Management Of Thrombotic Diseases Research Articles

Stress-Induced Hypercoagulability: Insights from Epidemiological and Mechanistic Studies, and Clinical Integration.

By integrating findings from comprehensive reviews, meta-analyses, and cutting-edge genetic studies, this article illuminates the significance of stress-induced hypercoagulability in clinical medicine. In particular, the findings from numerous prospective cohort studies indicate that stress and hemostatic factors of a hypercoagulable state are associated with increased incident risk and poor prognosis for atherosclerotic cardiovascular disease and venous thromboembolism. Mendelian randomization studies suggest that these associations are partially causal. The review synthesizes extensive research on the link between acute and chronic stress and hypercoagulability, outlining a potential pathway from stress to thrombosis risk. Consistent with the allostatic load concept, acute stress-induced hypercoagulability, initially adaptive, can turn maladaptive under chronic stress or excessive acute stress, leading to arterial or venous thrombotic events. Individuals with predisposing factors, including atherosclerosis, thrombophilia, or immobilization, may exhibit an increased risk of thrombotic disease during stress. Contextual sociodemographic characteristics, the stress experience, and coping resources additionally modulate the extent of stress-induced hypercoagulability. Research into the neuroendocrine, cellular, and molecular bases reveals how stress influences platelet activation coagulation and fibrinolysis. The activation of the sympathetic nervous system and the hypothalamic-pituitary-adrenal axis, along with vagal withdrawal, and the effects of catecholamines, cortisol, and vasopressin, are the central mechanisms involved. Hemoconcentration, inflammation, endothelial dysfunction, and thrombopoiesis additionally contribute to stress-induced hypercoagulability. Further research is needed to prove a causal link between chronic stress and hypercoagulability. This includes exploring its implications for the prevention and management of thrombotic diseases in stressed individuals, with a focus on developing effective psychosocial and pharmacological interventions.

April 2023 Medical Image of the Month: Atrial Myxoma in the setting of Raynaud’s Phenomenon: Early Echocardiography and Management of Thrombotic Disease

No abstract available. Article truncated after 150 words. A 43-year-old woman presents to the Emergency Department (ED) with right-sided weakness and numbness for several hours. Medical history is significant for Raynaud’s Phenomenon (RP), initially presenting six months prior to presentation, manifesting as intermittent episodes of painless discoloration of multiple fingers. Cardiac exam was unremarkable with regular rhythm and no discernable murmur. Neurological exam demonstrated right arm pronator drift. Other examination findings were unremarkable. Labs demonstrated a troponin of 0.00 ng/mL, C-reactive protein of 2.28 mg/dL, and an erythrocyte sedimentation rate of 40 mm/hr. The electrocardiogram (ECG) demonstrated sinus bradycardia and notable for T-wave inversion in lead III and aVF, but without any ST-segment deviations (Figure 1). Magnetic Resonance Imagining (MRI) of the brain demonstrated acute ischemic left frontal, left parietal, and right parietal infarcts along with mild subcortical left parietal infarct, concerning for venous or watershed distal embolic arterial infarct. MRI Angiogram of the brain showing diminutive bilateral …

Strategies for Therapeutic Amelioration of Aberrant Plasma Zn2+ Handling in Thrombotic Disease: Targeting Fatty Acid/Serum Albumin-Mediated Effects.

The initiation, maintenance and regulation of blood coagulation is inexorably linked to the actions of Zn2+ in blood plasma. Zn2+ interacts with a variety of haemostatic proteins in the bloodstream including fibrinogen, histidine-rich glycoprotein (HRG) and high molecular weight kininogen (HMWK) to regulate haemostasis. The availability of Zn2+ to bind such proteins is controlled by human serum albumin (HSA), which binds 70–85% of plasma Zn2+ under basal conditions. HSA also binds and transports non-esterified fatty acids (NEFAs). Upon NEFA binding, there is a change in the structure of HSA which leads to a reduction in its affinity for Zn2+. This enables other plasma proteins to better compete for binding of Zn2+. In diseases where elevated plasma NEFA concentrations are a feature, such as obesity and diabetes, there is a concurrent increase in hypercoagulability. Evidence indicates that NEFA-induced perturbation of Zn2+-binding by HSA may contribute to the thrombotic complications frequently observed in these pathophysiological conditions. This review highlights potential interventions, both pharmaceutical and non-pharmaceutical that may be employed to combat this dysregulation. Lifestyle and dietary changes have been shown to reduce plasma NEFA concentrations. Furthermore, drugs that influence NEFA levels such as statins and fibrates may be useful in this context. In severely obese patients, more invasive therapies such as bariatric surgery may be useful. Finally, other potential treatments such as chelation therapies, use of cholesteryl transfer protein (CETP) inhibitors, lipase inhibitors, fatty acid inhibitors and other treatments are highlighted, which with additional research and appropriate clinical trials, could prove useful in the treatment and management of thrombotic disease through amelioration of plasma Zn2+ dysregulation in high-risk individuals.

Pathogenesis and Management of Thrombotic Disease in Myeloproliferative Neoplasms.

Chronic myeloproliferative neoplasms (MPN) are characterized by clonal expansion of an abnormal hematopoietic stem/progenitor cell and include polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). Venous thrombosis, often at unusual sites, including splanchnic vein thrombosis and arterial thrombosis, as well as a hemorrhagic tendency and a propensity to transform into myelofibrosis or acute leukemia are common complications in patients with MPNs. The pathogenesis of thrombosis in MPN patients is complex and multifactorial. Disease related factors, such as an increase in blood cell counts (i.e., leukocytosis, erythrocytosis, and thrombocytosis), and more importantly presence of JAK2 mutation can interact with non-disease patient related factors such as age, previous history of thrombotic events, obesity, hypertension, hyperlipidemia, and presence of thrombophilic defects. The overall rate of recurrent thrombosis after venous thromboembolism (VTE) is 6.0 to 6.5 per 100 patient-years in patients with MPN compared to 2.7 to 3.7 per 100 patient-years in patients without MPN, and antithrombotic therapy with vitamin K antagonists (VKAs) is associated with a clear benefit, reducing the incidence of recurrence by 48 to 69%. Life-long oral anticoagulation with VKAs is the cornerstone of the antithrombotic treatment for splanchnic vein thrombosis (SVT). Patients with MPN-related cerebral venous thrombosis (CVT) should also be treated with long-term anticoagulation with VKAs. The role of direct acting oral anticoagulants in patients with thrombosis and MPN is not established and the use of these anticoagulants should be considered on an individual basis according to the risk of recurrent of VTE and bleeding.

Direct oral anticoagulants (DOACS): A necessary focus

In 2008, we decided to enter the era of direct oral anticoagulants (DOACS). Was that the right decision to make? The answer will depend on how well we meet the conditions of proper use. This means avoiding underdosing and overdosing as well as understanding how DOACS were validated so that our prescriptions fulfill their role in the management of thrombotic disease.

Quantification of ATP and ADP levels in platelets from healthy human donors: a potential novel indicator of cardiovascular risk

Background Understanding the biology of platelets is essential for the management of thrombotic diseases like stroke and cardiovascular disease. Platelets store ATP and ADP biomolecules and secrete them in response to thrombotic stimuli. However, patient-to-patient variability in storage of these biomolecules in platelets is poorly studied [1]. This study assesses ATP and ADP concentration in platelets and determines (1) the absolute values of these biomolecules per platelet, (2) the ratio of ATP and ADP in platelets and (3) the quantities released from dense granule storage sites in response to a discrete stimulus (Thrombin receptor activating peptide (TRAP); 10μM).

Ximelagatran: Pharmacology, Pharmacokinetics, and Pharmacodynamics

Thromboembolism is the largest cause of morbidity and mortality in the western world, yet oral anticoagulation is currently available only with vitamin K antagonists--most often, warfarin. Warfarin has been used for treatment of thrombotic disease for about 50 years. However, despite its widespread use, it is associated with several limitations, such as varied patient response, a narrow therapeutic window, numerous drug and food interactions, and need for frequent therapeutic monitoring. In addition, its full anticoagulant effect usually takes at least 4-5 days after the start of therapy or any dosage change, and it has a slow offset of therapy. A new oral anticoagulant, ximelagatran, has considerable advantages compared with warfarin. The agent requires no therapeutic monitoring, has a wide therapeutic window, and is not known to interact with food or drugs. The advantages ximelagatran brings to clinical practice should be a welcome addition to the options for management of thrombotic disease.

Inhibitors of Tissue Factor. Factor VIIa for anticoagulant therapy.

Factor VIIa (FVIIa) is a key serine protease involved in the initiation of the coagulation cascade. It is a glycosylated disulfide-linked heterodimer comprised of an amino-terminal gamma-carboxyglutamic acid-rich (Gla) domain and two epidermal growth factor (EGF)-like domains in the light chain, and a chymotrypsin-like serine protease domain in the heavy chain. FVIIa requires tissue factor (TF), a membrane bound protein, as an essential cofactor for maximal activity towards its biological substrates Factor X, Factor IX and Factor VII (FVII). Inhibition of TF.FVIIa activity may prevent the formation of fibrin clots and thus be useful in the management of thrombotic disease. The development of TF.FVIIa inhibitors to validate this target has been of great interest. A wide array of strategic approaches to inhibiting the biochemical and biological functions of the TF.FVIIa complex has been pursued. This has been greatly aided from our understanding of the structures for TF, FVII, FVIIa, and the TF.FVIIa complex. These approaches have resulted in inhibitors directed specifically towards either FVIIa or TF. Antagonists include active site inhibited FVIIa, TF mutants, anti-TF antibodies, anti-FVII/FVIIa antibodies, naturally-occurring protein inhibitors, peptide exosite inhibitors, and protein and small molecule active site inhibitors. These antagonists can inhibit catalysis directly at the active site as well as impair function by binding to exosites that may interfere with substrate, membrane, or cofactor binding. The rationale of TF.FVIIa as a target and the development, characteristics and biological uses of TF.FVIIa inhibitors are discussed.

Thrombosis in Cardiovascular Disorders

The seminal discovery more than a decade ago that coronary artery thrombosis, usually caused by atherosclerotic plaque disruption, is the cause of virtually all cases of acute transmural myocardial infarction and plays a critical role in the development of unstable angina and other ischemic syndromes brought about an intense clinical and scientific interest in the process of thrombosis. The fruits of these investigations are detailed in in Cardiovascular Disorders, a remarkably up-to-date and comprehensive book. Although somewhat weighted towards thrombosis relative to cardiologic problems (fully one third of the book is concerned with coronary ischemic syndromes and thromboembolism from cardiac chambers and valves), there is in-depth coverage of thrombotic problems in other arterial beds and excellent chapters on venous thromboembolism and disseminated intravascular coagulation. On the whole the book is well balanced and reflects the backgrounds of the two editors, both distinguished leaders in cardiology and hematology from opposite sides of the Atlantic Ocean. They have selected an international group of 49 expert contributors representing the disciplines of cardiology, hematology, neurology, epidemiology, biochemistry, pharmacology, clinical medicine, and surgery. This eclectic lineup of authors is appropriate because thrombotic diseases are unusual in that they are included in the practice of most doctors, regardless of training, background, or subspecialty practice. Although the book is clinically oriented and practical, there are lucid and pithy summaries of the biochemical, pharmacologic, and molecular mechanisms involved in thrombosis and antithrombotic drugs, anticoagulants, and thrombolytic agents. In addition new agents and future therapeutic directions are nicely covered in a chapter entitled Novelties in Antithrombotic and Thrombolytic Therapy: A Latest Update. The basic pathogenesis of thrombosis is well summarized in introductory chapters that emphasize the interrelationship between cell to cell, molecular, and biochemical interactions as influenced by changes in the deformation of blood flow. There is a fascinating early chapter entitled Interrelationship Between Atherosclerosis and Thrombosis that lends compelling modern scientific support for Duguid's encrustation theory of atherogenesis. The bulk of this book, however, is intensely practical, with solid advice from experts on the management of thrombotic disease. A hallmark is that the opinions are backed by scholarship based on data from sound clinical trials and a thorough understanding of basic and theoretic considerations. The book is well edited. Each editor independently refereed each chapter, most of which were resubmitted in revised form within a 3-month deadline. The entire project was completed within 6 months, and many of the references are within I year of the 1992 publication date. Although there is variation in emphasis and opinion, there is a minimum of overlap and redundancy. There are two reservations. First, the chapter on peripheral arterial disease is disappointing. That it is written by European internists (angiologists) is apparent in the idiomatic phrasing (terminoterminal anastomosis in the aorta for end-to-end anastomosis), occasional misstatements (Streptokinase has been the most widely used agent for peripheral arterial occlusion), and curious misunderstandings (the . . . so-called blue toe syndrome is secondary to obstruction of the microcirculation in patients with essential or secondary thrombocythemia). Although there is useful information to be gleaned from this chapter, most American vascaflar surgeons will find it somewhat rambling and difficult to understand. The second reservation is the paucity of coverage of prethrombotic or hypercoagulable states. Although mentioned in passing in several chapters, the book would benefit from an in-depth chapter on congenital and acquired hypercoagulable syndromes. Despite these reservations this book can be recommended as an up-to-date, authoritative, and scholarly resource on thrombotic disorders. Anyone treating patients with arterial and thromboembolic disease would benefit from owning it; obviously, this includes vascular surgeons.

Disorders of Hemostasis.

This book is the hard-backed version of the January and April 1971 issues of Seminars in Hematology . It contains comprehensive reviews on the pathophysiology of hemostasis, anticoagulant therapy, platelet reactions, management and diagnosis of life-long bleeding disorders, and disseminated intravascular coagulation. Each chapter is written by an authority in the particular area covered. The chapter on platelet reactions by Packham and Mustard is a very comprehensive review. It includes over 300 current references on a difficult and rapidly advancing field and contains many new observations of the authors, some of which have only recently appeared in press. The chapter on the management of thrombotic diseases is written by Douglas, who has had a long experience in this field. He describes a design for a clinical trial of an antithrombotic drug, and as he has been the guiding force of the British trials on the coumarin indanedione drugs, he is eminently

Anticoagulant and Thrombolytic Drugs1 II

Since platelets have a dominant role in the early stages of thrombosis, interference with fibrin formation by anticoagulant drugs can have only a limited place in the prevention or treatment of thrombosis. The precise indications for the use of anticoagulant drugs are not yet defined: there is evidence for their value in the prophylaxis and treatment of deep venous thrombosis and pulmonary embolism, in transient cerebral ischaemic attacks, to prevent emboli in rheumatic heart disease, and in ischaemic heart disease. Sensitivity reactions to the indanedione derivatives are relatively frequent: coumarin derivatives are therefore preferred for oral anticoagulant therapy. Heparin is valuable for the rapid induction of an anticoagulant effect. The place of ancrod is not established, but it holds promise as an agent in the management of thrombotic disease. Most surgical procedures can be carried out in patients under treatment with coumarinindanedione drugs, but heparin must be neutralised if surgery becomes necessary. In pregnancy coumarin-indanedione drugs should probably be avoided and heparin used if anticoagulant therapy is indicated. Breast-feeding should be stopped if oral anticoagulants are required in the post-partum period. Thrombolytic therapy has been used in a wide variety of thrombo-embolic disorders, but adequate evaluation in specific conditions is largely lacking. Disseminated intravascular coagulation presents a wide spectrum of clinical severity: treatment must take account of both the cause and the effects of the process and includes the elimination of the source of coagulant material and, where appropriate, the use of heparin, the replacement of depleted coagulation factors and treatment of the underlying disease. Difficulty in the maintenance of a stable therapeutic level of anticoagulant effect with the coumarin-indanedione derivatives may be due to erratic ingestion of the tablets, intercurrent illness, or the concurrent therapy with drugs which potentiate or decrease the anticoagulant effect of the coumarin drugs. The side-effects of the oral anticoagulant drugs fall into two groups: (i) haemorrhagic side-effects due to over-dosage and (ii) non-haemorrhagic side-effects. Non-haemorrhagic side-effects are rare with coumarin derivatives, but sensitivity reactions to indanedione derivatives are not uncommon and may be severe. Anticoagulant therapy is contra-indicated, unless reliable control can be maintained; in patients who have lesions of the gastrointestinal or renal tracts which are liable to bleed; in patients in whom there is danger of bleeding into the central nervous system (severe hypertension, previous cerebrovascular accident or recent surgery or trauma); and in patients with chronic renal failure.