Molecular and clinical characterization of transient antithrombin deficiency: A new concept in congenital thrombophilia.

Antithrombin deficiency, the most severe thrombophilia, might be underestimated, since it is only investigated in cases with consistent functional deficiency or family history. We have analyzed 444 consecutive, unrelated cases, from 1998 to 2021, with functional results supporting antithrombin deficiency in at least one sample. Plasma antithrombin was evaluated by functional and biochemical methods in at least two samples. SERPINC1 gene was analyzed by sequencing and MPLA. Hypoglycosylation was studied by electrophoresis and high-performance liquid chromatography (HPLC). In 260 of 305 cases (85.2%) with constitutive deficiency (activity < 80% in all samples), a SERPINC1 (N = 250), or N-glycosylation defect (N = 10) was observed, while 45 remained undetermined. The other 139 cases had normal antithrombin activity (≥ 80%) in at least one sample, what we called transient deficiency. Sixty-one of these cases (43.9%) had molecular defects: 48 had SERPINC1 variants, with two recurrent mutations (p.Ala416Ser[Cambridge II], N = 15; p.Val30Glu[Dublin], N = 12), and 13 hypoglycosylation. Thrombotic complications occurred in transient deficiency, but were less frequent, latter-onset, and had a higher proportion of arterial events than in constitutive deficiency. Two mechanisms explained transient deficiency: The limitation of functional methods to detect some variants and the influence of external factors on the pathogenic consequences of these mutations. Our study reveals a molecular defect in a significant proportion of cases with transient antithrombin deficiency, and changes the paradigm of thrombophilia, as the pathogenic effect of some mutations might depend on external factors and be present only at certain timepoints. Antithrombin deficiency is underestimated, and molecular screening might be appropriate in cases with fluctuating laboratory findings.

Investigation of congenital thrombophilic conditions: when, in whom, focusing on what or not at all?

Venous thromboembolism is a multifactorial disease. Inherited thrombophilia is linked with increased risk of VTE and we know about them more than 50 years. Through a robust thrombophilia work-up in the end of millenium, the criteria for testing have significantly gone down. It is associated with increased amount of information about clinical consequence of testing. We discuss current recommendations not only in the literature, but also in our clinic. Key words: criteria for testing - thrombophilia - venous thromboembolism.

Acquired and Hereditary Hypercoagulable States in Patients with Continuous Flow Left Ventricular Assist Devices: Prevalence and Thrombotic Complications.

BACKGROUND: Thrombotic events in patients with continuous flow left ventricular assist devices (CF-LVADs) are associated with significant morbidity and mortality. The objective of this study was to delineate the frequency, clinical characteristics, and outcomes of patients with hypercoagulable states who undergo CF-LVAD implantation. METHODS: We performed a retrospective review of 168 consecutive patients who underwent CF-LVAD implantation between 2010 and 2013. Chart and laboratory data were reviewed for the presence of a hereditary and/or acquired hypercoagulable state. Adverse outcomes were defined as death, confirmed pump thrombosis, aortic root clot, stroke, deep vein thrombosis, and pulmonary embolism. Fisher's exact test and Kaplan-Meier estimate were used to analyze frequency of adverse outcomes and event free survival, respectively. RESULTS: A hypercoagulable state was identified in 20 patients (11.9%). There were 18 patients with acquired, 1 with a congenital, and 1 with both congenital and acquired hypercoagulable states. The median follow-up was 429 days and 475 days in patients with and without hypercoagulable states, respectively. During the study period, 15% (3/20) of the patients with a hypercoagulable state had a diagnosis of deep vein thrombosis vs 3% (4/148) of the patients without a hypercoagulable state (P = .030). Only patients with a hypercoagulable state had a subarachnoid hemorrhage (3/20 vs 0/148; P < .01). The event-free survival was lower in the patients with hypercoagulable states (P = .005). CONCLUSION: Hypercoagulable states are not uncommon in patients with CF-LVADs and may be associated with increased morbidity. Prospective studies are needed to more accurately identify the incidence, prevalence, and significance of hypercoagulable states in patients being considered for CF-LVAD.

Middle Cerebral Artery Stroke in a Neonate With a Congenital Hypercoagulable Condition Following Repair of an H-type Tracheoesophageal Fistula.

We report a case of middle cerebral artery stroke with heterozygosity for 2 separate hypercoagulable conditions following repair of an H-type tracheoesophageal fistula (TEF) in an infant. Neonatal stroke is rare, occurring in 1 in 4000 births annually in the United States. Stroke after pediatric surgery occurs in approximately 0.05% of patients. Etiologies of stroke in neonates include cardiac, hematologic, vascular, traumatic, metabolic, pharmacologic, infectious, and hypoxemic insults. Thrombophilia has been described in 42% to 78% of neonates with neonatal stroke. Stroke after repair of an H-type TEF has not been reported as a postoperative complication. Manipulation of the carotid artery during this operation is presumed to have contributed to a thromboembolic event in this infant with a hypercoagulable state. Whereas preoperative workup may not be indicated due to the low prevalence of neonatal stroke, workup for a congenital hypercoaguable condition may be considered in infants with stroke as a postoperative complication. This report provides a concise review of the etiology and treatment of stroke and hypercoagulable states in neonates as well as presents the case of a previously undescribed complication of repair of an H-type TEF.

[Congenital thrombophilia].

Congenital thrombophilia is a thrombotic diathesis caused by a variety of genetic abnormalities in blood coagulation factors or their inhibitory factors associated with physiological thrombus formation. Patients with congenital thrombophilia often present with unusual clinical episodes of venous thrombosis (occasionally combined with pulmonary embolism, known as venous thromboembolism) at a young age and recurrence in atypical vessels, such as the mesenteric vein and superior sagittal sinus, often with a family history of this condition. Studies in Japan as well as in western countries have shown congenital thrombophilia to be caused by a wide variety of genetic abnormalities in natural anticoagulant proteins, such as antithrombin, protein C, and protein S. However, there may still be many unknown causes of hereditary thrombosis. We recently reported a case of hereditary thrombosis induced by a novel mechanism of antithrombin resistance, that is, congenital thrombophilia caused by a gain-of-function mutation in the gene encoding the coagulation factor prothrombin.

Maternal thrombophilia and adverse pregnancy outcome: a case-control study.

OBJECTIVE: To assess the risk of adverse pregnancy outcomes in patients with acquired and/or congenital thrombophilia factors. PATIENTS AND METHODS: A cohort of 130 women with a history of pregnancy loss and no successful gestation were investigated for the presence of congenital and acquired thrombophilia factors, and then compared with a control group of 130 healthy women who had had at least one successful gestation and no pregnancy loss, and were screened for congenital and acquired thrombophilia factors. RESULTS: Acquired and congenital thrombophilia factors were found in 30 (23%) patients and in 14 (10.8%) controls (p < 0.015). The presence of ≥1 congenital thrombophilia factor was associated with pregnancy loss with an odds ratio of 2.46 (p = 0.040). Moreover, women who had had >1 early fetal loss had a 2.85-fold risk of being carriers of congenital thrombophilia factors, compared to the controls. CONCLUSION: Our study showed the increased risk of miscarriage in patients with congenital thrombophilia factors and >1 early fetal loss.

Clinical presentation and molecular basis of congenital antithrombin deficiency in children: a cohort study.

In this study we report the largest descriptive cohort of congenital antithrombin (AT) deficiency in children, its clinical presentation, molecular basis and genotype-phenotype correlation. Paediatric patients diagnosed with AT deficiency at two tertiary care children's hospitals over a 10-year period were retrospectively reviewed. SERPINC1 gene sequencing was offered to subjects who did not already have the test performed. Molecular modelling and stability simulations were performed for the novel mutations identified. Twenty-nine subjects from 18 pedigrees were identified. Mean age (± standard deviation) at diagnosis and mean duration of follow-up were 8.4 (± 6.6 years and 6.6 (± 5.7 years respectively. Most recent mean AT activity and AT antigen levels (n = 20) were 0.5 (± 0.0) iu/ml and 0.6 (± 0.1) iu/ml respectively. Ten subjects were diagnosed secondary to low AT activity measured following venous thrombo-embolism (VTE). All 10 subjects had additional risk factors at the time of VTE. None of the 19 subjects diagnosed with AT deficiency in the setting of positive family history have had VTE with 7.4 (± 5.8) years follow-up. Mutation analysis has been completed on 19 subjects from 16 pedigrees. Nine unique mutations, including 4 novel mutations were identified.

Successful delivery of fetus with fetal inherited thrombophilia after two fetal deaths.

A pregnant woman with inherited thrombophilia (factor II mutation--20210A) had two late pregnancy losses. The first pregnancy was not well documented, but the second pregnancy was complicated by fetal thrombophilia and umbilical artery thrombosis, proven after fetal death. During the third pregnancy enoxaparine was introduced in the therapy and early amniocentesis was performed. Fetal thrombophilia was proven again. Early delivery was induced and performed with no complications, resulting in a live healthy infant. A history of miscarriages or recurrent fetal loss should raise suspicion of thrombophilia as a potential cause. It is debatable whether amniocentesis in pursuit of fetal thrombophilia should be performed and whether this will lead to a better perinatal outcome. When fetal thrombophilia is diagnosed, an earlier induction of delivery should be considered, taking into account the fetal extrauterine viability. The aforementioned approach of early delivery in cases of inherited fetal thrombophilia could be a possible solution for better perinatal outcomes.

Hereditary thrombophilia and recurrence of ischemic placental disease.

OBJECTIVE: We sought to evaluate whether testing for hereditary thrombophilia alone or in combination with second-trimester uterine artery Doppler (UAD) is useful in predicting recurrent complications in patients with previous preeclampsia, placental abruption, or stillbirth. STUDY DESIGN: Between 2001 and 2005, 110 consecutive women were included in the study and received 100 mg of aspirin daily. Adjustment was made for several maternal confounding factors using a logistic regression model. RESULTS: After multivariable logistic regression analyses, only abnormal UAD assessment was significantly associated with recurrent complications (odds ratio, 11.2; 95% confidence interval, 3.8-32.6) Combining the results of UAD and the presence of laboratory markers of thrombophilia failed to improve the accuracy of UAD to predict recurrent complications. CONCLUSION: Hereditary thrombophilia testing is not useful in predicting recurrent complications in subsequent pregnancy.

Deep venous thrombosis caused by inferior vena cava atresia and hereditary thrombophilia.

Inferior vena cava (IVC) atresia is a risk factor for deep vein thrombosis (DVT) in young patients. Although Doppler ultrasound diagnoses DVT, a contrast-enhanced computerized tomography (CT) or magnetic resonance angiography (MRA) diagnoses IVC atresia, other congenital IVC anomalies and must be considered in young patients presenting with idiopathic DVT. Patients with IVC atresia associated with hereditary thrombophilia are at increased risk for recurrent DVT and may require long-term anticoagulation. We report 2 cases: the first one, a 33-year-old man with lower extremity DVT caused by IVC atresia in association with multiple thrombophilic risk factors; the second one, a 34-year-old woman with lower extremity DVT caused by IVC atresia in association with prothrombin gene mutation. To our knowledge, this association has not been reported. The clinical presentation, tools for diagnosis, and the need for long-term anticoagulation are discussed.

Amaurosis fugax caused by hereditary thrombophilia due to mutation of gene.

We are presenting a 59-year-old woman and 37-year-old man with amaurosis fugax. They underwent a comprehensive ophthalmological and neurological examination. Standard diagnostic examination revealed no possible cause of this temporary condition, therefore additional genetic analysis for possible hereditary thrombophilia was performed. Examination established hereditary thrombophilia: the heterozygotic type gene for MTHFR (C677), deletion/insertion polymorphism for PAI-1 (4G/5G) in women and deletion/insertion polymorphism 4G/5G for PAI-1 and heterozygotic genotype DD (190 bp) for angiotensin converting enzyme (ACE) in man. In our patients, amaurosis fugax is probably caused by hereditary thrombophilia (Ref. 16). Full Text (Free, PDF) www.bmj.sk.

[Inherited thrombophilia]. / Le trombofilie congenite.

The paradigm of inherited thrombophilia as a cause of unprovoked venous thrombosis among young people and associated with a high clinical penetrance among members of the same kindred is challenged by many diagnosed cases not fitting this paradigm, although inherited thrombophilia is still the most likely diagnosis in most cases. However, all patients with venous thromboembolism are potential candidates for screening, regardless of the age at which the event occurs, the circumstances of thrombosis, and the severity of the clinical manifestations. A possible exclusion criterion is the contemporary presence of a high-risk disease for thrombosis such as cancer, since in such situations the presence of thrombophilic polymorphisms associated with a moderate risk for venous thromboembolism is not considered a significant additive risk factor. Potential candidates for screening are also women who have suffered from complications, other than venous thromboembolism, of a pregnancy. The inclusion of a large number of individuals with venous thromboembolism (or obstetric complications) in a diagnostic panel for inherited thrombophilia needs to be counterbalanced by a stringent selection of the laboratory tests. Screening should be limited to those traits that are more frequent or carry a higher thrombotic risk. A first-line diagnostic panel should include antithrombinheparin cofactor assay (functional amidolytic method), protein C assay (functional clotting or amidolytic method), and protein S assay (total and free fraction, measured by immunological methods). Analysis of DNA should include the search for factor V Leiden and the prothrombin G20210A. Genotyping for the C677T polymorphism in the methylenetetrahydrofolate reductase gene is quite meaningless, while homocysteine measurement is recommended. With the use of this panel, at least one third of the patients with venous thromboembolism can be diagnosed as carrying inherited thrombophilia; homocysteine measurement allows identification of at least a further 10% of patients with thrombophilia, achieving an overall diagnostic yield of more than 40%.

Congenital prothrombotic disorders in children with peripheral venous and arterial thromboses.

AIMS: To evaluate the prevalence of congenital prothrombotic disorders in children with peripheral venous and arterial thromboses. METHODS: Deficiencies in antithrombin (AT), proteins C (PC) and S (PS), and increased lipoprotein (a), and the presence of factor V (FV) G1691A, prothrombin G20210A and methylenetetrahydrofolate reductase (MTHFR) mutations were investigated. RESULTS: Forty-eight patients (mean age, 3.4 years) were investigated. Of these patients, 23 had venous thrombosis, 22 had arterial thrombosis, and 3 had both. No patients had AT, PC or PS deficiency. FV G1691A mutation was present in 2 (7.6%) and 3 (12%) patients with venous and arterial thromboses, respectively. The prothrombin G20210A mutation was present in 1 (4%) patient with arterial thrombosis. Homozygous MTHFR C677T mutation was detected in 4 (18%) and 2 (9%) patients with venous and arterial thromboses, respectively. Increased lipoprotein (a) was present in 2 (10%) and 1 (4.5%) patients with venous and arterial thromboses, respectively. Regarding acquired risk factors, 79% of all thrombotic events were related to catheter usage. An underlying disease was present in 96% of the patients. CONCLUSIONS: Compared to acquired risk factors, congenital prothrombotic disorders are rarely present in children with peripheral venous and arterial thromboses. These results do not support general screening of children with venous and arterial thromboses for congenital prothrombotic disorders.

Life threatening chylothorax in a patient with congenital thrombophilia: case report.

We reported here a case of bilateral chylothorax as a result of widespread thrombi formation in a patient who was heterozygote for factor V leiden gene mutation and who had antithrombin III deficiency. We performed bilateral chest tubes, thrombolytic and oral anticoagulant therapy. The patient responded to the therapy. She has been in follow up without symptoms for 18 months.

[Future of prenatal cytogenetic studies: rapid aneuploidy testing or full karyotype]. / Zasady postepowania oraz stosowanie profilaktyki przeciwzakrzepowej u ciezarnych z powiklaniami polozniczymi oraz trombofilia wrodzona.

Thrombophilia is a congenital or acquired disorder of haemostatic imbalance leading to clot formation. Congenital thrombophilia is a result of different genetic polymorphisms in the genes coding for particular elements in coagulation and fibrinolysis processes and is connected with excessive readiness to thrombosis in the carriers the mutated alleles. A higher coagulation activity has been observed in case of pregnant women who are carriers of congenital thrombophilia, when compared to the pre-pregnancy activity. These changes concern first of all utero-placental circulation, and may lead to many complications during pregnancy such as: recurrent miscarriages, intrauterine fetal death in second and third trimester, preeclampsia/eclampsia, intrauterine growth restriction and placental abruption. Numerous research indicates that anticoagulation prophylaxis in pregnant women with the abovementioned complications in medical history might prevent a similar condition in the following pregnancies. What is more, it underlines that administration of low molecular weight heparin and acetylsalicylic acid may improve perinatal outcome in thrombophilic women. However, the notion whether anticoagulant prophylaxis should be applied in women with preeclampsia, fetal hypotrophy or fetal loss remains disputable. Furthermore, the question of when the prophylaxis should start and of its duration remains unanswered. The following summary focuses on congenital thrombophilia in pregnant women with burdened anamnesis and suggested pattern of anticoagulation prophylaxis.

High prevalence of congenital thrombophilia in patients with pregnancy-related or idiopathic venous thromboembolism/pulmonary embolism.

Congenital thrombophilia which is characterized by deficiencies in proteins such as antithrombin (AT), protein C (PC) and protein S (PS), is a major cause of venous thromboembolism (VTE). A total of 130 patients with VTE were evaluated for congenital thrombophilia based on the activity of AT, PC, or PS. Fifteen VTE patients with congenital AT deficiency (11.5 %), 16 with congenital PC deficiency (12.3 %) and eight with congenital PS deficiency (6.2 %) were diagnosed using DNA analysis. The frequency of congenital AT deficiency was significantly higher in subjects with pregnancy-related and idiopathic VTE than in those with VTE due to other causes, and congenital PC and PS deficiency were frequently associated with idiopathic VTE. Among the groups examined, the plasma levels of AT were the lowest in subjects with pregnancy-related VTE. Although our findings may have been influenced by some unintentional bias, congenital thrombophilia is nevertheless a major cause of VTE in pregnant patients as well as in young or middle-aged patients without any underlying diseases.

Clinical Characteristics and Outcome of Budd-Chiari Syndrome at a Tertiary Care Hospital in Pakistan.

OBJECTIVE: To determine the clinical characteristics of Budd-Chiari syndrome (BCS), its causes and outcome at a tertiary care hospital. STUDY DESIGN: An observational study. PLACE AND DURATION OF STUDY: The Aga Khan University Hospital,Karachi, from 2004 to 2014. METHODOLOGY: Aretrospective analysis of data was conducted. Apredesigned questionnaire was filled from medical records of patients with BCS. Clinical features, etiology, management and outcome was noted from 2004 to 2014. Descriptive statistics were determined. RESULTS: Forty-five patients' charts were reviewed; 26 (57.8%) were male patients. The median (IQR) age at diagnosis was 26.0 (20.5 to 34.5) years. Primary BCS was seen in 27 (60.0%) patients. The most frequent clinical features included ascites (82.2%), abdominal pain (55.6%), and hepatomegaly (31.1%). Acombined hepatic vein/inferior vena cava block was found in 25 (55.6%) patients. Out of the 28 tested patients protein C and protein S deficiencies were detected in 22 (78.6%) and 17 (60.7%) patients, respectively. Antithrombin III deficiency was detected in 14 (58.3%) of those tested patients. Anticoagulants were used in 24 (53.3%) patients. TIPS was done in 11 (24.4%) patients. Mortality was 6.7% (n=3). CONCLUSION: Congenital thrombophilia was a major causal factor. Age, clinical features, biochemistry and management are important factors in survival.

Prospective study of the incidence and risk factors of postsplenectomy thrombosis of the portal, mesenteric, and splenic veins.

HYPOTHESIS: Splenectomy is recognized as a cause of portal, mesenteric, and splenic vein thrombosis. The exact incidence of the complication and its predisposing factors are not known. DESIGN: Prospective observational cohort study. The median follow-up time of the patients was 22.6 months. SETTING: University surgical clinic in a teaching hospital. PATIENTS: A total of 147 consecutive patients who underwent splenectomy in a 4-year period were enrolled in the study. INTERVENTIONS: Preoperative and postoperative evaluation included ultrasonography with color Doppler flow imaging of the portal system, results of blood coagulation tests, fibrinogen levels, D-dimer levels, and complete blood counts. Operative sheets were recorded and reviewed. When portal system thrombosis (PST) was diagnosed, a complete control for acquired and congenital thrombophilia disorders was obtained. MAIN OUTCOME MEASURES: Primary end points of the study were the assessment of the incidence of postsplenectomy PST and the identification of risk factors for its occurrence. RESULTS: Portal system thrombosis occurred in 7 (4.79%) of 146 patients who underwent splenectomy. The age, sex, type or length of the operation, and use of preoperative and postoperative thromboprophylaxis with low molecular weight heparin did not prove to be significant factors in the occurrence of PST. Platelet count of more than 650 x 10(3)/microL and greater spleen weight (>650 g) was associated with the development of PST (P = .01, P = .03). Normal D-dimer levels on diagnosis of the complication showed a negative predictive value of 98%. Two of the affected patients were diagnosed with thrombophilia disorders. In a median follow-up period of 22.6 months, no other case of PST was recorded. CONCLUSIONS: Postsplenectomy PST occurs in approximately 5% of patients. Possible risk factors are thrombocytosis, splenomegaly, and congenital thrombophilia disorders.

Inherited and acquired thrombophilia: pregnancy outcome and treatment.

Maternal thrombophilias increases the risk of an adverse pregnancy outcome. An extensive literature review highlights the role of inherited and acquired thrombophilic disorders in spontaneous abortion, both early and late, recurrent or isolate, in intrauterine growth retardation, in placenta abruption, in pre-eclampsia and in venous thromboembolism. We have particularly focused attention on the following factors: antithrombin III (ATIII), proteins C (PC) and S (PS) deficiencies, genetic mutations particularly factor V Leiden (FVL), prothrombin gene G20210A (PTM) and the thermolabile variant of the methylene tetrahydrofolate reductase C677T (MTHFR) gene, lupus anticoagulant (LAC) and anticardiolipin antibodies, VIIIc factor, hyperhomocysteinemia and acquired activated protein C resistance. Appropriate treatment can improve pregnancy outcome without teratogenic effects.