Management of thrombosis in children and neonates: practical use of anticoagulants in children

Abstract Venous thrombosis (VTE) in children and neonates presents numerous management challenges. Although increasing in frequency, VTE in children and neonates is still uncommon compared with adults. The epidemiology of VTE is vastly different in neonates vs children vs adolescents vs adults. In reality, pediatric thrombosis should be viewed as a multitude of rare diseases (eg, renal vein thrombosis, spontaneous thrombosis, catheter-related thrombosis, cerebral sinovenous thrombosis), all requiring different approaches to diagnosis and with different short- and long-term consequences, but linked by the use of common therapeutic agents. Further, children have fundamentally different physiology in terms of blood flow, developmental hemostasis, and, likely, endothelial function. The American Society ofHematology 2017 Guidelines for Management of Venous Thromboembolism: Treatment of Pediatric VTE provides up-to-date evidence-based guidelines related to treatment. Therefore, this article will focus on the practical use of therapeutic agents in the management of pediatric VTE, especially unfractionated heparin, low-molecular-weight heparin, and oral vitamin K antagonists, as the most common anticoagulants used in children. Direct oral anticoagulants (DOACs) remain in clinical trials in children and should not be used outside of formal trials for the foreseeable future.

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Noncanonical Effects of Oral Thrombin and Factor Xa Inhibitors in Platelet Activation and Arterial Thrombosis

Thrombosis and Haemostasis ◽

10.1055/s-0040-1716750 ◽

2020 ◽

Author(s):

Amin Polzin ◽

Lisa Dannenberg ◽

Manuela Thienel ◽

Martin Orban ◽

Georg Wolff ◽

...

Keyword(s):

Platelet Activation ◽

Arterial Thrombosis ◽

Thrombus Formation ◽

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Factor Xa ◽

Coagulation Cascade ◽

Platelet Activity ◽

Vein Thrombosis

AbstractNonvitamin K oral anticoagulants (NOACs) or direct oral anticoagulants comprise inhibitors of factor Xa (rivaroxaban, apixaban, edoxaban) or factor IIa (dabigatran). Both classes efficiently interfere with the final or penultimate step of the coagulation cascade and showed superior net clinical benefit compared with vitamin K antagonists for prevention of thromboembolic events in patients with AF and for prevention and therapy of deep vein thrombosis and pulmonary embolism. None the less, accumulating data suggested, that there may be differences regarding the frequency of atherothrombotic cardiovascular events between NOACs. Thus, the optimal individualized NOAC for each patient remains a matter of debate. Against this background, some basic and translational analyses emphasized NOAC effects that impact on platelet activity and arterial thrombus formation beyond inhibition of plasmatic coagulation. In this review, we will provide an overview of the available clinical and translational evidence for so-called noncanonical NOAC effects on platelet activation and arterial thrombosis.

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Newer Oral Anticoagulants in the Treatment of Acute Portal Vein Thrombosis in Patients with and without Cirrhosis

International Journal of Hepatology ◽

10.1155/2018/8432781 ◽

2018 ◽

Vol 2018 ◽

pp. 1-9 ◽

Cited By ~ 24

Author(s):

P. Priyanka ◽

J. T. Kupec ◽

M. Krafft ◽

N. A. Shah ◽

G. J. Reynolds

Keyword(s):

Molecular Weight ◽

Portal Vein ◽

Portal Vein Thrombosis ◽

Vitamin K ◽

Low Molecular Weight Heparin ◽

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Low Molecular Weight ◽

Vein Thrombosis

Background. Newer oral anticoagulants (NOACs) are being utilized increasingly for the treatment of venous thromboembolism (VTE). NOAC use is the standard of care for stroke prophylaxis in nonvalvular atrial fibrillation and treatment of acute VTE involving extremities and pulmonary embolism. In contrast, most guidelines in the literature support the treatment of acute portal vein thrombosis (PVT) with low molecular weight heparin (LMWH) and vitamin K antagonists (VKA). Literature evaluating NOAC use in the treatment of acute portal vein thrombosis is sparse. This review focuses on the safety and efficacy of the use of NOACs in the treatment of acute PVT in patients, with or without concomitant cirrhosis, based on the most recent data available in the current literature. Methods. A systematic review was conducted through a series of advanced searches in the following medical databases: PubMed, BioMed Central, Cochrane, and Google Scholar. Keywords utilized were as follows: NOAC, DOAC (direct oral anticoagulants), portal vein thrombosis, rivaroxaban, apixaban, dabigatran, and edoxaban. Articles related to newer anticoagulant use in patients with portal vein thrombosis were included. Results. The adverse events, including bleeding events (major and minor) and the failure of anticoagulation (propagation of thrombus or recurrence of PVT), are similar between the NOACs and traditional anticoagulants for the treatment of acute PVT, irrespective of the presence of cirrhosis. Conclusions. Newer oral anticoagulants are safe and efficacious alternatives to traditional anticoagulation with low molecular weight heparin and vitamin K antagonists in the treatment of acute portal vein thrombosis with or without cirrhosis.

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Prevention of the post thrombotic syndrome with anticoagulation: a narrative review

Thrombosis and Haemostasis ◽

10.1055/a-1711-1263 ◽

2021 ◽

Author(s):

Ilia Makedonov ◽

Susan R Kahn ◽

Jameel Abdulrehman ◽

Sam Schulman ◽

Aurélien Delluc ◽

...

Keyword(s):

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Economic Consequences ◽

Compression Stockings ◽

Vein Thrombosis ◽

Post Thrombotic Syndrome ◽

Preventative Measures ◽

Catheter Directed Thrombolysis ◽

Deep Vein

The post thrombotic syndrome (PTS) is chronic venous insufficiency secondary to a prior deep vein thrombosis (DVT). It is the most common complication of VTE and, while not fatal, it can lead to chronic, unremitting symptoms as well as societal and economic consequences. The cornerstone of PTS treatment lies in its prevention after DVT. Specific PTS preventative measures include the use of elastic compression stockings (ECS) and pharmacomechanical catheter directed thrombolysis (PCDT). However, the efficacy of these treatments has been questioned by large RCTs. So far, anticoagulation, primarily prescribed to prevent DVT extension and recurrence, appears to be the only unquestionably effective treatment for the prevention of PTS. In this literature review we present pathophysiological, biological, radiological and clinical data supporting the efficacy of anticoagulants to prevent PTS and the possible differential efficacy among available classes of anticoagulants (vitamin K antagonists (VKA), low molecular weight heparins (LMWHs) and direct oral anticoagulants (DOACs)). Data suggest that LMWHs and DOACs are superior to VKAs, but no head-to-head comparison is available between DOACs and LMWHs. Owing to their potentially greater anti-inflammatory properties, LMWHs could be superior to DOACs. This finding may be of interest particularly in patients with extensive DVT at high risk of moderate to severe PTS, but needs to be confirmed by a dedicated RCT.

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Treatment of Acute Renal Vein Thrombosis With Direct Oral Anticoagulants

American Journal of Therapeutics ◽

10.1097/mjt.0000000000001258 ◽

2020 ◽

Vol Publish Ahead of Print ◽

Author(s):

Ramsha Ahmed ◽

Fahrettin Covut ◽

Tariq Kewan ◽

Abdo Haddad ◽

Hamed Daw

Keyword(s):

Renal Vein ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Renal Vein Thrombosis ◽

Vein Thrombosis

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Anticoagulation for Splanchnic Vein Thrombosis in Myeloproliferative Neoplasms: The Drug and the Duration

Hemato ◽

10.3390/hemato2020015 ◽

2021 ◽

Vol 2 (2) ◽

pp. 255-263

Author(s):

Wafik G. Sedhom ◽

Brady Lee Stein

Keyword(s):

Complete Blood Count ◽

Myeloproliferative Neoplasms ◽

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Pegylated Interferon ◽

Janus Kinase ◽

Splanchnic Vein Thrombosis ◽

Vein Thrombosis ◽

Complementary Role

Myeloproliferative neoplasms are a common cause of splanchnic vein thrombosis, which causes significant morbidity and mortality. Indefinite anticoagulation is the mainstay of therapy, and vitamin K antagonists (VKAs) are routinely used since hematologists have the most experience with this drug class. The role of direct oral anticoagulants (DOACs) is promising, but still undergoing evaluation. Cytoreduction with hydroxyurea or pegylated interferon is often used when cytosis is present, but their roles are yet to be defined when the complete blood count is normal. Janus kinase (JAK) inhibition may have a complementary role in reducing splenomegaly and portal hypertension.

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Treatment of venous thromboembolism in pediatric patients

Blood ◽

10.1182/blood.2019001847 ◽

2020 ◽

Vol 135 (5) ◽

pp. 335-343 ◽

Cited By ~ 2

Author(s):

Char Witmer ◽

Leslie Raffini

Keyword(s):

Clinical Trials ◽

Venous Thromboembolism ◽

Randomized Clinical Trials ◽

Central Venous Access ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Venous Access ◽

Renal Vein Thrombosis ◽

Healthy Children ◽

Vein Thrombosis

Abstract Venous thromboembolism (VTE) is rare in healthy children, but is an increasing problem in children with underlying medical conditions. Pediatric VTE encompasses a highly heterogenous population, with variation in age, thrombosis location, and underlying medical comorbidities. Evidence from pediatric clinical trials to guide treatment of VTE is lacking so treatment is often extrapolated from adult trials and expert consensus opinion. Aspects unique to children include developmental hemostasis and the major role of central venous access devices. There is an absence of information regarding the optimal target levels of anticoagulation for neonates and infants and lack of suitable drug formulations. Anticoagulants, primarily low-molecular-weight heparin and warfarin, are used to treat children with symptomatic VTE. These drugs have significant limitations, including the need for subcutaneous injections and frequent monitoring. Randomized clinical trials of direct oral anticoagulants in pediatric VTE are ongoing, with results anticipated soon. These trials will provide new evidence and options for therapy that have the potential to improve care. International collaborative registries offer the ability to study outcomes of rare subgroups of pediatric VTE (eg, renal vein thrombosis), and will be important to ultimately guide therapy in a more disease-specific manner.

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Direct oral anticoagulants and venous thromboembolism

European Respiratory Review ◽

10.1183/16000617.0025-2016 ◽

2016 ◽

Vol 25 (141) ◽

pp. 295-302 ◽

Cited By ~ 10

Author(s):

Massimo Franchini ◽

Pier Mannuccio Mannucci

Keyword(s):

Venous Thromboembolism ◽

Vitamin K Antagonists ◽

Dabigatran Etexilate ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Factor Xa ◽

Thrombin Inhibitors ◽

Vein Thrombosis ◽

Direct Anticoagulants ◽

Deep Vein

Venous thromboembolism (VTE), consisting of deep vein thrombosis and pulmonary embolism, is a major clinical concern associated with significant morbidity and mortality. The cornerstone of management of VTE is anticoagulation, and traditional anticoagulants include parenteral heparins and oral vitamin K antagonists. Recently, new oral anticoagulant drugs have been developed and licensed, including direct factor Xa inhibitors (e.g. rivaroxaban, apixaban and edoxaban) and thrombin inhibitors (e.g. dabigatran etexilate). This narrative review focusses on the characteristics of these direct anticoagulants and the main results of published clinical studies on their use in the prevention and treatment of VTE.

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Direct Oral Anticoagulants in Patients With Inherited Thrombophilia and Venous Thromboembolism: A Prospective Cohort Study

Journal of the American Heart Association ◽

10.1161/jaha.120.018917 ◽

2020 ◽

Vol 9 (23) ◽

Author(s):

Elena Campello ◽

Luca Spiezia ◽

Chiara Simion ◽

Daniela Tormene ◽

Giuseppe Camporese ◽

...

Keyword(s):

Cohort Study ◽

Venous Thromboembolism ◽

Vitamin K ◽

Cumulative Incidence ◽

Prospective Cohort ◽

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Inherited Thrombophilia ◽

Vein Thrombosis

Background In this prospective cohort study, we aimed to evaluate the efficacy and safety of direct oral anticoagulants (DOACs) versus heparin/vitamin K antagonists for the treatment of venous thromboembolism (VTE) in patients with inherited thrombophilia. Methods and Results We enrolled consecutive patients with acute VTE and inherited thrombophilia treated with DOACs (cases) or heparin/vitamin K antagonists (controls), matched for age, sex, ethnicity, and thrombophilia type. End points were VTE recurrence and bleeding complications; residual vein thrombosis and post‐thrombotic syndrome; VTE recurrence after anticoagulant discontinuation. Two hundred fifty‐five cases (age 52.4±17.3 years, Female 44.3%, severe thrombophilia 33.1%) and 322 controls (age 49.7±18.1 years, Female 50.3%, severe thrombophilia 35.1%) were included. The cumulative incidence of VTE recurrence during anticoagulation was 1.09% in cases versus 1.83%, adjusted hazard ratio (HR) 0.67 (95% CI, 0.16–2.77). The cumulative incidence of bleeding was 10.2% in cases versus 4.97%, HR 2.24 (95% CI 1.10–4.58). No major bleedings occurred in cases (versus 3 in controls). No significant differences regarding residual vein thrombosis and post‐thrombotic syndrome. After anticoagulant discontinuation, DOACs yielded a significantly lower 2‐year VTE recurrence risk versus traditional anticoagulants (HR, 0.61 [95% CI, 0.47–0.82]). Conclusions DOACs and heparin/vitamin K antagonists showed a similar efficacy in treating VTE in patients with thrombophilia. Although major bleeding episodes were recorded solely with heparin/vitamin K antagonists, we noted an overall increased bleeding rate with DOACs. The use of DOACs was associated with a lower 2‐year risk of VTE recurrence after anticoagulant discontinuation.

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The efficacy and safety of direct oral anticoagulants in noncirrhotic portal vein thrombosis

Blood Advances ◽

10.1182/bloodadvances.2019001310 ◽

2020 ◽

Vol 4 (4) ◽

pp. 655-666 ◽

Cited By ~ 11

Author(s):

Leonard Naymagon ◽

Douglas Tremblay ◽

Nicole Zubizarreta ◽

Erin Moshier ◽

Kevin Troy ◽

...

Keyword(s):

Portal Vein ◽

Portal Vein Thrombosis ◽

Major Bleeding ◽

Primary Outcome ◽

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Efficacy And Safety ◽

Predisposing Factor ◽

Vein Thrombosis

Abstract Guidelines currently favor vitamin K antagonists or low-molecular-weight heparins for treatment of noncirrhotic portal vein thrombosis (ncPVT). Use of direct oral anticoagulants (DOACs) in PVT has been met with concern because of the lack of data. We conducted a retrospective study to investigate the efficacy and safety of DOACs for the treatment of ncPVT, and to compare them with standard therapies: 330 patients with ncPVT, followed-up for a mean 41.6 months, received warfarin (n = 108), enoxaparin (n = 70), rivaroxaban (n = 65), apixaban (n = 20), dabigatran (n = 8), fondaparinux (n = 2), or no anticoagulation (n = 57). The primary outcome was complete radiographic resolution (CRR) of PVT. Secondary outcomes included recanalization of occlusive PVT, cavernous transformation of the PV, development of chronic portal hypertensive symptoms (cPHS), and major bleeding. DOACs were associated with the highest CRR rates (dabigatran, 6/8 [75%]; apixaban, 13/20 [65%]; rivaroxaban, 42/65 [65%]). Enoxaparin was associated with a CRR rate similar to that of the DOACs (40/70 = 57%). Warfarin was associated with worse outcomes in this regard (CRR rate, 31% [33/108]; hazard ratio [HR] DOACs:warfarin, 2.91; 95% confidence interval [CI], 1.87-4.52; P < .0001). DOACs were associated with recanalization rates similar to enoxaparin and greater than warfarin (HR DOACs:warfarin, 3.45; 95% CI, 1.93-6.18; P < .0001). DOACs were associated with lower rates of cPHS, although this did not attain significance (DOACs, 8/93 [9%]; enoxaparin, 13/70 [19%]; warfarin, 31/108 [29%]). DOACs were associated with less major bleeding relative to warfarin (HR DOACs:warfarin, 0.20; 95% CI, 0.05-0.86; P = .0307). Patients harboring JAK2V617F, those with no evident predisposing factor for PVT, and those with occlusive thrombus demonstrated worse outcomes. DOACs appear effective and safe for the treatment of ncPVT.

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