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.

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.

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.

Púrpura retiforme asociada a déficit de proteína S / Retiform Purpura Associated With Protein S Deficiency

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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.

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.

Inherited antithrombin deficiency and anabolic steroids: a risky combination.

A 20-year-old male with asymptomatic inherited type 1 antithrombin deficiency and a family history of thrombosis started injecting himself with testosterone 250 mg intramuscularly twice weekly for 5 weeks. He presented to the hospital with progressive dyspnea on exertion, chest pain and hemoptysis. Workup revealed bilateral submassive pulmonary embolism and proximal right lower extremity deep vein thrombosis. He was treated with intravenous (IV) unfractionated heparin and underwent catheter-directed thrombolysis with alteplase to the main pulmonary arteries. Postprocedure, he remained on IV alteplase infusion for 24 h and unfractionated heparin in the intensive care unit. Concomitantly he received plasma-derived antithrombin concentrate. He was transitioned to subcutaneous enoxaparin twice daily and discharged from the hospital on oral rivaroxaban 15 mg twice a day. This case highlights the heightened thrombogenic effect of anabolic steroids in the setting of underlying thrombophilia especially in younger subjects.

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.

[The inherited procoagulant and prothrombotic condition as the main etiological factor for ischemic stroke in infants].

The data on the risk factors and etiology of ischemic stroke in 31 infants, aged under 3 years, are summarized. The results of genotyping of blood coagulation and folic acid gene polymorphisms in patients and 83 healthy people are presented. Significant differences were found for -455 G>A FGB (р=0.03) and 807 C>T ITGA2 (р=0,005) polymorphisms. Different gene-gene combinations that can cause hypercoagulation and arterial thrombosis in this age were identified. The most frequent combinations include polymorphisms of genes for FGB, fibrinolysis system and folate cycle enzymes (OR=3,79 and more, p<0.05). A clinical case of ischemic stroke in a girl, aged 10 months, after operated congenital heart malformation is presented.

Accidente cerebrovascular en el recién nacido a término / Cerebral stroke in the term newborn

Los accidentes cerebrovasculares (ACV) constituyen una patología relativamente frecuente en el periodo perinatal. Últimamente, los factores protrombóticos están adquiriendo especial protagonismo como favorecedores de los ACV, y pueden presentarse hasta en el 68% de los casos. La ecografía cerebral constituye la primera prueba de imagen diagnóstica, y la resonancia magnética (RM) es la prueba de elección. Se realiza una revisión de la casuística en un hospital de tercer nivel y se presentan los 2 casos de ACV neonatal en los que se constató una trombofilia hereditaria. De los 7 casos de ACV neonatal encontrados durante el periodo 2006-2011, sólo el 28% presentaba anomalías focales en el estudio ecográfico inicial, confirmándose posteriormente una lesión hemorrágica por RM craneal. Todos los ACV isquémicos presentaron ecografías cerebrales iniciales normales. Por ello, se destaca la conveniencia de realizar una RM craneal en todo neonato con sintomatología-semiología neurológica focal, aun cuando la ecografía inicial no muestre alteraciones. Asimismo, ante la sospecha de una etiología vascular se debe descartar la existencia de anomalías protrombóticas (AU)

Cerebral stroke (CS) is a relatively common pathology in the perinatal period. Recently, prothrombotic factors are acquiring special protagonism and can be present in up to 68% of cases. Cranial sonography is the first diagnostic option, but the MRI is the gold standard technique. We carry out a review of casuistry in a third level hospital and we present two cases of perinatal stroke where it was found hereditary thrombophilia. Only 28% showed focal injuries in first ultrasound study, subsequently confirming hemorrhagic lesion by cranial MRI. All ischemic CS presented normal initial cranial ultrasound. For this reason, we would like to emphasise the desirability of realization of cranial MRI in neonates with focal neurological symptoms or signs, even when the first cranial ultrasound does not show alterations. In the same way, when vascular ethiology is suspected, a screening of prothrombotic factors should be studied (AU)

[Resistance to warfarin in a patient with hereditary thrombophilia]. / Warfarinresistens hos en patient med hereditær trombofili.

We present a case report of a young man with spontaneous deep venous thrombosis. He tested positive for heterozygote factor V Leiden mutation and was treated with warfarin. However, he turned out to be resistant to warfarin, and another venous thrombosis occurred during the insufficient treatment. The antithrombotic treatment was then successfully replaced by phenprocoumon. This case report emphasizes the importance of critically evaluating the efficacy of a treatment and substitute if proven insufficient.

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.

[Physiological effects induced by dermorphin synthetic analogue--opilong].

The effects of repeated opilong injections in a dose of 50 microg/kg/day on subsequent learning of Wistar rats have been studied. The substance caused significant anxiolytic and analgesic effects, as the majority of animals could be learned (90% against 40% in control group) despite of painful stimulus preceding to education. Opilong in a small dose displaced a relation of excitatory-inhibit processes to significant prevalence of excitation although the substance was already absent in an organism for a long time. Raised peripheral sensitivity in all rats, provoked by opilong, correlated with CNS hyper excitability, expressed in stressful, neurotic psychoemotional reactions and in the form of active avoidance. The biochemical blood analysis in opilong-induced rats demonstrated the attributes of prethrombosis in the form of fibrinolysis depression and hypercoagulation. A view is expressed, that the neuromediator brain systems can be the basic point of opilong action, that are responsible for the excitatory-inhibit conditions of CNS functioning referred on maintenance of conditioned field stability.

Venous thromboembolism in neonates and children.

Thrombosis in children is gaining increased awareness, as advanced medical care has increased treatment intensity of hospitalized pediatric patients. Guidelines for diagnosis and treatment of children and neonates with venous thromboembolism (VTE) are mostly extrapolated from adult data, despite the uniqueness of their hemostatic system. Whereas inherited thrombophilia (IT) have been established as risk factors for VTE in adults, in children with idiopathic VTE and in pediatric populations in which thromboses were associated with medical diseases, IT have been described as additional risk factors. Follow-up data for VTE recurrence in children suggest a recurrence rate between 3% (neonates) and 21% (idiopathic VTE). Apart from underlying medical conditions, recently reported systematic reviews on pediatric VTE and stroke have shown significant associations between thrombosis and presence of factor V G1691A, factor II G20210A, protein C-, protein S- and antithrombin deficiency, even more pronounced when combined IT were involved. The pooled odds ratios (OR: single IT) for VTE onset ranged from 2.4 for the factor II G20210A mutation (cerebrovascular occlusion) to 9.4 in children with antithrombin deficiency (venous VTE). In addition, the pooled OR for persistent antiphospholipid antibodies/lupus anticoagulants was 6.6 for children with cerebrovascular occlusion and 4.9 for pediatric cases with venous VTE. The factor II G20210A mutation (OR: 2.1), protein C- (OR: 2.4), S- (OR: 3.1), and antithrombin deficiency (OR: 3.0) did also play a significant role at recurrence. Among primarily asymptomatic family members of pediatric VTE index cases annual VTE incidences were 2.82% (95% confidence interval [95% CI], 1.63-4.80%) in carriers of antithrombin, protein C, or protein S-deficiency, 0.42% (0.12-0.53%) for factor II G202010A, 0.25% (0.12-0.53%) for factor V G1691A, and 0.10% (0.06-0.17%) in relatives with no IT. Based on these data diagnosis, screening and treatment issues will be discussed.

Relation between maternal thrombophilia and stillbirth according to causes/associated conditions of death.

OBJECTIVE: To investigate maternal thrombophilia in cases of Stillbirth (SB), also an uncertain topic because most case series were not characterised for cause/associated conditions of death. STUDY DESIGN: In a consecutive, prospective, multicentre design, maternal DNA was obtained in 171 cases of antenatal SB and 326 controls (uneventful pregnancy at term, 1:2 ratio). Diagnostic work-up of SB included obstetric history, neonatologist inspection, placenta histology, autopsy, microbiology/chromosome evaluations. Results audited in each centre were classified by two of us by using CoDAC. Cases were subdivided into explained SB where a cause of death was identified and although no defined cause was detected in the remnants, 64 cases found conditions associated with placenta-vascular disorders (including preeclampsia, growth restriction and placenta abruption - PVD). In the remnant 79 cases, no cause of death or associated condition was found. Antithrombin activity, Factor V Leiden, G20210A Prothrombin mutation (FII mutation) and acquired thrombophilia were analysed. RESULTS: Overall, the presence of a thrombophilic defect was significantly more prevalent in mothers with SBs compared to controls. In particular, SB mothers showed an increased risk of carrying Factor II mutation (OR=3.2, 95% CI: 1.3-8.3, p=0.01), namely in unexplained cases. Such mutation was significantly associated also with previous SB (OR=8.9, 95%CI 1.2-70.5). At multiple logistic regression, Factor II mutation was the only significantly associated variable with SB (adj OR=3.8, 95% CI: 1.3-13.5). CONCLUSION: These data suggest that Factor II mutation is the only condition specifically associated with unexplained SB and could represents a risk of recurrence. PVD-associated condition is unrelated to thrombophilia.