Prim Care Clin Oce Pract 31 (2004) 685709

Genetic thrombophilia
W. Gregory Feero, MD, PhDa,b,*
Department of Community and Family Medicine, Dartmouth Medical School, Hanover, NH, 03755, USA b Maine-Dartmouth Family Practice Residency, 4 Sheridan Drive, Augusta, ME 04937, USA
a

Thrombophilia can be dened as a predisposition to form clots inappropriately. In current literature, thrombophilia typically refers to clotting events occurring in the venous side of the circulatory system. The predisposition to form clots may arise from genetic factors, acquired changes in clotting homeostasis, or, most commonly, an interaction between genetic and acquired factors [13]. Since the 1990s, there has been an explosion of literature relating to both aspects of thrombophilia, broadening understanding of causes of deep vein thrombosis (DVT) and many other important clinical phenomena. In particular, two common genetic abnormalities now are known to predispose to venous thrombotic events, the factor V Leiden (FVL) mutation and the prothrombin G20210A gene mutation [4,5]. This article focuses on clinically relevant aspects of genetic venous thrombophilia.

Case studies Case 1 A 32-year-old, G2P0020, white homemaker presented to her primary care clinician with a chief complaint of being unable to conceive for several years with a partner who had children via a previous marriage. She was particularly worried that her family history of DVT related to antithrombin deciency might play a role. Her personal history was positive for two miscarriages, depression, and smoking. Her only medication was citalopram (Celexa). Her family history was signicant for a brother with lower extremity DVT in his 30s. Her mother had several DVTs and a myocardial infarction at age 50. Her maternal uncle, who was known to be
* Maine Dartmouth Family Practice, 4 Sheridan Drive, Faireld, ME 04937, USA. E-mail address: gfeero@mainegeneral.org 0095-4543/04/$ - see front matter 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.pop.2004.04.014

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antithrombin decient, had a DVT at age 30 and a myocardial infarction in his 50s. Physical examination was unremarkable. Case 2 A 41-year-old white male roofer presented to a primary care oce with a chief complaint of left leg swelling and pain. He reported drinking heavily 2 nights previously, passing out, then waking in the morning with mild leg swelling and discomfort, which had gradually worsened. He had no pulmonary complaints or chest pain. The patients past medical history included alcohol abuse, smoking, and hemorrhoids. The patient was taking no medications. Family history was unremarkable for venous thrombotic events. On physical examination, he was mildly hypertensive and had normal respiratory parameters. Extremity examination revealed a swollen, mildly erythematous left calf that was painful on palpation. Homans sign was positive.

Homeostasis The circulatory system is remarkable in many ways, one of which is the elaborate way in which it overcomes the demands of ow. Blood, which can be thought of as a suspension of solids, must be able to ow freely through vessels ranging in diameter from 2.5 cm to 8 lm [6]. This feat is particularly incredible given that the diameter of some cellular constituents exceeds that of the smallest vessels. At the same time, the system may encounter instantaneous damage resulting in leakage that must be stemmed quickly to prevent exsanguination. This problem is overcome by an elaborate and redundant set of pathways consisting of soluble, inactive proteins and cellular components that can convert the usually free-owing liquid to a semisolid in a matter of seconds. There are two major pathways by which this process may be activatedthe intrinsic and extrinsic pathways. A brief description of these pathways is given; readers interested in more detail are referred to other publications [68]. Fig. 1 shows a simplied diagram of the pathways, with the factors that are identied as being involved in genetic thrombophilia highlighted. Clotting factors, when present in abnormal amounts or levels of activity, may tip the balance of the circulatory system to the generation of brin and clot formation.

Ecogenetics Despite the high-tech advances brought about by molecular genetics, Virchows [9] century-old description of factors predisposing to venous thrombosis (stasis, injury, and changes in blood chemistry) remains germane

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Protein C Protein S Extrinsic Pathway

+
Factor X

Prothrombin

+
Thrombin

+
Intrinsic Pathway Factor V

Fibrinogen Fibrin

Antithrombin

Fig. 1. Simplied diagram of the clotting cascade. Intrinsic and extrinsic pathways lead to activation of factor X, which plays a role in converting inactive prothrombin to thrombin. Thrombin converts soluble brinogen to brin, a major component of clots. Negative () symbols denote inhibitory actions on this process; positive () symbols denote procoagulant actions. Factors causing genetic thrombophilia are in boxes.

to understanding venous thrombosis. Although Virchow could not have known it, he was foreshadowing the concept of ecogenetics, which refers to the interaction of the environment with an individual or populations genotype (genetic makeup), resulting in phenotypic (clinical) manifestation [10]. For most genetic conditions that predispose to clot formation, stasis and injury are likely the triggers for clinical expression. These environmental triggers may or may not be easy to identify. Blood chemistry (eg, levels of clotting proteins, hormonal status) further inuences the phenotypic expression of thrombophilia [7,8,11]. Blood chemistry also is inuenced greatly by the environment. The complexity of these interactions makes the study of thrombophilia challenging [12]. The potential for interactions between specic genotypes and environmental factors complicates the study of the potential phenotypic eects of gene mutations. This situation may account for some of the conicting results found in the literature for certain gene mutations. Some studies show an increased risk for venous thrombosis in carriers of the C677T methylene tetrahydrofolate reductase (MTHFR) gene mutation, whereas others do not [13]. In this case, high or low folic acid intake might mask or exacerbate possible genotypic eects. Thrombophilia literature always must be interpreted with gene-environment issues in mind. Environmental context also must be considered by the clinician caring for aected individuals. The risks for venous thrombosis for a healthy 20-yearold man who is heterozygous (one mutant gene copy) for FVL mutation dier substantially from that of a genotypically identical 40-year-old obese

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female smoker 2 days after cesarean section. Genetic predisposition to thrombosis might be thought of as lifelong elevation of a baseline risk for thrombosis. This baseline risk is age dependent, is modied by circumstances such as stasis, and may exceed the threshold for clot formation in genetically predisposed individuals (Fig. 2). As with many chronic disease states, recognition and mitigation of environmental risks serves the clinician well in managing patients with thrombophilia.

Genetics of thrombophilia Genetic thrombophilia is a multifactorial or complex disorder [1416]: Mutations in several distinct genes or several distinct mutations in a single gene can result in a similar clinical outcome. In the case of the genetic thrombophilias, the most common clinical consequence is DVT of the lower extremities. To date, there are ve reasonably common genetic factors that clearly predispose to genetic thrombophilia [1315,17,18]. In whites, these factors may account for 35% of DVT occurring with no clear environmental trigger [15,19,20]. A myriad of other factors are likely contributors to disease. Some of these are not discussed here because of their rarity; others

Fig. 2. Risk curves for deep vein thrombosis (DVT) in two patients. The vertical axis units represent arbitrary risk units; the horizontal axis, patient age in years. The bold horizontal line represents an arbitrary threshold for DVT occurrence. Patient A has no hereditary predisposition to clot formation; patient B does. Peaks in the curves represent environmental inuences that temporarily elevate thrombotic risk (eg, fracture, use of oral contraceptives, pregnancy, hormone replacement therapy). Patient B exceeds the threshold for thrombosis twice (open circles), whereas patient A does not.

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are not discussed because of the lack of a well-dened genetic basis or because the causal association with venous thrombosis has not been clearly proven (Table 1) [12,15,2022]. Genetic thrombophilias seem to t in a middle ground between the classic genetic diseases that are caused by single-gene mutations (monogenic, eg, cystic brosis, Duchenne muscular dystrophy, and Huntingtons disease) and common, complex diseases (eg, type 2 diabetes and cardiac disease). Generally, monogenic disorders are caused by gene mutations that have low prevalence in the population and high penetrance (the probability of a clinical consequence given the mutation and little environmental interaction. In multifactorial or complex disorders, there are likely many common gene mutations that have a small risk of causing disease, which when assembled in one individual, in the proper environment, result in clinical disease [2325]. In thrombophilia, a handful of identied gene mutations have moderate penetrance, with relatively high prevalence, where environmental interactions are important. It seems likely that future studies will dene additional contributory genetic factors of lower penetrance and high population prevalence. Thrombophilia provides a conceptual middle ground for clinicians and researchers trying to understand and combat more common disorders. There are many mechanisms by which DNA mutations may aect their gene products. Geneticists frequently conceptualize two major divisions of mutations: (1) mutations that result in gain of function and (2) mutations that result in loss of function of the gene product. Gain-of-function mutations confer a new activity on their gene product, either by changing the gene products function or by boosting its activity. Gain-of-function
Table 1 Factors causing genetic thrombophilia Established genetic factors Factor V Leiden Prothrombin G20210A Protein C deciency Protein S deciency Antithrombin deciency Rare genetic factors Dysbrinogenemias Homocystinuria Factor V mutationsother Indeterminate factors Elevated factor VIII Elevated factor IX Elevated factor XI Plasminogen deciency Tissue plasminogen activator Hyperhomocysteinemia Elevated thrombin-activatable brinolysis inhibitor Elevated lipoprotein(a) Factor VII Factor XII Platelet glycoproteins Plasminogen activator inhibitor 1 Heparin cofactor II Thrombomodulin Histidine-rich glycoprotein

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mutations frequently result in disorders that are inherited in a dominant pattern (eg, Huntingtons disease). The FVL mutation and the prothrombin G20210A mutation are gain-of-function mutations, with a dominant pattern of inheritance [5,26]. Loss-of-function mutations result in diminished or eliminated gene product activity. Protein C, protein S, and antithrombin deciencies t into this category [19,20]. For most metabolic disorders, loss of function results in a recessive pattern of inheritance because 50% of normal protein function usually suces. This is not the case for genetic protein C, protein S, and antithrombin deciencies, however. In the context of the nely balanced homeostasis of the circulatory system, 50% activity of these proteins is low enough to cause disease. Heterozygotes have mild predisposition to disease, and homozygotes (two mutant copies of the gene in question) have severe, frequently fatal, disease [27]. Constructing a pedigree for a family with clinical evidence for inherited thrombophilia may not help predict whether or what type of genetic disorder aects the family because of variable penetrance, pleiotropy, the presence of phenocopies, and the issue of double heterozygosity. Penetrance is an extremely important concept to understand when considering genetic thrombophilia because the common FVL and prothrombin G20210A gene mutations have low penetrance [2730]. These gene mutations are inherited in an autosomal dominant pattern. Because these mutations are not fully penetrant, however, the pedigree of a family with DVT or related disorders may show skipped generations. Also, far less than 50% of the rst-degree relatives (parents, siblings, children) manifest venous thrombosis. Pleiotropy is the property of certain genetic mutations to manifest with dierent clinical pictures in aected individuals, even within one family. A family history of genetic thrombophilia might include a diagnosis not recognized as being thrombophilia related, such as stroke (cerebral vein thrombosis) or sudden death (pulmonary embolism), and rarely discussed diagnoses (recurrent spontaneous abortion or stillbirth). Unless the clinician and the patient are savvy history takers, the familial nature of the disorder might go unrecognized. Phenocopies, or individuals with clinical disease arising from nongenetic factors, can complicate interpreting the family history because thrombophilic events are common and not all genetically based. Finally, in some families with a high burden of thrombotic disease, two genetic thrombophilias might occur together, which can result in severely aected individuals and less severely aected individuals in the pedigree. In this situation, an analysis of the pedigree alone cannot tell whether severely aected individuals are homozygotes for one disorder or heterozygotes for mutations in two separate genes (double heterozygote). This situation arises with some frequency in genetic thrombophilia due to the relative high prevalence of the gene mutations in certain populations [31]. Finally, because racial diversity is a hallmark of many primary care practices, the clinician should be aware that the prevalence of these mutations varies among certain ethnic and racial groups. The two most

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commonly researched predisposing genetic factors for thrombophilia, FVL gene mutation and prothrombin G20210A gene mutation, have estimated prevalances of 5% and 2% in caucasians [5,32,33]. They are rare, however, in African and Asian populations (Table 2) [5,3237]. Among African Americans and Asian Americans, the gene prevalences are intermediate, likely a result of population admixture. Clinicians should use caution in applying studies of genetic thrombophilia derived from one population to members of a dierent ethnic group. The same panel of tests for thrombophilia that might work well in a clinic in central Maine (>95% caucasian) may be less helpful in a clinic populated by Somalians in New York City.

Spectrum of disease Thrombophilia in children Thrombotic events are rare in pediatric populations, with rates for DVT of about 1 in 100,000 [38]. Thrombotic events in children sometimes are not the same as in adults (Box 1) [3842]. In children, thrombotic events are frequently a consequence of identiable genetic or iatrogenic causes (eg, central lines) [39]. In pediatric populations, severe protein C, protein S, and antithrombin deciencies have been identied as causing genetic thrombophilia [39]. FVL and prothrombin G20210A gene mutations also cause spontaneous disease in children and may play a synergistic role with other factors in the development of thrombosis [41,43]. Although not typically considered among the genetic thrombophilias, sickle cell disease and b-thalassemia do predispose to venous thrombotic events in children as well [38]. Rarer disorders, not discussed here, such as homocystinuria (as a consequence of mutations in the cystathionine b-synthase gene) also cause thrombotic complications, often presenting in childhood [43]. Complete deciency of protein C or S (homozygous individuals) causes the most dramatic clinical consequence of the genetic thrombophilias neonatal purpura fulminans and disseminated intravascular coagulation (incidence about 1 in 160,000 to 1 in 360,000) [44]. This condition results in systemic, catastrophic clot formation. Patients present in the rst few days of life with a picture of skin necrosis and shock and frequently die, although

Table 2 Approximate prevalence of genetic thrombophilias by population Genetic abnormality Factor V Leiden Prothrombin G20210A Protein S Protein C Antithrombin Caucasian 5% 3% 0.0030.2% 0.20.4% 0.020.2% African \0.1% \0.1% ? ? ? Asian \0.1% \0.1% ? ? ?

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Box 1. Pediatric disorders associated with genetic thrombophilia Neonatal purpura fulminans Renal vein thrombosis Vena cava thrombosis Portal vein thrombosis Hepatic venous thrombosis Catheter-related thrombosis Central nervous system venous thrombosis Cerebral palsy Legg-Calve -Perthes disease Limb vein thrombosis Pulmonary embolism

there are reports of longer term survival in children treated with clotting factor derivatives or liver transplantation [38,39,44]. Complete deciency of functional antithrombin is rare, likely a result of its being lethal during embryonic development [15,45]. Partial deciency of protein C, protein S, or antithrombin and the FVL and prothrombin G20210A gene mutations have been linked to central nervous system venous thrombosis and abdominal venous thrombosis, although because the events are rare, data are sparse [42,44]. Frequently, thrombotic events occur in the setting of already compromised neonates with prematurity or other severe illness [39]. Anticoagulation with heparins and oral anticoagulants can treat and prevent recurring episodes of these disorders, although the event itself may have catastrophic consequences [4648]. Thrombophilia in adults In adults, the genetic thrombophilias most commonly manifest as lower extremity DVT (incidence 1 in 1000), although evidence for roles in many other disorders exists (Box 2) [2,8,15,19,20]. Most DVT can be attributed to extrinsic and other nongenetic factors (limb immobilization, surgery, malignancy, hormonal therapy), but known genetic factors can be identied in 35% of spontaneously occurring DVT [19,20]. DVT can aect upper and lower extremities, and its incidence increases with age [1]. The most dreaded consequence of DVT is pulmonary embolism. Typically arising from clots mobilized from leg or pelvic veins, pulmonary embolism has a mortality rate of about 15% [49]. Another important consequence of DVT is postphlebitic syndrome. Occurring in about 20% of DVT patients, postphlebitic syndrome may cause signicant pain and chronic edema in the aected

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Box 2. Adult disorders associated with genetic thrombophilia Deep vein thrombosis Pulmonary embolism Supercial venous thrombosis Chronic venous ulceration Colonic ischemia Warfarin-induced skin necrosis Cerebral vein thrombosis Myocardial infarction Portal vein thrombosis

limb [50]. Genetic thrombophilia also may predispose to supercial thrombophlebitis and chronic lower extremity venous ulceration [51,52]. Mesenteric and cerebral venous thromboses also occur in adults, although at lower rates than DVT [15,5356]. Genetic thrombophilias are thought to contribute to these disorders to varying degrees, but the data for these associations is less robust than that for DVT, owing to their rarity. Predicting the consequences of genetic thrombophilia is problematic for some venous thrombotic disorders. There is no clear association between most retinal venous thromboses and mutations in genes known to cause thrombophilia [57]. Womens health issues Genetic thrombophilia and womens health issues intersect at three pointsoral contraceptive pill (OC) usage, hormone replacement therapy (HRT), and pregnancy (Table 3) [5864]. For OC, the risks for women with genetic thrombophilia are reasonably well dened [59]. In the setting of pregnancy and HRT, the risks of genetic thrombophilia are less well dened [60,65,66]. The nature of these intersections highlights the importance of gene-environment interactions in genetic thrombophilia. OC usage results in extensive alterations in the levels of clotting factors [67]. Even in normal individuals, the administration of estrogens and progesterones exogenously results in a prothrombotic situation, with the level of risk depending on the quantity and quality of the hormones introduced [62,68,69]. Given that DVT is rare in young, nonpregnant women (incidence 1 in 10,000), absolute risks of DVT with OC use is still low (34 in 10,000) [62]. The benecial eects of convenient, highly eective contraception result in this risk of thrombosis being accepted by society. OC synergistically increase the risk of DVT for individuals with the FVL and prothrombin gene mutations to about 40 to 50 fold baseline (see Table 3) [70,71]. Given the high frequency of FVL and the prothrombin G20210A

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Table 3 Interaction of genetic thrombophilias, oral contraceptive pills, hormone replacement therapy, and pregnancy on deep vein thrombosis risk* Genetic thrombophilia No mutation Factor V Leiden Prothrombin G20210A Protein C Protein S Antithrombin Risk increase Risk increase with OC Risk increase with HRT ? ? ? Risk increase with pregnancy

Abbreviations: HRT, hormone replacement therapy; OC, oral contraceptive pills. * Table depicts risks semiquantitatively and is for rough comparison only.

gene mutations in whites, some authors have suggested genetic screening of individuals interested in using OC [72,73]. Several groups have analyzed carefully potential consequences of such a screening program and found that the societal costs of such a program would be prohibitive [74,75]. As with OC, HRT results in altered levels of clotting factors with the development in normal individuals of a prothrombotic state [76]. Although the magnitude of the increased risk of DVT may be lower (22.5 fold) than with OC, the overall risk of DVT may be higher in the HRT population because of the increasing risk of DVT with age [60,76,77]. Analogous to the situation with OC use, the risk for thrombosis in persons with a genetic thrombophilia when taking HRT is magnied (see Table 4). In light of studies showing negative health consequences of HRT unrelated to thrombosis, it seems likely that fewer women would choose to take HRT long-term [7882]. Many clinicians are likely to continue prescribing HRT, however, for short-term control of perimenopausal symptoms. In this setting, potential interactions between genetic thrombophila and HRT must be considered because many HRT-related complications occur in the rst year of therapy [60,81]. In the setting of pregnancy, altered hormone levels and hemodynamics result in an acquired thrombophilia with a risk of about 1 in 1000 of DVT [65,83]. Pulmonary embolism is the leading cause of maternal mortality in developed countries [83]. In the setting of genetic thrombophilia, the risk for maternal DVT is increased to a varying degree depending on the particular gene defect (see Table 4). Women with antithrombin deciency seem at particularly high risk with about a 1 in 3 incidence of DVT per pregnancy [63]. Some literature suggests a role for not only acquired, but also genetic thrombophilias in intrauterine growth restriction, pre-eclampsia, and HELLP (hemolysis, elevated liver enzymes and low platelets) syndrome, although a clear association is not universally evident [66,8489]. For the fetus of a mother with genetic thrombophilia, risks seem to be greatest for stillbirth after 20 weeks of gestation, likely as a consequence of

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Table 4 Treatment and prophylaxis options for individuals with known genetic thrombophilia in various clinical settings Patient characteristics Asymptomatic Treatment/prophylaxis Vigorous prophylaxis during high-risk periods (eg, surgery), avoidance of hormonal products and prolonged immobility Add low-dose aspirin, warfarin during postpartum period* Therapeutic heparin/low-molecular-weight heparin, followed by 6 mo of oral anticoagulation Therapeutic heparin/low-molecular-weight heparin, followed by lifelong oral anticoagulation

Pregnant, asymptomatic Single DVT Life-threatening thrombosis Atypical thrombosis Recurrent thrombosis Homozygous or heterozygous for two defects* Antithrombin decient* Pregnant, single prior thrombotic event Pregnant, antithrombin decient Pregnant, asymptomatic, other risks Pregnant, asymptomatic (optional*) Pregnant, current thrombotic event Pregnant, recurrent thrombosis Pregnant, prior lifelong anticoagulation

Antepartum prophylactic dose of low-molecularweight heparin, postpartum oral anticoagulation for 6 wk

Antepartum therapeutic dose of low-molecularweight heparin, postpartum oral anticoagulation

Abbreviation: DVT, deep venous thrombosis. * Controversial.

placental infarction [66,90]. There is some debate about the role of genetic thrombophilia in recurrent spontaneous abortion before 20 weeks of gestational age, with multiple small studies of varying quality showing conicting results [66,90,91]. Whether genotype of the fetus aects pregnancy outcome is not clear. Thrombophilia in the elderly As previously stated, thrombotic risk is age dependent, and in the elderly population the risk of DVT is 1 in 100 [92]. The role of genetic thrombophilias in the elderly is not well studied and is confounded by the increasing incidence of many other age-related risk factors for thrombosis, such as diabetes, malignancy, medications, and need for joint replacement. In individuals with FVL mutation, advancing age further increases the risk for DVT [93]. Homocysteine levels also seem to increase with age [94]. Factor VIII also has been shown to play a role in DVT in the elderly [95]. The eects of genetic thrombophilia on the elderly are likely to become of increasing interest as the population ages, and more previously asymptomatic individuals with genetic thrombophilia experience DVT.

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Specic disorders Factor V Leiden mutation In 1994, Bertina et al [4] described a defect in the factor V gene that renders factor V substantially less susceptible to inactivation by activated protein C. The change in protein function is the result of a single base-pair alteration that causes an amino acid substitution at a critical site for the cleavage of active factor V by activated protein C. Constitutively active factor V (gain-of-function mutation) enhances the function of factor X [96]. The consequence of this excess activity is a propensity for inappropriate clot formation that is inherited in an autosomal dominant pattern. Before description of the genetic mutation, it was recognized that addition of activated protein C to patients plasma fails to prolong the activated partial thromboplastin time, hence the term activated protein C resistance [97,98]. Although several other mutations are known to occur in the factor V gene that result in clinically indistinguishable disease, the FVL mutation accounts for 90% of activated protein C resistance in whites [8,19,20]. As a result of the 10% risk that an alternative genetic defect might be overlooked by testing patients only for the FVL mutation, many experts recommend the use of second-generation activated protein C resistance assays in the initial screening of patients. As of the writing of this article, there were 528 PubMed articles containing factor V Leiden as a keyword listed since 2001 (www.ncbi.nlm. nih.gov/PubMed/). These articles implicate the FVL mutation in clinical disorders ranging from inammatory bowel disease to renal vein thrombosis in transplant recipients [99101]. The quality of evidence linking FVL to these clinical disorders varies, with many small retrospective analyses with conicting conclusions and case reports being the norm. The strength of evidence implicating FVL as a cause of DVT among caucasian is substantial [102]. Although estimates vary, the risk increase for DVT in FVL heterozygotes is roughly 4 to 7 fold above baseline; for homozygotes, the risk may be 80 fold [2,15,102,103]. The risk of DVT may be overestimated in the average individual heterozygous for FVL because at least part of the original data arose from families with high burdens of thrombotic disease [28,104]. Heterozygotes usually present later in life than do homozygotes, and most patients present in adulthood [15]. Aected individuals may present with DVT in typical distributions and in atypical sites. It is not clear that the FVL mutation is as great a risk factor for pulmonary embolism as it is for DVT [105107]. Additionally, data suggest that the risk for recurrent DVT in carriers of FVL is not higher than that for patients with idiopathic DVT [108110]. FVL causes an increased risk of DVT in pregnant patients with risk elevations of approximately 10-fold [58,111,112]. FVL mutation also has been implicated in late term pregnancy loss [90,91]. As with the other genetic

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thrombophilias, the data supporting a role for FVL in recurrent spontaneous abortion, intrauterine growth restriction, and pre-eclampsia are conicting. Prothrombin G20210A In 1996, Poort et al [5] described a single amino acid change in the 39 untranslated region of the gene encoding prothrombin. Through unclear mechanisms, this change causes elevated levels of prothrombin and thrombin, an enzyme key to the conversion of brinogen to brin (gainof-function mutation, autosomal dominant inheritance) [30]. The prevalence of the prothrombin gene mutation is about 2% to 3% in whites, making it the second most common genetic thrombotic risk factor [27]. Similar to FVL, the prothrombin gene mutation is uncommon in noncaucasian populations. No reliable biochemical test is available for the prothrombin G20210A mutation. The prothrombin G20210A gene mutation also is associated with an elevated risk of DVT, albeit to a lesser degree than with FVL, with heterozygotes having about a 2 to 4 fold risk increase over baseline [30,31]. Prothrombin G20210A gene mutations also have been associated with venous thrombosis in unusual sites, such as cerebral vein thrombosis [53,113]. The prothrombin G20210A gene mutation probably also increases the risk of DVT when combined with OC, HRT, or pregnancy [60,62,65]. The prothrombin G20210A gene mutation may have less of a role in adverse pregnancy outcome than FVL, but it is not as well studied [66,86]. As is the case for FVL, the risk of recurrent DVT does not seem higher with the prothrombin G20210A gene mutation than with sporadic DVT in nonpregnant individuals [110,114]. Protein C deciency Protein C deciency is less common than FVL gene mutation or the prothrombin G20210A gene mutation by an order of magnitude, with prevalences in caucasians estimated at 0.2% to 0.4% [1]. Originally detected biochemically, genetic analysis of aected families has revealed more than 100 distinct disease-causing mutations in the protein C gene [115]. These mutations cause diminished levels of protein function, by aecting either the amount (type I disease) or the functionality of the gene product (type II disease) [15,27]. Diminished inhibitory feedback on clotting resulting from lower levels of functioning protein C causes a propensity for excess clot formation [27]. Most patients have type I disease [19]. Both categories represent loss-of-function mutations that result in disease because 50% of normal inhibitory clotting function is insucient. Genetic testing of a patients DNA for large numbers of possible mutations is technically challenging and expensive; biochemical assays normally are used to test for protein C deciency. Thrombosis, treatment

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of thrombosis, and pregnancy alter levels of protein C [19,20,61,116]; in these conditions, testing for protein C deciency should be postponed. The spectrum of disorders caused by protein C deciency is dierent than that of the FVL gene mutation and the prothrombin G20210A gene mutation. Homozygous individuals present in infancy with purpura fulminans and disseminated intravascular coagulation [19,20,44,61,116]. Heterozygotes face increased risk of DVT with an incidence 3.4 to 30 fold above population baseline [15,20,49,117]. Additionally, treatment of protein C (and protein S) decient individuals with warfarin can result in a rare condition called warfarin-induced skin necrosis. This disorder is thought to arise as a result of the transient decrease in protein C and protein S levels caused by warfarin binding in the bloodstream, which worsens a preexisting hypercoagulable state [118]. Protein C deciency seems to increase risk of DVT in users of OC [62]. Protein C deciency also has been implicated in adverse pregnancy outcomes, including DVT, preeclampsia, intrauterine growth restriction, and recurrent pregnancy loss [63,66,86]. Data quality in pregnancy suers as the disorder is uncommon and pregnant patients are a small population group. Protein S deciency Protein S deciency, with an estimated prevalence of 0.003% to 0.2%, is similar to protein C deciency clinically, biochemically, and genetically [20,27,119]. First described biochemically, protein S deciency results from one of more than 100 mutations in the protein S gene, most of which cause type I disease [19,119]. Protein S, as a cofactor with protein C, acts to dampen the tendency for clot formation [27]. As with protein C deciency, genetic testing is impractical in patients suspected of having the disorder. Biochemical testing for protein S also is aected by a myriad of factors and is the most problematic of the biochemical tests for genetic thrombophilia [119]. Clinically, homozygous protein S deciency causes neonatal purpura fulminans [44]. Heterozygous disease is associated with elevated risk of thrombosis and warfarin-induced skin necrosis [19,20,118]. Interaction with other genetic thrombophilias to elevate thrombotic risk further has been shown [120]. Protein S deciency is a risk factor for thrombosis in pregnancy and probably elevates risk of DVT in users of OC and HRT [60,62,63,83]. Additionally, some studies link protein S deciency to preeclampsia more strongly than the other genetic thrombophilias [86]. As with protein C deciency, the information linking protein S to other adverse pregnancy outcomes is not robust. Antithrombin deciency Antithrombin (formerly known as antithrombin III) deciency was described biochemically by Egeberg [121] in 1965 and has a prevalence of 0.02% to 0.2% in whites [1]. Subsequent genetic studies of aected families identied numerous mutations resulting in type I and type II disease [122].

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Antithrombin deciency results in an increase in the level of thrombin activity and increased conversion of brinogen to brin and tendency toward thrombosis [27]. As with protein C and S deciencies, biochemical testing for the disorder is preferred and is subject to many of the same caveats [19,20]. Homozygosity for type I antithrombin deciency is not likely compatible with life [15]. Heterozygotes seem to have a higher burden of thrombotic disease than patients aected with the other genetic thrombophilias [123]. It is thought that antithrombin deciency is similar in risk to protein C or S deciency in its interaction with OC and HRT. Pregnant women who are antithrombin decient have a risk of DVT approximately 300-fold greater than that of the normal nonpregnant population [63]. Few data relate to the risk of adverse pregnancy outcome and antithrombin deciency [66,86]. Hyperhomocysteinemia Hyperhomocysteinemia may be a risk factor for venous thrombosis; however, a causal role has not been determined [13,17,18,124]. Elevated levels of homocysteine can result from dietary and genetic factors, and the interplay between these factors likely determines plasma levels of homocysteine. Prospective studies suggest that elevated levels of homocysteine do not clearly increase the potential for a rst venous thrombotic event [18]. A common mutation in the methylene tetrahydrofolate reductase gene, C677T, occurring in approximately 5% to 15% of whites, may result in increased levels of plasma homocysteine in aected individuals [15]. Initially, it was thought that the methylene tetrahydrofolate reductase gene mutation contributed substantially to the risk of venous thrombosis. Subsequent studies have not conrmed this association, and routine testing for this mutation is not recommended [17].

Testing and treatment Testing for genetic thrombophilia The least costly and most available tool for any clinician interested in genetic thrombophilia is a good history, although there is some debate as to its value [125127]. The risk for recurrent disease in individuals with a single personal event of idiopathic DVT is about 5% to 10% per year [109]. In young people (\50 years old), idiopathic DVT identied by history is an indication for further testing, exclusion from use of OC and HRT, heightened attention to DVT prophylaxis in predisposing situations, and consideration of prophylaxis in pregnancy. Similarly, eliciting a strong family history of events associated with genetic thrombophilia in an asymptomatic individual should prompt the clinician to consider testing the patient for thrombophilia. Various organizations and individuals have presented guidelines for whom to test and what tests to perform in the

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setting of suspected thrombophilia. Table 5 distills these recommendations for the primary care clinician [15,19,20,22,32,38,61,65,117,128,129]. Clinicians most commonly order testing for genetic thrombophilia when presented with an individual with idiopathic DVT. The results of testing in these individuals may be helpful in determining duration of therapy and in counseling family members. Another common testing scenario is that of patients presenting with a personal or family history of thrombotic events. In this case, the results of genetic testing might be used to guide thrombosis prophylaxis in high-risk situations, to guide the choice of contraceptives, or possibly to spur the primary care physician to engage the aid of a perinatologist in management of a pregnancy. There is no indication for routine use of these tests in screening asymptomatic individuals without personal or family history of disorders suggesting thrombophilia, even in the setting of pregnancy or the perioperative situation [130132]. Primary care physicians should consider several issues when choosing tests to perform in suitable individuals. First, testing for the genetic thrombophilias can be costly. Second, there are no large prospective studies of which the author is aware that have examined the ecacy of genetic or biochemical testing for any of the thrombophilias from the standpoint of cost-eectiveness or years of life saved [133]. Third, the use of panels of tests, although common, is not the most appropriate approach. Testing should be individualized to the clinical situation. For example, the panel for thrombophilia at the authors hospital includes a prothrombin time, partial thromboplastin time, protein C levels, protein S levels, antithrombin levels, activated protein C resistance, lupus anticoagulant, and a mixing study. Prothrombin G20210A gene mutation testing, FVL gene mutation testing, and homocysteine level determination require a separate order

Table 5 Testing recommendations for thrombophilia Patients to consider for testing Any patient with DVT \50 years old Idiopathic DVT any age Tests to consider

Prothrombin G20210A gene testing Activated protein C resistance/Factor V Leiden gene testing Strong family history of thrombosis Protein S level Venous thrombosis in unusual site Protein C level Recurrent venous thrombosis Antithrombin level Life-threatening thrombotic event Thrombin time Relatives of patients with thrombophilia Activated partial thromboplastin time* Recurrent adverse pregnancy outcome Lupus anticoagulant* Stillbirth Anticardiolipin antibodies* Homocysteine levely Factor VIII, IX, and XI levelsy Abbreviation: DVT, deep venous thrombosis. * Tests for nongenetic thrombophilias. y Controversial as to value.

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(MaineGeneral Medical Center, Augusta, ME). Commonly this panel is ordered when a patient presents with idiopathic DVT, and many of these tests are aected by the presence of the thrombosis itself. Clinicians sometimes order the testing soon after the institution of anticoagulant therapy, making interpretation of many of the tests impossible. Only genetic testing for the prothrombin G20210A and FVL gene mutations can be reliably interpreted in the setting of a recent thrombotic event or oral anticoagulant therapy. In the case of protein-based, functional assays, testing should be done after at least 2 weeks without oral anticoagulants, in the nonpregnant state, and about 6 months after any thrombotic event [15,20,61,63,129]. Some authorities recommend additional conrmatory testing some weeks after the initial positive test for the genetic thrombophilias if protein-based testing is used [61]. Finally, testing an unaected individual with a family history is nearly pointless in the absence of a proven genetic risk factor in an aected family member. Although one might rule out specic known defects, a not yet described defect might cause disease in that family, making prediction of the individuals risk problematic. Treatment Treatment of genetic thrombophilia can be divided into two categories, prophylaxis and therapy. Prophylaxis can range from avoidance of prolonged car or airplane rides without breaks to administration of lowmolecular-weight heparin from the time an aected asymptomatic individual is found to be pregnant. Therapy might be as simple as the standard heparin and warfarin given for treatment of lower extremity DVT in an individual heterozygous for FVL gene mutation. Alternatively, it might be as complicated as the administration of puried factor concentrate to a newborn with purpura fulminans in the neonatal intensive care unit. Table 4 reviews the proposed prophylaxis and treatment options for the genetic thrombophilias in several commonly encountered clinical situations [15,22,49,61,65,83,128,129,133135]. Anticoagulant dosing is the same for individuals with a genetic basis for their thrombotic event. Little more than a decade has elapsed since the two most common genetic thromophilias were described. Few long-term prospective data on outcomes of therapy have been published, and treatment guidelines are based largely on expert opinion, especially in the setting of pregnancy. As more is learned from prospective studies of the treatment of genetic thrombophilia, treatment recommendations are likely to change. As previously discussed, prospective data suggest that the risk of recurrent DVT in individuals with FVL and prothrombin G20210A gene mutations does not dier from individuals with no genetic thrombophilia. Given these ndings, it seems reasonable that both categories of patients should be treated similarly. The complex and evolving clinical understanding of genetic thrombophilias suggests that primary care physicians and their patients may benet

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from enlisting the aid of specialists. In a nonpregnant patient, a hematology or genetics consultation should be considered, particularly in the setting of a complex family history or a symptomatic individual with a proven defect. In a pregnant patient, a genetics consultation might be helpful. The aid of a perinatologist or high-risk obstetrician should be enlisted to guide antepartum and postpartum care.

Case studies Case 1 Because of the family history of antithrombin deciency, the primary care physician ordered antithrombin levels, protein C levels, protein S levels, and antiphospholipid antibodies. Testing revealed that the patient had normal antithrombin levels but low levels of protein S. At that time, the patient was counseled for smoking cessation and started on daily aspirin therapy, and a genetics consultation was obtained. Repeat thrombophilia testing was undertaken with a panel of tests more broad than the tests chosen by the primary care clinician. These tests conrmed that the patient was protein S decient, with normal levels of antithrombin. No further testing or information could be obtained from the maternal side of the family because they were estranged from the patient. The patient was counseled that the role for protein S in infertility was unknown and that she should have a complete workup for other causes of infertility. She was counseled on her elevated risk of DVT, and it was suggested that she avoid taking any form of OC. She was told to continue a daily aspirin. This case illustrates many points. First, primary care physicians do not always make ideal decisions regarding the choice of tests for thrombophilia evaluation. Second, two genetic thrombophilias can present in the same family, resulting in a high burden of thrombotic disease. Third, because these disorders are relatively rare, the natural histories are not known for all possibly related disorders (eg, infertility). Finally, prophylaxis and therapy options for thrombophilia are poorly dened and are driven largely by clinical judgment, rather than prospective data for benet. Case 2 Arrangements were made for the patient to have conrmatory lower extremity Doppler studies. A thrombophilia panel was obtained, including testing for the FVL gene mutation, and the patient was started on heparin. His symptoms improved, but the patient declined warfarin therapy, citing his job as a roofer and drinking as reasons he did not want to take the drug. Subsequently, his studies showed he was heterozygous for the FVL gene mutation, and the patient was referred to a genetic counselor. He continued to refuse warfarin therapy. Approximately 1 year later, the patient required

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hospitalization for a jaw abscess related to dental decay. During his hospitalization and despite use of multiple thromboprophylaxis modalities, he developed idiopathic bowel perforation and required a partial colectomy. It was unclear if the bowel perforation resulted from a thrombotic event, although no other etiology was identied. The patient subsequently accepted alcohol counseling, began eorts at smoking cessation, and consented to therapy with warfarin. The second case illustrates several other points germane to genetic thrombophilia. First, immobilization likely interacted with this patients thrombophilia to cause the rst DVT, pointing out the gene-environment interactions prevalent in the genetic thrombophilias. Second, patient compliance with long-term warfarin therapy, a central feature of treatment of thrombophilia, sometimes can be problematic. Third, thrombotic complications may occur despite adherence to current guidelines for care. Summary 1. Primary care physicians frequently encounter situations in which genetic thrombophilia may play a role. Idiopathic DVT is probably the most commonly encountered clinical manifestation. 2. There are ve major known genetic thrombophilias, including the FVL gene mutation, the prothrombin G20210A gene mutation, and numerous mutations resulting in deciencies of protein C, protein S, and antithrombin. Many other conditions rarely contribute or remain unproven genetic contributors. 3. Testing is available by genetic or biochemical means for these abnormalities. 4. Although testing for genetic thrombophilia is warranted in certain situations, careful consideration must be given to the choice of patient tested, the tests to be ordered, and their interpretation. 5. Prophylactic and therapeutic options for the genetic thrombophilias remain largely unproven, and specialist involvement in care of these patients may be helpful. References
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