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AND VENOUS THROMBOEMBOLISM
International Consensus Statement
Guidelines According to Scientific Evidence The Cardiovascular Disease Educational and Research Trust, The International Union of Angiology and The Mediterranean League on Thromboembolism A. N. NICOLAIDES (Cyprus) (Chairman); H. K. BREDDIN (Germany); P. CARPENTIER (France); S. COCCHERI (Italy); J. CONARD (France); V. DE STEFANO (Italy); N. ELKOOFY (Egypt); G. GEROTZIAFAS (France); S. GUERMAZI (Tunesia); S. HAAS (Germany); R. HULL (Canada); E. KALODIKI (UK) (Scientific secretary); V. KRISTOF (Hungary); J. J. MICHIELS (Netherlands); K. MYERS (Australia); G. PINEO (Canada); P. PRANDONI (Italy); G. ROMEO (Italy); M. M. SAMAMA (France); S. SIMONIAN (USA); S. XENOPHONTOS (Cyprus) Thrombophilia is the term now used to describe Venous thromboembolism:
predisposition to increased risk of venous and magnitude of the problem
occasionally arterial thromboembolism due tohematological abnormalities.1-4 It can be a mul- VTE causing deep vein thrombosis (DVT) or tifactorial disorder where congenital defects of pulmonary embolism (PE) is a major international anticoagulant or procoagulant factors may be health problem. At one extreme, PE can be fatal.
combined with acquired hematological abnor- In North America and Europe, the annual inci- malities.1, 2 It should be considered in patients dence is approximately 160 per 100 000 for DVT, 20 per 100 000 for symptomatic non fatal PE and episode or a positive family history.1, 2, 5, 6 50 per 100 000 for fatal autopsy-detected PE.7-11 The aim of this document is to provide guide- Often, overlooked is the fact that DVT can lead to lines for investigation and management of patients post-thrombotic deep venous reflux or obstruc- with thrombophilia in the presence or absence of tion causing leg skin changes and ulceration, which adversely impacts on quality of life and escalates health care costs. The prevalence of venous ulcer-ation is at least 300 per 100 000 and approximately Disclaimer.—Due to the evolving field of medicine, new resear- 25% are due to DVT.12, 13 The annual cost result- ch may, in due course, modify the recommendations presented in ing from venous ulceration has been estimated to this document. At the time of publication, every attempt has been be £ 400 to 600 million for the UK 14, 15 and more made to ensure that the information provided is up to date andaccurate. It is the responsibility of the treating physician to deter- mine the best treatment for the patient. The authors, committee VTE should be an appealing target for maxi- members, editors, and publishers cannot be held responsible forany legal issues that may arise from the citation of this statement.
mum prophylaxis, but it has been difficult to achieve consensus on its prevention and man- vein recanalization after treatment with low mol- agement. The diagnosis can be difficult and elu- ecular weight heparin (LMWH) and early mobi- sive since many venous thromboembolic events lization than with intravenous unfractionated are not detected clinically, either because they are heparin (UH) and immobilization in bed.44 Clin- asymptomatic or they cause symptoms attributed ical PE occurs only when thrombosis is extensive to other conditions. It is important for medical and proximal to the calf 43 and iliofemoral throm- practitioners to understand the epidemiology, rec- bosis is the principal cause of fatal PE.45 ognize high-risk groups, be familiar with new diag- Approximately 30% of symptomatic calf DVTs nostic methods,18, 19 and follow the ever-changing recur, and anticoagulation appears to limit exten- sion, embolization and early recurrence.43, 46-48 Virchow’s triad of factors that predispose to VTE Recurrence is more likely in patients without a are venous stasis, alterations in blood constituents, reversible risk factor and in those with throm- and changes in the endothelium; these are as true bophilia.49-52 The post-thrombotic syndrome con- today as when postulated in the 19th century. It is sists of pain, swelling and pigmentation, with or often necessary for at least two of these changes without ulceration.53 It occurs within several to coexist for VTE to occur. Principal clinical fac- months or years in many patients after DVT. It is tors are immobilization, trauma, surgery, infec- due to persisting deep venous obstruction and/or tion and the postpartum period.21 Other factors reflux from damaged valves resulting in venous that predispose to VTE are age, obesity, malig- hypertension, increase in transmural pressure in nancy, previous history of venous thrombosis, vari- postcapillary vessels, skin capillary damage, fluid cose veins, dehydration and hormone therapy.22- exudation, edema, and tissue malnutrition. This 36 In the background for all of these is predispo- predisposes to inflammation, infection, throm- bosis, and tissue necrosis with lipodermatoscle- Patients admitted to hospital are particularly at risk for VTE. Without prophylaxis, the approx- In the past the incidence of the post-thrombot- imate incidence of DVT is 25% after general ic syndrome 55 was found to be approximately surgery, 45% after hip fracture, 51% after hip joint 35% to 70% at 3 years and 50% to 100% at 5 to replacement, 47% after knee joint replacement, 10 years after DVT, depending on the extent of 32% after retropubic prostatectomy (but only 9% thrombosis.56-66 It is uncommon in patients with after transurethral prostatectomy), 22% after thrombi confined to the calf, but the risk increas- gynecological surgery for malignancy (but only es with more proximal thrombosis.56, 57, 67-70 14% in the absence of malignancy), 50% after Patients with both chronic obstruction and reflux multiple trauma, 35% after spinal cord injury, have the highest risk for skin changes or ulcera- 22% after neurosurgery, 17% in general medical tion.71 Other factors that predispose to the post- patients, 22% after myocardial infarction, 56% thrombotic syndrome are ipsilateral recurrent following stroke, 9% in geriatric patients,37 15% DVT, increasing age,72 inadequate anticoagulant in acutely ill medical patients 38 and 13% to 31% therapy,73 and obesity.74 Ulceration is more fre- in critically ill patients admitted in intensive care Recent randomized controlled studies with treat- ment of proximal thrombosis by adequate anti- Natural history of venous thrombosis
coagulation, early mobilization and long-termelastic compression show that skin changes or The development of the 125I-fibrinogen uptake ulceration develop in 4-8% depending on the sever- test (FUT) in the late 1960s made early detection ity of hemodynamic changes, duration of follow- and propagation of DVT possible when the patient up and cause.52, 75, 76 The prognosis of venous leg was asymptomatic.43 In hospital patients, it could ulceration is poor since only 50% heal at 4 be demonstrated that most thrombi start in the months,77 20% remain open at 2 years, and 8% calf, that spontaneous lysis of thrombi in the calf occurs in some 35%, and that thrombus propa- The relationship between thrombophilia and gates into the popliteal or more proximal veins in extent and recurrence of DVT, and development approximately 20%.43 There is a higher rate of of the post-thrombotic syndrome is unknown.
TABLE I.—The prevalence of inherited thrombophilias and associated relative risk (RR) for VTE. Thrombophilia is the term used to describe pre- disposition to venous and occasionally arterial thromboembolism. Abnormal clotting can result from hereditary or acquired hematological abnor-malities. Of these, the most common is activated protein C (APC) resistance that is caused by the The frequency of hereditary thrombophilia in patients with confirmed idiopathic thrombosis occurring outside the clinical setting of surgery, In 1865, Armand Trousseau first stated that in cancer a special condition of the blood predisposes Abnormalities of the fibrinolytic system and hyper- to spontaneous coagulation even in the absence homocysteinemia may contribute to increased of inflammatory reactions. Overt cancer is asso- risk of VTE, but their clinical relevance has not ciated with a 4.1-fold increase in risk for VTE which been well established. Dysfibrinogenemia and increases to 6.5 fold with treatment by chemother- increased levels of plasminogen activator inhibitor- apy.78, 79 The most common tumors associated with 1 (PAI-1) are rarer and a causal relationship is not VTE are cancers of the pancreas, lung, stomach studies have suggested that a significant number These include high plasma level of Factors VIII, of passengers on long-haul flights develop silent DVT. A recent review has indicated that 72% ofindividuals with travel-related DVT have associ- DEFICIENCY OF PHYSIOLOGICAL ANTITHROMBOTIC FAC- ated coagulation defects.87 However, prospective studies that include a thrombophilia screen are These include deficiency of antithrombin (AT) previously known as antithrombin III, Protein C, Different congenital defects leading to throm- Protein S, and possibly heparin cofactor II or Fac- bophilia as well as lupus inhibitors play an impor- tant role in thrombotic complications in preg- Combined abnormalities of Factor V Leiden, nancy, and they can cause miscarriage and fetal Protein C, Protein S, AT or the prothrombin muta- tion G20210A have been frequently described andthey lead to a higher risk of thrombosis. There is Etiology of thrombophilia
an important interaction of Factor V and FactorII mutations that leads to true synergistic poten- tiation with other transient risk factors for VTE Hereditary thrombophilia is associated with an such as pregnancy and oral contraceptives (see increased risk of usually venous and in rare cases arterial thrombosis for which the causal relation- ship is less established.1, 2 The prevalence of differ-ent inherited thrombophilias and the associated A non-sense mutation (null allele) does not pro- increased risk for VTE are summarized in Table I.
duce a protein. A missense mutation produces a Abnormalities can be classified as following.
mutant protein with loss of function of the involvedprotein. Heterozygotes of a null and one normal allele produce only 50% of normal protein (quan- The most common genetic predisposition in titative deficiency). Heterozygotes of a mutant populations of European origin is APC resistance (missense) and normal allele produce equal caused by Factor V Leiden mutation. Another amounts of normal and abnormal protein (quali- cause is prothrombin G20210A gene mutation.
tative deficiency). With regard to congenital throm- bophilia, non-sense mutations are featured by been identified in many ethnic groups.105 Het- absence of a protective (anticoagulant factor) pro- erozygote AT deficiency is rare in the asympto- tein by preventing synthesis and result in type 1 matic normal population with a frequency of 0.07- quantitative deficiency of the involved anticoagu- 0.16%. An AT defect is of clinical relevance if the lant factor protein. A missense mutation is fea- AT level is below 60-70% on repeat testing. It is tured by the synthesis of an abnormal mutant anti- found in 1-3% of patients with venous thrombo- coagulant factor protein with loss of function and sis and in 4% of families with thrombophilia.106, 107 results in a type 2 deficiency. A large number of The lifetime risk of thrombosis varies between non-sense and missense mutations have been 5-50%. Several types of AT deficiency have been reported for congenital type I and type II antithrom- identified: quantitative type I and qualitative type bin, Protein C and Protein S deficiencies respec- II (reduced activity, normal antigen). There are 3 tively. Some genetic risk factors of thrombophilia variants of type II reactive site defect (RS), concern single point mutations (missense muta- pleiotropic site effect and heparin binding site tion) that result in gain of function of procoagu- defect (HBS). One of them, AT deficiency type II lant proteins such as prothrombin gene G20210A HBS, is associated with low risk in the heterozy- mutation. Mutations that result in gain of func- gous form. Combinations of AT deficiency with tion of a procoagulant factor are rare and much the Factor V Leiden mutation increase the risk of less common than those that result in loss of func- thrombosis, which tends to occur at a younger tion of an anticoagulant factor. Factor V mediates age.108 Homozygotes or double heterozygotes withvery low or undetectable AT levels have not been both procoagulant and anticoagulant activity. Fac- described, except for the case of HBS, as this prob- tor V gene G1691A mutation is a missense muta- tion with a loss of function in the anticoagulantAPC resistance of Factor V (Factor V Leiden).
Protein C (PC) gene is located on chromosome 2. It is a vitamin K dependent plasma protein. It APC resistance is associated with a single point acts as an anticoagulant by proteolysis degrading mutation, guanine instead of adenine at nucleotide procoagulant Factors Va and VIIIa. Quantitative 1691 in exon X of the Factor V gene 90, 91 which is type I heterozygote is the most frequent with a located on human chromosome 1. This Factor V prevalence of about 75% amongst all subtypes.
Leiden mutation creates a coagulation Factor V More than 160 unique mutations have been iden- that is 10 times less susceptible to APC-induced tified.109 Heterozygote PC is present in 0.2-0.4% inactivation. Heterozygote Factor V Leiden is pre- of the normal population and in 3-5% of patients sent in 0-15% of the normal population depend- with venous thrombosis.106 The risk of thrombo- ing on the ethnicity of those studied, in 20% of sis is similar in type I and II deficiency. Throm- patients with venous thrombosis and in 40% of botic complications in individuals with PC defi- families with thrombophilia.100 The prevalence of ciency frequently occur when other congenital or this disorder is much higher in people of Euro- acquired risk factors are present. Homozygous pean descent and absent in African and Asian pop- PC deficiency has been observed in new-borns ulations.101, 102 The homozygote Factor V Leiden with purpura fulminans 110 and in a small num- is found in only about 0.02% of the normal popu- ber of adults with skin necrosis at the initiation lation but the relative thrombotic risk is high. Other of treatment with vitamin K antagonists.111, 112 mutations have been described in Factor V gene: Arg306Gly in Factor V Hong-Kong, and Arg306Thr Protein S (PS) gene is located on chromosome in Factor V Cambridge.103, 104 An association 3. Protein S is a vitamin K dependent plasma pro- between these mutations and thrombosis has not tein. It functions as a cofactor for degradation of Factors Va and VIIIa by APC. More than 130unique mutations have been identified.113 These mutations lead to increased risk through decreased The AT gene is located on human chromosome plasma antigen levels, decreased activity or both.114 1 (q23-25), and more than 79 point mutations have Heterozygote PS deficiency is present in 0.03- 0.13% of the normal population, and in 1-5% of TABLE II.—The most likely pathogenic mechanisms of acqui- patients with venous thrombosis.106 PS deficiency red thrombophilia and their associated conditions. can lead to thrombotic venous and arterial events 92 including VTE 115 or ischemic stroke in younger individuals.116 Familial PS deficiency as well as other forms of thrombophilia have been shown to cause osteonecrosis of the hip, probably by pro- moting venous thrombosis in major veins that drain the head of the femur.117 Heterozygote type I PS deficiency has low levels of free and total PS anti- gen with decreased APC cofactor activity. Homozy- gote PS deficiency is typically associated with neona- The prothrombin mutation G20210A, localized on chromosome 11, is found in about 1-2% of the asymptomatic population, 4-7% of patients with thrombosis, and 18% of families with throm- bophilia. The relative risk for VTE is calculated to be 2-3 fold for the mutation alone and 20-foldfor a combination with Factor V Leiden.98 Thereis an increased risk of cerebral venous thrombo- XI or IX as well as some gene polymorphisms of sis in women with hereditary thrombophilia and thrombin activatable fibrinolysis inhibitor (TAFI) thrombosis at unusual sites especially when tak- are also associated with an increased risk of VTE, ing oral contraceptives.118 The prothrombin muta- but this awaits confirmation from larger trials.125- tion G20210A increases the risk of myocardial 128 In addition, in patients with a first VTE a high TAFI level (75th or higher percentile in thrombosis patients) is associated with a 2-fold higher risk for recurrence compared with lower levels.129 acquired. Between the normal value and 100µmol/L MTHFR polymorphisms should be con- sidered.120 A causal relationship has not yet been Several pathological conditions are associated established between hyperhomocysteinemia and with acquired thrombophilia and Table II lists the venous or arterial thrombosis. The very rare homo- most likely mechanisms and associated condi- cysteinuria due to cystathionine β synthese (CBS) tions. Abnormalities such as lupus inhibitor (for- mutation or cobalamine mutation should be con- merly known as lupus anticoagulant) 130, 131 and sidered if blood levels are in excess of 100 µmol/L.
anticardiolipin antibodies 132 are associated with Homocysteine levels rather than MTHFR poly- predisposition to VTE, arterial thrombosis and morphisms are preferred in the investigation of pregnancy complications. They have the most adverse outcomes due to a high rate of recurrence and high mortality rate if anticoagulation is dis- Elevated Factor VIII levels have been identified recently as a risk factor for venous thrombosis,123 Like inherited thrombophilia, acquired throm- but it is still not clear whether an inherited dis- bophilic diseases can vary widely in their clinical order leading to high Factor VIII levels exists. High penetrance depending on whether or not there Factor VIII levels are associated with increased are concomitant triggering factors for VTE such risk of VTE recurrence in patients with a first idio- as cancer and the use of chemotherapy or central venous lines which further increase the throm- Some data indicate that elevated levels of Factor CHRONIC MYELOPROLIFERATIVE DISORDERS AND VENOUS VTE can occur in a large proportion of patients with cancer, especially in those with advanced dis- A broad spectrum of arterial thrombotic com- ease receiving anticancer therapy.133, 134 Patients plications, VTE and splanchnic vein thrombosis with hematological malignancies also have a high related to either increased platelet, blood volume risk for thrombotic complications.135 Neoplastic and/or thrombophilia has been reported in patients cells produce factors with procoagulant activities with chronic myeloproliferative disorders (CMPD), 78 of which tissue factor (TF) and cancer procoag- namely polycythemia vera (PV) and essential ulant (CP) are the most characteristic.136 Paraneoplastic thrombophilia is more likely to A retrospective study of 304 ET/PV patients found Factor V Leiden in 14/304 (4.6%) and was cause VTE with circumstantial risk factors such as associated with VTE in 5/27 (16%). However, the bed rest, vascular compression, administration of prevalence of Factor V Leiden in these ET/PV antineoplastic or hormonal agents and use of cen- patients with and without arterial thrombosis was tral venous lines. Physicians should be aware that similar: 5/78 (6%) and 9/211 (4%).147 In the same apparently spontaneous VTE should prompt them study, a correlation between hyperhomocys- to consider a diagnosis of cancer 137, 138 and to fol- teinemia and thrombosis was not found.
low these patients carefully. Preclinical cancer has The prevalence of the allele for Factor V Leiden been diagnosed in 3% of patients with spontaneous in 50 myeloproliferative disorder patients with a DVT of the lower limbs and up to 18% of patients CMPD (17 PV, 15 ET and 18 myelofibrosis) and with DVT of the upper limbs,139 while an addition- 30 controls was 9% in the myeloproliferative dis- al 8% of patients develop overt cancer within 1 to order patients and 3.4% in controls.148 This study suggests that thrombophilic factors may increasethe cumulative venous thrombotic risk in myelo- proliferative disorders on top of/besides the arte-rial thrombotic risk imposed by activation of The prevalence of antiphospholipid antibodies hypersensitive thrombocythemic platelets and/or has been reported as 4-20% in patients with VTE.141 Diagnosis of antiphospholipid antibody syndrome Congenital or acquired thrombophilia was found should be made on the basis of contemporary pres- in about 1/3 of patients with portal vein thrombo- ence of at least one clinical and one laboratory cri- sis and in about 60% of patients with hepatic vein terion.142 Clinical criteria include venous or arter- thrombosis (Budd Chiari Syndrome).149, 150 Throm- ial thrombosis in any tissue or organ objectively bosis in splanchnic veins (portal or hepatic) is rare diagnosed and/or history of previous obstetric com- at time of diagnosis of CMPD but may develop in plications with at least 3 consecutive spontaneous a few patients during long-term follow up. In con- abortions before the 10th week, at least one fetal trast, a CMPD (ET, PV or myelofibrosis) can be death >10th week, or at least one premature birth diagnosed in up to 30% of patients with hepatic <24th week.143 Laboratory criteria consist of detec- vein thrombosis (Budd-Chiari syndrome), and in tion of lupus inhibitor and/or IgG or IgM anticar- about 15% to 20% of patients with portal vein diolipin antibodies at moderate or high level on 2 thrombosis.149, 150 Heparin or LMWH followed by or more occasions at least 6 weeks apart. The pres- vitamin K antagonists is the treatment of choice in ence of lupus inhibitor is associated with a 4.1-fold patients with acute splanchnic vein thrombosis. to 16.2 fold increase in risk of VTE.144, 145 In con-trast, the presence of anticardiolipin antibodies has CHRONIC MYELOPROLIFERATIVE DISORDERS AND ARTE- been found to be significantly associated with VTE in only a minority of reports, with an increase in Arterial thrombotic manifestations of ET in 809 risk not exceeding 2.5-fold.144 Other antiphospho- patients from 10 retrospective studies were lipid antibodies such as anti-β2-glycoprotein I and described as platelet-mediated microvascular dis-antiprothrombin antibodies 146 are related to throm- turbances involving the extremities in 24%, cere- bral circulation with atypical or typical cerebral transient ischemic attacks (TIAs) in 17%, and mutation in the Mediterranean region has cul- major arterial thrombosis in 20%.151 VTE includ- minated in many studies that highlight their fre- ing portal and splenic vein thrombosis was rare in this retrospective review of 809 ET (4%).151 InET and in thrombocythemia associated with PV in remission, a high incidence (60-80%) of Table III 162-182 lists the frequencies for Factor microvascular disturbances including ery- V Leiden in the general population and in patients thromelalgia, migraine-like atypical and typical with DVT in Mediterranean countries. As expect- TIAs have been reported.152-157 These clinical man- ed, where general population frequency is high ifestations which are caused by spontaneous in then more patients have DVT attributed to Fac- vivo platelet activation at high shear stress in the end-arterial circulation are highly sensitive to low An international comparative study of allele fre- dose aspirin, but not to vitamin K antagonists, quencies for Factor V Leiden indicates that East- heparin, or LMWH (level 1A evidence).152-157 ern Mediterranean populations harbor a relatively Essential thrombocythemia frequently precedes high mutant allele frequency similar to some Scan- PV, and PV is usually associated with thrombo- dinavian and Northern European populations.183- cythemia complicated microvascular disturbances, 187 The frequency is less in Asians and South Amer- which are not relieved by bloodletting because icans and the condition appears to be absent in thrombocythemia persists. On top of the microvas- Oriental and other non European populations.100, cular disturbances of thrombocythemia,152-157 major thrombotic complications have been report- Lebanon exhibits one of the highest general pop- ed in 20-40% of untreated patients with uncon- ulation frequencies for Factor V Leiden mutation trolled PV, involving the arterial system in 2/3 and in the Eastern Mediterranean region with a gen- venous system in 1/3.158-159 These major arterial eral population frequency of 7.4% and 39.7% fre- and venous thrombotic events are related to quency in patients with venous thrombosis.164 This increased hematocrit, red cell mass and con- high frequency may be due to a high rate of comitant increased blood viscosity.152-160 Correc- inbreeding resulting in conservation of the gene tion of increased blood viscosity and hematocrit pool; it also suggests that the mutation may have to normal (<0.44 males, <0.42 females) values, by bloodletting alone, will reduce the major throm- Another report shows an extremely high fre- botic complications. However, the microvascular quency in Israeli Arabs (13.6%) and low frequen- circulation disturbances persist, do not respond cy in Israeli Jews (2.8%) and this difference is to anti vitamin K treatment, but are best treated probably explained by a high consanguinity rate and prevented with low dose aspirin, or when indi- in the Israeli Arab population.172 The latter reflects cated by platelet lowering agents, anagrelide, inter- European frequencies for Factor V Leiden possi- feron or hydroxyurea.152-160 Based on the efficacy and safety of low dose aspirin for the treatment Jordan is located at the Eastern border of Israel.
and prevention of platelet mediated microvascu- The Factor V Leiden mutation frequency is 7% in lar thrombotic complications in patients with the Jordan general population, similar to the value thrombocythemia of various CMPDs,152-157 low in Lebanon, this being the most common genet- dose aspirin has been compared with placebo to ic lesion associated with venous thrombosis in show that it also can safely prevent major and minor arterial and venous thrombotic complica- The Factor V Leiden allele frequency in a ran- tions in patients with polycythemia in remission dom population in Greece (2.5-2.7%) is lower than after bloodletting and/or hydroxyurea (Level 1A that in Cyprus (4-7%).162, 168, 169, 179 Another study in the Greek population reported a frequency of2.4% in controls and 16% in patients with DVT.167 Thrombophilia in Mediterranean countries APC resistance was found to be present in 21% of Molecular investigation of inherited throm- women with recurrent abortions compared to 12% bophilias, Factor V Leiden and the prothrombin TABLE III.—FV Leiden allele frequencies in the general and DVT populations of Mediterranean countries. Irani-Hakim et al.164Irani-Hakim et al.178 Awidi et al.165Eid et al.166 Antoniadi et al.168Zalavras et al.169Lambropoulos et al.167 Angelopoulou et al.162Xenophontos et al.179 Gurgey et al.171Demir et al.170 Garcia-Gala et al.181Santamaria et al.182 The general population frequency for Factor the population frequencies for prothrombotic V Leiden is 3.5% in Turkey, 2.4% in Southern mutations to allow more efficient screening. Italy 180 and 1-1.7% in Spain 181, 182 although the Haplotype analyses in carriers of Factor V Lei- frequency in patients with DVT is 23%, 12.1% and den and Factor II G20210 mutations indicate a single origin for both mutations in European pop- The Iranian general population frequency for ulations. There were probably fewer migrations Factor V Leiden mutation is reported to be 2.7%.174 to more distant geographical regions inhabited Data for the general population of Egypt does not exist but a recent study demonstrates that 30% of It would certainly be interesting from an evo- pediatric patients with portal vein thrombosis are lutionary standpoint to determine the haplotypes attributed to Factor V Leiden mutation (in press).
segregating with the Factor V Leiden mutation in General population frequencies for Tunisia, Alge- Mediterranean carriers as this will show us ria and Morocco are 5.4%, 1.4% and 0% respec- whether a common origin exists for all Factor V tively,175-177 suggesting a decline in frequency from The distribution of thrombophilia mutations in Saudi Arabia is different to that of other EasternMediterranean countries.173 Factor II G20210A mutation has also a geo- Geographical clustering is obviously apparent graphic distribution. It has been detected and in the distribution of Factor V Leiden indicating implicated in DVT in the Mediterranean region.
a probable origin in the Eastern Mediterranean This mutation has an allele frequency of 1.3-2.2% with spread over Europe by migration.101, 102, 191- in the general population of Greece and 2-3.9% 193 These findings suggest that the emphasis in in Cyprus.162, 168, 169, 179 In Greece, the frequency of thrombophilia screening should be tailored to this mutant allele in patients with DVT (3.4%) was accommodate a population’s risk profile. Differ- significantly higher than in controls (1.3%).169 ences noted between different ethnic groups, as Southern Italian allele frequencies were 7.1% for in Israel with respect to Factor V Leiden, and epi- DVT cases and 2.2% for the general population.180 demiological studies are important to establish It is apparent that this defect accounts for more DVT cases in Southern Italy than other Mediter- sitivity and drugs and external conditions do not ranean countries. The general population fre- quency in Spanish is 3.25%, similar to the fre-quency in Cyprus.182 The Iranian general popula- tion frequency for Factor II G20210A mutation isreported to be 1.5%.
AT slowly inactivates thrombin activity (pro- Factor II G20210A mutation was present in 3.4% gressive activity). Thrombin is rapidly inactivat- of Turkish patients with DVT compared to 1.1% ed in the presence of heparin, and this test called in the general population.171, 194 In addition, PC, the heparin cofactor activity is the test recom- PS and antithrombin deficiency were present in mended for screening. AT has two functional 13.5%, 13.5% and 5.4% of patients with DVT domains: the reactive site (RS) Arg393 Ser394 and respectively.170 In contrast, MTHFR C677T was heparin binding site (HBS) located at the N-ter- not associated with DVT.195 Lack of association of minus of the AT molecule. Four types of heredi- the C677T mutation and DVT was also demon- tary AT deficiency can be distinguished by two functional tests in the absence or presence of In Israeli thrombophilia patients, thrombosis heparin, immunological and a crossed immuno- was attributed to PC, PS and antithrombin defi- electrophoresis immunoassay test (CIE). Quanti- ciency, in 5.6%, 2.8% and 7.5% respectively.197 In tative AT deficiency type I has equal values for AT 179 Saudi Arabian patients with DVT, 1.1% was heparin cofactor activity, progressive activity and attributed to Factor V Leiden (allele frequency- concentration. AT deficiency type IIRS is charac- 0.6), 1.1% to Factor II, 8.4% to PC deficiency and terized by decreased heparin cofactor and pro- gressive activity, but a normal AT concentration.
AT type IIHBS is characterized by normal concen-tration and normal progressive activity due to RS Laboratory diagnosis of thrombophilia
being intact, but selective decrease of the heparincofactor activity due to loss of HBS from the Genetic defects in hereditary antithrombin, PC mutant AT molecule. In AT type II HBS, muta- and PS deficiencies are multiple and diverse, which tions are mainly located at position 41 and 47.105 makes routine DNA diagnosis impossible. The AT deficiency with a pleiotropic effect is a quan- Factor V Leiden mutant can easily be diagnosed titative and qualitative defect featured by decreased by highly sensitive and specific tests followed by heparin cofactor and progressive activity togeth- DNA confirmation to differentiate between het- er with decreased or near normal antigen con- erozygous and homozygous individuals. There is centration of AT. In AT type II pleiotropic effect, no functional test available for the prothrombin mutations are mainly at sites between 401 and gene mutant G20210A variant, which can only be detected by a simple PCR-based DNA test.
Laboratory evaluation of hereditary throm- bophilia detects quantitative or qualitative defectsby the following three investigations: functional, The combination of an immunological assay, functional clot assay and functional amidolytic Functional and immunological investigations assay for PC will detect quantitative type I and are phenotypic tests that study activity and anti- two types of type II functional PC deficiencies.
gen levels. They are used for AT, PC and PS defi- There is an overlap in absolute values for PC anti- ciency, and Factor V Leiden. They have the limi- gen and activity between patients with congen- tation that sensitivity and specificity are variable ital PC deficiency and normal individuals. Ami- under different conditions such as pregnancy, liver dolytic activity selectively measures the amount insufficiency, and with certain medications.
of serine protease activity of PC. The clot assay Molecular investigations are gene specific and provides information not only concerning ser- therefore more accurate. They are used for Fac- ine protease activity of PC but also regarding tor V Leiden confirmation and for Factor II mutant other functional defects of APC interactions with detection. They have the advantage of good sen- phospholipid membranes of the GLA domain, cofactor PS, and Factors Va and VIIIa. However, pregnancy or with inflammation, and by the pres- the PC clotting assay could be influenced by APC ence of antiphospholipid antibodies. However, resistance, elevated Factor VIII and lupus this test can detect all congenital or acquired APC inhibitors, so that chromogenic assays are more resistance that could be associated with an frequently used. Very rare cases of PC deficiency increased risk of thrombosis. It detects APC resis- detected by the clotting assay and not the ami- tance related to Factor V or VIII mutations as well dolytic assay have been reported. PC dysfunction as quantitative modifications of procoagulant fac- is restricted to the active site responsible for inac- tors leading to a hypercoagulable state. The sec- tivation of the natural substrates, but not to the ond generation APC resistance test using Factor site responsible for splitting synthetic substrates.
V depleted plasma to correct for coagulation fac- However, only a limited number of affected patients tors has demonstrated a specificity and sensitiv- would be missed by a diagnostic strategy using ity very close to 1 to detect the Factor Leiden muta- only amidolytic assays for PC measurement.198 tion.201, 202 It can be used in patients taking vita-min K antagonists or under heparin treatment (if a heparin inhibitor is added to the reagent) butcan be affected by high levels of lupus inhibitor.
The method used for PS activity is not robust. It Van Oerle et al.,203 developed a new prothrombi- may be better to measure PS free antigen rather nase-based functional APC resistance test, which than activity because it is more robust. APC resis- is much more sensitive and even distinguishes tance, lupus inhibitors or Factor VIII excess could heterozygous from homozygous Factor V Leiden influence PS activity clotting assays. The only draw- thrombophilic individuals and detects acquired back of PS antigen assays is that they might miss APC resistance associated with the use of vitamin rare cases of type II PS deficiency.199, 200 Levels of total and free PS are influenced by binding of PS to C4b binding protein (C4b-BP).
Only free PS expresses APC-cofactor activity.
Who should be tested for thrombophilia
Three types of hereditary PS deficiencies havebeen identified. Hereditary PS deficiency type I Screening for thrombophilia should be per- is featured by reduced total and free PS antigen and decreased PS activity. Type II is featured by 1) all patients with a first episode of sponta- normal total and free PS antigen but decreased functional PS activity. Type III is defined by nor- 2) patients with VTE under the age of 50 even mal total PS antigen, decreased free PS antigen and decreased PS activity. Type I and III appeared 3) patients with VTE whose only risk factor is to be phenotypic variants of the same genetic defect oral contraceptive therapy, estrogen replacement within one family. Increased levels of C4b-BP at therapy or pregnancy. However, screening with an older age or in case of the acute phase syn- other than the molecular (PCR) tests should be drome result in consistently low levels of free PS performed at least two months after delivery or antigen and activity levels but pseudo-normal 4) patients with recurrent VTE irrespective of 5) patients with recurrent superficial throm- The standard APC resistance test measures the bophlebitis without cancer and in the absence of APTT of recalcified plasma in the presence and absence of a standardized amount of APC. The 6) patients with VTE at unusual sites such as reliability and specificity for APC resistance from cerebral venous sinus, mesenteric or hepatic veins, the first generation test is limited because this test and retinal vein occlusion under the age of 50; is influenced by deficiencies during oral antico- 7) patients with warfarin-induced skin necro- agulant treatment or excess of other coagulation sis and neonates with purpura fulminans not relat- factors such as Factor VIII particularly during 8) asymptomatic first-degree relatives of indi- viduals with proven symptomatic thrombophilia.
Non-clot based assays as PCR for detection of This is particularly important for females in the Factor V Leiden and Factor II mutant can be per- formed at any time. Clot-based assays such as PS 9) two consecutive or three non-consecutive or Factor VIII assays, may be influenced by the abortions at any gestational age, or one fetal death acute phase of thrombosis or by conditions at the time of thrombosis (e.g. pregnancy, oral contra- ception) or by treatment with vitamin K antago- nists (PC and PS assays). The AT assay may be There is no point for screening for thrombophilia important at the time of diagnosis of the throm- for patients in whom the decision has been made botic episode because AT concentrates may be for prolonged anti vitamin K therapy, such as can- required for a few days together with heparin or cer and VTE. Also, routine preoperative screen- LMWH. PC and PS deficiency should be looked ing for thrombophylaxis before surgery is not rec- for one month after cessation of vitamin K antag- ommended since a positive result will not modi-fy the prophylactic strategy in the majority of onist treatment. The presence of a PC, PS or patients. Preoperative thrombophilia screening antithrombin deficiency should only be accepted should be reserved only for patients with person- al or family history of VTE of unknown etiologywho have not been investigated.
Thrombophilia in patients
with chronic venous disease
The first line of tests to be performed are full It is surprising how little interest has been paid blood cell count, antithrombin (heparin cofactor to thrombophilic states in patients with chronic activity), PC (amidolytic assay), PS (free antigen), venous disease (CVD). Review of the literature fasting homocysteine blood levels, APC resistance only shows observational data, mainly with case (modified using Factor V depleted plasma), Fac- reports and uncontrolled series. The paucity of tor II G20210A mutation, activated partial throm- case control studies is a strong limitation when boplastin time and search for lupus inhibitor, and taking into account the high variability and methodology. Furthermore, documentation of APC resistance per se when not due to Factor V venous dysfunction is rarely performed, and the Leiden mutation is a risk factor for thrombosis diagnosis of the post-thrombotic syndrome is often and a potentiating factor for the thrombogenic based only upon the patient’s report of a history effect of oral contraceptives. This test in the absence of Factor V depleted plasma is not rec- The post-thrombotic syndrome is responsible ommended for a basic screening. Some labora- for a significant proportion (25-66%) of CVD.
tories perform Factor V Leiden molecular tests as Thrombophilic states are associated with an an alternative to basic screening for the APC resis- increased incidence, earlier onset and increased tance modified test. It has to be performed whenthe modified test is abnormal in order to confirm recurrence rate of DVT, which might favor the the mutation and to determine whether it is a het- occurrence of the post-thrombotic syndrome. DVT episodes appear spontaneously more often with Measurement of plasma Factor II cannot sub- thrombophilic states than in other subjects and stitute for the molecular test of Factor II muta- are therefore more likely to be overlooked poten- tially leading to unrecognized post-thrombotic If these tests are negative in the presence of a strong family history or thrombosis at unusual Data regarding PC, PS and AT deficiencies are sites or spontaneous thrombosis in young patients, scarce and non conclusive. Mutation of Factor II then the patients may have some other uncom- G20210A was investigated in only one series of mon defects and should be referred to specialized small size with negative result. Uncontrolled series found a high prevalence of antiphospholipid anti- bodies in patients with leg ulcers but few cases of gen was suspected to increase the risk for VTE, lupus inhibitors. Finally, the most relevant find- second generation oral contraceptives were intro- ings were related to APC Resistance and Factor V duced that contained less than 50 µg of estrogen Leiden, especially in two case control studies of (usually 30-40 µg) and a new progestin, lev- 92 and 100 patients with non invasive vascular onorgestrel. The incidence of VTE in women who investigations that gave consistent results.204, 205 take second generation oral contraceptives com- Both found an increased prevalence (37% and pared with non users is about 15 per 100 000 36%) of Factor V Leiden in patients with the post- women per year of use i.e. they still have a 3-4- thrombotic syndrome, compared to controls (7.5% and 5%), and to patients with CVD related to pri- Third generation oral contraceptives contain 35 mary varicose veins (2% and 6%). This confirms µg or less ethinyl estradiol and a newer progestin that CVD related to the post-thrombotic syndrome (desogestrel, gestodene, and norgestimate). Sur- is a clinical situation that frequently allows detec- prisingly, third generation oral contraceptives tion of Factor V Leiden mutation, and it is prob- appear to increase the risk of VTE by about 2-fold able that the post-thrombotic syndrome could be over that seen in second generation users 210-214 and 1.7 in a meta-analysis.215 In another study, an At present, the practical conclusion is that every increased risk was confirmed the first year of pill patient with CVD should be screened for the post- intake as well as the increased risk of third gen- thrombotic syndrome at least clinically and eration progestagen although the odds ratio was through ultrasound duplex examination. Demon- lower (1.4).216 In addition, the risk with ethinyl- stration of the post-thrombotic syndrome should estradiol was dose dependent. The incidence of be taken as evidence of past DVT for instituting VTE in these women is about 25 per 100 000 diagnostic and therapeutic strategies for throm- women per year of use. Third generation oral con- bophilia. Further case control studies assessing traceptives enhance APC resistance.214, 217 the prevalence of thrombophilia in the post-throm- A combined contraception by a non oral route is now available (patch or vaginal ring). Althoughthe risk of this route of administration has notbeen studied until now, elevated levels of the SHBG Contraception and thrombophilia
(sex hormone binding protein), a marker of estro-genicity, have been observed.218 Thus, an increased Effect of contraceptives on the risk of VTE risk of venous thrombosis is likely.
Combined oral contraception includes a syn- Progestin only contraception (oral, implant, thetic estrogen (ethinyl-estradiol) and a progestin.
intrauterine device) has received little attention The incidence of DVT in women who do not use but has not been associated with an increased riskof venous thrombosis.219, 220 oral combined contraceptives is 8 per 100 000women years, and this increases to 30 per 100 000among women who used oral contraceptives, 57 The risk of oral contraception in the presence of per 100 000 in female carriers of Factor V Leiden, and 285 per 100 000 with both oral contraceptives Administration of oral combined contraceptives and thrombophilia (one event per 350 women in heterozygotes for Factor V Leiden mutation years).206 The incidence of VTE in healthy, non increases the risk of VTE by ≈20-fold (95% CI: 4- pregnant women who are not taking oral contra- 29) 119 to ≈35-fold (95% CI: 7.8-154).206 This risk ceptives is about 5 cases per 100 000 per year while is further increased in users of third generation there are about 90 cases of VTE per 100 000 deliv- oral contraceptives to ≈50-fold compared with eries (about 1 per 1 000 deliveries).207 In all patients, the risk of VTE increases with age and Heterozygotes for prothrombin (Factor II) vari- ant (G20210A) on oral contraceptives have an ≈16- First generation oral contraceptives included at fold increased risk for VTE compared to an ≈6- least 50 µg of ethinyl estradiol or mestranol and fold increased risk of non users.88, 119 This variant a progestin, typically norethindrone. Because estro- may carry a higher ≈150-fold risk (95% CI:31-711) for the rare condition of cerebral vein thrombosis Hormone replacement therapy (HRT) is achie- with the use of oral contraceptives.221-223 These ved with the association of an estrogen (conju- results may overestimate the risk and need to be gated equine estrogen or estradiol, the physiolog- confirmed taking into account the other risk fac- ical estrogen) and a progestin (progesterone or tors associated with contraception. High Factor other). An increased risk of venous thrombosis has II levels even in women without prothrombin been observed in case control and randomized mutation also potentiate the prothrombotic effect studies in women receiving HRT containing con- jugated equine estrogens 234, 235 or oral estradiol.236 Data for the risk for rare inherited thrombophilic Factor V Leiden mutation increased the risk.237, 238 conditions such as PC, PS or antithrombin defi- Consequently, HRT with oral estrogen is con- ciency comes from retrospective case review type traindicated in women with thrombophilia. analyses.224-226 Oral combined contraception is In contrast, no increased risk was found in discouraged, but although the relative risk is high women receiving estradiol by transdermal route the absolute risk is low so that it is not cost effec- (patch or gel) in a case control study.239 These tive to screen every woman before the first pre- results are in accordance with the differential scription of contraception. In contrast, screening effects of oral and transdermal estrogens on coag- could be recommended in women with family his- ulation factors and APC resistance.240-244 The effects Elevated Factor VIII levels have been associat- of oral and transdermal HRT on thrombotic vari- ed with an ≈4-fold increased risk of VTE 227-230 and ables may be relevant to their relative thrombot-this appears to increase to ≈10-fold in oral con- ic risk.242 Two studies found that transdermal estra-tractive users.210 It should be emphasized that tran- diol decreases the anticoagulant response to sient elevated factor VIII levels are common and APC,243, 245 while others have found no difference.246 no abnormality of the factor VIII gene is present- ly associated with high levels of Factor VIII.
osteonecrosis, hyperglucagonemia, diarrhea and Women with thrombophilia are more likely to abdominal pain via mesenteric artery or vein develop VTE early in their course of oral contra- thrombosis, and intestinal or pancreatic ische- ceptive use. The risk is increased 19-fold during mia.247 Exogenous estrogen can be a cofactor in the first 6 months and 11-fold during the first thromboembolism, augmenting the thrombotic complications of PS deficiency.245, 248, 249 Oral estro- Based on a nested case control analysis, there gens can reduce antigenic, functional and free PS appears to be no association between VTE and levels, thus promoting thrombophilia.245, 248, 249 Estrogen induced lowering of PS, when super- Progestin only contraception with chlormadi- imposed on familial PS deficiency amplifies the none acetate was not associated with an increased hypercoagulable state.213, 245, 248 This is similar to risk of venous thrombosis in a case control study estrogen induced resistance to activated PC, including women with thrombophilia and/or pre- which when superimposed on the Factor V Lei- den mutation, further increases resistance to acti-vated PC.250-252 In such cases, the risk of venousthrombosis is increased by 80 to 100 fold.250-252 Hormone therapy and thrombophilia
Tamoxifen, an estrogen receptor antagonist used In their lifetimes, women are likely to face sit- as the adjuvant hormonal treatment of choice in uations associated with an increased risk of VTE, women with estrogen receptor positive breast can- be it through hormonal therapy or pregnancy.233 cer and in advanced malignant melanoma, sig- Hormones are used in various forms for contra- nificantly increases the risk of VTE.253 Anastro- ception (see above), perimenopausal and post- zole, a non steroidal aromatase inhibitor is anoth- menopausal hormone replacement therapy (osteo- er alternative. It was compared to Tamoxifen in a porosis and menopausal symptoms), treatment randomized, double blind, multicenter study. The of hormone responsive cancers and breast cancer incidence of thromboembolic events was lower TABLE IV.—Classification of pregnant women with throm- Caesarean section, obesity, or immobilization dur- Women with thrombophilia should be informed — PC deficiency, PS deficiency*, Homozygote V Lei- den, Homozygote II mutation, Combined V and II about the risk of VTE during pregnancy before they become pregnant. Advice will depend on the type of thrombophilia. Women who are taking oral anti- coagulants should change to subcutaneous LWMH or UFH as soon as they become pregnant because * PS is normally decreased during pregnancy and it is not well documen- of the risk of embryopathy between the 6th and 12th ted if PS deficiency is responsible for high risk.
week of pregnancy. Patients with a history of VTEshould have a duplex ultrasound scan to serve as a Prevention in patients with thrombophilia
reference, and they should be advised to wear elas-tic stockings.259 The efficacy of primary thrombosis prophylax- is is not yet known in asymptomatic patients with congenital thrombophilia. Patients should be pro- Pregnant women are classified into very high, tected during surgery or in the presence of any high and moderate risk (Table IV) and prophy- medical condition associated with an increased laxis is administered according to risk as shown risk of thrombosis even when they have minor surgery or minor trauma e.g. ankle sprain. Inpatients with acquired thrombophilic abnormal- ities, the decision regarding prophylaxis shouldbe made on an individual basis (Grade 2C).
than heterozygous type II HBS are consideredto be at very high risk. Women without a histo- Prevention of VTE in pregnant women
ry of thrombosis before pregnancy should receive with thrombophilia
high-dose LMWH prophylaxis throughout preg-nancy, for example with enoxaparin 40 to 60 mg Grade C recommendations published by sever- or 4000 to 6000 U, or dalteparin 5000 U once al groups 255-257 are based on observational stud- daily. Injections are stopped when labor starts ies and are subject to change when more infor- to allow epidural anesthesia 12 hours after the Inherited thrombophilias are associated with Women with a history of thrombosis before an increased risk of VTE and the risk is further pregnancy should receive LMWH prophylaxis increased during pregnancy.258 However, not all throughout pregnancy commencing as soon as thrombophilias carry the same attributable risk the pregnancy is diagnosed, for example with during pregnancy. Deficiencies in coagulation enoxaparin 40 to 60 mg or 4000 to 6000 U, or dal- inhibitors and especially in antithrombin are rare teparin 5000 U 12-hourly. Antithrombin concen- but are associated with a higher risk than the trates at a dose of 30-50 U/kg body weight should more frequent Factor V Leiden or prothrombin be considered on the day of delivery and for 2 days (Factor II) 20210A mutations. Additional differ- subsequently. Anti-Xa activity 3-4 hours after injec- ences may occur depending on heterozygosity or homozygosity of the defects and on the presenceof an additional thrombophilia or personal risk A personal or family history of DVT further Women with heterozygous PC deficiency, PS increases the global risk. Other risk factors should deficiency, homozygous Factor V Leiden or Fac- be taken into account such as age of the mother, tor II G20210A, or combined heterozygous Fac- TABLE V.—Prophylaxis in pregnancy in the presence of thrombophilia. Homozyg. V LeidenHomozyg. II mutationCombined V and II tor V Leiden and Factor II G20210A are consid- Treatment of patients with thrombophilia
Women with or without a history of thrombo- sis should receive LMWH throughout pregnancy In general, treatment of a patient with heredi- with high prophylactic dose such as enoxaparin tary thrombophilia who suffers an acute DVT or PE should not differ from that advised for patientswithout thrombophilia, except for selected patients with AT deficiency who might require AT con- Women with heterozygous Factor V Leiden or centrates in addition to heparin treatment. For Factor II G20210A mutations are considered to many years there has been a controversy as to the be at moderate risk. Additional risk factors should optimal duration for treatment with oral antico- agulants in thrombophilia patients after acute VTE. Before discussing general rules it should be pregnancy should receive prophylaxis is unknown stressed that the presence and relevance of dif- and further studies are needed. Clinical surveil- ferent risk factors and of underlying diseases in lance and elastic stockings should be used unless individual patients have to be considered before there are additional risk factors such as family giving advice as to the intensity and duration of Women with a history of thrombosis should receive LMWH prophylaxis throughout pregnan- Treatment of VTE in pregnant women with throm- cy (enoxaparin 40 mg or dalteparin 5000 U daily).
All recommendations are grade C. UH or sub- Prophylaxis immediately after pregnancy cutaneous LMWH are the treatment of choice forVTE in pregnant women with or without throm- In all women with thrombophilia, the pro- bophilia. Heparin treatment in pregnant women phylactic treatment after pregnancy should be with thrombophilia is not different from that used with LMWH (enoxaparin 40 mg or dalteparin in non pregnant women without thrombophilia 5000 U daily) or oral anticoagulants aiming at except in rare patients with a severe congenital an international normalized ratio (INR) of 2.5 AT deficiency where AT concentrates may be with graduated elastic stockings for at least 6 required especially at the acute phase of throm- weeks. Oral contraception with combined estro- bosis and at the time of delivery. Both drugs do gen-progestogen is contraindicated, but progesto- not cross the placenta in contrast to vitamin K gen only contraception can be offered safely.
LMWHs are increasingly preferred to UH since is indicated in order to prevent bleeding during their safety has been shown in two large series of delivery and allow epidural anesthesia. Anti-Xa pregnant women with dalteparin and enoxa- or APTT can be useful to control the absence of a parin.260-262 Data with tinzaparin have been persistent anticoagulation activity at the time of obtained in a small group of pregnant women.
delivery. Treatment with LMWH should be restart- LMWHs carry a lower risk of HIT and osteo- porosis. Although they are administered to patientswith VTE in 1 or 2 injections per day there is nogood evidence to prefer either regimen in preg- Management of recurrent VTE
Heparin treatment should be continued until Long-term follow-up studies have now recog- delivery and in the post partum period for at least nized that recurrent VTE occurs more frequent- 4-6 weeks. However, when the VTE episode occurs ly than previously thought. One-third of patients in the beginning of pregnancy, the question has develop a new confirmed venous thrombotic com- been raised whether to continue the treatment at plication within 8 years after a first episode of the same full dose or reduce the dose after the DVT.11, 52, 263 Recurrent VTE is manifest by PE in first weeks of treatment in accordance with the approximately 1/5 of these patients, whereas the remaining patients present with a new DVT in the A vitamin K antagonist can replace heparin in lower limb. Recurrent DVT occurs with similar the post partum period. Use of LMWH is not con- frequency in the limb that was initially involved traindicated during pregnancy and breast feed- and the previously unaffected contralateral limb.11, ing, although it is discouraged in information 52, 263 Patients initially presenting with DVT tend leaflets approved by health authorities in some to have DVT as a recurrence and those present- countries. Warfarin can be used during breast ing with PE tend to have recurrent PE.264, 265 feeding although some pediatricians recommendvitamin K supplementation to the newborn.
Risk factors associated with recurrent VTE The most common factors associated with an Once anticoagulant treatment has been dis- increased risk of recurrent VTE are inadequate continued, patients with thrombophilia should be initial anticoagulation 266-268 and inadequate anti- informed to use LMWH for any medical, surgical coagulation following the initial treatment.269-271 or obstetrical circumstance that could increase Conditions associated with increased risk of recurrent VTE during adequate anticoagulation Clinical surveillance is mandatory during anti- or after interruption of anticoagulant treatment coagulant treatment in pregnant women with a are the presence of active cancer, antiphospho- VTE episode. Laboratory monitoring includes lipid antibody syndrome, medical diseases requir- platelet counts before treatment then twice a week ing immobilization, or inherited thrombophilia.11, during the 3 subsequent weeks in order to detect 272-274 Less frequently, this results from deficien- heparin induced thrombosis. In the rare cases of heparin induced thrombosis, danaparoid (orgaran) Recurrence is more likely after idiopathic pre- can be used as an alternative anticoagulant. Anti- sentation 266-268 and thrombosis in proximal Xa activity and/or APTT are measured in the acute veins.51, 277 Long-term persistence of venous phase, then once a month although no specific obstruction 278, 279 and the presence of elevated D- recommendation has been made. Monitoring anti- Dimer at the time of cessation of oral anticoagu- Xa activity can be useful since the response to lant therapy have also been found to be associat- LMWH can vary as the pregnancy progresses.
ed with increased risk of recurrent VTE.272, 280, 281 Anti-Xa activity 3 to 4 hours after subcutaneousinjection of LMWH should be in the expected tar- get range according to the drug used (usually 0.5-1 IU).
While the initial diagnosis of DVT should not Elective induction of labor and interruption of be difficult, diagnosis may not be easy for patients heparin administration 24 hours before delivery presenting with clinical manifestations sugges- tive of recurrent ipsilateral DVT. Clinical diagno- bleeding is four times as high for the initial VTE sis is highly non specific and other diagnostic as that observed in patients with recurrent VTE.289 strategies have serious limitations. The presence The recurrence risk is increased in patients with of a well documented duplex ultrasound exami- spontaneous presentation of VTE or when VTE nation showing the presence and extent of the first is associated with concurrent thrombophilic DVT must be available for comparison.282 Repeat- abnormalities.290, 291 However, the role of throm- bophilia in predicting development of recurrent popliteal vein diameters with the transducer in VTE is controversial. Available information sug- transverse section during compression performed gests that carriers of antiphospholipid antibody twice weekly following the first episode of DVT is syndrome exhibit both a recurrence risk 141, 286 and a simple additional useful method.278-283 On the risk of death 141 that is higher than for control sub- occasion of a suspected recurrent ipsilateral DVT, the vein diameter is measured and compared with It is generally accepted but not firmly demon- earlier ultrasound results. Recurrent DVT can be strated that carriers of AT, PC and PS exhibit a excluded if the diameter remains the same or recurrence risk that is higher than control sub- decreases whereas recurrent DVT is diagnosed jects.52, 292 Whether heterogenous carriers of Fac- with certainty if the vein diameter increases by at tor V Leiden and prothrombin G20210 variant least 4 mm. Phlebography should be considered have a higher risk of recurrence is disputed. There if the increase of vein diameter is between 2 and is data in favor 272, 293-296 and data against this asso- 4 mm, or for all patients with positive ultrasound ciation.286, 297-301 The recurrence risk is increased findings where earlier tests are not available.
by spontaneous presentation and by concurrent Diagnosis of recurrent PE requires a sympto- thrombophilic abnormalities.290, 291 Among them, matic patient with a new perfusion defect or a hyperhomocysteinemia is likely to play a major new filling defect on spiral computed tomogra- role.302, 303 Homozygous carriers of Factor V Lei- den and prothrombin G20210A variant and car-riers of double heterozygosity exhibit a higher recurrence risk than that of control subjects.299, 300 Hyperhomocysteinemia 304, 305 and increased To reduce the risk of recurrent VTE,275 it is essen- levels of Factor VIII 99 and IX 125 seem to be asso- tial to provide prompt treatment with adequate ciated with higher recurrence risk, but these find- doses of UH or LMWH and overlap treatment with a vitamin K antagonist within the first 3 days New strategies and new drugs are currently maintaining the initial heparin therapy until the under investigation to optimize long-term treat- INR has achieved a targeted value of 2.5 (2-3) for ment of VTE. Recent studies suggest that low two consecutive determinations 24 hours apart.
intensity warfarin therapy after an initial three to It is necessary to provide an adequate duration six-month period of conventional anticoagulation and intensity of oral anticoagulants according to may confer additional protection without an exces- internationally accepted guidelines.37, 284 sive bleeding risk.306 However, this strategy is clear- The optimal duration of treatment for acute ly less effective than conventional anticoagula- VTE remains to be determined. Prospective cohort tion.307 Finally, new categories of drugs some of studies,52, 263 population based studies,11, 32 and which are oral such as specific inhibitors of Fac- randomized clinical trials 277, 285-288 show that 5- tor Xa and IIa are emerging which have the poten- 10% of patients with secondary DVT from tran- tial to simplify long term treatment of VTE by sient risk factors have a recurrent VTE after three obviating the need for periodic laboratory moni- months of oral anticoagulant therapy; 15-30% of toring while being associated with a favorable ben- patients with idiopathic DVT have a recurrent VTE after 3 months and this rate does not change Based on available information, the following by prolonging oral anticoagulant therapy for up recommendations for the duration of treatment to 6-12 months. The annual incidence of major with a vitamin K antagonist can be presented for bleeding from oral anticoagulant therapy is 1.5- carriers of thrombophilia after the first episode 2%. The “case-fatality rate” of an episode of major 1) In patients with a provoked (transient) 6. Greaves M, Baglin T. Laboratory testing for heritable episode, 3 to 6 months of anticoagulation (Grade thrombophilia: impact on clinical management of throm-botic disease annotation. Br J Haematol 2000;109:699- 2) In patients with a spontaneous episode: 7. Lindblad B, Sternby NH, Bergqvist D. Incidence of venous thromboembolism verified by necropsy over 30 years. Br — long term anticoagulation in carriers of PC and PS defects, and in particular homozygous 8. Anderson FA Jr, Wheeler HB, Goldberg RJ, Hosmer DW, Forcier A. The prevalence of risk factors for venous throm- Factor V Leiden and prothrombin mutation, com- boembolism among hospital patients. Arch Intern Med bined heterozygotes for Factor V Leiden and pro- 9. Nordstrom M, Lindblad B, Bergqvist D, Kjellstrom T. A prospective study of the incidence of deep-vein throm- — a shorter duration (3 to 6 months) in all other bosis within a defined urban population. J Intern Med 10. Heit JA, Silverstein MD, Mohr DN, Petterson TM, O’Fal- 3) Lifelong anti vitamin K therapy should be con- lon WM, Melton LJ 3rd. Predictors of survival after deep sidered on an individual basis in selected patients vein thrombosis and pulmonary embolism: a population- with continuing risk factors such as cancer, AT defi- based, cohort study. Arch Intern Med 1999;159:445-53.
11. Heit JA, Mohr DN, Silverstein MD, Petterson TM, O’Fal- ciency or the APLA syndrome (Grade 2C).
lon WM, Melton LJ 3rd. Predictors of recurrence afterdeep vein thrombosis and pulmonary embolism: a pop-ulation-based cohort study. Arch Intern Med 2000;160: 12. Nelzen O, Bergqvist D, Lindhagen A. Leg ulcer etiology- A multicentre trial addressing the optimal dura- a cross sectional population study. J Vasc Surg 1991;14: tion of oral anticoagulant therapy after a second 13. Nelzen O, Bergqvist D, Lindhagen A, Hallbook T. Chron- episode of VTE found considerable reduction in ic leg ulcers: an underestimated problem in primary health the risk for recurrent VTE from 21% to 3% in care among elderly patients. J Epidemiol Community patients allocated to receive four years as com- 14. Callam MJ, Harper DR, Dale JJ, Ruckley CV. Chronic pared to 6 months of warfarin.310 However, this ulcer of the leg: clinical history. Br Med J (Clin Res Ed) benefit was offset by a remarkably higher inci- dence of major bleeding (8.6% versus 2.7%) so 15. Jantet G. The socioeconomic impact of venous patholo- gy in Great Britain. Phlebologie 1992;45:433-7.
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17. Goldhaber SZ, Visani L, De Rosa M. Acute pulmonary Aknowledgements.—This document was the result of an embolism: clinical outcomes in the International Coop- educational course held in Limassol, Cyprus (29th November- erative Pulmonary Embolism Registry (ICOPER). Lancet 2nd December 2003) which was part of a EUMEDIS Grant and a subsequent grant from the CDER Trust to support addi- 18. Kearon C, Ginsberg JS, Hirsh J. The role of venous ultra- tional meetings of the secretariat with members of the fac- sonography in the diagnosis of suspected deep venous ulty for several revisions of the document that enabled it to thrombosis and pulmonary embolism. Ann Intern Med reach its current form. The authors are grateful to the CDER Trust also for permission to reproduce parts of the “Interna- 19. van Strijen MJ, de Monye W, Schiereck J, Kieft GJ, Prins tional Consensus Document on the Prevention of Venous MH, Huisman MV et al. Single-detector helical comput- Thromboembolism” published in 2001 and to use the latter ed tomography as the primary diagnostic test in suspected as the basis of the current document.
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AC- MMEL/MEL Advisory Circulars AC-MMEL/MEL Contents SUBPART A SUBPART B SUBPART C AC- MMEL/MEL Advisory Circulars SUBPART A AC-MMEL/MEL.001 (a) Limit of MEL Applicability If a failure occurs during the taxi phase before the start of the take-off roll, any decision to continue the flight should be subject to pilot judgment and good airma