and, thus, influences length of anticoagulation treatment decisions; (b) identifying a thrombophilia has implications on management of asymptomatic family members who are carriers of the detected thrombophilia; (c) a patient wishes to better understand why a thrombotic event occurred. Testing may be helpful in patients with venous thromboembolism at intermediate risk of recurrence in whom the finding of a strong thrombophilia can be one of the arguments for long-term anticoagulation - the ‘‘risk-of-recurrence-triangle’’ may be a useful aid in this decision process. Patients whose venous thromboembolism was provoked by a major transient risk factor should not be tested for thrombophilia. Thrombophilia tests should only be ordered by health care professionals who can provide 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 thromboembolism, it is advisable to be done at the time of decision making whether to stop or continue anticoagulation, i.e. typically after 3 months of anticoagulant therapy. Thrombophilia testing is best not done at the time of an acute thrombotic event and while a patient is on an anticoagulant.
S. Moll (&) Division of Hematology-Oncology, Department of Medicine, University of North Carolina School of Medicine, CB 7035, Chapel Hill, NC 27599, USA e-mail: [email protected]
Keywords Thrombophilia Testing Venous thromboembolism Deep vein thrombosis DVT Pulmonary embolism Abbreviations ACCP American College of Chest Physicians APC-R Activated protein C resistance APLA Antiphospholipid antibodies DVT Deep vein thrombosis EGAPP Evaluation of Genomic Applications in Practice and Prevention FVL Factor V Leiden (R506Q) DOAC Direct oral anticoagulant (i.e. apixaban, dabigatran, edoxaban, rivaroxaban) PAI-1 Plasminogen activator inhibitor-1 PE Pulmonary embolism tPA Tissue plasminogen activator VTE Venous thromboembolism II G20210A Prothrombin G20210A
Introduction Thrombophilias can be inherited or acquired. Thrombosis— either venous or arterial—is typically multifactorial, with individual risk factors potentiating each other, often in more than just additive fashion. When evaluating a patient with thrombosis and making treatment decisions, particularly on the length of anticoagulation treatment in patients with venous thromboembolism (VTE), it is, therefore, appropriate to consider all thrombosis risk factors and not focus exclusively or too majorly on biochemical or genetic thrombophilias. This manuscript discusses clinical–practical aspects of thrombophilias, with focus on why to test, whom
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to test, what to test, what not to test, test interpretation, and clinical management consequences for individuals having been identified with a thrombophilia.
Patient selection Reasons to test Three legitimate reasons exist to consider thrombophilia testing in clinical practice in a patient who has had a thrombotic event: a) b)
c)
A patient’s wish to understand why a thrombotic event happened, Predicting recurrent thrombosis and, thus, obtaining information that helps influence length of anticoagulation treatment decisions, Family implications for asymptomatic carriers of the detected thrombophilia.
A variety of thrombophilias are risk factor for a first VTE (Table 1) and, thus, if detected in a patient with VTE, can be listed as risk factors for and contributors to the first VTE event. However, the common and mild thrombophilias [e.g. heterozygous prothrombin G20210A, heterozygous Factor V Leiden (FVL)] are not or only mild risk factors for VTE recurrence (Table 1) and, thus, their presence typically has no major impact on the decision how long to treat with anticoagulation. The purpose of thrombophilia testing is to detect a strong thrombophilia that (a) has an impact in a VTE patient
on the risk of recurrence (Table 1) and, thus, length of anticoagulation therapy or (b) influences management of family members for the primary prevention of VTE. Acknowledging that limited scientific data exist on the uncommon thrombophilias, I view the following as ‘‘strong thrombophilias’’ at this point: (1) Homozygous FVL, (2) Homozygous prothrombin G20210A mutation, (3) the double heterozygous state of FVL plus II20210 mutation, (4) protein C deficiency, (5) protein S deficiency, (6) antithrombin deficiency, and (7) antiphospholipid antibody syndrome. Elevated Factor VIII activity (FVIII) levels appear to increase the risk for recurrent VTE if levels are more extremely elevated ([230 IU/dL [1] or exceed the 90th percentile [2, 3]), but an effect is not present or less impressive and statistically not significant in studies of mildly to moderately elevated levels, such as values [155 IU/dL [4] or [166 IU/dL [5]. It is difficult to know how to clinically use a FVIII value obtained for an assessment of risk of recurrent VTE in an individual patient. This is because differences between published studies in respect to when after an acute VTE event FVIII levels were measured, methodologies for FVIII measurements, normal range definition and variable correlations between percentiles and absolute FVIII levels make it impossible to interpret the FVIII value obtained for its clinical significance. The ‘‘4P Approach’’ Whatever patient is selected for testing, four components 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 ? heterozygous II G20210Aa
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]
Homozygous FVLa Protein S deficiency
18 (95 % CI 4.1–41) [33] 30.6 (95 % CI 26.9–55.3) [30]
1.2 (95 % CI 0.5–2.6) [32] or 2.65 (95 % CI 1.18–5.97) [31] 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 heterogenous for accurate risk assessment
Available evidence is of very low quality: Any APLA positive: 1.41 (95 % CI 0.99–2.00) [35] Anticardiolipin positive: 1.53 (95 % CI 0.76–3.11) [35] Lupus anticoagulant positive: 2.83 (95 % CI 0.83–9.64) [35]
APLA antiphospholipid antibody, FVL Factor V Leiden, 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 surgery, 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 bleeding 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. Pregnancy complications a. C3 unexplained pregnancy losses before week 10, or C1 loss after week 10 b. unexplained pregnancy complications (preeclampsia, intrauterine growth restriction, placental abruption) 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’’ (which, for simplification, is referred to here as the ‘‘4P Approach’’): (1) Patient selection, (2) Pre-test counseling, (3) Proper laboratory test interpretation, and (4) Provision of education and advice [6]. The health care professional ordering thrombophilia tests should be able to provide all 4 components.
and to be comprehensive as to who should be tested, as there is a lack of scientific data for a number of clinical scenarios. Table 2 summarizes the patient groups in which I consider, but not inevitably recommend, thrombophilia testing.
Whom to test
In the patient with VTE, the decision to treat with anticoagulation for only 3 months or long-term (indefinite, ‘‘lifelong’’, for extended duration) depends on 3 factors: (1) the risk of recurrent VTE, (2) the risk for major bleeding, and (3) the patient’s preference (Fig. 1). Patient-individualized assessment of all 3 components needs to take place in the process of decision-making. The ‘‘risk of recurrence triangle’’ (Fig. 2a) is a visual aid that helps explain the complex ‘‘length of anticoagulation’’ decision issues [9]:
No full agreement exists between guidelines, societies and medical experts who should be tested for thrombophilia. It is easier to conclude who should NOT be tested than to identify patients in whom testing should be considered. Most experts agree that testing unselected patients with thrombosis has no clinical value [7]. In addition, the Choosing Wisely campaign appropriately recommends to not test for thrombophilia patients with VTE associated with a major transient risk factor, such as major surgery [8]. Beyond that, it remains difficult to give clear guidance
Venous thromboembolism
•
VTE associated with a major transient risk factor A 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 “Warfarin hate factor” or “DOAC dislike factor”
VTE = venous thromboembolism; DOAC = direct oral anticoagulant
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factor, such as major surgery, immobility or trauma, has a low risk of recurrent VTE and 3 months of anticoagulation is the appropriate and recommended length of treatment [8]. Such a patient is in the top of the ‘‘recurrence triangle’’ (Fig. 2a). Thrombophilia workup in such a patient is not helpful and not recommended [10]. The patient’s risk of recurrent VTE is low even if a thrombophilia is detected. Unprovoked VTE These patients have a higher risk of recurrence and are in the lower (broad-based) part of the ‘‘recurrence triangle’’ (Fig. 2a): men with unprovoked VTE have the highest risk for recurrence and, thus, are in the lowest part; women with unprovoked, non-hormone associated VTE are also in the lower part of the triangle, but above where men are. These patients’ high risk of recurrent VTE is the reason behind guidelines’ recommendations to treat patients with unprovoked VTE with long-term anticoagulation, if they tolerate it well and find it acceptable [11]. Presence or absence of a thrombophilia does not change that recommendation, as finding a thrombophilia would only push a patient lower in the triangle, but absence would not move the patient higher up in the triangle. Thrombophilia testing in these patients is, therefore, not helpful for their management. However, if a patient with unprovoked VTE is either at higher risk for bleeding or finds long-term anticoagulation fairly unacceptable, further blood testing might be helpful: a positive D-dimer or finding a strong thrombophilia would move the patient down in the triangle and would be reasons to consider long-term anticoagulation in spite of the higher bleeding risk or degree of a patient’s dislike of being on long-term anticoagulation. VTE associated with a minor transient risk factor A patient with VTE associated with a minor transient risk factor (estrogen-containing contraceptives, estrogen replacement therapy, minor surgery, minor immobility) appear to have an intermediate risk of recurrent VTE and are in the middle of the ‘‘recurrence triangle’’ [12, 13] (Fig. 2a). However, for several conditions, such as VTE associated with longer or shorter airline travel, minor surgeries, estrogen-containing contraceptives, the risk of recurrence is not well known. It is in these patients that I 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 recurrence triangle and are reasons to consider longterm anticoagulation. However, presence of a mild thrombophilia, i.e. the heterozygous prothrombin G20210A or heterozygous Factor V Leiden, mutation,
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does not or only slightly, respectively, push the position of the patient downward in the triangle. Arterial thrombosis Thrombophilias play less of a role in arterial thrombosis than in VTE, as arteriosclerosis is usually the predominant cause of arterial occlusive events. However, in the younger person with an unexplained arterial event, thrombophilia enters into the differential diagnosis. A systematic approach to the evaluation of such patients is advisable (Table 3). Heterozygous FVL and heterozygous prothrombin G20210A mutation are not, or only minimal, respectively, contributors to arterial thrombosis [14]. It is not known whether the uncommon thrombophilias homozygous FVL, homozygous prothrombin G20210A mutation, or the double heterozygous (FVL ? prothrombin G20210A) state increase the risk for arterial thrombosis. A large family study showed no association of arterial thrombosis with antithrombin deficiency, but a clear association with protein C and protein S deficiency [15]. Antiphospholipid antibodies (APLA) are known risk factors for arterial thrombosis. I discuss thrombophilia work-up with the younger patient with unexplained arterial thrombosis, with the goal of identifying one of the stronger thrombophilias.However, it is not known whether patients with non-arteriosclerotic arterial thrombosis and a strong thrombophilia are more effectively treated with antiplatelet or anticoagulant therapy. This lack of knowledge, obviously, needs to be discussed with the patient. From a pathophysiology point of view it makes sense to hypothesize that anticoagulant therapy might be effective for the prevention of recurrent arterial thrombotic events prophylaxis, as the prothrombotic defect with these non-APLA thrombophilias is in the plasmatic coagulation pathway (i.e. the coagulation cascade). Alternatively, it also makes sense to postulate that antiplatelet therapy might be effective, as arterial thrombosis, in general, is predominantly a platelet-driven process. And, finally, it is also reasonable to postulate that the combination of anticoagulant and anti-platelet agent might be most effective. Of course, a patient’s risk for bleeding needs to be factored into the decision-making, but this is typically low, as the patient is young. In summary, in this area of absence of evidence I have a preference to treat young patients with unexplained arterial thrombosis and strong thrombophilia with anticoagulation ± an anti-platelet agent, with re-evaluation after several months and periodically thereafter. However, the patient’s preference should also strongly factor into the decision-making. Pregnancy complications Women with thrombophilia are at increased risk for VTE ante- and post-partum and with assisted reproduction. They also have a higher rate of placenta-mediated pregnancy
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a VTE, major transient risk factor
3 months
Long-term
• DVT • PE
Strong Thrombophilia
Woman, unprovoked VTE
- D-dimer +
VTE due to minor transient risk, woman with VTE on hormones
Man, unprovoked VTE • DVT • PE
VTE = venous thromboembolism; DVT = deep vein thrombosis; PE = pulmonary embolism
b
c 1a
1a
4b
3 months
4b
3 months
C 1b 4a
A
4a
3b
3b
2b
Long-term 2a
4c 3a
3c
Fig. 2 a–c ‘‘Risk of recurrence triangle’’—how long to anticoagulate? a Position in the lower part of the triangle indicates a higher risk of recurrence; position in the tip of the triangle a low risk. Position above dotted red line is the area where the risk from major bleeding on anticoagulation is higher than the risk of a recurrent VTE (case-fatality) and, thus, discontinuation of anticoagulation is indicated. A position below the red line indicates that the case-fatality from a recurrent VTE is higher than that of a bleed. The position of the red line varies from patient to patient, depending on bleeding risk, as well as patient preference to be on an anticoagulant or not (‘‘anticoagulant hate factor’’). b Patient examples how the ‘‘recurrence triangle’’ can be used in the decisionmaking and discussion with the patient: Patient #1: VTE associated with major risk factor; low risk for recurrent VTE (position 1a); no benefit form thrombophilia or D-dimer testing; while a positive D-dimer or presence of a strong thrombophilia would push the patient down in the triangle (to position 1b) the patient would still be above the red line, where discontinuation of anticoagulation is indicated. Patient #2: Man with unprovoked VTE; high risk of recurrence (position 2a); no benefit from thrombophilia or D-dimer testing: while a negative D-dimer moves the patient somewhat up to a lower risk of recurrence, he is still below the red line and long-term anticoagulation is indicated. Patient #3: Woman with unprovoked VTE; risk of recurrence is on the high side (position 3a); no benefit from thrombophilia or D-dimer testing; while a negative D-dimer moves the patient up some to a lower risk of recurrence (position 3b), it is still below the red line where long-term anticoagulation is indicated. Patient #4: Man or woman with minor risk factor (short distance travel; minor surgery, such as arthroscopic surgery, outpatient surgery, etc.; cast or boot immobilizer) or woman with hormone-
2b
Long-term 2a
4c 3a
B
3c
associated VTE (position 4a); thrombophilia and D-dimer testing help decide on length of anticoagulation: a positive D-dimer (on and off anticoagulation) and finding of a strong thrombophilia push the patient down in the triangle (position 4c), below the red line. A negative D-dimer and absence of a strong thrombophilia push the patient above the red line (position 4c) where anticoagulation can be discontinued. c Length of anticoagulation based on bleeding risk and ‘‘Anticoagulant hate factor’’. High bleeding risk, high ‘‘anticoagulant hate factor (line ‘‘B’’). The red line is moved down in the patient with bleeding risk factors (such as old age, renal impairment, liver synthetic function, concomitant anti-platelet therapy, history of bleed, widely fluctuating INRs on warfarin etc.). The threshold to take a patient off anticoagulation is lowered for fear of bleeding. The same downward move of the red line occurs in the patient whose preference is not to be on anticoagulation. A positive D-dimer or the finding of a strong thrombophilia, which both indicate a higher risk for recurrence, would be arguments to keep the patient on anticoagulation, accepting the higher risk for bleeding. Example: the woman with unprovoked VTE (position 3a) at increased risk for bleeding or with a high ‘‘anticoagulant hate factor’’ may now decide to come off anticoagulation, particularly if she has a negative D-dimer and no strong thrombophilia (position 3b). However, finding a positive D-dimer or a strong thrombophilia (position 3c) may argue for continued anticoagulation. Low bleeding risk, low ‘‘anticoagulant hate factor (line ‘‘C’’): The red line is moved up in the patient at low risk for bleeding risk or a low ‘‘anticoagulant hate factor’’. The threshold to keep a patient on anticoagulation is lowered. Example: the woman with unprovoked VTE (position 3a) may more comfortably decide to stay on anticoagulation, even if her D-dimer is negative (position 3b)
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complications (recurrent early pregnancy losses, late pregnancy loss, preeclampsia, intrauterine growth restriction (IUGR), and placental abruption), even though these associations are somewhat controversial. These topics have recently been discussed in detail elsewhere [16–18]. •
•
Increased VTE risk Women with or without thrombophilia and at increased VTE risk ante- and postpartum should be treated per existing evidence-based guidelines. [19–21] Pregnancy loss and placenta-mediated pregnancy complications It is unclear whether anticoagulation in
pregnant women with thrombophilia is beneficial to prevent recurrent early or late pregnancy loss. Clinical studies have not clearly and unequivocally shown benefit of anticoagulation. An ongoing study (ALIFE2) is trying to address this issue further [22]. While my practice is to offer (but not inevitably recommend) thrombophilia testing to women with unexplained pregnancy loss (C3 before week 10 or C1 after week 10) and women with unexplained placenta-mediated pregnancy complications, my recommendations for management of future pregnancy, if a thrombophilia
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 Obesity 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 autoimmune disease (arthritis, purpura, 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) Hemoglobin and platelet count Antiphospholipid antibodies Anticardiolipin IgG and IgM antibodies Anti-b2-glycoprotein-I IgG and IgM antibodies Lupus anticoagulant Protein C activity Protein S activity and free protein S antigen Antithrombin activity Homocysteine 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 limitations of our current knowledge than a true recommendation. Family testing Table 4 summarizes my approach to thrombophilia testing in family members of patients with known thrombophilia. It is worth noting that a family history of VTE by itself— independent of the identification of a thrombophilia—increases an asymptomatic person’s VTE risk two- to threefold, and even more so when several family members have had VTE, independent of the presence of a thrombophilia [23, 24]. And, to no surprise, the VTE risk for the asymptomatic individual increases further, the more VTE risk factors the person has, such as obesity, estrogen-containing contraceptive use, underlying thrombophilia [23– 25]. Thus, individualized recommendations need to be given on what impact the presence of these various risk factors has on a person in respect to the absolute risk of VTE. That absolute risk then determines what recommendation to give regarding choice of contraceptives, pregnancy management, and VTE prophylaxis in risk situation. Unfortunately, for many of these risk factors it is not known how they interact (additive, multiplicative, etc.). Figure 3 depicts a summary of contraceptives for discussion with the woman at risk for VTE, with the safest methods listed in green at the bottom of the triangle and the ones with the highest risk of VTE shown at the tip of the triangle. Broadening of the triangle while moving up reflects increased VTE risk. Whom NOT to test
‘‘indiscriminate’’ approach to thrombophilia testing that was promoted in earlier guidelines is not supported by 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 (\50 years old) and have an unprovoked VTE, (c) with VTE in unusual locations, (d) with VTE of unusual extent, or (e) with VTE recurrence in spite of anticoagulation. Instead, a rather more selective approach to testing seems most appropriate, as discussed above and summarized in Table 2. Existing guidelines Various guidelines have incorporated statements on thrombophilia, but given the broadness of the topic and the limited knowledge of some of the clinical aspects, the guidelines have significant limitations, tend to generalize, and are of limited helpfulness in a number of patient situations that clinicians encounter in clinical practice. • The British Society for Haematology in 2010 in its ‘‘Clinical guidelines for testing for heritable thrombophilia’’ gives the most comprehensive recommendations—summarized in 30 bulleted points—as to (a) who should be tested, (b) who should not be tested, and (c) in which individuals no validated recommendations can be made about benefit of testing given a lack of evidence base [7]. Many of the recommendations and suggestions are weak recommendations, reflecting that for many clinical scenarios there is only moderate or low quality evidence as to who should and should not be tested. • The ACCP 2012 guideline (a)
In the last few years it has become clear that the presence of a thrombophilia often does not influence clinical management. Therefore, a more wide-spread, ‘‘unselected’’, or
In regard to VTE, the guideline concludes that while hereditary thrombophilias and antiphospholipid antibodies predict recurrence of VTE, 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 Sons
Female family member 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
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• Ring (Etonogestrel & estradiol)
Estrogen combination pill
• Patch (Norelgestromin & ethinyl estradiol) • 4th generation pills (Drospirenone & ethinyl estradiol)
• 3rd generation
• 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. 2. Rosendaal FR, et al. Thromb Haemost. 2001;6:112-23.
3. Conard J, et al. Contraception. 2004;70:437-441. 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
(b)
(c)
•
enough to influence recommendations on duration of anticoagulant therapy’’, once the ‘‘primary [provoked versus unprovoked event] and secondary factors [(a) distal DVT versus proximal DVT or PE; (b) first versus recurrent VTE] have been considered’’ [11]. In respect to arterial thrombosis, the ACCP 2012 guideline takes only reference to APLA, and states that ‘‘subgroup analyses of secondary prevention studies have not identified effects that warrant separate treatment recommendations for any specific subset of patients with noncardioembolic stroke’’ and that ‘‘recommendations for all subgroups, therefore, follow the general recommendations regarding patients with non-cardioembolic stroke’’ [26]. In respect to women and pregnancy, the ACCP 2012 guideline gives detailed management suggestions for women with and without VTE, and for women with and without thrombophilia [20]. They also suggest that women with a history of pregnancy complications not be screened for inherited thrombophilias [20].
The 2012 NICE Guideline is a guideline from the British National Institute for Health and Clinical Excellence (NICE), published by the National Clinical Guideline Centre (NCGC) and others [27, 28]. The expert panel’s conclusions and recommendations are:
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(a)
Do not offer testing to •
• (b)
(c)
Patients with provoked VTE (due to transient major risk factor, such as trauma, surgery, prolonged immobility, pregnancy, postpartum state) or VTE due to hormonal therapy (oral contraceptive pill, hormone replacement therapy), as these patients need short-term anticoagulation no matter whether a thrombophilia is present or not. Patients with VTE who are going to be on long-term anticoagulation anyway.
Do not routinely offer testing to first degree relatives of patients with VTE and thrombophilia, as thrombophilia results would usually not—except for rare circumstances—alter the decision-making regarding thrombo-prophylaxis. Consider testing in patients with unprovoked VTE in whom discontinuation of anticoagulant therapy is planned, for • •
APLA, as finding APLA may be a reason to continue long-term anticoagulation. Hereditary thrombophilia if the patient also has a family history of VTE in a first degree relative, as finding a deficiency of protein C, protein S or antithrombin may be a reason to continue long-term anticoagulation. Homozygous FVL, homozygous prothrombin
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G20210A, and double heterozygous state are not mentioned in this statement. •
•
•
EGAPP (Evaluation of Genomic Applications in Practice and Prevention) Working Group in 2011 limits its testing recommendations to patients with unprovoked VTE and recommends against ROUTINE testing of such patients for FVL and prothrombin G20210A mutation. However, this recommendation does not extend to ‘‘patients with other risk factors for thrombosis, such as contraceptive use’’ [29]. The Choosing Wisely 2013 campaign from the American Society of Hematology made a very focused recommendation to ‘‘not test for thrombophilia in adult patients with VTE occurring in the setting of major transient risk factors (surgery, trauma, or prolonged immobility). [10] The ACOG (American College of Obstetrics Gynecology) 2013 Practice Bulletin on inherited thrombophilias in pregnancy gives detailed guidance on management of pregnant women with and without thrombophilia [19].
Thromobphilia testing What to test Table 5 lists the thrombophilia tests that seem reasonable to the author to consider when testing is indicated. Testing caveats Tables 6 and 7 summarize the most important points to consider when interpreting thrombophilia test results. One
could well argue to NOT do thrombophilia testing in the setting of an acute VTE or while a patient is on an anticoagulant given that (a) acute thrombosis and being on an anticoagulant influence many of the test results and (b) the management of acute VTE in the first 3 months is the same no matter whether a thrombophilia is present or not. When to test It seems like a reasonable clinical management approach to treat a patient with VTE with anticoagulation for 3 months and then, in the patient in whom one concludes that thrombophilia testing will contribute to the length of anticoagulation management decision, to obtain a D-dimer and those thrombophilia tests that can be reliably done on anticoagulation (FVL, prothrombin G20210A, anticardiolipin and anti-b2-glycoprotein-I antibodies). If these tests are negative/normal, then one can discontinue anticoagulation and 4 weeks later obtain a repeat D-dimer and the residual thrombophilia laboratory test (lupus anticoagulant, activities of protein C, S and antithrombin, free protein S antigen). If any of these tests are clearly abnormal, moving the patient down in the ‘‘recurrence triangle’’, then one can resume anticoagulation. If anticoagulation resumption with warfarin occurs, then bridging with a fastacting anticoagulant for five days may be safest, particularly if the patient is found to have protein C or S deficiency; alternatively, a direct oral anticoagulant (DOAC) could be started without a bridging parenteral anticoagulant. Additional comments: •
It could be argued that blood testing done to determine length of anticoagulation could be limited to D-dimer testing (on and off anticoagulation) and that individual
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 venous thrombosis (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 Protein C
Condition 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 Heparin therapy Liver disease Nephrotic syndrome 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 would be expected to capture the presence of a strong thrombophilia by being positive. At present, evidence for this assumption does not exist. When discontinuing anticoagulation for 4 weeks to obtain reliable results for protein C and protein S activities and an off-anticoagulation D-dimer, the author does not bridge the patient with low molecular weight heparin or another anticoagulant, as that would defeat the goal of getting a D-dimer test with the patient having been off anticoagulation for 4 weeks. Patients likely have to be off DOACs, low molecular weight heparin and fondaparinux for ca. 48 h (and for longer if renal function is impaired) for valid functional coagulation test results for protein C, protein S and antithrombin activities, and lupus anticoagulant. Warfarin should have been discontinued for 3 or more weeks before protein C and S testing is done.
Patient education and support resources •
•
www.clotconnect.org: Clot Connect, a non-profit information/education resource of the University of North Carolina (UNC) at Chapel Hill, has information for patients on DVT, PE, thrombophilia and anticoagulation. stoptheclot.org: The National Blood Clot Alliance (NBCA) is a non-profit patient-led advocacy organization for patients with blood clots, with a focus on national VTE advocacy and patient information.
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www.natfonline.org: The North American Thrombosis Forum is a non-profit health organization with, in respect to patients, a focus on creating VTE patient support groups.
Summary points •
Only a physician who is able to provide the ‘‘4P’’ should order thrombophilia tests: 1: 2: 3: 4:
Appropriately select which patient should be tested Provide pre-test counseling Properly interpret the lab tests Provide education and advice to the patient.
•
Do not do thrombophilia testing at the time of an acute thrombotic event. If testing is needed, test at 3 months, together with a D-dimer.
•
Do not do thrombophilia testing while a patient is on an anticoagulant.
•
Do not test for thrombophilia in patients whose VTE was provoked by a major transient risk factor, such as surgery.
•
Be aware of the influences of anticoagulants on thrombophilia test results (Table 7).
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Table 7 Influence of acute thrombosis and anticoagulants on thrombophilia test results Test
Acute thrombosis
Unfractionated heparin
Low molecular weight heparin
Vitamin K antagonists
DOACs
Factor V Leiden genetic test
Reliable
Reliable
Reliable
Reliable
Reliable
a
???
???
b
Reliable
a
a
Unreliableh
APC resistance assay
Reliable
Prothrombin G20210A genetic test Protein C activity
Reliable
Reliable
Reliable
Reliable
Reliable
???c
Reliable
Reliable
Low
Elevatedf
c
Protein C antigen
???
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
Anti-ß2-glycoprotein-I antibodies
Accurated
Reliable
Reliable
Reliable
Reliable
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 APC resistance assay may be falsely normal (i.e. false negative) [39]
h i
Lupus anticoagulant tests can be false positive on the NOACs [40]
Conflict of interest
None.
References 1. Eischer L, Gartner V, Schulman S, Kyrle PA, Eichinger S (2009) 6 versus 30 months anticoagulation for recurrent venous thrombosis in patients with high factor VIII. Ann Hematol 88:485–490 2. Kyrle PA, Minar E, Hirschl M et al (2000) High plasma levels of factor VIII and the risk of recurrent venous thromboembolism. N Engl J Med 343:457–462 3. Legnani C, Cosmi B, Cini M, Frascaro M, Guazzaloca G, Palareti G (2004) High plasma levels of factor VIII and risk of recurrence of venous thormboembolism. Br J Haematol 124:504–510 4. Shrivastava S, Ridker PM, Glynn RJ et al (2006) D-dimer, factor VIII coagulant activity, low-intensity warfarin and the risk of recurrent venous thromboembolism. J Thromb Haemost 4: 1208–1214 5. Christiansen SC, Cannegieter SC, Koster T, Vandenbroucke JP, Rosendaal FR (2005) Thrombophilia, clinical factors, and recurrent venous thrombotic events. JAMA 293:2352–2361 6. Cushman M (2014) Thrombophilia testing in women with venous thrombosis: the 4 P’s approach. Clin Chem 60:134–137
7. Baglin T, Gray E, Greaves M et al (2010) Clinical guidelines for testing for heritable thrombophilia. Br J Haematol 149:209–220 8. Hicks LK, Bering H, Carson KR et al (2014) Five hematologic tests and treatments to question. Blood 124:3524–3528 9. Moll S (2014) New insights into treatment of venous thromboembolism. Hematology 2014. American Society of Hematology Education Program: American Society of Hematology, American Society of Hematology, pp 297–305 10. Hicks LK, Bering H, Carson KR et al (2013) The ASH Choosing Wisely(R) campaign: five hematologic tests and treatments to question. Blood 122:3879–3883 11. Kearon C, Akl EA, Comerota AJ et al (2012) Antithrombotic therapy for VTE disease: antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 141:e419S– e494S 12. Le Gal G, Kovacs MJ, Carrier M et al (2010) Risk of recurrent venous thromboembolism after a first oestrogen-associated episode. Data from the REVERSE cohort study. Thromb Haemost 104:498–503 13. Iorio A, Kearon C, Filippucci E et al (2010) Risk of recurrence after a first episode of symptomatic venous thromboembolism provoked by a transient risk factor: a systematic review. Arch Intern Med 170:1710–1716
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thrombophilia testing: summary of NICE guidance. BMJ 344:e3979 Recommendations from the EGAPP Working Group (2011) Routine testing for Factor V Leiden (R506Q) and prothrombin (20210G [ A) mutations in adults with a history of idiopathic venous thromboembolism and their adult family members. Genet Med 13:67–76 Lijfering WM, Brouwer JL, Veeger NJ, et al (2009) Selective testing for thrombophilia in patients with first venous thrombosis: results from a retrospective family cohort study on absolute thrombotic risk for currently known thrombophilic defects in 2479 relatives. Blood 113:5314–5322 Segal JB, Brotman DJ, Necochea AJ, et al (2009) Predictive value of factor V Leiden and prothrombin G20210A in adults with venous thromboembolism and in family members of those with a mutation: a systematic review. Jama 301:2472–2485 Lijfering WM, Middeldorp S, Veeger NJ, et al (2010) Risk of recurrent venous thrombosis in homozygous carriers and double heterozygous carriers of factor V Leiden and prothrombin G20210A. Circulation 121:1706–1712 Juul K, Tybjaerg-Hansen A, Schnohr P, Nordestgaard BG (2004) Factor V Leiden and the risk for venous thromboembolism in the adult Danish population. Ann Intern Med 140:330–337 Emmerich J, Rosendaal FR, Cattaneo M, et al (2001) Combined effect of factor V Leiden and prothrombin 20210A on the risk of venous thromboembolism—pooled analysis of 8 case-control studies including 2310 cases and 3204 controls. Study Group for Pooled-Analysis in Venous Thromboembolism. Thromb Haemost 86:809–816 Garcia D, Akl EA, Carr R, Kearon C (2013) Antiphospholipid antibodies and the risk of recurrence after a first episode of venous thromboembolism: a systematic review. Blood 122:817–824 Aldrighi JM, De Campos LS, Eluf Gebara OC, Petta CA, Bahamondes L (2006) Effect of a combined oral contraceptive containing 20 microg ethinyl estradiol and 75 microg gestodene on hemostatic parameters. Gynecol Endocrinol 22:1–4 Wiegratz I, Stahlberg S, Manthey T, et al (2008) Effects of conventional or extended-cycle regimen of an oral contraceptive containing 30 mcg ethinylestradiol and 2 mg dienogest on various hemostasis parameters. Contraception 78:384–391 Adcock DM, Gosselin R, Kitchen S, Dwyre DM (2013) The effect of dabigatran on select specialty coagulation assays. Am J Clin Pathol 139:102–109 Johnson NV, Khor B, Van Cott EM (2012) Advances in laboratory testing for thrombophilia. Am J Hematol 87(Suppl 1):S108–S112 Martinuzzo ME, Barrera LH, D’adamo MA, Otaso JC, Gimenez MI, Oyhamburu J (2014) Frequent false-positive results of lupus anticoagulant tests in plasmas of patients receiving the new oral anticoagulants and enoxaparin. Int J Lab Hematol 36:144-50
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 for thrombophilia, mainly due to the lack of good quality clinical outcome data in relationship to presence or absence of a given thrombophilia. Testing may be considered if (a) finding a thrombophilia predicts recurrent thrombosis and, thus, influences length of anticoagulation treatment decisions; (b) identifying a thrombophilia has implications on management of asymptomatic family members who are carriers of the detected thrombophilia; (c) a patient wishes to better understand why a thrombotic event occurred. Testing may be helpful in patients with venous thromboembolism at intermediate risk of recurrence in whom the finding of a strong thrombophilia can be one of the arguments for long-term anticoagulation - the ‘‘risk-of-recurrence-triangle’’ may be a useful aid in this decision process. Patients whose venous thromboembolism was provoked by a major transient risk factor should not be tested for thrombophilia. Thrombophilia tests should only be ordered by health care professionals who can provide 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 thromboembolism, it is advisable to be done at the time of decision making whether to stop or continue anticoagulation, i.e. typically after 3 months of anticoagulant therapy. Thrombophilia testing is best not done at the time of an acute thrombotic event and while a patient is on an anticoagulant.
S. Moll (&) Division of Hematology-Oncology, Department of Medicine, University of North Carolina School of Medicine, CB 7035, Chapel Hill, NC 27599, USA e-mail: [email protected]
Keywords Thrombophilia Testing Venous thromboembolism Deep vein thrombosis DVT Pulmonary embolism Abbreviations ACCP American College of Chest Physicians APC-R Activated protein C resistance APLA Antiphospholipid antibodies DVT Deep vein thrombosis EGAPP Evaluation of Genomic Applications in Practice and Prevention FVL Factor V Leiden (R506Q) DOAC Direct oral anticoagulant (i.e. apixaban, dabigatran, edoxaban, rivaroxaban) PAI-1 Plasminogen activator inhibitor-1 PE Pulmonary embolism tPA Tissue plasminogen activator VTE Venous thromboembolism II G20210A Prothrombin G20210A
Introduction Thrombophilias can be inherited or acquired. Thrombosis— either venous or arterial—is typically multifactorial, with individual risk factors potentiating each other, often in more than just additive fashion. When evaluating a patient with thrombosis and making treatment decisions, particularly on the length of anticoagulation treatment in patients with venous thromboembolism (VTE), it is, therefore, appropriate to consider all thrombosis risk factors and not focus exclusively or too majorly on biochemical or genetic thrombophilias. This manuscript discusses clinical–practical aspects of thrombophilias, with focus on why to test, whom
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to test, what to test, what not to test, test interpretation, and clinical management consequences for individuals having been identified with a thrombophilia.
Patient selection Reasons to test Three legitimate reasons exist to consider thrombophilia testing in clinical practice in a patient who has had a thrombotic event: a) b)
c)
A patient’s wish to understand why a thrombotic event happened, Predicting recurrent thrombosis and, thus, obtaining information that helps influence length of anticoagulation treatment decisions, Family implications for asymptomatic carriers of the detected thrombophilia.
A variety of thrombophilias are risk factor for a first VTE (Table 1) and, thus, if detected in a patient with VTE, can be listed as risk factors for and contributors to the first VTE event. However, the common and mild thrombophilias [e.g. heterozygous prothrombin G20210A, heterozygous Factor V Leiden (FVL)] are not or only mild risk factors for VTE recurrence (Table 1) and, thus, their presence typically has no major impact on the decision how long to treat with anticoagulation. The purpose of thrombophilia testing is to detect a strong thrombophilia that (a) has an impact in a VTE patient
on the risk of recurrence (Table 1) and, thus, length of anticoagulation therapy or (b) influences management of family members for the primary prevention of VTE. Acknowledging that limited scientific data exist on the uncommon thrombophilias, I view the following as ‘‘strong thrombophilias’’ at this point: (1) Homozygous FVL, (2) Homozygous prothrombin G20210A mutation, (3) the double heterozygous state of FVL plus II20210 mutation, (4) protein C deficiency, (5) protein S deficiency, (6) antithrombin deficiency, and (7) antiphospholipid antibody syndrome. Elevated Factor VIII activity (FVIII) levels appear to increase the risk for recurrent VTE if levels are more extremely elevated ([230 IU/dL [1] or exceed the 90th percentile [2, 3]), but an effect is not present or less impressive and statistically not significant in studies of mildly to moderately elevated levels, such as values [155 IU/dL [4] or [166 IU/dL [5]. It is difficult to know how to clinically use a FVIII value obtained for an assessment of risk of recurrent VTE in an individual patient. This is because differences between published studies in respect to when after an acute VTE event FVIII levels were measured, methodologies for FVIII measurements, normal range definition and variable correlations between percentiles and absolute FVIII levels make it impossible to interpret the FVIII value obtained for its clinical significance. The ‘‘4P Approach’’ Whatever patient is selected for testing, four components 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 ? heterozygous II G20210Aa
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]
Homozygous FVLa Protein S deficiency
18 (95 % CI 4.1–41) [33] 30.6 (95 % CI 26.9–55.3) [30]
1.2 (95 % CI 0.5–2.6) [32] or 2.65 (95 % CI 1.18–5.97) [31] 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 heterogenous for accurate risk assessment
Available evidence is of very low quality: Any APLA positive: 1.41 (95 % CI 0.99–2.00) [35] Anticardiolipin positive: 1.53 (95 % CI 0.76–3.11) [35] Lupus anticoagulant positive: 2.83 (95 % CI 0.83–9.64) [35]
APLA antiphospholipid antibody, FVL Factor V Leiden, 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 surgery, 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 bleeding 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. Pregnancy complications a. C3 unexplained pregnancy losses before week 10, or C1 loss after week 10 b. unexplained pregnancy complications (preeclampsia, intrauterine growth restriction, placental abruption) 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’’ (which, for simplification, is referred to here as the ‘‘4P Approach’’): (1) Patient selection, (2) Pre-test counseling, (3) Proper laboratory test interpretation, and (4) Provision of education and advice [6]. The health care professional ordering thrombophilia tests should be able to provide all 4 components.
and to be comprehensive as to who should be tested, as there is a lack of scientific data for a number of clinical scenarios. Table 2 summarizes the patient groups in which I consider, but not inevitably recommend, thrombophilia testing.
Whom to test
In the patient with VTE, the decision to treat with anticoagulation for only 3 months or long-term (indefinite, ‘‘lifelong’’, for extended duration) depends on 3 factors: (1) the risk of recurrent VTE, (2) the risk for major bleeding, and (3) the patient’s preference (Fig. 1). Patient-individualized assessment of all 3 components needs to take place in the process of decision-making. The ‘‘risk of recurrence triangle’’ (Fig. 2a) is a visual aid that helps explain the complex ‘‘length of anticoagulation’’ decision issues [9]:
No full agreement exists between guidelines, societies and medical experts who should be tested for thrombophilia. It is easier to conclude who should NOT be tested than to identify patients in whom testing should be considered. Most experts agree that testing unselected patients with thrombosis has no clinical value [7]. In addition, the Choosing Wisely campaign appropriately recommends to not test for thrombophilia patients with VTE associated with a major transient risk factor, such as major surgery [8]. Beyond that, it remains difficult to give clear guidance
Venous thromboembolism
•
VTE associated with a major transient risk factor A 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 “Warfarin hate factor” or “DOAC dislike factor”
VTE = venous thromboembolism; DOAC = direct oral anticoagulant
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•
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factor, such as major surgery, immobility or trauma, has a low risk of recurrent VTE and 3 months of anticoagulation is the appropriate and recommended length of treatment [8]. Such a patient is in the top of the ‘‘recurrence triangle’’ (Fig. 2a). Thrombophilia workup in such a patient is not helpful and not recommended [10]. The patient’s risk of recurrent VTE is low even if a thrombophilia is detected. Unprovoked VTE These patients have a higher risk of recurrence and are in the lower (broad-based) part of the ‘‘recurrence triangle’’ (Fig. 2a): men with unprovoked VTE have the highest risk for recurrence and, thus, are in the lowest part; women with unprovoked, non-hormone associated VTE are also in the lower part of the triangle, but above where men are. These patients’ high risk of recurrent VTE is the reason behind guidelines’ recommendations to treat patients with unprovoked VTE with long-term anticoagulation, if they tolerate it well and find it acceptable [11]. Presence or absence of a thrombophilia does not change that recommendation, as finding a thrombophilia would only push a patient lower in the triangle, but absence would not move the patient higher up in the triangle. Thrombophilia testing in these patients is, therefore, not helpful for their management. However, if a patient with unprovoked VTE is either at higher risk for bleeding or finds long-term anticoagulation fairly unacceptable, further blood testing might be helpful: a positive D-dimer or finding a strong thrombophilia would move the patient down in the triangle and would be reasons to consider long-term anticoagulation in spite of the higher bleeding risk or degree of a patient’s dislike of being on long-term anticoagulation. VTE associated with a minor transient risk factor A patient with VTE associated with a minor transient risk factor (estrogen-containing contraceptives, estrogen replacement therapy, minor surgery, minor immobility) appear to have an intermediate risk of recurrent VTE and are in the middle of the ‘‘recurrence triangle’’ [12, 13] (Fig. 2a). However, for several conditions, such as VTE associated with longer or shorter airline travel, minor surgeries, estrogen-containing contraceptives, the risk of recurrence is not well known. It is in these patients that I 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 recurrence triangle and are reasons to consider longterm anticoagulation. However, presence of a mild thrombophilia, i.e. the heterozygous prothrombin G20210A or heterozygous Factor V Leiden, mutation,
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does not or only slightly, respectively, push the position of the patient downward in the triangle. Arterial thrombosis Thrombophilias play less of a role in arterial thrombosis than in VTE, as arteriosclerosis is usually the predominant cause of arterial occlusive events. However, in the younger person with an unexplained arterial event, thrombophilia enters into the differential diagnosis. A systematic approach to the evaluation of such patients is advisable (Table 3). Heterozygous FVL and heterozygous prothrombin G20210A mutation are not, or only minimal, respectively, contributors to arterial thrombosis [14]. It is not known whether the uncommon thrombophilias homozygous FVL, homozygous prothrombin G20210A mutation, or the double heterozygous (FVL ? prothrombin G20210A) state increase the risk for arterial thrombosis. A large family study showed no association of arterial thrombosis with antithrombin deficiency, but a clear association with protein C and protein S deficiency [15]. Antiphospholipid antibodies (APLA) are known risk factors for arterial thrombosis. I discuss thrombophilia work-up with the younger patient with unexplained arterial thrombosis, with the goal of identifying one of the stronger thrombophilias.However, it is not known whether patients with non-arteriosclerotic arterial thrombosis and a strong thrombophilia are more effectively treated with antiplatelet or anticoagulant therapy. This lack of knowledge, obviously, needs to be discussed with the patient. From a pathophysiology point of view it makes sense to hypothesize that anticoagulant therapy might be effective for the prevention of recurrent arterial thrombotic events prophylaxis, as the prothrombotic defect with these non-APLA thrombophilias is in the plasmatic coagulation pathway (i.e. the coagulation cascade). Alternatively, it also makes sense to postulate that antiplatelet therapy might be effective, as arterial thrombosis, in general, is predominantly a platelet-driven process. And, finally, it is also reasonable to postulate that the combination of anticoagulant and anti-platelet agent might be most effective. Of course, a patient’s risk for bleeding needs to be factored into the decision-making, but this is typically low, as the patient is young. In summary, in this area of absence of evidence I have a preference to treat young patients with unexplained arterial thrombosis and strong thrombophilia with anticoagulation ± an anti-platelet agent, with re-evaluation after several months and periodically thereafter. However, the patient’s preference should also strongly factor into the decision-making. Pregnancy complications Women with thrombophilia are at increased risk for VTE ante- and post-partum and with assisted reproduction. They also have a higher rate of placenta-mediated pregnancy
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a VTE, major transient risk factor
3 months
Long-term
• DVT • PE
Strong Thrombophilia
Woman, unprovoked VTE
- D-dimer +
VTE due to minor transient risk, woman with VTE on hormones
Man, unprovoked VTE • DVT • PE
VTE = venous thromboembolism; DVT = deep vein thrombosis; PE = pulmonary embolism
b
c 1a
1a
4b
3 months
4b
3 months
C 1b 4a
A
4a
3b
3b
2b
Long-term 2a
4c 3a
3c
Fig. 2 a–c ‘‘Risk of recurrence triangle’’—how long to anticoagulate? a Position in the lower part of the triangle indicates a higher risk of recurrence; position in the tip of the triangle a low risk. Position above dotted red line is the area where the risk from major bleeding on anticoagulation is higher than the risk of a recurrent VTE (case-fatality) and, thus, discontinuation of anticoagulation is indicated. A position below the red line indicates that the case-fatality from a recurrent VTE is higher than that of a bleed. The position of the red line varies from patient to patient, depending on bleeding risk, as well as patient preference to be on an anticoagulant or not (‘‘anticoagulant hate factor’’). b Patient examples how the ‘‘recurrence triangle’’ can be used in the decisionmaking and discussion with the patient: Patient #1: VTE associated with major risk factor; low risk for recurrent VTE (position 1a); no benefit form thrombophilia or D-dimer testing; while a positive D-dimer or presence of a strong thrombophilia would push the patient down in the triangle (to position 1b) the patient would still be above the red line, where discontinuation of anticoagulation is indicated. Patient #2: Man with unprovoked VTE; high risk of recurrence (position 2a); no benefit from thrombophilia or D-dimer testing: while a negative D-dimer moves the patient somewhat up to a lower risk of recurrence, he is still below the red line and long-term anticoagulation is indicated. Patient #3: Woman with unprovoked VTE; risk of recurrence is on the high side (position 3a); no benefit from thrombophilia or D-dimer testing; while a negative D-dimer moves the patient up some to a lower risk of recurrence (position 3b), it is still below the red line where long-term anticoagulation is indicated. Patient #4: Man or woman with minor risk factor (short distance travel; minor surgery, such as arthroscopic surgery, outpatient surgery, etc.; cast or boot immobilizer) or woman with hormone-
2b
Long-term 2a
4c 3a
B
3c
associated VTE (position 4a); thrombophilia and D-dimer testing help decide on length of anticoagulation: a positive D-dimer (on and off anticoagulation) and finding of a strong thrombophilia push the patient down in the triangle (position 4c), below the red line. A negative D-dimer and absence of a strong thrombophilia push the patient above the red line (position 4c) where anticoagulation can be discontinued. c Length of anticoagulation based on bleeding risk and ‘‘Anticoagulant hate factor’’. High bleeding risk, high ‘‘anticoagulant hate factor (line ‘‘B’’). The red line is moved down in the patient with bleeding risk factors (such as old age, renal impairment, liver synthetic function, concomitant anti-platelet therapy, history of bleed, widely fluctuating INRs on warfarin etc.). The threshold to take a patient off anticoagulation is lowered for fear of bleeding. The same downward move of the red line occurs in the patient whose preference is not to be on anticoagulation. A positive D-dimer or the finding of a strong thrombophilia, which both indicate a higher risk for recurrence, would be arguments to keep the patient on anticoagulation, accepting the higher risk for bleeding. Example: the woman with unprovoked VTE (position 3a) at increased risk for bleeding or with a high ‘‘anticoagulant hate factor’’ may now decide to come off anticoagulation, particularly if she has a negative D-dimer and no strong thrombophilia (position 3b). However, finding a positive D-dimer or a strong thrombophilia (position 3c) may argue for continued anticoagulation. Low bleeding risk, low ‘‘anticoagulant hate factor (line ‘‘C’’): The red line is moved up in the patient at low risk for bleeding risk or a low ‘‘anticoagulant hate factor’’. The threshold to keep a patient on anticoagulation is lowered. Example: the woman with unprovoked VTE (position 3a) may more comfortably decide to stay on anticoagulation, even if her D-dimer is negative (position 3b)
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complications (recurrent early pregnancy losses, late pregnancy loss, preeclampsia, intrauterine growth restriction (IUGR), and placental abruption), even though these associations are somewhat controversial. These topics have recently been discussed in detail elsewhere [16–18]. •
•
Increased VTE risk Women with or without thrombophilia and at increased VTE risk ante- and postpartum should be treated per existing evidence-based guidelines. [19–21] Pregnancy loss and placenta-mediated pregnancy complications It is unclear whether anticoagulation in
pregnant women with thrombophilia is beneficial to prevent recurrent early or late pregnancy loss. Clinical studies have not clearly and unequivocally shown benefit of anticoagulation. An ongoing study (ALIFE2) is trying to address this issue further [22]. While my practice is to offer (but not inevitably recommend) thrombophilia testing to women with unexplained pregnancy loss (C3 before week 10 or C1 after week 10) and women with unexplained placenta-mediated pregnancy complications, my recommendations for management of future pregnancy, if a thrombophilia
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 Obesity 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 autoimmune disease (arthritis, purpura, 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) Hemoglobin and platelet count Antiphospholipid antibodies Anticardiolipin IgG and IgM antibodies Anti-b2-glycoprotein-I IgG and IgM antibodies Lupus anticoagulant Protein C activity Protein S activity and free protein S antigen Antithrombin activity Homocysteine 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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Thrombophilia
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is found, are often more of a discussion of the limitations of our current knowledge than a true recommendation. Family testing Table 4 summarizes my approach to thrombophilia testing in family members of patients with known thrombophilia. It is worth noting that a family history of VTE by itself— independent of the identification of a thrombophilia—increases an asymptomatic person’s VTE risk two- to threefold, and even more so when several family members have had VTE, independent of the presence of a thrombophilia [23, 24]. And, to no surprise, the VTE risk for the asymptomatic individual increases further, the more VTE risk factors the person has, such as obesity, estrogen-containing contraceptive use, underlying thrombophilia [23– 25]. Thus, individualized recommendations need to be given on what impact the presence of these various risk factors has on a person in respect to the absolute risk of VTE. That absolute risk then determines what recommendation to give regarding choice of contraceptives, pregnancy management, and VTE prophylaxis in risk situation. Unfortunately, for many of these risk factors it is not known how they interact (additive, multiplicative, etc.). Figure 3 depicts a summary of contraceptives for discussion with the woman at risk for VTE, with the safest methods listed in green at the bottom of the triangle and the ones with the highest risk of VTE shown at the tip of the triangle. Broadening of the triangle while moving up reflects increased VTE risk. Whom NOT to test
‘‘indiscriminate’’ approach to thrombophilia testing that was promoted in earlier guidelines is not supported by 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 (\50 years old) and have an unprovoked VTE, (c) with VTE in unusual locations, (d) with VTE of unusual extent, or (e) with VTE recurrence in spite of anticoagulation. Instead, a rather more selective approach to testing seems most appropriate, as discussed above and summarized in Table 2. Existing guidelines Various guidelines have incorporated statements on thrombophilia, but given the broadness of the topic and the limited knowledge of some of the clinical aspects, the guidelines have significant limitations, tend to generalize, and are of limited helpfulness in a number of patient situations that clinicians encounter in clinical practice. • The British Society for Haematology in 2010 in its ‘‘Clinical guidelines for testing for heritable thrombophilia’’ gives the most comprehensive recommendations—summarized in 30 bulleted points—as to (a) who should be tested, (b) who should not be tested, and (c) in which individuals no validated recommendations can be made about benefit of testing given a lack of evidence base [7]. Many of the recommendations and suggestions are weak recommendations, reflecting that for many clinical scenarios there is only moderate or low quality evidence as to who should and should not be tested. • The ACCP 2012 guideline (a)
In the last few years it has become clear that the presence of a thrombophilia often does not influence clinical management. Therefore, a more wide-spread, ‘‘unselected’’, or
In regard to VTE, the guideline concludes that while hereditary thrombophilias and antiphospholipid antibodies predict recurrence of VTE, 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 Sons
Female family member 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
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• Ring (Etonogestrel & estradiol)
Estrogen combination pill
• Patch (Norelgestromin & ethinyl estradiol) • 4th generation pills (Drospirenone & ethinyl estradiol)
• 3rd generation
• 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. 2. Rosendaal FR, et al. Thromb Haemost. 2001;6:112-23.
3. Conard J, et al. Contraception. 2004;70:437-441. 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
(b)
(c)
•
enough to influence recommendations on duration of anticoagulant therapy’’, once the ‘‘primary [provoked versus unprovoked event] and secondary factors [(a) distal DVT versus proximal DVT or PE; (b) first versus recurrent VTE] have been considered’’ [11]. In respect to arterial thrombosis, the ACCP 2012 guideline takes only reference to APLA, and states that ‘‘subgroup analyses of secondary prevention studies have not identified effects that warrant separate treatment recommendations for any specific subset of patients with noncardioembolic stroke’’ and that ‘‘recommendations for all subgroups, therefore, follow the general recommendations regarding patients with non-cardioembolic stroke’’ [26]. In respect to women and pregnancy, the ACCP 2012 guideline gives detailed management suggestions for women with and without VTE, and for women with and without thrombophilia [20]. They also suggest that women with a history of pregnancy complications not be screened for inherited thrombophilias [20].
The 2012 NICE Guideline is a guideline from the British National Institute for Health and Clinical Excellence (NICE), published by the National Clinical Guideline Centre (NCGC) and others [27, 28]. The expert panel’s conclusions and recommendations are:
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(a)
Do not offer testing to •
• (b)
(c)
Patients with provoked VTE (due to transient major risk factor, such as trauma, surgery, prolonged immobility, pregnancy, postpartum state) or VTE due to hormonal therapy (oral contraceptive pill, hormone replacement therapy), as these patients need short-term anticoagulation no matter whether a thrombophilia is present or not. Patients with VTE who are going to be on long-term anticoagulation anyway.
Do not routinely offer testing to first degree relatives of patients with VTE and thrombophilia, as thrombophilia results would usually not—except for rare circumstances—alter the decision-making regarding thrombo-prophylaxis. Consider testing in patients with unprovoked VTE in whom discontinuation of anticoagulant therapy is planned, for • •
APLA, as finding APLA may be a reason to continue long-term anticoagulation. Hereditary thrombophilia if the patient also has a family history of VTE in a first degree relative, as finding a deficiency of protein C, protein S or antithrombin may be a reason to continue long-term anticoagulation. Homozygous FVL, homozygous prothrombin
Thrombophilia
375
G20210A, and double heterozygous state are not mentioned in this statement. •
•
•
EGAPP (Evaluation of Genomic Applications in Practice and Prevention) Working Group in 2011 limits its testing recommendations to patients with unprovoked VTE and recommends against ROUTINE testing of such patients for FVL and prothrombin G20210A mutation. However, this recommendation does not extend to ‘‘patients with other risk factors for thrombosis, such as contraceptive use’’ [29]. The Choosing Wisely 2013 campaign from the American Society of Hematology made a very focused recommendation to ‘‘not test for thrombophilia in adult patients with VTE occurring in the setting of major transient risk factors (surgery, trauma, or prolonged immobility). [10] The ACOG (American College of Obstetrics Gynecology) 2013 Practice Bulletin on inherited thrombophilias in pregnancy gives detailed guidance on management of pregnant women with and without thrombophilia [19].
Thromobphilia testing What to test Table 5 lists the thrombophilia tests that seem reasonable to the author to consider when testing is indicated. Testing caveats Tables 6 and 7 summarize the most important points to consider when interpreting thrombophilia test results. One
could well argue to NOT do thrombophilia testing in the setting of an acute VTE or while a patient is on an anticoagulant given that (a) acute thrombosis and being on an anticoagulant influence many of the test results and (b) the management of acute VTE in the first 3 months is the same no matter whether a thrombophilia is present or not. When to test It seems like a reasonable clinical management approach to treat a patient with VTE with anticoagulation for 3 months and then, in the patient in whom one concludes that thrombophilia testing will contribute to the length of anticoagulation management decision, to obtain a D-dimer and those thrombophilia tests that can be reliably done on anticoagulation (FVL, prothrombin G20210A, anticardiolipin and anti-b2-glycoprotein-I antibodies). If these tests are negative/normal, then one can discontinue anticoagulation and 4 weeks later obtain a repeat D-dimer and the residual thrombophilia laboratory test (lupus anticoagulant, activities of protein C, S and antithrombin, free protein S antigen). If any of these tests are clearly abnormal, moving the patient down in the ‘‘recurrence triangle’’, then one can resume anticoagulation. If anticoagulation resumption with warfarin occurs, then bridging with a fastacting anticoagulant for five days may be safest, particularly if the patient is found to have protein C or S deficiency; alternatively, a direct oral anticoagulant (DOAC) could be started without a bridging parenteral anticoagulant. Additional comments: •
It could be argued that blood testing done to determine length of anticoagulation could be limited to D-dimer testing (on and off anticoagulation) and that individual
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 venous thrombosis (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 Protein C
Condition 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 Heparin therapy Liver disease Nephrotic syndrome 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 would be expected to capture the presence of a strong thrombophilia by being positive. At present, evidence for this assumption does not exist. When discontinuing anticoagulation for 4 weeks to obtain reliable results for protein C and protein S activities and an off-anticoagulation D-dimer, the author does not bridge the patient with low molecular weight heparin or another anticoagulant, as that would defeat the goal of getting a D-dimer test with the patient having been off anticoagulation for 4 weeks. Patients likely have to be off DOACs, low molecular weight heparin and fondaparinux for ca. 48 h (and for longer if renal function is impaired) for valid functional coagulation test results for protein C, protein S and antithrombin activities, and lupus anticoagulant. Warfarin should have been discontinued for 3 or more weeks before protein C and S testing is done.
Patient education and support resources •
•
www.clotconnect.org: Clot Connect, a non-profit information/education resource of the University of North Carolina (UNC) at Chapel Hill, has information for patients on DVT, PE, thrombophilia and anticoagulation. stoptheclot.org: The National Blood Clot Alliance (NBCA) is a non-profit patient-led advocacy organization for patients with blood clots, with a focus on national VTE advocacy and patient information.
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•
www.natfonline.org: The North American Thrombosis Forum is a non-profit health organization with, in respect to patients, a focus on creating VTE patient support groups.
Summary points •
Only a physician who is able to provide the ‘‘4P’’ should order thrombophilia tests: 1: 2: 3: 4:
Appropriately select which patient should be tested Provide pre-test counseling Properly interpret the lab tests Provide education and advice to the patient.
•
Do not do thrombophilia testing at the time of an acute thrombotic event. If testing is needed, test at 3 months, together with a D-dimer.
•
Do not do thrombophilia testing while a patient is on an anticoagulant.
•
Do not test for thrombophilia in patients whose VTE was provoked by a major transient risk factor, such as surgery.
•
Be aware of the influences of anticoagulants on thrombophilia test results (Table 7).
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Table 7 Influence of acute thrombosis and anticoagulants on thrombophilia test results Test
Acute thrombosis
Unfractionated heparin
Low molecular weight heparin
Vitamin K antagonists
DOACs
Factor V Leiden genetic test
Reliable
Reliable
Reliable
Reliable
Reliable
a
???
???
b
Reliable
a
a
Unreliableh
APC resistance assay
Reliable
Prothrombin G20210A genetic test Protein C activity
Reliable
Reliable
Reliable
Reliable
Reliable
???c
Reliable
Reliable
Low
Elevatedf
c
Protein C antigen
???
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
Anti-ß2-glycoprotein-I antibodies
Accurated
Reliable
Reliable
Reliable
Reliable
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 APC resistance assay may be falsely normal (i.e. false negative) [39]
h i
Lupus anticoagulant tests can be false positive on the NOACs [40]
Conflict of interest
None.
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