Thrombosis in rare bleeding disorders

Inherited deficiencies of blood coagulation factors are usually associated with lifelong bleeding tendency. In addition to Haemophilias A and B and von Willebrand disease, congenital deficiencies of such factors as fibrinogen, prothrombin (FII)), FV, FVII, FX, FXI, FXIII, and combined deficiencies occur and can lead to a diversity of clinical conditions. Paradoxically, for some of these disorders associated with significant bleeding tendency there are reports of thrombotic events, both arterial and venous. Thrombosis in hemophilia patients has a multifactorial pathogenesis and the main conditions associated with this complication are the use of long-term central venous catheters, intensive replacement therapy usually in the setting of surgical procedures, the use of bypassing agents or the coexistence of acquired or inherited prothrombotic risk factors. Regarding other rare bleeding disorders, thrombotic phenomena has been described particularly in patients with afibrinogenemia, FXI and FVII deficiency and the events can occur even in young patients, in the presence of concomitant risk factors or spontaneously. Replacement therapy must be individualized and should take into account past history of haemostatic challenges, family history of bleeding and thrombosis, just like the level of factor. For mild deficiencies when patients are asymptomatic the use of antithrombotic prophylaxis must be considered with or without concomitant use of replacement therapy. In patients with history of thrombosis it may be helpful to perform a thrombophilia screening to exclude coexisting prothrombotic defects and for all patients it is recommended to control known cardiovascular disease risk factors.     

Thrombosis and thrombophilia in children: a systematic review

Thrombotic events are uncommon disorders in childhood but increasingly recognized due to the progress made in the understanding of the hemostasis system and the importance of thromboembolic disorders in children. Multiple clinical underlying conditions and prothrombotic disorders contribute to the development of thrombosis in neonates and children. In recent years programs have emerged that specialize in the diagnosis, prevention, and treatment of thrombosis in children. This review summarizes the current knowledge of the risk factors for thromboembolic events in the venous and arterial systems in children, the use of antithrombotic prophylaxis, and the role of thrombophilia. First, the clinical manifestations and the problems of diagnosing venous thromboembolic diseases and cerebrovascular diseases in children are reviewed. The prophylactic use of anticoagulants in children is also discussed. Unfortunately there are no large prospective randomized trials in children, thus guidelines are based on small studies or on extrapolation of data from adults. Second, the impact of prothrombotic defects in pediatric patients and the issue of routine testing for these disturbances are reviewed.     

Symptomatic venous thromboembolism and thrombophilic status in adult acute leukemia: a single-center experience of 114 patients at diagnosis

Inherited and acquired thrombophilia are associated with venous thromboembolic events (TE). The prevalence of inherited and acquired prothrombotic risk factors and the incidence of symptomatic TE were evaluated in a cohort of 114 adult acute leukemia patients. The most frequent prothrombotic risk factor was hyperhomocysteinemia which occurred in 46.6% of patients. The incidence of TE was 9.6%, mainly in the first month of follow-up. In multivariate analysis, hyperhomocysteinemia was the only risk factor for TE (OR 33.90; 95% CI 1.53-751.33; p = 0.026). The results of this study indicate that measurements of homocysteinemia could be useful in determining the risk of early TE in adult acute leukemia patients, while systematic thrombophilia screening should not be justified.     

Evaluation of thrombotic children with malignancy

The purpose of this study was to evaluate inherited and acquired prothrombotic risk factors among children with malignancies who have thrombosis and emphasize the importance of inherited prothrombotic risk factors. Thirty-seven consecutive children with thrombosis and malignancy were included in this study. The patients were evaluated separately for time of development of thrombosis, insertion of a central venous line (CVL), history of l-asparaginase usage, and recent infections. Prothrombotic risk factors such as factor V G1691A and prothrombin G20210A mutation, protein C, protein S, antithrombin III deficiencies, factor VIII and lipoprotein(a) elevation, and antiphospholipid antibodies were analyzed for all patients. Of 387 children with thrombosis, 37 (9.5%) had a malignancy. Thrombosis was detected in 9 patients at the time of diagnosis, during maintenance therapy in 25 patients, and after the discontinuation of treatment in 3 patients. One or two additional prothrombotic risk factors other than l-asparaginase therapy and insertion of central venous lines were present in 20 of these patients (54%). It was found that eight patients had the factor V G1691A mutation in the heterozygote state. One of them had the factor V G1691A mutation associated with a history of infection and one patient had the factor V G1691A mutation associated with factor VIII elevation. One had the the prothrombin G20210A mutation in the heterozygote state, four had lipoprotein(a) elevation, two had factor VIII elevation, one had a decreased protein S level, one had a decreased protein C level, one had antiphospholipid positivity, and two had histories of infection. Malignancy is an important risk factor for the development of childhood thrombosis. However, the risk of thrombosis increases when accompanied by additional prothrombotic risk factors. For this reason, especially children with malignancy and at high risk for the development of thrombosis, such as those who have received l-asparaginase or a replaced CVL during their therapy, might be screened for additional prothrombotic risk factors and appropriate measures might be taken to prevent the development of thrombosis.     

Extrahepatic portal vein thrombosis in children and adolescents: Influence of genetic thrombophilic disorders

AIM:To explore the prevalence of local and genetic thrombophilic disorders as risk factors for portal vein thrombosis (PVT) in our series,the largest ever published in pediatric literature. METHODS:We conducted a case-control study enrolling 31 children with PVT and 26 age-matched controls. All were screened for thrombophilia,including genetic disorders,protein C,protein S and homocysteine deficiencies. All coagulation parameters were studied at least 3 mo after the diagnosis of portal vein obstruction.RESULTS:In our study we showed that most pediatric patients with PVT have local prothrombotic risk factors,which are probably the most important factors leading to PVT. However,there is a clear association between the presence of prothrombotic disorders and PVT,suggesting that these increase the risk of thrombosis in patients with local factors such as perinatal umbilical vein catheterization or sepsis. CONCLUSION:Patients with PVT should be screened for inherited prothrombotic disorders regardless of a history of an obvious local risk factor.     

Inherited thrombophilia and venous thromboembolism

The term thrombophilia includes any inherited and acquired disorders associated with an increased tendency to venous thromboembolism (VTE). Inherited thrombophilia is one of the main determinants of VTE, and the presence of inherited thrombophilic defects exposed carriers to increased risks for VTE compared with noncarriers. There is no clear relationship between clinical manifestations and the type of underlying thrombophilic defect. Thus, the diagnosis of inherited thrombophilia has to be established on a laboratory basis. Carriers of thrombophilic defects may experience thrombosis at a younger age than noncarriers. However, a first thrombotic manifestation that occurs late in life may also be an expression of thrombophilia and this remains in many cases the only etiopathogenetic explanation for the event. Screening of family members of symptomatic probands has the potential to identify still asymptomatic carriers who may benefit from more appropriate thromboprophylaxis during high-risk situations for VTE. Women of fertile age who belong to these thrombophilic families might receive the greatest advantage from screening. Many inherited thrombophilic disorders can be considered risk factors for recurrent VTE, especially if more than one defect is present in the same patient. More intensive or prolonged duration of VTE treatment might be requested for the prevention of recurrent VTE in the most severe thrombophilic conditions. The availability of new methods for the assessment of thrombin generation in terms of endogenous thrombin potential are very promising tools for the identification of those carriers of inherited thrombophilia who will develop thrombosis or who will encounter recurrence of VTE.     

Inherited and acquired risk factors for arterial ischemic stroke in childhood

Ischemic stroke in childhood is a rare but serious disorder, which is associated with significant morbidity and mortality. The lack of causal homogeneity in the aetiology of this disorder presents problems for predicting and preventing it, making the ischemic stroke in childhood a real dilemma for the clinician. Although a variety of potential inherited and acquired causes have been now identified, including cardiac pathologies, infections, prothrombotic, metabolic and vascular disorders, the aetiology of ischemic stroke in the young remains still unknown in more than one third of the patients. Presently, an appropriate evaluation of some hypercoagulable conditions seems justified in adults with stroke. However, the etiologic contribution of several thrombophilic conditions to initial and recurrent stroke in affected children has not been definitely clarified, since more powerful and influential non-thrombophilic risk factors are usually present, making the thrombophilia screening in such circumstance a matter of debate. In particular, the diagnostic yield of the screening is reportedly lower in children, the role of several prothrombotic abnormalities is uncertain, especially in recurrent stroke, and there is no evidence-based guidance to stroke prevention and therapy in children carrying a hypercoagulable state. Additional studies are needed to quantify the risk for a cerebrovascular event in children with a prothrombotic disorder and to determine which combination of endogenous and exogenous risk factors leads to greater rates of initial and recurrent stroke.     

Testing children for inherited thrombophilia: more questions than answers

Thrombotic events in children have become an increasingly common problem, particularly in paediatric tertiary care hospitals. The prevalence of inherited thrombophilia in children who develop thrombosis varies substantially depending on the population. Children who develop thrombosis, as well as those who have not but have a positive family history, are frequently tested for inherited thrombophilia. The clinical utility of performing such tests has been questioned, in both adults and children. This review will examine the practise of testing for inherited thrombophilia in children, focusing on the rationale for testing and highlighting areas in which more evidence is needed prior to making strong recommendations. Future studies, many of which are currently being performed or proposed, are necessary to address many of the unanswered questions.     

Thromboembolism in children

Acquired and inherited prothrombotic risk factors increase the risk of thrombosis in children. This review is based on "milestone" pediatric reports and new literature data (January 2001-February 2002) on the presence of acquired and inherited prothrombotic risk factors, imaging methods, and treatment modalities in pediatric thromboembolism. After confirming clinically suspected thromboembolism with suitable imaging methods, pediatric patients should be screened for common gene mutations (factor V G1691A, prothrombin G20210A and MTHFR C677T genotypes), rare genetic deficiencies (protein C, protein S, antithrombin, and plasminogen), and new candidates for genetic thrombophilia causing elevated levels of lipoprotein(a), and homocysteine, and probable genetic risk factors (elevations in fibrinogen, factor IX, and factor VIIIC, and decreases in factor XII). Data interpretation is based on age-dependent reference ranges or the identification of causative gene mutations/polymorphisms with respect to individual ethnic backgrounds. Pediatric treatment protocols for acute thromboembolism, including thrombolytic and anticoagulant therapy, are mainly adapted from adult patient protocols.     

Using the laboratory to predict recurrent venous thrombosis

Characterisation of heritable thrombophilic defects has facilitated an understanding of the complex mechanisms influencing risk of venous thromboembolism. In parallel with this, the importance of gene-environment interaction in the development of this disease has become apparent. However, testing for a limited number of heritable thrombophilic defects (first generation thrombophilia testing) has not been shown to predict likelihood of recurrent venous thrombosis to any useful degree. This paradox whereby thrombophilia testing identifies defects associated with an increased risk of a first venous thrombosis but not of a particularly high risk of recurrence is likely the result of limitations imposed by a limited dichotomous testing strategy compounded by test inaccuracy and imprecision. Consequently, the observed intermediate phenotype (defined by limited dichotomous testing) is not concordant with the risk of recurrent venous thrombosis. Whilst a simple dichotomous testing strategy for a limited number of heritable thrombophilic defects has not been shown to have useful clinical predictive value, proof-of-principle is emerging for testing of multiple genetic factors in predicting the likelihood of recurrent thrombosis. In addition, recent studies indicate that measurement of the global activity of the coagulation system using either biomarkers or measuring the thrombin generating potential (second generation thrombophilia testing) may have useful clinical predictive value for recurrent thrombosis. The assessment of the intermediate phenotype by global coagulation tests and genome-wide mutation and SNP (single nucleotide polymorphisms) detection may provide complimentary approaches to the quantification of risk of recurrence and enable a move towards more patient-focussed rather than disease-focussed care.     

Perinatal aspects of inherited thrombophilia

The identified main causes of inherited thrombophilia are deficiencies of antithrombin, protein C and protein S, activated protein C (APC) resistance and the factor V Leiden mutation, mutant factor II, and inherited hyperhomocysteinemia. In women from symptomatic families these defects may be associated with an increased risk of venous thrombosis in pregnancy and recurrent fetal loss. Inherited thrombophilia is common and appears to be a multigene disorder. The thrombotic risk would seem to be greatest in women with antithrombin deficiency and more than one thrombophilia defect. The abnormalities that are now recognized represent only part of the genetic predisposition to thrombosis. In assessing thrombotic risk in pregnancy, acquired risk factors as well as genetic predisposition should be considered. Increasing age, obesity, immobility, and delivery by cesarean section are major risk factors. Pregnancy should be planned, and each patient should be managed on an individual basis. In pregnancy, heparin is the anticoagulant of choice, and as far as possible, treatment with warfarin should be avoided because of the risks to the fetus. When patients are on long-term treatment with warfarin, pregnancy should be avoided, and warfarin should be discontinued prior to embarking on a pregnancy or as soon as pregnancy is suspected and before 6 weeks' gestation. In women from symptomatic families with antithrombin deficiency, adjusted dose heparin throughout pregnancy is recommended and warfarin for at least 3 months post partum. In protein C and protein S deficiency, factor V Leiden, or mutant factor II, treatment can be based on personal and family history. Thromboprophylaxis in late pregnancy and post partum should be considered. Fetal loss may be increased in women with inherited thrombophilia. The risk appears greatest in women with antithrombin deficiency and women with more than one thrombophilia defect. A number of reports have claimed that prophylactic treatment with heparin during pregnancy has resulted in successful pregnancy in women with recurrent fetal death and inherited thrombophilia.     

Thrombophilia as a multigenic disease

BACKGROUND AND OBJECTIVE: Venous thrombosis is a common disease annually affecting 1 in 1000 individuals. The multifactorial nature of the disease is illustrated by the frequent identification of one or more predisposing genetic and/or environmental risk factors in thrombosis patients. Most of the genetic defects known today affect the function of the natural anticoagulant pathways and in particular the protein C system. This presentation focuses on the importance of the genetic factors in the pathogenesis of inherited thrombophilia with particular emphasis on those defects which affect the protein C system. INFORMATION SOURCES: Published results in articles covered by the Medline database have been integrated with our original studies in the field of thrombophilia. STATE OF THE ART AND PERSPECTIVES: The risk of venous thrombosis is increased when the hemostatic balance between pro- and anti-coagulant forces is shifted in favor of coagulation. When this is caused by an inherited defect, the resulting hypercoagulable state is a lifelong risk factor for thrombosis. Resistance to activated protein C (APC resistance) is the most common inherited hypercoagulable state found to be associated with venous thrombosis. It is caused by a single point mutation in the factor V (FV) gene, which predicts the substitution of Arg506 with a Gln. Arg506 is one of three APC-cleavage sites and the mutation results in the loss of this APC-cleavage site. The mutation is only found in Caucasians but the prevalence of the mutant FV allele (FV:Q506) varies between countries. It is found to be highly prevalent (up to 15%) in Scandinavian populations, in areas with high incidence of thrombosis. FV:Q506 is associated with a 5-10-fold increased risk of thrombosis and is found in 20-60% of Caucasian patients with thrombosis. The second most common inherited risk factor for thrombosis is a point mutation (G20210A) in the 3' untranslated region of the prothrombin gene. This mutation is present in approximately 2% of healthy individuals and in 6-7% of thrombosis patients, suggesting it to be a mild risk factor of thrombosis. Other less common genetic risk factors for thrombosis are the deficiencies of natural anticoagulant proteins such as antithrombin, protein C or protein S. Such defects are present in less than 1% of healthy individuals and together they account for 5-10% of genetic defects found in patients with venous thrombosis. Owing to the high prevalence of inherited APC resistance (FV:Q506) and of the G20210A mutation in the prothrombin gene, combinations of genetic defects are relatively common in the general population. As each genetic defect is an independent risk factor for thrombosis, individuals with multiple defects have a highly increased risk of thrombosis. As a consequence, multiple defects are often found in patients with thrombosis.     

The role of thrombophilia in splanchnic vein thrombosis

In the last few years, the mechanistic role of thrombophilia due to hypercoagulability and of clonal disorders of hemopoiesis such as chromosome Philadelphia-negative chronic myeloproliferative disorders has been increasingly recognized in primary splanchnic vein thrombosis. As in deep venous thrombosis of the lower limbs, the frequent finding of several prothrombotic disorders in the same individual has led to the concept of primary splanchnic vein thrombosis as a multifactorial disease. Significant progress has been made in determining the molecular bases of inherited thrombophilia, and particularly in the identification of molecular markers of clonal disease in the so-called occult or latent myeloproliferative disorders. In this review article, the authors discuss the current knowledge on the role of thrombophilia in extrahepatic portal vein obstruction and in the Budd-Chiari syndrome, two of the most clinically relevant splanchnic vein thromboses.     

Associated prothrombotic conditions are probably responsible for the occurrence of thrombosis in almost all patients with congenital FVII deficiency. Critical review of the literature

The occasional occurrence of thrombosis in patients with congenital bleeding disorders has received considerable attention during the past decade. Myocardial infarction, ischemic strokes and venous thromboembolism have been reported in hemophilia A or B patients, in von Willebrand disease and, also, in rare coagulation disorders, especially in factor VII (FVII) deficiency. To explain the relatively high frequency of thrombotic phenomena, mainly venous, seen in the last condition, it was speculated that a special form or variant of FVII deficiency could exist. The presence of associated prothrombotic risk factors has been occasionally reported to be present in these patients but the matter has never been duly evaluated and emphasized. The purpose of the present paper was to evaluate if the clinical setting in which thrombosis appeared in these patients could explain the occurrence of the thrombosis. All reported cases of thrombosis seen in patients with FVII deficiency have been analyzed and the presence of associated risk factors recorded. Out of a population of 33 documented cases, the presence of prothrombotic risk factors was reported in 30 instances. In two of the remaining cases, no mention is made about associated risk factors. In the last case they were explicitly excluded. The critical evaluation of the literature suggests that the occurrence of thrombosis in FVII deficiency may be due to common prothrombotic risk factors. As a consequence it may be only stated that FVII deficiency does not protect from thrombosis.     

Coexistence of factor V Leiden and primary antiphospholipid syndrome: a patient with recurrent myocardial infarctions and thrombocytopenia

Increased thrombin generation associated with resistance to activated protein C makes the latter a likely candidate for an increased risk of acute coronary events. Activated protein C resistance (factorV Leiden) on its own, however, appears to have no significant effect in this regard. We describe a case of recurrent myocardial infarction caused by coronary thrombosis in a patient with persistent thrombocytopenia who was found to have a coexistence of heterozygous factor V Leiden and primary antiphospholipid syndrome. Since both thrombophilic disorders interfere with the protein C anticoagulant system, the simultaneous existence of inherited and acquired resistance against activated protein C could account for an increased thrombophilia with manifestation in the coronary arteries. This case suggests that evaluation of patients who present with recurrent acute coronary events should also consider these coagulation defects.     

Association of idiopathic hepatic sinusoidal dilatation with the immunological features of the antiphospholipid syndrome

BACKGROUND: Isolated sinusoidal dilatation is an uncommon hepatic lesion and the cause is largely unknown. OBJECTIVE: To investigate whether prothrombotic disorders or perisinusoidal cell changes could be involved in pure idiopathic hepatic sinusoidal dilatation (HSD). METHODS: Evaluation for associated conditions, prothrombotic disorders, and studies of hepatic perisinusoidal cell activation in consecutive patients, seen between 1993 and 2002, with isolated sinusoidal dilatation unrelated to outflow block, sinusoidal infiltration, or hepatic granulomas. RESULTS: Among 11 patients, associated conditions were prothrombotic disorders (n = 5) and oral contraceptive use (n = 3). Prothrombotic disorders were polycythemia vera (n = 1) and anticardiolipin antibodies combined with lupus anticoagulant (n = 4). No genetic thrombophilia factor was found. Of four patients with lupus anticoagulant, three had antinuclear factors and high serum levels of anticardiolipin antibodies at repeated testing. There was no evidence of intrahepatic or extrahepatic thrombosis in any of the patients. Sinusoidal dilatation was marked in six of 11 patients (54%), including two patients with antiphospholipid antibodies. Activated perisinusoidal cells were only found around markedly dilated sinusoids. CONCLUSION: Idiopathic pure HSD is frequently associated with the immunological features of the antiphospholipid syndrome. Therefore, finding pure HSD in a liver biopsy specimen should prompt the search for antiphospholipid antibodies.     

High prevalence of inherited thrombophilia in 'presumed peri-neonatal' ischemic stroke

The aim of this study was to assess the prevalence of inherited thrombophilia in 'peri-neonatal arterial ischemic stroke' (AIS), and its possible correlation with type of stroke and long-term neurological outcome. A cohort of twenty-four infants affected by AIS were analysed for risk factors, clinical and neuroradiological features, coagulation and thrombophilia profile and outcome. Two subgroups were considered, based on clinical presentation: infants symptomatic in the neonatal period, acute AIS (aAIS) and those with a delayed presentation (presumed peri-neonatal onset, pAIS). The mean follow-up on patients was 3 yr and 1 month (range 1–15 yr). Inherited thrombophilia, consisting of factor V Leiden and prothrombin G20210A mutations, protein C and/or protein S deficiencies, was detected in 28.6%. A significantly higher prevalence of inherited thrombophilia was observed in infants with pAIS compared with aAIS (Fisher's exact test, P  = 0.011). Infants with pAIS had a significantly worse neurological outcome with respect to aAIS (Fisher's exact test, P  = 0.014). Inherited thrombophilia was significantly higher in patients with a poor neurological outcome (Fisher's exact test P  = 0.002). Although the clinical presentation (aAIS vs. pAIS) was associated with future neurological disabilities, it is the thrombophilia but not the clinical presentation, which remains the only significant prognostic factor in the logistic regression analysis. Although preliminary, these data suggest an association of unfavourable neurological outcome and inherited prothrombotic defects in neonatal AIS. The higher prevalence of inherited thrombophilia identified in pAIS and the worse neurological outcome encourage further investigations in population-based studies.     

Risk assessment for recurrent venous thrombosis

Venous thrombosis is a common disease that frequently recurs. Recurrence can be prevented by anticoagulants, albeit at the cost of bleeding. Thus, assessment of the risk of recurrence is important to balance the risks and benefits of anticoagulation treatment. Many clinical and laboratory risk factors for recurrent venous thrombosis have been established. Nevertheless, prediction of recurrence in an individual patient remains a challenge. Detection of some laboratory markers is associated with only a moderate risk of recurrence, and the relevance of others is not known. Many patients have several risk factors and the effect of combined defects is obscure. Routine screening for these laboratory markers should therefore be abandoned. Risk assessment can be improved by measurement of global markers that encompass the effects of clotting and fibrinolytic disorders. Analysis of preliminary data suggests that risk assessment can also be refined through integration of prothrombotic coagulation changes and clinical risk factors.     

Thrombocytosis and thrombocythemia

Thrombocytosis is caused by three major pathophysiological mechanisms: (1) reactive or secondary thrombocytosis; (2) familial thrombocytosis; and (3) clonal thrombocytosis, including essential thrombocythemia and related myeloproliferative disorders. Recent work has begun to elucidate the abnormal megakaryocytopoiesis of essential thrombocythemia, which is associated with paradoxically elevated plasma levels of thrombopoietin. The clonal nature of all cases of essential thrombocythemia has been challenged. Thrombotic complications are the major causes of morbidity and mortality in this disease. Indications for platelet cytoreduction and antiplatelet therapy, as well as complications of treatment, are being clarified.     

Inherited thrombophilia in arterial disease: a selective review

Thrombophilia may be defined as an acquired or congenital abnormality of hemostasis predisposing to thrombosis. Because arterial thrombosis is usually linked with classical risk factors such as smoking, hypertension, dyslipidemia, or diabetes, a thrombophilia workup is usually not considered in case of arterial thrombosis. The most accepted inherited hemostatic abnormalities associated with venous thromboembolism are factor V Leiden (FVL) and factor II (FII) G20210A mutations, as well as deficiencies in antithrombin (AT), protein C (PC), and protein S (PS). This review focuses on the link between these abnormalities and arterial thrombosis. Overall, the association between these genetic disorders and the three main arterial complications (myocardial infarction [MI], ischemic stroke [IS], and peripheral arterial disease [PAD]) is modest. Routine screening for these disorders is therefore not warranted in most cases of arterial complications. However, when such an arterial event occurs in a young person, inherited abnormalities of hemostasis seem to play a role, particularly when associated with smoking or oral contraceptive use. These abnormalities also seem to play a role in the risk of premature occlusion after revascularization procedures. Therefore thrombophilia tests may be informative in a very restricted population with arterial events. Anticoagulants rather than antiplatelet therapy may be preferable for these patients, although this remains to be proven.