What Happened to Baby Jane What Happens When Autophagia Is Left Untreated
Haemostasis and thrombosis are complex, multifactorial processes. There is an evolving understanding of the mechanisms influencing vascular occlusion and the function of inflammation and immunity. Despite major advances in elucidating the mechanistic pathways mediating platelet function and thrombosis, challenges in the treatment of vascular occlusive diseases persist. Pharmacological advances have greatly affected thrombotic outcomes, but this has led to the unwanted side result of bleeding. Detailed assessment of the touch on of non-thrombotic diseases on haemostasis and thrombosis is necessary to better evaluate thrombotic risk and found optimal handling. This review will focus on contempo advances in agreement the contribution of evolving chance factors to thrombosis.
Introduction
Middle disease is the leading cause of death in many developed countries and approximately 50% of all deaths associated with cancerous neoplasms are due to thrombotic events. Damage to and extravasation of blood from the vascular circulatory system commonly occurs throughout life. Haemostasis is the process that maintains the regulation of vascular integrity and blood flow. Normal haemostasis may be overwhelmed by pathological factors, leading to uncontrolled clot formation and vessel occlusion in either the arteries or veins. Platelets, together with endothelial cells and circulating coagulation proteins, are crucial mediators of vascular haemostasis and thrombosis.
Arterial thrombosis is the cause of myocardial infarction (MI) and stroke, while venous thrombosis (VT) leads to venous thromboembolism (VTE) and pulmonary embolism (PE). Structurally, arterial and venous thrombi are distinct. Arterial thrombi are rich in platelets and course at the sides of or around ruptured atherosclerotic plaques. Venous thrombi are rich in fibrin and red claret cells and may occur despite an intact endothelial wall. Finally, arterial thrombosis occurs at places of high shear flow while VT occurs in the setting of wearisome shear menstruation (Figure 1).
Figure 1
Major differences between arterial and venous thrombosis. (A) Arterial thrombosis occurs under high shear flow when platelet rich thrombi are formed effectually ruptured atherosclerotic plaques and damaged endothelium. (B) Venous thrombosis occurs under low shear catamenia and mostly effectually intact endothelial wall. Venous thrombi are fibrin rich, encapsulating a big corporeality of red blood cells in addition to activated platelets.
Figure 1
Major differences between arterial and venous thrombosis. (A) Arterial thrombosis occurs nether high shear flow when platelet rich thrombi are formed around ruptured atherosclerotic plaques and damaged endothelium. (B) Venous thrombosis occurs under low shear flow and mostly effectually intact endothelial wall. Venous thrombi are fibrin rich, encapsulating a large amount of carmine blood cells in addition to activated platelets.
Two major mechanisms mediate vascular homeostasis and thrombosis depending on vascular harm or vessel construction. one One is mediated by collagen and the other is tissue gene (TF) dependent. During normal haemostasis, damage to the endothelial cell layer may occur and collagen from the subendothelial infinite is exposed. Platelets, through their glycoproteins (GP) GPVI and GPIb/V/9, collaborate with collagen and von Willebrand gene (vWF). Collagen exposure leads to platelet adhesion and germination of a platelet monolayer. Platelets form a iii-dimensional structure past aggregating through their activated GPIIb/IIIa (αIIbβ3) integrins. Activated platelets recruit other circulating platelets by secreting aggregatory mediators such as thromboxane A2, ADP, 2 ultra-large vWF (ulvWF) multimers and serotonin equally well every bit past producing thrombin (Figure ii). Deeper tissue damage leads to release of TF from smooth muscle, adventitial cells, and pericytes. TF mediates the conversion of pro-thrombin to thrombin, fibrin generation, and activation of the clotting cascade one (Figure two). Endothelial cells play a major function in thrombus propagation control and its subsequent resolution.
Figure 2
Mechanisms of platelet-mediated thrombosis. (A) Collagen-mediated platelet thrombus germination occurs when subendothelial collagen becomes exposed to the circulation. Platelets, through their glycoproteins, interact with collagen and collagen-deposited vWF, change their shape and adhere to the site of injury. The zipper leads to secretion of ADP, serotonin and thromboxane (TxA2) leading to the recruitment and activation of more platelets. Activated platelets release thrombin (IIa) leading to platelet aggregation and three-dimensional jell germination. In certain instances, damage to the vessel may extend beyond the endothelium into the adventitial layer. In those instances, thrombosis is mediated through (B) Tissue factor (TF). Agile TF is expressed by smooth muscle and adventitial cells and is able to generate thrombin (IIa). TF-generated thrombin, in turn, activates platelets, fibrin generation and the coagulation cascade to form a thrombus. Of note, circulating active TF may also exist secreted by monocytes and is present in tumor-secreted microparticles. (C) Platelet thrombosis mediated by ultra large vWF multimers (ULvWF). Endothelial cells activated by high shear stress and/or epinephrine secrete large multimers of vWF forming strings that grab and crosslink platelets to the surface of the morphologically intact endothelium. The contact between the ULvWF and GPIb leads to platelet activation. Similarly as in (A). adherent platelets release ADP and TxA2 which pb to activation of more platelets and ultimately three-dimensional jell formation and retraction. (D) Neutrophil extracellular trap (Internet)-mediated platelet thrombosis. In the presence of pathogens, platelets and neutrophils collaborate to form NETs that are highly thrombotic and resistant to tissue plasminogen activator-mediated fibrinolysis. By and large, the size of a thrombus formation is regulated by limiting the level of clot propagation. The endothelium plays a major function by expressing certain thrombo-regulators (NO, prostacyclins, and CD39-ectonucleotidase) that preclude the clot from spreading. Clots are resolved past initiation of fibrinolysis through generation of plasmin from plasminogen and breakdown of fibrin. Depending on the vessel in which the jell forms, the thrombus can be platelet-rich (white clots, class in arteries) or fibrin- and scarlet blood prison cell-rich (red clots, form in veins). Each step in thrombus formation tin can atomic number 82 to uncontrolled clot formation that can result in arterial or venous thrombosis, ultimately presenting a risk for MI, stroke or VTE.
Figure 2
Mechanisms of platelet-mediated thrombosis. (A) Collagen-mediated platelet thrombus formation occurs when subendothelial collagen becomes exposed to the circulation. Platelets, through their glycoproteins, collaborate with collagen and collagen-deposited vWF, modify their shape and adhere to the site of injury. The attachment leads to secretion of ADP, serotonin and thromboxane (TxA2) leading to the recruitment and activation of more than platelets. Activated platelets release thrombin (IIa) leading to platelet assemblage and 3-dimensional jell formation. In certain instances, impairment to the vessel may extend across the endothelium into the adventitial layer. In those instances, thrombosis is mediated through (B) Tissue gene (TF). Active TF is expressed by smooth musculus and adventitial cells and is able to generate thrombin (IIa). TF-generated thrombin, in turn, activates platelets, fibrin generation and the coagulation cascade to class a thrombus. Of note, circulating active TF may too be secreted past monocytes and is present in tumor-secreted microparticles. (C) Platelet thrombosis mediated by ultra large vWF multimers (ULvWF). Endothelial cells activated by high shear stress and/or epinephrine secrete large multimers of vWF forming strings that catch and crosslink platelets to the surface of the morphologically intact endothelium. The contact between the ULvWF and GPIb leads to platelet activation. Similarly equally in (A). adherent platelets release ADP and TxA2 which lead to activation of more platelets and ultimately three-dimensional clot formation and retraction. (D) Neutrophil extracellular trap (Cyberspace)-mediated platelet thrombosis. In the presence of pathogens, platelets and neutrophils collaborate to form NETs that are highly thrombotic and resistant to tissue plasminogen activator-mediated fibrinolysis. Generally, the size of a thrombus formation is regulated by limiting the level of jell propagation. The endothelium plays a major role by expressing certain thrombo-regulators (NO, prostacyclins, and CD39-ectonucleotidase) that preclude the jell from spreading. Clots are resolved by initiation of fibrinolysis through generation of plasmin from plasminogen and breakdown of fibrin. Depending on the vessel in which the clot forms, the thrombus tin can be platelet-rich (white clots, form in arteries) or fibrin- and cherry blood cell-rich (red clots, course in veins). Each step in thrombus formation tin atomic number 82 to uncontrolled clot formation that can result in arterial or venous thrombosis, ultimately presenting a risk for MI, stroke or VTE.
Arterial thrombosis
Mechanism of activation
Arterial thrombosis results from clot formation in the setting of atherosclerotic plaque rupture, leading to platelet aggregation, thrombus germination, vessel occlusion and possible MI or ischemic stroke. Thus, arterial thrombi are treated with therapies that target platelet activation and assemblage (Effigy ane). In recent years, in that location has been an increase in the prevalence of angina and no obstructive coronary artery illness (ANOCA) or MI and not-obstructed coronary arteries (MINOCA). The underlining mechanism or optimal antithrombotic therapies are unclear, notwithstanding it has been proposed that in these cases arterial thrombosis occurs in the absenteeism of plaque rapture.
Pathophysiologically, thrombus formation has been linked to the secretion of poly peptide disulfide isomerases (PDI, ERp5, ERp57) by platelets and activated endothelial cells. 1 PDIs can react with nitric oxide (NO) and reactive oxygen species (ROS) contributing to the initiation of thrombus formation. 1 , three PDIs are known to contribute to thrombus formation by activating TF and increasing generation of fibrin. 3 In add-on, PDI role is essential for platelet assemblage iv and regulates the rapid increase in thrombin production on the surface of activated platelets. five
Healthy arterial endothelial cells limit thrombosis by releasing NO and prostacyclins leading to control of clot size. Endothelial cells besides express CD39, an enzyme that hydrolyzes ADP to AMP. This process of ADP elimination prevents further pro-thrombotic platelet activation. In addition to CD39, endothelial cells express CD73, an enzyme that converts AMP to adenosine. Adenosine, in plough, limits thrombosis past blocking platelet activation and acting as an anti-inflammatory mediator through its receptors. half dozen Endothelial cells located effectually atherosclerotic lesions lose their ability to regulate thrombotic propagation due to compromised release of NO and prostacyclin. vii , eight
Established and evolving run a risk factors for arterial thrombosis
Various factors increase the take a chance of developing arterial thrombosis. Classically, the risk factors implicated in thrombosis take been hypertension, high levels of low-density lipoprotein (LDL)-cholesterol, and smoking. However, diabetes, pregnancy, age, chemotherapeutics, infectious burden, man immunodeficiency virus (HIV) and high vWF in plasma also pose a risk. Recently, studies study boosted run a risk factors that may contribute to thrombosis. Low activity of ADAMTS13, an enzyme that cleaves vWF multimers, was associated with an increased hazard of ischemic stroke and improved the accuracy of risk predictions for ischemic stroke beyond traditional risk factors. 9 Stillbirth and loss of multiple pregnancies increment the risk of ischemic stroke and MI. 10 A big retrospective cohort study showed an association between VT /anticoagulation therapy and the risk for arterial thrombosis (in ∼1.5% of all patients). 11
Systemic lupus erythematosus (SLE) is at present a well-recognized risk for thrombosis. The incidence of thrombosis in patients with SLE is 25–fifty-fold college than in the full general population. In patients with contempo onset of SLE, the incidence rate for thrombosis is 31/1000 patients per year. Hazard for VT in SLE patients is higher than for arterial thrombosis and it is mostly contained from lupus anticoagulant therapy. 12 Arterial (two.4%) and VT(three.half dozen%) are also increased in paediatric patients with SLE. 13 Factors contributing to thrombosis in this paediatric population are vasculitis, avascular necrosis, or antiphospholipid antibody. 13
Hormone therapy (HT) is also known to be associated with increased risk of both arterial (MI and stroke) and VT, particularly, in the first years of therapy. 14 , 15 The origin for thrombosis in this case is multifactorial. A contempo cross-exclusive study of 2787 post-menopausal women on HT suggests that elevated levels of estradiol and sex hormone binding globulin were associated with elevated levels of C-reactive poly peptide (CRP) and lower levels of TF pathway inhibitor, both of which contribute to the prothrombotic events in HT users. xvi
Hereditary thrombophilia is another risk factor associated with a slight increment in gamble of arterial thromboembolism. Presence of cardiovascular risk factors such as diabetes mellitus, notwithstanding, may lead to stronger take a chance clan between thrombophilia and arterial thrombosis. It would be beneficial to establish the thrombophilia risk in populations with high prevalence of traditional cardiovascular gamble factors. 17
Venous thrombosis
Mechanism of activation
The mechanisms mediating VT are distinct and venous thrombi contain an affluence of reddish claret cells and fibrin in improver to platelets (Figure 1) and are typically treated with drugs targeting proteins mediating coagulation. The residue between blood period and composition together with venous endothelial health must be altered for a venous jell to form. Venous thrombi are not tightly adherent to the endothelium and can hands dislodge, leading to distant vessel occlusive disease such as PE.
Mechanistically, it has been proposed that the venous endothelium offset becomes activated and, as a result of inflammation, surface selectin expression increases 18 and autophagy regulates vWF secretion. 19 Endothelial activation causes attachment of platelets and leukocytes. Attached leukocytes become activated and initiate expression of TF that, in plow, activates the coagulation cascade. The protective anticoagulant effect of the endothelial surface is negated by depression blood menses. 18 Low blood menses may lead to hypoxic weather that are described to increment the expression of endothelial adhesion molecules and consequent attachment of leukocytes. More contempo studies have shown that red blood cells play a office clot germination. 20 Erythrocytes in the jell change shape from double concave to polyhedral allowing for tight packaging and resistance to fibrinolysis. twenty
Established and evolving risk factors for venous thrombosis
An array of different factors contributes to the hazard of VT. Information technology is notable that women and men of all ages, races, and ethnicities are at take a chance for VTE. Age and obesity are important risk factors for VTE and, after the age of 40, the risk for VTE doubles with each decade of life. Prior episodes of VTE and atherothrombosis as well contribute to the increased risk. A recent report demonstrated that MI is associated with an increased adventure of transient VTE and PE contained of traditional atherosclerotic take a chance factors. 21
Fibrin degradation products, equally measured past plasma D-dimer levels are associated with acute VTE. The concentration of D-dimer remains increased in VTE patients even later treatment. College basal level of plasma D-dimer is a stiff, long-term take a chance marker for first VTE. 22
An increment in oestrogen levels due to pregnancy, obesity, or, oral contraceptive use is as well a chance factor for VTE. Elevated levels of oestrogen pb to a rise in coagulation factors which are crucial to prevent claret loss during child birth but concomitantly increase take chances for deep vein thrombosis (DVT). eighteen The take chances is further increased in overweight or obese women who use oral contraceptives. 18 Similarly, the take a chance for cognitive VT (CVT) was associated with an increased body mass alphabetize (BMI). 23 The dose-dependent association between BMI and CVT was not found in women who did non take oral contraceptives. 23 Multiple pregnancies and older maternal age are risk factors for VTE. Immobility due to bed balance, long distance travel or surgery is associated with a higher gamble of VTE.
Anaemia may be an of import risk factor for CVT. A stronger clan between anaemia and CVT was found in men every bit compared to women and haemoglobin was inversely associated with CVT. 24 It has been suggested that endothelial hypoxia may be responsible for the increased VT. xviii
Advanced stages of cancer likewise as chemotherapy treatment are also associated with increased chance for VTE. Cancer patients have an approximately iv-fold increased risk of VTE as compared with the general population, and cancer patients with VTE take reduced survival. This VTE hazard is notable for pancreatic and cerebral cancer followed by stomach and float cancer. 25 Certain haematological malignancies such as acute leukaemia are also associated with a high incidence of VTE. 26 Evidence shows that TF-containing microvesicles secreted past cancerous tissues are able to actuate platelets via thrombin and lead to increased coagulability and VTE. 27 The process could be further complicated past increases in platelet and leukocyte number, soluble P-selectin, and D-dimer all contributing to platelet pro-thrombotic properties and VTE. 28
In add-on to ecology and acquired risk factors, there are particular genetic mutations that also increase the take a chance for VTE. A classic instance is Factor 5 Leiden mutation that leads to hypercoagulability. This detail variation leads to the inability of activated poly peptide C to dethrone and inactivate factor V. Other genetic adventure factors that increase risk for VTE are mutations in prothrombin (G20210A) and fibrinogen (C10034T) 18 and mutations in proteins mediating anticoagulation. The last are mutations in antithrombin, protein C and protein S. In addition, non-O blood types accept also been associated with increased take chances for VTE. 29 The mechanism by which these blood group increases VTE risk is non well understood; however, information technology has been proposed that people with blood groups unlike than O accept higher levels of factor VIII, protein C, and vWF. 29
Using meta-analyses and genome-wide association studies (GWAS), new mutations have been suggested to increment thrombotic gamble. An alanine to cytosine mutation (A1298C) in the methylenetetrahydrofolate reductase (MTHFR) factor is associated with DVT. 30 The 4G/5G polymorphism in the plasminogen activator inhibitor (PAI-1, responsible for fibrinolysis) is associated with increased risk of DVT 30 and coronary artery affliction risk. 31 Recently, trauma exposure and mail-traumatic stress disorder accept also been linked to MI and stroke in women and lead to a two-fold increased risk for VTE. 32
Hateful platelet volume and thrombosis
Equally previously discussed, platelets vary in size. Large platelets are more than reactive, take greater prothrombotic potential, and are more resistant to inhibition with aspirin and clopidogrel (P2Y12). Big platelets are presumed to be immature and their number increases when in that location is a rise in factors affecting platelet turnover. Recent studies take shown that elevated mean platelet book (MPV) is associated with increased risk for DVT and MI. A meta-analysis of cohort-studies suggests that MPV might be a useful prognostic mark in patients with cardiovascular affliction (CVD). Elevated MPV in these analyses was significantly higher in patients with acute MI and or coronary angioplasty. 33 Elevated MPV is besides identified as a predictor for VTE, peculiarly VTE of unprovoked origin. 34
Trends in anti-thrombotic and -coagulant therapies
Although beyond the telescopic of this review, at that place has been not bad progress in the development of antithrombotic therapies for the treatment of acute and chronic CVD, atrial fibrillation, and VT. For decades aspirin, the irreversible inhibitor of platelet cyclooxygenase activity, has provided constructive secondary prevention of arterial thromboembolic events for a wide range of arterial occlusive diseases with recent data also suggesting a role in venous disease. 35 P2Y12 inhibitors are valuable treatment options for many patients. Adjunctive antiplatelet or anticoagulant therapies, such as the PAR-1 inhibitor, vorapaxar, or the FXa inhibitor, rivaroxaban, respectively, have also been recently introduced. The machinery backside rivaroxaban benefit in acute coronary syndrome (ACS) is not articulate, as rivaroxaban does non interfere with platelet activation by classical agonists (Brodde and Kehrel, unpublished).
Adherence to the European Society of Cardiology guidelines on antithrombotic management has led to significantly meliorate outcomes of cardiovascular events, including those related to bloodshed and bleeding. 36 Additionally, the apply of clinical tools that consider both patient genetics and prove-based medicine have led to meliorate clinical outcomes, peculiarly when using anticoagulants. Unfortunately, there are no long-term risk assessment tools that can aid the prevention of reoccurring events in patients with previous MI. 37
Emerging mechanisms: pathogens, immunothrombosis, and platelets
There is rising and convincing evidence that diverse pathogenic infections pose significant risk for thrombosis that includes arterial thrombosis, VTE, and atherosclerosis. 38–40 In response to claret borne pathogens and tissue harm at that place is a coordinated intravascular coagulation recently termed 'immunothrombosis'. 41 This allows platelets and allowed cells to form a concrete barrier of confinement to prevent dissemination of pathogens and to activate the allowed organisation. 41 Platelets, in turn, conduct the transcripts for all pathogen responsive toll-like receptors. 42 During certain bacterial infections, platelets are able to induce prothrombotic events, secrete cytokines, chemokines, and antimicrobial peptides, leading to sequestration and destruction of bacteria. 2 Platelets are also known to engulf certain viruses such every bit HIV, hepatitis C virus (HCV) and encephalomyocarditis (EMCV) 43 and to interact with bacteria such as Staphylococcus aureus 44 and Staphylococcus pneumoniae. 45
Viruses such every bit HIV, HCV, and Dengue are also known to cause elevated levels of thrombosis. It is unclear if the thrombosis during viral infections is reactive or if it serves a like function as in bacterial infections. Immune cells predominantly contribute to prothrombotic risk during immunothrombosis. Monocytes are known to carry the pro-coagulant TF and microvesicles with activated TF are observed during flu infection. 46 Neutrophils, in turn, are able to release their Deoxyribonucleic acid forming highly prothrombotic neutrophil extracellular traps (NETs) in a process chosen netosis. The released Deoxyribonucleic acid enables neutrophils to trap and neutralize bacteria and to mediate the upshot of viral infection with poxvirus. 47 Although the process of netosis is beneficial for a successful immune response, it is as well a highly prothrombotic process. NETs are known to increment thrombin levels, activate platelets and coagulation. 48 Further, netosis significantly increases the adventure for DVT. 48 Elevated levels of DNA and chromatin in the circulation are independently associated with severe atherosclerosis and thrombosis. 49 Clots removed from the coronary arteries of patients with ST-superlative ACS prove that neutrophils undergo netosis at the culprit lesion site. Coronary Internet brunt and DNase activity are shown to be predictors of myocardial infarct size. fifty Thus, immunothrombosis may exist an efficient fashion of enabling the immune system to fight diverse infections; nonetheless, it significantly contributes to thrombosis and the overall cardiovascular burden.
Thrombosis and platelets: future implications
Despite major advances in understanding the mechanistic pathways of platelet function and the interaction of coagulation and thrombosis, challenges in the treatment of vascular occlusive diseases continue to persist. This is due to the complication of these various diseases and the impact of immunological and inflammatory processes on haemostasis and thrombosis. All the same, the growing understanding of these processes is also opening up new avenues for the use of antithrombotics. Despite the successful development of new classes of drugs, there is a cracking-unmet clinical need for developing more effective and prophylactic antithrombotic agents. These drugs may incorporate important mechanistic platelet and coagulation-based discoveries, while others will utilise targets established by traditional herbal medicines (Tabular array 2). Additionally, pharmacological advances accept greatly impacted thrombotic outcomes but accept led to the unwanted side effect of bleeding. Compounding this issue is the lack of articulate biomarkers to rest risk and do good of treatments, peculiarly when used in combination. Future studies are necessary to evaluate the balance of thrombotic chance, affect of non-vascular diseases, progressive treatments and side effects.
Table 1
Summary of updated hazard factors for arterial or venous thrombosis
| Arterial thrombosis-adventure factors | Venous thrombosis-take chances factors | ||
|---|---|---|---|
| Atderosclerosis 51 | Hypertension 51 | Age 51 | Obesity 51 |
| LDL 51 | Smoking 51 | Atherothrombotic events 51 | Prior VTE episodes 51 |
| Chemotherapeutics 51 | Diabetes 51 | Non-O blood type 29 | Oestrogen 18 |
| Infections 39 , 40 | Pregnancy/multiple pregnancies 10 | Pregnancy/multiple pregnancies x | Oral contraceptives eighteen , 51 |
| Thrombophilia 17 | SLE 12 , 13 | Older maternal age 51 | Immobility/long distance travel 51 |
| Stillbirth 10 | Hormone therapy 14 , 15 , 18 | Anaemia 24 | Cancer/chemotherapy 24–28 |
| Low levels of ADAMTS13 9 | MPV 33 | PTSD 32 MPV 34 | Mutations in Factor V (Leiden), prothrombin and fibrinogen 18 , 51 |
| Arterial thrombosis-risk factors | Venous thrombosis-risk factors | ||
|---|---|---|---|
| Atderosclerosis 51 | Hypertension 51 | Historic period 51 | Obesity 51 |
| LDL 51 | Smoking 51 | Atherothrombotic events 51 | Prior VTE episodes 51 |
| Chemotherapeutics 51 | Diabetes 51 | Non-O blood type 29 | Oestrogen 18 |
| Infections 39 , xl | Pregnancy/multiple pregnancies ten | Pregnancy/multiple pregnancies 10 | Oral contraceptives xviii , 51 |
| Thrombophilia 17 | SLE 12 , 13 | Older maternal historic period 51 | Immobility/long altitude travel 51 |
| Stillbirth 10 | Hormone therapy 14 , fifteen , 18 | Anaemia 24 | Cancer/chemotherapy 24–28 |
| Low levels of ADAMTS13 9 | MPV 33 | PTSD 32 MPV 34 | Mutations in Gene 5 (Leiden), prothrombin and fibrinogen 18 , 51 |
PTSD, post-traumatic stress disorder; MPV, mean platelet volume; VTE, venous thromboembolism; LDL, depression-density lipoprotein; SLE, Systemic lupus erythematosus; ADAMTS13, a disintegrin and metalloproteinase with a thrombospondin blazon 1 motif, member xiii.
Table 1
Summary of updated risk factors for arterial or venous thrombosis
| Arterial thrombosis-risk factors | Venous thrombosis-risk factors | ||
|---|---|---|---|
| Atderosclerosis 51 | Hypertension 51 | Age 51 | Obesity 51 |
| LDL 51 | Smoking 51 | Atherothrombotic events 51 | Prior VTE episodes 51 |
| Chemotherapeutics 51 | Diabetes 51 | Not-O claret type 29 | Oestrogen 18 |
| Infections 39 , 40 | Pregnancy/multiple pregnancies x | Pregnancy/multiple pregnancies 10 | Oral contraceptives eighteen , 51 |
| Thrombophilia 17 | SLE 12 , thirteen | Older maternal age 51 | Immobility/long distance travel 51 |
| Stillbirth 10 | Hormone therapy xiv , 15 , 18 | Anaemia 24 | Cancer/chemotherapy 24–28 |
| Low levels of ADAMTS13 9 | MPV 33 | PTSD 32 MPV 34 | Mutations in Factor V (Leiden), prothrombin and fibrinogen 18 , 51 |
| Arterial thrombosis-risk factors | Venous thrombosis-adventure factors | ||
|---|---|---|---|
| Atderosclerosis 51 | Hypertension 51 | Historic period 51 | Obesity 51 |
| LDL 51 | Smoking 51 | Atherothrombotic events 51 | Prior VTE episodes 51 |
| Chemotherapeutics 51 | Diabetes 51 | Non-O blood type 29 | Oestrogen 18 |
| Infections 39 , 40 | Pregnancy/multiple pregnancies 10 | Pregnancy/multiple pregnancies 10 | Oral contraceptives 18 , 51 |
| Thrombophilia 17 | SLE 12 , 13 | Older maternal age 51 | Immobility/long distance travel 51 |
| Stillbirth 10 | Hormone therapy xiv , 15 , eighteen | Anaemia 24 | Cancer/chemotherapy 24–28 |
| Low levels of ADAMTS13 ix | MPV 33 | PTSD 32 MPV 34 | Mutations in Cistron Five (Leiden), prothrombin and fibrinogen 18 , 51 |
PTSD, mail service-traumatic stress disorder; MPV, mean platelet volume; VTE, venous thromboembolism; LDL, low-density lipoprotein; SLE, Systemic lupus erythematosus; ADAMTS13, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13.
Table 2
Existing and novel antithrombotic agents in use and under evolution
| Antithrombotic agents | Specific Class | Subclasses/Specific Therapies |
|---|---|---|
| Platelet Inhibitors | P2Y12 Receptor Blockade |
|
| Glycoprotein IIb/IIIa inhibition |
| |
| Cyclooxygenase inhibition | Aspirin | |
| Thrombin Receptor Antagonists (PAR-1) |
| |
| Phosphodiesterase II inhibitor | Cilostazol | |
| Adenosine uptake blockade | Dipyridamole | |
| Anticoagulants | Vitamin Thousand Antagonists |
|
| Antithrombin III activation |
| |
| Synthetic pentasaccharide inhibitors of cistron Xa |
| |
| Thrombin inhibitor | Dabigatran | |
| Factor Xa inhibitor |
| |
| Novel Antithrombotic and Antiplatelet Targets | Synergistic inhibition of P2Y1 and P2Y12 ADP Receptors | |
| Immunotherapy |
| |
| Platelet Inhibitors: Targets of tumor-metastasis | Aspirin | |
| Platelet Inhibitors: Targets of tumor-metastasis | Platelet-derived exosomes | |
| Nucleotide based inhibitors | ||
| Second generation selective thrombin inhibitors | ||
| Alternative 2nd generation GPIIb/IIIa oral inhibitors | ||
| Medicinal herbals |
|
| Antithrombotic agents | Specific Class | Subclasses/Specific Therapies |
|---|---|---|
| Platelet Inhibitors | P2Y12 Receptor Blockade |
|
| Glycoprotein IIb/IIIa inhibition |
| |
| Cyclooxygenase inhibition | Aspirin | |
| Thrombin Receptor Antagonists (PAR-1) |
| |
| Phosphodiesterase II inhibitor | Cilostazol | |
| Adenosine uptake blockade | Dipyridamole | |
| Anticoagulants | Vitamin K Antagonists |
|
| Antithrombin 3 activation |
| |
| Synthetic pentasaccharide inhibitors of cistron Xa |
| |
| Thrombin inhibitor | Dabigatran | |
| Cistron Xa inhibitor |
| |
| Novel Antithrombotic and Antiplatelet Targets | Synergistic inhibition of P2Y1 and P2Y12 ADP Receptors | |
| Immunotherapy |
| |
| Platelet Inhibitors: Targets of tumor-metastasis | Aspirin | |
| Platelet Inhibitors: Targets of tumor-metastasis | Platelet-derived exosomes | |
| Nucleotide based inhibitors | ||
| Second generation selective thrombin inhibitors | ||
| Alternative 2nd generation GPIIb/IIIa oral inhibitors | ||
| Medicinal herbals |
|
Table 2
Existing and novel antithrombotic agents in use and under development
| Antithrombotic agents | Specific Class | Subclasses/Specific Therapies |
|---|---|---|
| Platelet Inhibitors | P2Y12 Receptor Blockade |
|
| Glycoprotein IIb/IIIa inhibition |
| |
| Cyclooxygenase inhibition | Aspirin | |
| Thrombin Receptor Antagonists (PAR-one) |
| |
| Phosphodiesterase II inhibitor | Cilostazol | |
| Adenosine uptake blockade | Dipyridamole | |
| Anticoagulants | Vitamin Thousand Antagonists |
|
| Antithrombin III activation |
| |
| Synthetic pentasaccharide inhibitors of factor Xa |
| |
| Thrombin inhibitor | Dabigatran | |
| Factor Xa inhibitor |
| |
| Novel Antithrombotic and Antiplatelet Targets | Synergistic inhibition of P2Y1 and P2Y12 ADP Receptors | |
| Immunotherapy |
| |
| Platelet Inhibitors: Targets of tumor-metastasis | Aspirin | |
| Platelet Inhibitors: Targets of tumor-metastasis | Platelet-derived exosomes | |
| Nucleotide based inhibitors | ||
| Second generation selective thrombin inhibitors | ||
| Alternative iind generation GPIIb/IIIa oral inhibitors | ||
| Medicinal herbals |
|
| Antithrombotic agents | Specific Class | Subclasses/Specific Therapies |
|---|---|---|
| Platelet Inhibitors | P2Y12 Receptor Blockade |
|
| Glycoprotein IIb/IIIa inhibition |
| |
| Cyclooxygenase inhibition | Aspirin | |
| Thrombin Receptor Antagonists (PAR-i) |
| |
| Phosphodiesterase II inhibitor | Cilostazol | |
| Adenosine uptake blockade | Dipyridamole | |
| Anticoagulants | Vitamin K Antagonists |
|
| Antithrombin 3 activation |
| |
| Constructed pentasaccharide inhibitors of factor Xa |
| |
| Thrombin inhibitor | Dabigatran | |
| Factor Xa inhibitor |
| |
| Novel Antithrombotic and Antiplatelet Targets | Synergistic inhibition of P2Y1 and P2Y12 ADP Receptors | |
| Immunotherapy |
| |
| Platelet Inhibitors: Targets of tumor-metastasis | Aspirin | |
| Platelet Inhibitors: Targets of tumor-metastasis | Platelet-derived exosomes | |
| Nucleotide based inhibitors | ||
| Second generation selective thrombin inhibitors | ||
| Alternative 2nd generation GPIIb/IIIa oral inhibitors | ||
| Medicinal herbals |
|
The authors do hereby declare that all illustrations and figures in the manuscript are entirely original and exercise not require reprint permission.
Acknowledgements
We repent to all whose work was not cited due to limited space and limited number of citations. This work was supported by National Institute of Health grant U01HL126495 (to J.E.F.) and by American Heart Association grant 16SDG30450001 (to M.G.).
Conflict of involvement: none declared.
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What Happened to Baby Jane What Happens When Autophagia Is Left Untreated
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Comments
1 Comment
Drug induced thrombosis or platelets abnormalities
13 July 2017
champion.seb@wanadoo.fr
Réanimation, clinique de Parly 2, Ramsay Générale de Santé, 21 rue Moxouris, 78150 Le Chesnay, France.
Drug induced thrombosis or platelets abnormalities
I would like to give thanks the authors for shedding lite on a topic cardiologists may not be friendly with, and for emphasizing a detail facet very common in the intensive intendance unit (ICU), but under reported in their article. The ICU is a complex setting in which many hemostasis aspects may exist profoundly disturbed. Accordingly, mutual procedures induce obvious perturbations including blood transfusions constantly associated with increased thrombosis risk. Many drugs may induce thrombosis, including only not restricted to vitamin Chiliad,1 erythropoietin,two activated or inactivated prothrombin circuitous concentrates… Some drugs are associated with more subtle platelet activation, such as adrenaline and dobutamine.3,4 There is business organization that other unremarkably prescribed drugs may exist associated with clinically relevant venous thrombosis and increased long term mortality, such as antipsychotics.5 When evaluating individual thrombosis hazard, one should carefully appraise treatments administered. This is especially truthful in the ICU were patients are more prone to thrombosis and receive multiple drugs.
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Financial Disclosures: None
Conflicts of Interest: None
Funding: none
Acknowledgement: none
Submitted on 13/07/2017 3:52 PM GMT