Elevated factor Xa activity in the blood of asymptomatic patients with congenital antithrombin deficiency.

SummaryAntithrombin (AT), a serin protease inhibitor (serpin) produced in the liver, inhibits mainly thrombin and factor Xa. Antithrombin deficiency (AD) is associated with a higher incidence of thrombosis. Case report: We report a newborn with uncomplicated birth in the 40+5 week of gestation and postnatal appearance of a reticular, livide haematoma on the right upper arm and a tonic clonic epileptic seizure. Clinical examination revealed weak pulses in the A. radialis and ulnaris. MRI scan showed a large thrombus in the A. carotis interna and externa with large cerebral infarction and a thrombus in the A. subclavia. Laboratory work up showed elevated D-dimers and antithrombin levels < 20% (lowest 15%), age-related values for protein C, protein S, plasminogen, and no other inherited thrombophilia. Therapy: We started anticoagulation with unfractionated heparin intravenously (aPTT: 50–60 s) and under suspicion of an AD the substitution of AT (70 U/kg body weight). In course of time we changed anticoagulation to low molecular weight heparin (Anti Xa 0.6–0.8 U/ml) and substitution of 250 E/kg AT every second day. In the molecular work up we found a homozygous missense mutation in exon 2 of SERPINC1 gene (type „Budapest 3”). Molecular analysis showed also heterozygous mutations in both parents and a homozygous mutation in the asymptomatic brother aged three years. At age of six months we changed the anticoagulation to coumadin (INR 2.5–3.5). Anticoagulation with coumadin was also started in the brother. Discussion: Hereditary AD is associated with an increased risk of thrombosis. The homozygous status mainly leads to intrauterine fetal loss or the occurrence of peri- and postnatal thrombosis. Therapy consists in the substitution of AT and a lifelong anticoagulation with vitamin K antagonists also in asymptomatic patients.

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Antithrombin Deficiency in Pregnancy.

Blood ◽

10.1182/blood.v110.11.1879.1879 ◽

2007 ◽

Vol 110 (11) ◽

pp. 1879-1879

Author(s):

Retter J. Andrew ◽

Hunt J. Beverley

Keyword(s):

Caesarean Section ◽

Post Partum ◽

Case Series ◽

Fold Increase ◽

First Trimester ◽

Antithrombin Deficiency ◽

Sagittal Sinus ◽

Asymptomatic Patients ◽

Estimated Blood Loss ◽

In Pregnancy

Abstract Background: During pregnancy untreated antithrombin deficiency is associated with up to a 50% risk of venous thromboembolism (VTE) and a relative risk of pregnancy loss of 2.1 with a 5-fold increase in stillbirths. Thus thromboprophylaxis is widely used, but little data is available to select type, dose & duration of anticoagulation. Method: We performed a retrospective, single centre observational study of our antithrombin deficient pregnancies since 1996. Results: There were 9 pregnancies in 8 women; median age at conception 33 (age-range 19–37). They separated into 3 groups (1) 4 asymptomatic patients diagnosed on family screening. They received unmonitored enoxaparin 40mg until 16 weeks then 40mg BD. (2) 2 with previous VTE, received intermediate dose enoxaparin (1mg/kg), increased to BD at 16 weeks. Monitoring was done to maintain an anti-Xa trough of <0.12 iu/ml and peak <0.8iu.ml. (3) 2 referred after presenting with VTE in pregnancy. They received enoxaparin 1mg/kg BD and the same monitoring These included a known antithrombin deficient woman, referred in her second pregnancy at 26weeks gestation with premature rupture of the membranes and an iliofemoral deep vein thrombosis which developed on enoxaparin 60mg OD. Enoxaparin was increased to 1mg/kg BD and an IVC filter inserted. Despite the filter however she had a pulmonary embolism. The filter was removed after Caesarean section at 31 weeks. Two had sagittal sinus thromboses in the first trimester associated with severe hyperemesis requiring IV fluids. One was our only thromboprophylaxis failure, receiving enoxaparin 40mg OD, she weighed 80Kg. The second presented at 11weeks gestation. She was intolerant of self injecting and so switched to warfarin at 15 weeks until 35 weeks as did one other mother. All mothers had close feto-maternal monitoring with uterine artery Doppler at 24 weeks if possible and then monthly growth scans thereafter. Delivery: Thromboprophylaxis was stopped at labour initiation or 12hrs prior to Caesarean section (3 women) and 50iu/kg of antithrombin concentrate was given. Anticoagulation was restarted 24hrs after delivery. Six weeks enoxaparin post-partum thromboprophylaxis was given or the women converted back to warfarin. Estimated blood loss at delivery was a median of 200ml (range 200–500ml), no transfusions were required. There were no post partum VTEs. Nine births occurred at a median gestation of 38weeks (range 31–41), median birth weight 3045g (range 1420–4120g). One child has West’s syndrome. Conclusion: This is the largest case series on the management of antithrombin deficiency in pregnancy. The combined use of enoxaparin in pregnancy and post partum combined with antithrombin concentrate during labour appears to improve pregnancy outcome and reduce the rate of VTE. Larger studies are required to confirm this finding.

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Efficacy of Oral Factor Xa Inhibitor for Venous Thromboembolism in a Patient with Antithrombin Deficiency

Internal Medicine ◽

10.2169/internalmedicine.0483-17 ◽

2018 ◽

Vol 57 (14) ◽

pp. 2025-2028 ◽

Cited By ~ 6

Author(s):

Kentaro Minami ◽

Koji Kumagai ◽

Yoshinao Sugai ◽

Kohki Nakamura ◽

Shigeto Naito ◽

...

Keyword(s):

Venous Thromboembolism ◽

Factor Xa ◽

Factor Xa Inhibitor ◽

Antithrombin Deficiency

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Decreased Levels Of Procoagulant Phospholipids In Bleeding Patients With Overcoagulation By Vitamin K Antagonists

Blood ◽

10.1182/blood.v122.21.4768.4768 ◽

2013 ◽

Vol 122 (21) ◽

pp. 4768-4768

Author(s):

Patrick Van Dreden ◽

Dominique François ◽

Emmanuel Mathieu ◽

Matthieu Grusse ◽

Marc Vasse

Keyword(s):

Vitamin K ◽

Conflicts Of Interest ◽

Vitamin K Antagonists ◽

Factor Xa ◽

International Normalized Ratio ◽

Bleeding Complications ◽

Functional Assay ◽

Minor Bleeding ◽

Asymptomatic Patients ◽

Increased Risk

Background The major adverse effect of vitamin K antagonists (VKA) is the increased risk for bleeding complications. In addition to well-identified risk factors such as age, prior gastrointestinal tract bleeding, or hypertension, the intensity of anticoagulation evaluated by the International Normalized Ratio (INR) measurement is a major determinant of VKA-induced bleeding. However, for the same degree of VKA overcoagulation and comorbidities, some patient will bleed, whereas others remain asymptomatic. Therefore, identifying specific biological markers that identify patients at high risk of bleeding would have great clinical impact. Microparticles, derived from different cellular origins (endothelium, red blood cells, leukocytes, platelets or apoptotic tissues), can be detected in plasma and express procoagulant phospholipids (PPL). The presence of PPL has been associated with various diseases complicated by an hypercoagulable state. Therefore, we hypothesize that the procoagulant activity of PPL could protect against haemorrhage in patients with VKA overcoagulation. Patients and methods 53 consecutive patients who were referred to the emergency department of our institution and with an INR > 5 were enrolled in the study: 22 (10 females; 12 males, median age 82 years) were symptomatic (20 cases of minor bleeding, 2 cases of non-fatal major bleeding), whereas 31 (18 females, 13 males, median age 78 years) were asymptomatic. Median INR was 7.36 (range: 5 – 22.6) and 6.3 (range: 5 – 10.7) in symptomatic and asymptomatic patients, respectively (p = 0.17, not significant). PPL were evaluated using a factor Xa-based coagulation assay (STA-Procoag-PPL, Diagnostica Stago) in which shortened clotting times are associated with increased levels of PPL. We also quantified thrombomodulin (TM) by an ELISA assay (Asserachrom Thrombomodulin, Diagnostica Stago) and by a functional assay based on the ability of TM to activate Protein C in the presence of thrombin, since high plasma levels of TM were previously identified as a predictor of bleeding complications. Results Clotting times were significantly lower in asymptomatic patients than in bleeding patients [respective median values 36.5 seconds (range: 27.1 – 72.2) and 47.2 seconds (range : 30.5 – 72.8); p = 0.03. In contrast, there were no significant differences for TM levels, whatever the assay used (functional or immunological). Conclusion Increased PPL could contribute to decrease the haemorrhagic risk of patients treated by VKA. It is not clear if the decrease of PPL is directly responsible of the hemorrhagic syndrom, or if PPL are decreased because of a consumption during the hemorrhagic episode. In order to answer this question, it could be of interest to analyse if a prospective follow-up of this parameter could help to identify patients with an increased hemorrhagic risk when treated by VKA. Disclosures: No relevant conflicts of interest to declare.

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Healing gone wrong: convergence of hemostatic pathways and liver fibrosis?

Clinical Science ◽

10.1042/cs20191102 ◽

2020 ◽

Vol 134 (16) ◽

pp. 2189-2201

Author(s):

Jessica P.E. Davis ◽

Stephen H. Caldwell

Keyword(s):

Wound Healing ◽

Liver Disease ◽

Hepatic Fibrosis ◽

Cell Activation ◽

Stellate Cell ◽

Factor Xa ◽

Clinical Trial Data ◽

Chronic Liver ◽

Healing Response ◽

Wound Healing Response

Abstract Fibrosis results from a disordered wound healing response within the liver with activated hepatic stellate cells laying down dense, collagen-rich extracellular matrix that eventually restricts liver hepatic synthetic function and causes increased sinusoidal resistance. The end result of progressive fibrosis, cirrhosis, is associated with significant morbidity and mortality as well as tremendous economic burden. Fibrosis can be conceptualized as an aberrant wound healing response analogous to a chronic ankle sprain that is driven by chronic liver injury commonly over decades. Two unique aspects of hepatic fibrosis – the chronic nature of insult required and the liver’s unique ability to regenerate – give an opportunity for pharmacologic intervention to stop or slow the pace of fibrosis in patients early in the course of their liver disease. Two potential biologic mechanisms link together hemostasis and fibrosis: focal parenchymal extinction and direct stellate cell activation by thrombin and Factor Xa. Available translational research further supports the role of thrombosis in fibrosis. In this review, we will summarize what is known about the convergence of hemostatic changes and hepatic fibrosis in chronic liver disease and present current preclinical and clinical data exploring the relationship between the two. We will also present clinical trial data that underscores the potential use of anticoagulant therapy as an antifibrotic factor in liver disease.

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Case Example: Adjacent Segment Disease: What Is It, and How Is It Rated?

Guides Newsletter ◽

10.1001/amaguidesnewsletters.2011.marapr02 ◽

2011 ◽

Vol 16 (2) ◽

pp. 8-9

Author(s):

Marjorie Eskay-Auerbach

Keyword(s):

Clinical Symptoms ◽

Lumbar Fusion ◽

Adjacent Segment Degeneration ◽

Adjacent Segment Disease ◽

Adjacent Segment ◽

Disc Space Narrowing ◽

Disc Disease ◽

Disc Space ◽

Radiographic Findings ◽

Asymptomatic Patients

Abstract The incidence of cervical and lumbar fusion surgery has increased in the past twenty years, and during follow-up some of these patients develop changes at the adjacent segment. Recognizing that adjacent segment degeneration and disease may occur in the future does not alter the rating for a cervical or lumbar fusion at the time the patient's condition is determined to be at maximum medical improvement (MMI). The term adjacent segment degeneration refers to the presence of radiographic findings of degenerative disc disease, including disc space narrowing, instability, and so on at the motion segment above or below a cervical or lumbar fusion. Adjacent segment disease refers to the development of new clinical symptoms that correspond to these changes on imaging. The biomechanics of adjacent segment degeneration have been studied, and, although the exact mechanism is uncertain, genetics may play a role. Findings associated with adjacent segment degeneration include degeneration of the facet joints with hypertrophy and thickening of the ligamentum flavum, disc space collapse, and translation—but the clinical significance of these radiographic degenerative changes remains unclear, particularly in light of the known presence of abnormal findings in asymptomatic patients. Evaluators should not rate an individual in anticipation of the development of changes at the level above a fusion, although such a development is a recognized possibility.

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