Original article 649
Thrombophilia diagnosis: a retrospective analysis of a single-center experience Marta Spychalska-Zwolin´skaa, Tomasz Zwolin´skib, Artur Mieczkowskia and Jacek Budzyn´skia,c It is estimated that 30–50% of patients suffering from deep vein thrombosis (DVT) could be diagnosed with congenital or acquired thrombophilia. Its diagnosis, however, rarely changes the clinical management, but is associated with significant costs and negative psychological and social aspects. The aim of this study was to perform a retrospective analysis of the causes and clinical consequences of diagnostics for thrombophilia. A retrospective review of the medical records of 5600 patients was performed, 62 of whom had, at the time, been diagnosed for thrombophilia because of a thromboembolic event. A review of the current literature on the validity of diagnostic tests for hypercoagulability in certain clinical conditions was also performed. The most common reason for thrombophilia testing was episodes of lower limb DVT (56%). The most frequently diagnosed abnormalities were the heterozygous form of the V Leiden gene (18%), protein S deficiency (11%), and the anti cardiolipin antibody IgG (11%). In 45% of the patients, laboratory results did not confirm the presence of any congenital thrombophilia. After receiving the results, 11% of the respondents completed oral anticoagulation therapy after 3 months, and 28% of patients qualified for indefinite use of oral anticoagulant
Introduction Venous thromboembolic disease, defined as a deep vein thrombosis (DVT) and its most dangerous complication, pulmonary embolism, is still a serious healthcare problem. The annual incidence of DVT in the general population is estimated at 1:1000. It is estimated that 30–50% of these patients could be diagnosed with a congenital or acquired condition called a hypercoagulable state or thrombophilia, predisposing them to the occurrence of thrombosis [1]. In the available literature, terms ‘thrombophilia’ and ‘hypercoagulable states’ seem to be used synonymously and this is how we used them in this article; however, there are reports making distinction between them justifying it by a different pathogenesis of both and therefore, need for a different treatment [2]. Thrombophilia is a hereditary or acquired coagulation defect leading to a greater predisposition to thrombosis. It is possible to distinguish between genetic (congenital), acquired, or mixed thrombophilias (resulting from a combination of genetic and environmental factors). The most common defects are caused by genetic mutations in the genes for factors V and II. Acquired thrombophilias refer to conditions in which patients without a genetic predisposition suffer from an imbalance 0957-5235 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved.
therapy. In most of the cases examined, the diagnosis of thrombophilia did not significantly affect the treatment. A common aberration identified in patients with a history of thromboembolic incidents was the coexistence of risk factors for atherosclerosis. Blood Coagul Fibrinolysis 26:649–654 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved.
Blood Coagulation and Fibrinolysis 2015, 26:649–654 Keywords: acquired thrombophilia, genetic thrombophilia, thrombophilia diagnostics, venous thromboembolic disease a Department of Vascular and Internal Diseases, bDepartment of General, Gastroenterological, Colorectal and Oncological Surgery, Jan Biziel University Hospital No. 2, Bydgoszcz and cChair of Vascular and Internal Diseases, The Ludwik Rydygier Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, Torun´, Poland
Correspondence to Marta Spychalska-Zwolin´ska, Oddział Choro´b Naczyn´ i Choro´b Wewne˛trznych, Szpital Uniwersytecki nr 2 im. dr. Jana Biziela, ul. Ujejskiego 75, 85–168 Bydgoszcz, Poland Tel: +48 52 36 55 347; fax: +48 52 36 55 347; e-mail: [email protected] Received 25 November 2014 Revised 6 April 2015 Accepted 16 April 2015
between coagulation factors and their inhibitors, with a predominance of the former. Examples of such conditions include: antiphospholipid syndrome, diabetes, cancer, and inflammatory thrombophilia (e.g. in the course of inflammatory bowel disease or systemic lupus erythematosus) [1]. The presence of thrombophilia increases the risk of venous thromboembolism throughout a patient’s life. This risk also increases with age and when additional risk factors appear. In one-third of cases, a thromboembolic incident occurs in patients with congenital thrombophilia in the presence of reversible (temporary) risk factors such as trauma, pregnancy or taking oral contraceptives. A diagnosis of thrombophilia is based on the results of laboratory tests, which are best done within 3 to 6 months after the thrombotic event. Recommended tests for the diagnosis of thrombophilia include assessment of the following: activated protein C (APC) resistance ratio, Factor V Leiden and prothrombin gene mutation, protein C activity and the concentration of free protein S, antithrombin, lupus anticoagulant, and anticardiolipin antibodies (IgM and IgG) [3,4]. In the case of diagnostics for antiphospholipid syndrome (APS), DOI:10.1097/MBC.0000000000000332
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
650 Blood Coagulation and Fibrinolysis 2015, Vol 26 No 6
it is necessary to confirm laboratory abnormalities after at least 12 weeks, but not later than 5 years after the thromboembolic episode [5]. The incidence of thrombophilia is low, but its presence should be considered in the case of any venous thrombosis occurrence without a transient risk factor or cancer in patients under 50 years of age, in thrombosis in an unusual location (abdominal veins or veins of the central nervous system), in the case of patients with strong family history of unprovoked recurrent thrombosis, as well as in the case of warfarin skin necrosis, neonates and children with purpura fulminans, in case of women with a previous non-oestrogen-related venous thromboembolic event (VTE) due to a minor provoking factor or thrombosis related to pregnancy, in asymptomatic pregnant women with a family history of VTE in first degree relative if the thrombosis was unprovoked, provoked by a minor risk factor, related to pregnancy or combined oral contraceptive, in the development of thrombosis in women under age of 50 years taking oral contraceptives or hormone replacement therapy, and, last but not least, in women with recurrent miscarriages before 12 weeks of gestation, preterm births before 34th week due to severe preeclampsia, eclampsia or placental insuficiency or after morphologically normal fetal deaths after 12 years of gestation [3,4]. Additionally, testing for thrombophilia should be carried out also in patients with symptoms of arterial thrombosis without risk factors for atherosclerosis, such as young patients with myocardial infarction or cerebral ischemia [3,5]. Diagnostic tests should be carried out mainly to plan the type and duration of secondary prevention; the diagnosis of thrombophilia is less important in the planning of primary prevention, and even less important in the treatment of acute thrombotic event. The diagnosis of thrombophilia, apart from that in the case of pregnancy and secondary prevention planning in some instances, rarely changes the clinical management, but is associated with some significant costs, as well as negative psychological (anxiety, a feeling of concern for loved ones) and social ones (e.g. risk of rising health insurance premiums, restrictions in access to exercising certain professions, and so on) impact [1,6,7]. Therefore, routine testing for thrombophilia is increasingly being often considered unjustified [1,3,6–9]. The aim of this study was a retrospective analysis of the reasons for and clinical consequences of the diagnostic tests for thrombophilia in patients assessed in the Department because of a history of thromboembolism, in the years 2012–2013. A review of the current literature on the validity of diagnostic tests for hypercoagulable states in certain clinical conditions was also performed.
Materials and methods A retrospective review of the medical records of 5600 patients hospitalized in the aforementioned department in 2012–2013 was made. Sixty-two (about 1%) of them
were diagnosed at the time for thrombophilia because of a history of thromboembolism, either without the coexistence of a transient risk factor, or during pregnancy or puerperium. Diagnostics were not performed in patients in whom thrombosis was associated with the presence of an identified transient risk factor (e.g. surgery, immobilization, among others), with the exception of pregnancy and the use of oral contraceptives. It was also not performed in those whose history and physical examination suggested an obvious cause of thrombosis, cancer, for example. For each patient, we performed a retrospective analysis of the following information collected during hospitalization: case and family history, physical examinations, basic laboratory tests (morphology, platelet count, electrolytes, creatinine, glucose, low-density lipoprotein cholesterol, triglycerides), hemostasis tests (international normalized ratio, activated partial thromboplastin time (APTT), fibrinogen, protein C, protein S, antithrombin, D-dimer), immunological tests (connective tissue disease screen, lupus anticoagulant, antiphospholipid antibodies IgG and IgM and anti-B2-glycoprotein), genetic testing for mutations in the factor V Leiden gene and mutations of the prothrombin gene 20210A, as well as imaging studies (including abdominal ultrasound, Doppler ultrasound and chest X-ray). Depending on the reported symptoms, routine diagnostics were completed with a gynecological examination, an endoscopy, a CT scan, amomg others. All of the tests were always performed in the same units. A follow-up of recommendations for patients diagnosed for thrombophilia and their treatment in outpatient care was performed, with an observation period of approximately 1 year.
Results In 2012–2013, because of a history of thromboembolic incidents, either idiopathic or associated with pregnancy, 62 patients (1% of all those hospitalized) were diagnosed for thrombophilia in the department. The characteristics of the study group are shown in Table 1 and the location of any prior thrombotic event in Table 2. The most common reason for performing diagnostics for thrombophilia in the study group was a past episode of lower limb DVT (56%) (Table 2). Patients with a history of arterial thrombosis, that is, brain episodes before 50 years of age (ischemic stroke, transient ischemic attack]) and patients after myocardial infarction before 35 years of age accounted for more than 20% of the studied group. Almost 16% of the patients had an episode of venous thrombosis in a ‘atypical localization,’ including cerebral venous thrombosis (8%), and 6% of the study group were women who had experienced DVT during pregnancy. Table 2 shows the results of laboratory testing for congenital thrombophilia. The most frequently diagnosed abnormalities were the heterozygous form of the V
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Thrombophilia diagnosis Spychalska-Zwolin´ska et al. 651
Table 1
Characteristics of the study group
Characteristic
Percentage of the studied group, n (%)
Sex Female 32 (52%) Male 30 (48%) Age (years) 20–29 17 (27%) 30–39 11 (18%) 40–49 21 (34%) >50 12 (19%) Concomitant diseases, without a certain connection with venous thrombosis Hypertension 8 (13%) Patent foramen ovale 4 (6%) Thyroid dysfunction 8 (13%) Factors contributing to the occurrence of thrombosis Hypercholesterolemia 32 (51%) Obesity/overweight 17 (27%) Diabetes 2 (3%) Nicotinism 11 (18%) Pregnancy 4 (6%) Immobilization during journey 2 (3%) Crural varices 4 (6%) Surgery prior to thrombotic episode 2 (3%) Oral hormonal contraceptives 5 (7%) Family history History of thromboembolic disease/pulmonary embolism 7 (11%)
Leiden gene (18%), protein S deficiency (11%) and anticardiolipin IgG antibodies (11%). Of the five patients (8% of the study group) who were diagnosed with the heterozygous prothrombin gene mutation, and 11 (18%) diagnosed with the V Leiden gene mutation, only in two (13% and 3% of the total) did both mutations occur at the Table 2
same time. Three patients (5%) were diagnosed with antiphospholipid syndrome. Abnormal results were found in one of the four women following an episode of thrombosis during pregnancy: antithrombin deficiency, the heterozygous form of the V Leiden gene and a lowpositive result for anticardiolipin IgM antibodies. Laboratory results did not confirm the presence of any congenital thrombophilia in 45% of patients. One patient (2%) was diagnosed with colon cancer. One patient with recurrent thrombosis of the left lower limb was diagnosed with May-Thurner syndrome and qualified for subsequent intravascular treatment. The most common risk factor for atherosclerosis, which is increasingly being perceived as a factor associated with thromboembolic venous disease, was hypercholesterolemia (Table 1). The average cost of hospitalization of patients diagnosed for thrombophilia was 500 s. The impact of a congenital thrombophilia diagnosis for the further medical management of patients is shown in Fig. 1. After receiving the results of the diagnostics, 11% of the patients completed oral anticoagulation therapy after 3 months, and 28% of the patients, after taking into account risk factors and patient preference, qualified for indefinite use of oral anticoagulant by their leading doctor. No significant statistical relationship between a diagnosis of a hypercoagulable state and a recommendation of indefinite anticoagulation was shown. Statin
Location of prior thrombotic event in the studied group and the results of laboratory testing for congenital thrombophilia
Reason for thrombophilia testing
Percentage of the studied group n (%)
Lower limb deep vein thrombosis
35 (56%)
Protein C deficiency Protein S deficiency Prothrombin gene mutation-heterozygous mutant V Leiden gene mutation heterozygous mutant ACA IgG ACA IgM B2GP
1 5 3 7 5 1 1
Arterial thrombosis incidents: brain episodes at < 50 years of age (ischemic stroke/TIA) and after myocardial infarction < 35years of age
13 (21%)
Protein S deficiency Antithrombin deficiency Prothrombin gene mutation-heterozygous mutant V Leiden gene mutation-heterozygous mutant (P. S deficiency þ V Leiden - 1, V Leiden, ACA IgG - 1) ACA IgG
2 (3%) 1 (2%) 1 (2%) 2 ( 3%) 1 (2%)
Unusual location of venous thrombosis (intra-abdominal, retinal, cerebral)
10 (16%)
Prothrombin gene mutation-heterozygous mutant V Leiden gene mutation-heterozygous mutant
1 (2%) 1 (2%)
Deep vein thrombosis during pregnancy
4 (6%)
Antithrombin deficiency (antithrombin deficiency þ heterozygous V Leiden þ ACA IgM) V Leiden gene mutation-heterozygous mutant ACA IgG ACA IgM
1 (2%)
Total
Diagnosis
V Leiden gene mutation-heterozygous mutant Protein S deficiency ACA IgG Prothrombin gene mutation-heterozygous mutant ACA IgM Antithrombin deficiency Protein C deficiency B2GP No thrombophilia diagnosed
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
n (%) (2%) (8%) (5%) (11%) (8%) (2%) (2%)
1 (2%) 1 (2%) 1 (2%) 11 7 7 5 2 2 1 1 28
(18%) (11%) (11%) (8%) (3%) (3%) (2%) (2%) (45%)
652 Blood Coagulation and Fibrinolysis 2015, Vol 26 No 6
Fig. 1 28 30
14
11
20
3
10 0 Indefinite anticoagulation therapy
Discontinuation of anticoagulant therapy after 3 months
LMWH during pregnancy
Statin therapy implemented
Percentage of the studied group [%]
Impact of congenital thrombophilia diagnosis on further medical management of patients. LMWH, low-molecular-weight heparin.
therapy was implemented for 14% of the patients because of SCORE Risk Estimation above 5%; 6% of the patients stopped smoking, and each patient with overweight was recommended to reduce diet and do moderate physical activity. In one of the subjects treated with an oral anticoagulant during the 2-year follow-up, there was an episode of gastrointestinal bleeding, but there was no recurrence of thrombosis. It was also noted that 11% of the patients did not turn up for the follow-up visit.
Discussion In the research group, nearly 55% of the patients with a history of thromboembolism had at least one congenital thrombophilia diagnosed. In the literature, this number is estimated at about 30–50%, depending on the population studied [1,7], so the results of our study did not differ significantly from the available data. The majority of the sources reported that the most common cause of congenital thrombophilia in whites is the factor V Leiden. The heterozygous form of the V Leiden gene can occur in 1–15% of the general population [1]. The presence of factor V Leiden increases the risk of thrombosis by three to eight times in the general population, and in women using oral hormonal contraception up to 35 times [10]. In patients with venous thromboembolic disease, this mutation can affect 10–50% of patients [1]. This genetic abnormality was found in 18% of the patients in our group (Tab. 2). The question arises of whether such a number justifies moving the diagnostics in the direction of including hypercoagulable states, especially when taking into account the results of our analysis of the impact of the diagnosis of thrombophilia for the further management of patients in our study (Fig. 1), which demonstrated that it had no significant effect on the recommendation of indefinite anticoagulation, and that its average cost per patient exceeded 500 s. Expert opinions concerning necessity for thrombophilia testing are divided. Nevertheless, they recommend indefinite anticoagulation in secondary prevention after a first episode of venous thromboembolism in patients with such types of thrombophilia, which should be diagnosed
before: antithrombin deficiency; the homozygous form of factor V Leiden or prothrombin gene variant 20210A or the heterozygous form of factor V Leiden combined with the heterozygous form of the variant 20210A prothrombin gene or antiphospholipid syndrome. In other cases, indefinite prophylaxis is recommended only when a second thromboembolic incident occurs or when there are solid coexisting reasons for a hypercoagulable state, unhealed cancer, for instance [11]. However, a significant proportion of the experts do not agree with this opinion, and do not recommend the routine diagnostics of hypercoagulable states in patients with venous thromboembolic disease, justifying this with the scarcity of documented evidence of the influence of thrombophilia on the risk of thrombosis recurrence as well as the high costs of diagnostics, and its negative psychological (fear of illness and death) and social (e.g. increase of health insurance premiums) effects [1,6–10,12,13]. These experts recommend instead that indefinite anticoagulation should be proposed based on the individual balancing of the risk of thrombosis and bleeding. A separate diagnosed group of patients were those with a history of an ‘unusual location of venous thrombosis.’ Central retinal vein thrombosis was the reason for thrombophilia testing in 5% of these patients. According to the current guidelines [4], this location of a thrombotic process is not an indication for routine testing of hypercoagulable states. Nevertheless, these tests were performed following the suggestions of ophthalmologists, at the request of patients, because of young age of the patient (26, 37 and 56 years old) and in cases wherein there was no other obvious cause of retinal vein thrombosis, except from potential thrombophilia. Central retinal vein thrombosis may be caused by both local (retinal vein pressure by hardened arteries, increased intraocular pressure, hindrance of the outflow of venous blood from the eyeball to the heart, for example due to thrombosis in the venous sinuses of the dura mater or stenosis of the internal jugular vein) and general factors (hypertension, hyperlipidemia, diabetes and congenital and acquired hypercoagulable states) [14]. It is worth taking into consideration that it is not completely certain whether the use of anticoagulants in patients with retinal vein thrombosis makes any clinical sense at all [4]. Similarly expressed is the issue of cerebral venous thrombosis, although the recommendations for the use of anticoagulants in this case are clearly formulated [15]. The relationship between thrombosis of the cranial sinuses and congenital thrombophilias, however, seems to be poorly documented, so the validity of research in the direction of the latter also raises doubts [16]. There are also no data on the impact of the early diagnosis of most thrombophilias for the subsequent therapeutic decisions, the extension of secondary prevention, for example [4]. Only a diagnosis of antiphospholipid syndrome results in a recommendation of indefinite anticoagulation [15], just as in the case of venous thromboembolic disease.
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Thrombophilia diagnosis Spychalska-Zwolin´ska et al. 653
In our study, there were four patients with a history of a thrombotic episode in pregnancy and/or puerperium. The likelihood of its occurrence is six times higher in this group than the general population and increases with the coexistence of thrombophilia. Venous thromboembolic disease is the leading cause of pregnancy-related deaths in developed countries [11]. In our group, abnormal test results for thrombophilia were found in one patient. She had a combination of three abnormalities: antithrombin deficiency, the heterozygous form of the gene V Leiden and a low-positive result for the anticardiolipin antibody IgM. It is worth pointing out that women who are burdened with a deficit of antithrombin, proteins C and S and a factor V Leiden mutation have a higher risk of venous thrombosis, not only during pregnancy, but also while they are taking oral hormonal contraception (five-fold compared with women not using oral contraceptives and loaded with inherited thrombophilia [10]). It is worth mentioning that women without a thrombophilia diagnosis using this form of birth control also have an increased risk of thrombosis compared with the general population (0.7 vs. 0.03% per year of use [6]). In practical terms, the fact that there is an increased risk of thrombosis in women using hormonal contraception and/or a high probability of thrombosis recurrence in patients with a history of a thrombotic episode during pregnancy should justify carrying out diagnostic tests for thrombophilia in these patients [1]. However, a negative test for thrombophilia in a woman planning to start oral contraceptives can give her a sense of false security in the face of the risks associated with the therapy alone [4,6]. Our patients were advised not to use oral contraception after pregnancy and a patient with a complex thrombophilia was recommended to use prophylactic doses of low-molecular-weight heparin (LMWH) during her next pregnancy. Bouvier et al. [17] pointed out the benefits of LMWH in a group of pregnant patients with a history of miscarriages and a diagnosis of thrombophilia, expressed in a lower incidence of fetal death, premature births and preeclampsia. In our study, there were also patients diagnosed because of a past episode of arterial thrombosis. Recent guidelines do not recommend routine testing for thrombophilia in patients with arterial thrombosis (level of evidence: 1B) [4]. This is because of the fact that thrombophilia is seen mainly as a predisposing factor of venous thromboembolism. However, according to some experts, it can also promote arterial thrombosis clinically manifested as myocardial infarction with normal coronarogram or ischemic stroke. It is essential particularly for APS, but not only this. Guidelines for 2012 suggest that young adults (
Thrombophilia diagnosis: a retrospective analysis of a single-center experience Marta Spychalska-Zwolin´skaa, Tomasz Zwolin´skib, Artur Mieczkowskia and Jacek Budzyn´skia,c It is estimated that 30–50% of patients suffering from deep vein thrombosis (DVT) could be diagnosed with congenital or acquired thrombophilia. Its diagnosis, however, rarely changes the clinical management, but is associated with significant costs and negative psychological and social aspects. The aim of this study was to perform a retrospective analysis of the causes and clinical consequences of diagnostics for thrombophilia. A retrospective review of the medical records of 5600 patients was performed, 62 of whom had, at the time, been diagnosed for thrombophilia because of a thromboembolic event. A review of the current literature on the validity of diagnostic tests for hypercoagulability in certain clinical conditions was also performed. The most common reason for thrombophilia testing was episodes of lower limb DVT (56%). The most frequently diagnosed abnormalities were the heterozygous form of the V Leiden gene (18%), protein S deficiency (11%), and the anti cardiolipin antibody IgG (11%). In 45% of the patients, laboratory results did not confirm the presence of any congenital thrombophilia. After receiving the results, 11% of the respondents completed oral anticoagulation therapy after 3 months, and 28% of patients qualified for indefinite use of oral anticoagulant
Introduction Venous thromboembolic disease, defined as a deep vein thrombosis (DVT) and its most dangerous complication, pulmonary embolism, is still a serious healthcare problem. The annual incidence of DVT in the general population is estimated at 1:1000. It is estimated that 30–50% of these patients could be diagnosed with a congenital or acquired condition called a hypercoagulable state or thrombophilia, predisposing them to the occurrence of thrombosis [1]. In the available literature, terms ‘thrombophilia’ and ‘hypercoagulable states’ seem to be used synonymously and this is how we used them in this article; however, there are reports making distinction between them justifying it by a different pathogenesis of both and therefore, need for a different treatment [2]. Thrombophilia is a hereditary or acquired coagulation defect leading to a greater predisposition to thrombosis. It is possible to distinguish between genetic (congenital), acquired, or mixed thrombophilias (resulting from a combination of genetic and environmental factors). The most common defects are caused by genetic mutations in the genes for factors V and II. Acquired thrombophilias refer to conditions in which patients without a genetic predisposition suffer from an imbalance 0957-5235 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved.
therapy. In most of the cases examined, the diagnosis of thrombophilia did not significantly affect the treatment. A common aberration identified in patients with a history of thromboembolic incidents was the coexistence of risk factors for atherosclerosis. Blood Coagul Fibrinolysis 26:649–654 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved.
Blood Coagulation and Fibrinolysis 2015, 26:649–654 Keywords: acquired thrombophilia, genetic thrombophilia, thrombophilia diagnostics, venous thromboembolic disease a Department of Vascular and Internal Diseases, bDepartment of General, Gastroenterological, Colorectal and Oncological Surgery, Jan Biziel University Hospital No. 2, Bydgoszcz and cChair of Vascular and Internal Diseases, The Ludwik Rydygier Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, Torun´, Poland
Correspondence to Marta Spychalska-Zwolin´ska, Oddział Choro´b Naczyn´ i Choro´b Wewne˛trznych, Szpital Uniwersytecki nr 2 im. dr. Jana Biziela, ul. Ujejskiego 75, 85–168 Bydgoszcz, Poland Tel: +48 52 36 55 347; fax: +48 52 36 55 347; e-mail: [email protected] Received 25 November 2014 Revised 6 April 2015 Accepted 16 April 2015
between coagulation factors and their inhibitors, with a predominance of the former. Examples of such conditions include: antiphospholipid syndrome, diabetes, cancer, and inflammatory thrombophilia (e.g. in the course of inflammatory bowel disease or systemic lupus erythematosus) [1]. The presence of thrombophilia increases the risk of venous thromboembolism throughout a patient’s life. This risk also increases with age and when additional risk factors appear. In one-third of cases, a thromboembolic incident occurs in patients with congenital thrombophilia in the presence of reversible (temporary) risk factors such as trauma, pregnancy or taking oral contraceptives. A diagnosis of thrombophilia is based on the results of laboratory tests, which are best done within 3 to 6 months after the thrombotic event. Recommended tests for the diagnosis of thrombophilia include assessment of the following: activated protein C (APC) resistance ratio, Factor V Leiden and prothrombin gene mutation, protein C activity and the concentration of free protein S, antithrombin, lupus anticoagulant, and anticardiolipin antibodies (IgM and IgG) [3,4]. In the case of diagnostics for antiphospholipid syndrome (APS), DOI:10.1097/MBC.0000000000000332
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
650 Blood Coagulation and Fibrinolysis 2015, Vol 26 No 6
it is necessary to confirm laboratory abnormalities after at least 12 weeks, but not later than 5 years after the thromboembolic episode [5]. The incidence of thrombophilia is low, but its presence should be considered in the case of any venous thrombosis occurrence without a transient risk factor or cancer in patients under 50 years of age, in thrombosis in an unusual location (abdominal veins or veins of the central nervous system), in the case of patients with strong family history of unprovoked recurrent thrombosis, as well as in the case of warfarin skin necrosis, neonates and children with purpura fulminans, in case of women with a previous non-oestrogen-related venous thromboembolic event (VTE) due to a minor provoking factor or thrombosis related to pregnancy, in asymptomatic pregnant women with a family history of VTE in first degree relative if the thrombosis was unprovoked, provoked by a minor risk factor, related to pregnancy or combined oral contraceptive, in the development of thrombosis in women under age of 50 years taking oral contraceptives or hormone replacement therapy, and, last but not least, in women with recurrent miscarriages before 12 weeks of gestation, preterm births before 34th week due to severe preeclampsia, eclampsia or placental insuficiency or after morphologically normal fetal deaths after 12 years of gestation [3,4]. Additionally, testing for thrombophilia should be carried out also in patients with symptoms of arterial thrombosis without risk factors for atherosclerosis, such as young patients with myocardial infarction or cerebral ischemia [3,5]. Diagnostic tests should be carried out mainly to plan the type and duration of secondary prevention; the diagnosis of thrombophilia is less important in the planning of primary prevention, and even less important in the treatment of acute thrombotic event. The diagnosis of thrombophilia, apart from that in the case of pregnancy and secondary prevention planning in some instances, rarely changes the clinical management, but is associated with some significant costs, as well as negative psychological (anxiety, a feeling of concern for loved ones) and social ones (e.g. risk of rising health insurance premiums, restrictions in access to exercising certain professions, and so on) impact [1,6,7]. Therefore, routine testing for thrombophilia is increasingly being often considered unjustified [1,3,6–9]. The aim of this study was a retrospective analysis of the reasons for and clinical consequences of the diagnostic tests for thrombophilia in patients assessed in the Department because of a history of thromboembolism, in the years 2012–2013. A review of the current literature on the validity of diagnostic tests for hypercoagulable states in certain clinical conditions was also performed.
Materials and methods A retrospective review of the medical records of 5600 patients hospitalized in the aforementioned department in 2012–2013 was made. Sixty-two (about 1%) of them
were diagnosed at the time for thrombophilia because of a history of thromboembolism, either without the coexistence of a transient risk factor, or during pregnancy or puerperium. Diagnostics were not performed in patients in whom thrombosis was associated with the presence of an identified transient risk factor (e.g. surgery, immobilization, among others), with the exception of pregnancy and the use of oral contraceptives. It was also not performed in those whose history and physical examination suggested an obvious cause of thrombosis, cancer, for example. For each patient, we performed a retrospective analysis of the following information collected during hospitalization: case and family history, physical examinations, basic laboratory tests (morphology, platelet count, electrolytes, creatinine, glucose, low-density lipoprotein cholesterol, triglycerides), hemostasis tests (international normalized ratio, activated partial thromboplastin time (APTT), fibrinogen, protein C, protein S, antithrombin, D-dimer), immunological tests (connective tissue disease screen, lupus anticoagulant, antiphospholipid antibodies IgG and IgM and anti-B2-glycoprotein), genetic testing for mutations in the factor V Leiden gene and mutations of the prothrombin gene 20210A, as well as imaging studies (including abdominal ultrasound, Doppler ultrasound and chest X-ray). Depending on the reported symptoms, routine diagnostics were completed with a gynecological examination, an endoscopy, a CT scan, amomg others. All of the tests were always performed in the same units. A follow-up of recommendations for patients diagnosed for thrombophilia and their treatment in outpatient care was performed, with an observation period of approximately 1 year.
Results In 2012–2013, because of a history of thromboembolic incidents, either idiopathic or associated with pregnancy, 62 patients (1% of all those hospitalized) were diagnosed for thrombophilia in the department. The characteristics of the study group are shown in Table 1 and the location of any prior thrombotic event in Table 2. The most common reason for performing diagnostics for thrombophilia in the study group was a past episode of lower limb DVT (56%) (Table 2). Patients with a history of arterial thrombosis, that is, brain episodes before 50 years of age (ischemic stroke, transient ischemic attack]) and patients after myocardial infarction before 35 years of age accounted for more than 20% of the studied group. Almost 16% of the patients had an episode of venous thrombosis in a ‘atypical localization,’ including cerebral venous thrombosis (8%), and 6% of the study group were women who had experienced DVT during pregnancy. Table 2 shows the results of laboratory testing for congenital thrombophilia. The most frequently diagnosed abnormalities were the heterozygous form of the V
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Thrombophilia diagnosis Spychalska-Zwolin´ska et al. 651
Table 1
Characteristics of the study group
Characteristic
Percentage of the studied group, n (%)
Sex Female 32 (52%) Male 30 (48%) Age (years) 20–29 17 (27%) 30–39 11 (18%) 40–49 21 (34%) >50 12 (19%) Concomitant diseases, without a certain connection with venous thrombosis Hypertension 8 (13%) Patent foramen ovale 4 (6%) Thyroid dysfunction 8 (13%) Factors contributing to the occurrence of thrombosis Hypercholesterolemia 32 (51%) Obesity/overweight 17 (27%) Diabetes 2 (3%) Nicotinism 11 (18%) Pregnancy 4 (6%) Immobilization during journey 2 (3%) Crural varices 4 (6%) Surgery prior to thrombotic episode 2 (3%) Oral hormonal contraceptives 5 (7%) Family history History of thromboembolic disease/pulmonary embolism 7 (11%)
Leiden gene (18%), protein S deficiency (11%) and anticardiolipin IgG antibodies (11%). Of the five patients (8% of the study group) who were diagnosed with the heterozygous prothrombin gene mutation, and 11 (18%) diagnosed with the V Leiden gene mutation, only in two (13% and 3% of the total) did both mutations occur at the Table 2
same time. Three patients (5%) were diagnosed with antiphospholipid syndrome. Abnormal results were found in one of the four women following an episode of thrombosis during pregnancy: antithrombin deficiency, the heterozygous form of the V Leiden gene and a lowpositive result for anticardiolipin IgM antibodies. Laboratory results did not confirm the presence of any congenital thrombophilia in 45% of patients. One patient (2%) was diagnosed with colon cancer. One patient with recurrent thrombosis of the left lower limb was diagnosed with May-Thurner syndrome and qualified for subsequent intravascular treatment. The most common risk factor for atherosclerosis, which is increasingly being perceived as a factor associated with thromboembolic venous disease, was hypercholesterolemia (Table 1). The average cost of hospitalization of patients diagnosed for thrombophilia was 500 s. The impact of a congenital thrombophilia diagnosis for the further medical management of patients is shown in Fig. 1. After receiving the results of the diagnostics, 11% of the patients completed oral anticoagulation therapy after 3 months, and 28% of the patients, after taking into account risk factors and patient preference, qualified for indefinite use of oral anticoagulant by their leading doctor. No significant statistical relationship between a diagnosis of a hypercoagulable state and a recommendation of indefinite anticoagulation was shown. Statin
Location of prior thrombotic event in the studied group and the results of laboratory testing for congenital thrombophilia
Reason for thrombophilia testing
Percentage of the studied group n (%)
Lower limb deep vein thrombosis
35 (56%)
Protein C deficiency Protein S deficiency Prothrombin gene mutation-heterozygous mutant V Leiden gene mutation heterozygous mutant ACA IgG ACA IgM B2GP
1 5 3 7 5 1 1
Arterial thrombosis incidents: brain episodes at < 50 years of age (ischemic stroke/TIA) and after myocardial infarction < 35years of age
13 (21%)
Protein S deficiency Antithrombin deficiency Prothrombin gene mutation-heterozygous mutant V Leiden gene mutation-heterozygous mutant (P. S deficiency þ V Leiden - 1, V Leiden, ACA IgG - 1) ACA IgG
2 (3%) 1 (2%) 1 (2%) 2 ( 3%) 1 (2%)
Unusual location of venous thrombosis (intra-abdominal, retinal, cerebral)
10 (16%)
Prothrombin gene mutation-heterozygous mutant V Leiden gene mutation-heterozygous mutant
1 (2%) 1 (2%)
Deep vein thrombosis during pregnancy
4 (6%)
Antithrombin deficiency (antithrombin deficiency þ heterozygous V Leiden þ ACA IgM) V Leiden gene mutation-heterozygous mutant ACA IgG ACA IgM
1 (2%)
Total
Diagnosis
V Leiden gene mutation-heterozygous mutant Protein S deficiency ACA IgG Prothrombin gene mutation-heterozygous mutant ACA IgM Antithrombin deficiency Protein C deficiency B2GP No thrombophilia diagnosed
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n (%) (2%) (8%) (5%) (11%) (8%) (2%) (2%)
1 (2%) 1 (2%) 1 (2%) 11 7 7 5 2 2 1 1 28
(18%) (11%) (11%) (8%) (3%) (3%) (2%) (2%) (45%)
652 Blood Coagulation and Fibrinolysis 2015, Vol 26 No 6
Fig. 1 28 30
14
11
20
3
10 0 Indefinite anticoagulation therapy
Discontinuation of anticoagulant therapy after 3 months
LMWH during pregnancy
Statin therapy implemented
Percentage of the studied group [%]
Impact of congenital thrombophilia diagnosis on further medical management of patients. LMWH, low-molecular-weight heparin.
therapy was implemented for 14% of the patients because of SCORE Risk Estimation above 5%; 6% of the patients stopped smoking, and each patient with overweight was recommended to reduce diet and do moderate physical activity. In one of the subjects treated with an oral anticoagulant during the 2-year follow-up, there was an episode of gastrointestinal bleeding, but there was no recurrence of thrombosis. It was also noted that 11% of the patients did not turn up for the follow-up visit.
Discussion In the research group, nearly 55% of the patients with a history of thromboembolism had at least one congenital thrombophilia diagnosed. In the literature, this number is estimated at about 30–50%, depending on the population studied [1,7], so the results of our study did not differ significantly from the available data. The majority of the sources reported that the most common cause of congenital thrombophilia in whites is the factor V Leiden. The heterozygous form of the V Leiden gene can occur in 1–15% of the general population [1]. The presence of factor V Leiden increases the risk of thrombosis by three to eight times in the general population, and in women using oral hormonal contraception up to 35 times [10]. In patients with venous thromboembolic disease, this mutation can affect 10–50% of patients [1]. This genetic abnormality was found in 18% of the patients in our group (Tab. 2). The question arises of whether such a number justifies moving the diagnostics in the direction of including hypercoagulable states, especially when taking into account the results of our analysis of the impact of the diagnosis of thrombophilia for the further management of patients in our study (Fig. 1), which demonstrated that it had no significant effect on the recommendation of indefinite anticoagulation, and that its average cost per patient exceeded 500 s. Expert opinions concerning necessity for thrombophilia testing are divided. Nevertheless, they recommend indefinite anticoagulation in secondary prevention after a first episode of venous thromboembolism in patients with such types of thrombophilia, which should be diagnosed
before: antithrombin deficiency; the homozygous form of factor V Leiden or prothrombin gene variant 20210A or the heterozygous form of factor V Leiden combined with the heterozygous form of the variant 20210A prothrombin gene or antiphospholipid syndrome. In other cases, indefinite prophylaxis is recommended only when a second thromboembolic incident occurs or when there are solid coexisting reasons for a hypercoagulable state, unhealed cancer, for instance [11]. However, a significant proportion of the experts do not agree with this opinion, and do not recommend the routine diagnostics of hypercoagulable states in patients with venous thromboembolic disease, justifying this with the scarcity of documented evidence of the influence of thrombophilia on the risk of thrombosis recurrence as well as the high costs of diagnostics, and its negative psychological (fear of illness and death) and social (e.g. increase of health insurance premiums) effects [1,6–10,12,13]. These experts recommend instead that indefinite anticoagulation should be proposed based on the individual balancing of the risk of thrombosis and bleeding. A separate diagnosed group of patients were those with a history of an ‘unusual location of venous thrombosis.’ Central retinal vein thrombosis was the reason for thrombophilia testing in 5% of these patients. According to the current guidelines [4], this location of a thrombotic process is not an indication for routine testing of hypercoagulable states. Nevertheless, these tests were performed following the suggestions of ophthalmologists, at the request of patients, because of young age of the patient (26, 37 and 56 years old) and in cases wherein there was no other obvious cause of retinal vein thrombosis, except from potential thrombophilia. Central retinal vein thrombosis may be caused by both local (retinal vein pressure by hardened arteries, increased intraocular pressure, hindrance of the outflow of venous blood from the eyeball to the heart, for example due to thrombosis in the venous sinuses of the dura mater or stenosis of the internal jugular vein) and general factors (hypertension, hyperlipidemia, diabetes and congenital and acquired hypercoagulable states) [14]. It is worth taking into consideration that it is not completely certain whether the use of anticoagulants in patients with retinal vein thrombosis makes any clinical sense at all [4]. Similarly expressed is the issue of cerebral venous thrombosis, although the recommendations for the use of anticoagulants in this case are clearly formulated [15]. The relationship between thrombosis of the cranial sinuses and congenital thrombophilias, however, seems to be poorly documented, so the validity of research in the direction of the latter also raises doubts [16]. There are also no data on the impact of the early diagnosis of most thrombophilias for the subsequent therapeutic decisions, the extension of secondary prevention, for example [4]. Only a diagnosis of antiphospholipid syndrome results in a recommendation of indefinite anticoagulation [15], just as in the case of venous thromboembolic disease.
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Thrombophilia diagnosis Spychalska-Zwolin´ska et al. 653
In our study, there were four patients with a history of a thrombotic episode in pregnancy and/or puerperium. The likelihood of its occurrence is six times higher in this group than the general population and increases with the coexistence of thrombophilia. Venous thromboembolic disease is the leading cause of pregnancy-related deaths in developed countries [11]. In our group, abnormal test results for thrombophilia were found in one patient. She had a combination of three abnormalities: antithrombin deficiency, the heterozygous form of the gene V Leiden and a low-positive result for the anticardiolipin antibody IgM. It is worth pointing out that women who are burdened with a deficit of antithrombin, proteins C and S and a factor V Leiden mutation have a higher risk of venous thrombosis, not only during pregnancy, but also while they are taking oral hormonal contraception (five-fold compared with women not using oral contraceptives and loaded with inherited thrombophilia [10]). It is worth mentioning that women without a thrombophilia diagnosis using this form of birth control also have an increased risk of thrombosis compared with the general population (0.7 vs. 0.03% per year of use [6]). In practical terms, the fact that there is an increased risk of thrombosis in women using hormonal contraception and/or a high probability of thrombosis recurrence in patients with a history of a thrombotic episode during pregnancy should justify carrying out diagnostic tests for thrombophilia in these patients [1]. However, a negative test for thrombophilia in a woman planning to start oral contraceptives can give her a sense of false security in the face of the risks associated with the therapy alone [4,6]. Our patients were advised not to use oral contraception after pregnancy and a patient with a complex thrombophilia was recommended to use prophylactic doses of low-molecular-weight heparin (LMWH) during her next pregnancy. Bouvier et al. [17] pointed out the benefits of LMWH in a group of pregnant patients with a history of miscarriages and a diagnosis of thrombophilia, expressed in a lower incidence of fetal death, premature births and preeclampsia. In our study, there were also patients diagnosed because of a past episode of arterial thrombosis. Recent guidelines do not recommend routine testing for thrombophilia in patients with arterial thrombosis (level of evidence: 1B) [4]. This is because of the fact that thrombophilia is seen mainly as a predisposing factor of venous thromboembolism. However, according to some experts, it can also promote arterial thrombosis clinically manifested as myocardial infarction with normal coronarogram or ischemic stroke. It is essential particularly for APS, but not only this. Guidelines for 2012 suggest that young adults (
