Genetic risk factors of venous thrombosis

Venous thrombosis, whose main clinical presentations include deep vein thrombosis and pulmonary embolism, represents a major health problem worldwide. Numerous conditions are known to predispose to venous thrombosis and these conditions are commonly referred to as risk indicators or risk factors. Generally accepted or "classically" acquired risk factors for venous thromboembolism include advanced age, prolonged immobilisation, surgery, fractures, use of oral contraceptives and hormone replacement therapy, pregnancy, puerperium, cancer and antiphospholipid syndrome. In addition to these well-established risk factors for venous thrombosis, several lines of evidence that have emerged over the past few decades indicate a role of novel genetic risk factors, mainly related to the haemostatic system, in influencing thrombotic risk. The most significant breakthrough has been the confirmation of the concept that inherited hypercoagulable conditions are present in a large proportion of patients with venous thromboembolic disease. These include mutations in the genes that encode antithrombin, protein C and protein S, and the factor V Leiden and factor II G20210 A mutations. Moreover, plasmatic risk indicators, such as hyperhomocysteinemia and elevated concentrations of factors II, VIII, IX, XI and fibrinogen, have also been documented. This extensive list of genetic and acquired factors serves to illustrate that a single cause of venous thrombosis does not exist and that this condition should be considered as a complex or multifactorial trait. Complex traits can be understood by assuming an interaction between different mutations in candidate susceptibility genes. The risk that is associated with each genetic defect may be relatively low in isolation but the simultaneous presence of several mutations may dramatically increase disease susceptibility. Moreover, environmental factors may interact with one or more genetic variations to add further to the risk. The analysis of genetic risk factors and plasmatic factors, together with private life style and environmental factors, has contributed significantly to our understanding of the genetic predisposition to venous thrombosis.     

Clinical disorders of fibrinolysis: a critical review

Much progress has recently been made in understanding the biochemistry and physiology of endogenous fibrinolysis. As a result, a better understanding of the mechanisms and clinical consequences of disordered fibrinolysis has emerged. Increased fibrinolytic activity is an uncommon but important cause of hemorrhagic disease. Congenital disorders of fibrinolysis which cause bleeding include increased plasma plasminogen activator activity and deficiency of alpha-2 antiplasmin. Acquired disorders associated with increased fibrinolytic activity and bleeding include liver cirrhosis, amyloidosis, acute promyelocytic leukemia, some solid tumors, and certain snake envenomation syndromes. Increased fibrinolysis is important to recognize because epsilon-aminocaproic acid (EACA) may be required to prevent or control bleeding. Diminished fibrinolytic activity has been associated with a variety of thrombotic disorders, but a direct cause-and-effect relationship has yet to be established. Congenital abnormalities of fibrinolysis associated with thrombosis include plasminogen deficiency, decreased endothelial generation of plasminogen activator activity, and certain abnormal fibrinogens. Thrombosis in these disorders is effectively managed with warfarin. Diminished fibrinolysis has also been reported in "idiopathic" venous thrombosis, oral contraceptive-induced and post-operative venous thrombosis, coronary artery disease, cerebrovascular disease, systemic lupus erythematosus, and thrombotic thrombocytopenic purpura, but the significance of abnormal fibrinolysis in these disorders is uncertain. Large, prospective studies of fibrinolytic variables as risk factors for vascular and thrombotic disease are needed to determine whether pharmacologic augmentation of impaired fibrinolysis could be useful in the prevention or treatment of these disorders.     

Brachial Artery Thrombosis in a Covid-19 Positive Patient with Thoracic Outlet Syndrome

Severe coronavirus disease 2019 (COVID-19) has been complicated by coagulopathy and thrombotic events including venous thromboembolism, pulmonary embolism, and arterial thrombus at a rate higher than has traditionally been seen with sepsis-induced coagulopathy or disseminated intravascular coagulation leading most centers to treat hospitalized patients with prophylactic anticoagulation. We present a case of a patient with thoracic outlet syndrome who presents with brachial artery thrombosis in the setting of infection with COVID-19. Both thoracic outlet syndrome and COVID-19 infection are independently associated with increased risk of thrombotic events. The induced hypercoagulable state from COVID-19 infection may result in acute arterial thrombosis in patients with predisposing anatomic differences consistent with thoracic outlet syndrome.Level of Evidence: V     

Pathophysiology of thrombophilic states

The coagulation system can be considered as a balance in which clotting and fibrinolysis have to be in a state of equilibrium. Increased fibrin formation or decreased fibrinolysis can predispose to thromboembolic diseases. Derailments in the clotting system leading to thrombosis center around the regulatory mechanisms, antithrombin III, protein C, protein S and possibly heparin cofactor II. Many cases of congenital or acquired deficiencies or abnormalities or antithrombin III, protein C and S have been described, all predisposing to thrombotic events. Alterations of the fibrinolytic system can also be associated with thromboembolisms. In particular, abnormalities of plasminogen, tissue plasminogen activator release and elevated tissue plasminogen activator inhibitor levels seem to be associated with thromboses. Conceivably also factor XIIa (Hageman factor) and prekallikrein deficiencies, when associated with thrombosis, exert their mechanism through the fibrinolytic system. Finally, about 50% of patients with lupus anticoagulant seem to suffer from thromboembolic disorders. The pathophysiology of this particular association is not known with certainty. Undoubtedly, there will be more disturbances discovered in the hemostasis system that are associated with increased intravascular fibrin formation. The understanding of these derailments is at this time only in its earliest stages of development.     

Thrombosis in pregnancy and maternal outcomes

Pregnancy increases the risk of thrombosis four‐ to five‐fold. Seventy‐five to eighty percent of pregnancy‐related thrombotic events are venous and twenty to –twenty‐five percent are arterial. The main reason for the increased risk is hypercoagulability. Women are hypercoagulable because they have evolved so that they are protected against the bleeding challenges of pregnancy, miscarriage, or childbirth. Both genetic and acquired risk factors can further increase the risk of thrombosis. The maternal consequences of thrombosis of pregnancy include permanent vascular damage, disability, and death. While the maternal outcomes of thrombosis can be modified by anticoagulation therapy, management of thrombosis during pregnancy is the subject of another paper in this issue (see paper by B. Konkle). This review will focus on the epidemiology, pathophysiology, risk factors, and maternal consequences of thrombosis in pregnancy. Birth Defects Research (Part C) 105:159–166, 2015. © 2015 Wiley Periodicals, Inc.     

Familial lupus anticoagulant

The antiphospholipid antibody syndrome (APS) is defined by widespread arterial and venous thromboses associated with elevated plasma levels of antiphospholipid antibodies (APLA). The primary antiphospholipid antibody syndrome (PAPS) appear to be a fairly homogeneous disease, and HLA, family and other studies provide new insights into this cause of thrombosis and vascular disease. We describe two patients with PAPS (lupus anticoagulant positive), whose family members were analyzed for clinical and laboratory abnormalities associated with APS. Familial screening seems to be important, in order to prevent the thrombotic events. Low dose aspirin is the first line treatment in asymptomatic subjects with APLA, previous or present thrombosis requiring long-term, possibly life-long anticoagulation.     

TNFα activation and TGFβ blockage act synergistically for smooth muscle cell calcification in patients with venous thrombosis via TGFβ/ERK pathway

Venous calcification has been observed in post‐thrombotic syndrome (PTS) patients; yet, the cell types and possible mechanisms regulating this process are still unclear. We evaluated the calcium deposition within the venous wall, the cell type involved in the calcified remodelling of the venous wall after thrombosis and explored possible mechanisms in vitro. Calcium deposition was found in human specimens of superficial thrombotic veins and was co‐localized with VSMCs markers αSMA and TAGLN (also known as SM22α). Besides, the expression of osteogenesis‐related genes was dramatically changed in superficial thrombotic veins. Moreover, the inhibition of the TGFβ signalling pathway after TNFα treatment effectively induced the expression of osteogenic phenotype markers, the calcium salt deposits and the obvious phosphorylation of ERK1/2 and JNK2 in the VSMCs calcification model. Supplementing TGFβ2 or blocking the activation of the ERK/MAPK signalling pathway prevented the transformation of VSMCs into osteoblast‐like cells in vitro. Taken together, VSMCs have an important role in venous calcification after thrombosis. Supplementing TGFβ2 or inhibiting the ERK/MAPK signalling pathway can reduce the appearance of VSMCs osteogenic phenotype. Our findings may present a novel therapeutic approach to prevent of vascular calcification after venous thrombosis.     

Postmenopausal hormone replacement therapy and venous thromboembolism

Background:Women taking hormone replacement therapy (HRT) have a 2- to 5-fold increased risk of venous thrombosis compared with nonusers. Increasingly, evidence has suggested that the size of the risk increase varies according to related factors, such as the type of estrogen used, the mode of delivery, and the presence of other predisposing factors.Objective:The aim of this study was to examine the current literature to assess the varying risk of venous thrombosis among women taking HRT.Methods:An extensive search was carried out on all major electronic databases including MEDLINE 1995 to October 2005 and BIS (EMBASE) 1980 to October 2005. Relevant keywords relating to thrombosis (venous thromboembolism, venous thrombosis, deep vein thrombosis, and pulmonary embolism) combined with hormones (hormone replacement therapy and estrogen) were used to capture all potentially relevant studies.Results:The increased risk of a first episode of venous thrombosis in women currently taking HRT compared with nonusers ranged from 1.22 (95% CI, 0.76–1.94) to 4.50 (95% CI, 1.30–15.10). Similar increases in risks for deep vein thrombosis and pulmonary embolism were found. The risk of venous thrombosis is the highest in the first year of therapy, durich which as much as a greater than 6-fold increase was found. Women taking estrogen-progestin HRT had a significantly greater risk of venous thrombosis than those using estrogen-only preparations (odds ratio [OR], 1.60; 95% CI, 1.13–2.26). Studies have also suggested a dose-related effect, suggesting high-dose estrogen therapy is associated with a greater increased risk of venous thrombosis than low-dose preparations. Comparisons between oral and transdermal HRT have shown a significant difference in the relative risk of venous thrombosis (OR, 4.0; 95% CI, 1.9–8.3) favoring the use of transdermal preparations. The presence of thrombophilia, particularly factor V Leiden, further amplifies the risk of venous thrombosis in women using HRT (OR, 13.16; 95% CI, 4.28–40.47). The presence of other risk factors, such as increasing age and being overweight, were all shown to be associated with a further increase in the risk of venous thrombosis.ConclusionsRecent studies have confirmed that current users of HRT are at increased risk of venous thrombosis. The increase in risk has been shown to vary according to duration of use, with the risk being greatest during the first year of use. Moreover, the increased risk varies according to the type of preparation and presence of additional risk factors such as increasing age, obesity, cancer, and recent surgery. Few studies have examined the relationship between thrombophilia, HRT and venous thrombosis; thus, more research is required in this area before accurate estimates of the risk can be made.     

Co-activation of platelets by prolactin or leptin--pathophysiological findings and clinical implications.

Platelet activation is involved in the pathogenesis of atherosclerosis and venous thromboembolism, and might therefore be a possible link between the two entities. Prolactin and leptin have recently been recognized as potent co-activators of ADP-dependent platelet aggregation or P-selectin expression, and are therefore suspected as additional risk factors for both arterial and venous thrombosis. There are clinical situations that have a known association with higher prolactin or leptin levels (pregnancy, obesity or anti-psychotic therapy) and increased risk of thromboembolic events. We compared the impact of both hormones on platelet activation in vitro and in vivo, indicating that prolactin has a stronger effect on platelet activation as leptin in vitro and in vivo. We have also demonstrated that prolactin levels are increased in so called idiopathic thrombosis, and that conversely, patients with prolactinoma have an increased frequency of thrombosis during the hyperprolactinemic state, in a retrospective analysis. Moreover, we have demonstrated increased prolactin values in stroke and myocardial infarction. Prospective studies have yet to be performed to give this theory its final confirmation. The involvement of hormonal factors in platelet aggregation and venous or arterial thrombosis may have important clinical implications such as for risk stratification of patients with venous and arterial thrombosis or new therapeutic options such as decreasing pro-coagulant hormone levels in certain risk situations.     

Portal vein thrombosis and high factor VIII in Turner syndrome

BACKGROUNDS/AIMS: Turner syndrome is not usually associated with thrombotic events. The aim of this study is to report 3 Turner syndrome patients with portal vein thrombosis and, in 2 of them, high factor VIII. These findings are compared to values in Turner syndrome patients without thrombosis and controls. METHODS: In different years, 3 patients with Turner syndrome were initially seen at the Gastroenterology Clinic of Hospital de Clínicas de Porto Alegre, Brazil, for portal vein thrombosis. After the most common causes of portal vein thrombosis and thrombophilias had been excluded, the 2 surviving patients were studied for clotting factors VIII, IX and von Willebrand factor. The same factors were also assessed in 25 Turner syndrome patients without thrombosis and 25 normal girls. RESULTS: One of the patients with portal vein thrombosis died before the study. In the 2 surviving patients, factors VIII and von Willebrand levels were >150 IU/dl, which is considered to be high. In Turner syndrome patients without thrombosis, the mean factor VIII level was 127.2 +/- 41.1 IU/dl and for von Willebrand factor 101.2 +/- 26.9 IU/dl, while in control girls these were 116.0 +/- 27.6 and 94.28 +/- 27.5 IU/dl, respectively. Factor VIII and von Willebrand factor were not different between these 2 groups. When non-O blood group Turner syndrome patients and normal girls were compared, the former had significantly higher levels of factor VIII. CONCLUSIONS: This is the first report on the unusual finding of portal thrombosis in patients with Turner syndrome in whom high levels of factor VIII and von Willebrand factor were found. Factor VIII is higher in the non-O blood group Turner syndrome patients without thrombosis when compared to normal girls.     

Peripheral venous thrombosis in children and adolescents with adipsic hypernatremia secondary to hypothalamic tumors

OBJECTIVE: To determine the clinical presentation and laboratory follow-up in patients with the syndrome of adipsic hypernatremia complicated with a peripheral thrombosis event. METHODS: Report of 3 patients (6-19 years old) with chronic hypernatremia with sustained difficulties to normalize their serum osmolality levels. RESULTS: During post-surgical management the 3 patients developed a peripheral venous thrombotic event as a complication of their chronic hyperosmolality. CONCLUSIONS: Chronic hypernatremia in patients with prolonged immobilization is associated with an increased risk for development of deep venous thrombosis.     

Prevalence of the fibrinogen β‐chain,angiotensin‐converting enzyme and plasminogen activator inhibitor‐1 polymorphisms in Costa Rican young adults with thrombotic disease

Thrombotic disease is a multifactorial condition that involves both classical and genetic risk factors. We studied the association between the classical risk factors of hypertension and smoking, and polymorphisms on the genes of the angiotensin‐converting enzyme (ACE), the β‐chain of fibrinogen (FG), and the plasminogen activator inhibitor‐1 (PAI‐1) in patients with venous and arterial thrombosis. The present investigation is a retrospective case–control study. A total of 340 participants were analyzed, including 162 patients and 178 healthy controls. Hypertension and smoking showed a significant association with thrombotic disease (p < 0.05) but FG level was found significant risk factor only for the venous thrombosis (VT) group (p < 0.04). Significant differences between thrombotic groups were found for the studied polymorphisms of PAI‐1 (p < 0.0014), but for both FG β‐chain gene polymorphisms, none of the molecular analyses showed a positive sample for any mutating allele (p > 0.05). For the ACE polymorphism, the I allele present a protective effect in the general thrombotic group. This is one of the first reports in a Latin‐American population dealing with these molecular markers and thrombotic diseases. Copyright © 2010 John Wiley & Sons, Ltd.     

FXIII polymorphisms, fibrin clot structure and thrombotic risk

Fibrin clot structure is highly dependent on factor XIII activity. Activated FXIII catalyzes the formation of the peptide bonds between the gamma and alpha chains in noncovalently bound fibrin polymers and incorporates various adhesive and antifibrinolytic proteins into the final fibrin clot. In the absence of activated FXIII, clots are unstable and susceptible to fibrinolysis. Several studies have examined the effects of FXIII polymorphisms on final fibrin clot structure and clinical thrombotic risk. The Val34Leu FXIII polymorphism is associated with increased activation by thrombin. In the presence of saturating thrombin concentrations, however, FXIIIa specific enzyme activity is not affected by genetic polymorphisms. Fibrin clots formed in the presence of the FXIII 34Leu polymorphisms do tend to be thinner and less porous, however. The effects of prothrombin concentrations on clot structure have suggested that thinner clots are more resistant to fibrinolysis and associated with increased thrombotic risk. Most clinical studies of 34Leu FXIII carriers, however, have demonstrated a lower incidence of both venous and arterial thrombosis in carriers of the mutant allele compared to Val/Val carriers. One recent study has suggested that the interactions between FXIII phenotype and plasma fibrinogen concentrations significantly influence clinical thrombotic risk.     

Evaluation of lipoprotein(a) as a prothrombotic factor: progress from bench to bedside

PURPOSE OF REVIEW: Since the homology between apolipoprotein(a) (apo(a)) and plasminogen was discovered in 1987, the role of lipoprotein(a) (Lp(a)) as an inhibitor of the normal fibrinolytic role of plasmin(ogen) has been a major research focus. In this review we summarize recent basic research aimed at identifying mechanisms by which Lp(a) can either inhibit fibrinolysis or promote coagulation, as well as recent clinical studies of Lp(a) as a risk factor for thrombosis either in the presence or absence of atherosclerosis. RECENT FINDINGS: It has recently been reported that the inhibition of plasminogen activation by apo(a) results from the interaction of apo(a) with the ternary complex of tissue-type plasminogen activator, plasminogen and fibrin, rather than competition of apo(a) and plasminogen for binding sites on fibrin. Lp(a) species containing smaller apo(a) isoforms bind more avidly to fibrin and are better inhibitors of plasminogen activation. Recent clinical studies have provided strong evidence that Lp(a), either alone or in synergy with other thrombotic risk factors, significantly increases the risk of venous thromboembolism and ischemic stroke. SUMMARY: Lp(a) both attenuates fibrinolysis, through inhibition of plasminogen activation, and promotes coagulation, through alleviation of extrinsic pathway inhibition. Further basic and clinical studies are required to more clearly define the role of Lp(a) in thrombotic disorders, and to determine the extent to which thrombotic risk is dependent on apo(a) isoform size.     

Action of granulopoiesis-stimulating cytokines rhG-CSF, rhGM-CSF, and rmGM-CSF on murine haematopoietic progenitor cells for granulocytes and macrophages (GM-CFC)

The aim of this study was to provide new data to the knowledge of mechanisms by which recombinant human granulocyte colony-stimulating factor (rhG-CSF), recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) and recombinant murine granulocyte-macrophage colony-stimulating factor (rmGM-CSF) enhance the numbers of colonies growing from hematopoietic progenitor cells for granulocytes and macrophages (GM-CFC) in the murine bone marrow. The in vitro technique for cultivating GM-CFC from normal bone marrow cells was used. For evaluation of stimulatory actions of the drugs studied, the factors themselves or sera of mice given these factors were added to the cultures. The factors or the sera were present in the cultures either as the only potentially stimulatory agents or acted jointly with a suboptimum concentration of recombinant murine interleukin-3 (rmIL-3). It was found that both rhG-CSF and rmGM-CSF stimulate the proliferation of GM-CFC by a combination of direct mechanisms (direct actions on the target cells) and indirect effects (effects mediated through the induction of other cytokines and/or growth factors in the murine organism). The rhGM-CSF exhibited somewhat weaker in vitro effects in comparison with the other two factors and only indirect effects were noted. Additional in vivo experiments documented that, in spite of differences in mechanisms of action of the individual drugs studied on murine bone marrow cells in vitro, equal in vivo doses of the factors induce quantitatively similar effects on the production of GM-CFC in vivo.     

Circulating and tissue microRNAs as a potential diagnostic biomarker in patients with thrombotic events

Venous and arterial thrombosis are conditions that have a considerable burden if left untreated. The hypoxia-induced by the occluded vessel can disrupt the circulation of any organ, the cornerstone of treating thrombosis is rapid diagnosis and appropriate treatment. Diagnosis of thrombosis may be made by using laboratory tests or imaging techniques in individuals who have clinical manifestations of a thrombotic event. The use of serum micro ribonucleic acids (RNAs) has recently been applied to the diagnosis of thrombosis. These small RNA molecules are emerging as new diagnostic markers but have had very limited applications in vascular disease. Most of the articles provided various microRNAs with different levels of accuracy. However, there remains a lack of an appropriate panel of the most specific microRNA in the literature. The purpose of the present review was to summarize the existing data on the use of microRNAs as a diagnostic biomarker for venous thrombosis.     

Higher risk of venous thrombosis associated with drospirenone-containing oral contraceptives: a population-based cohort study

Background:

Combined oral contraceptives are a common method of contraception, but they carry a risk of venous and arterial thrombosis. We assessed whether use of drospirenone was associated with an increase in thrombotic risk relative to third-generation combined oral contraceptives.

Methods:

Using computerized records of the largest health care provider in Israel, we identified all women aged 12 to 50 years for whom combined oral contraceptives had been dispensed between Jan. 1, 2002, and Dec. 31, 2008. We followed the cohort until 2009. We used Poisson regression models to estimate the crude and adjusted rate ratios for risk factors for venous thrombotic events (specifically deep vein thrombosis and pulmonary embolism) and arterial thromboic events (specifically transient ischemic attack and cerebrovascular accident). We performed multivariable analyses to compare types of contraceptives, with adjustment for the various risk factors.

Results:

We identified a total of 1017 (0.24%) venous and arterial thrombotic events among 431 223 use episodes during 819 749 woman-years of follow-up (6.33 venous events and 6.10 arterial events per 10 000 woman-years). In a multivariable model, use of drospirenone carried an increased risk of venous thrombotic events, relative to both third-generation combined oral contraceptives (rate ratio [RR] 1.43, 95% confidence interval [CI] 1.15–1.78) and second-generation combined oral contraceptives (RR 1.65, 95% CI 1.02–2.65). There was no increase in the risk of arterial thrombosis with drospirenone.

Interpretation:

Use of drospirenone-containing oral contraceptives was associated with an increased risk of deep vein thrombosis and pulmonary embolism, but not transient ischemic attack or cerebrovascular attack, relative to second- and third-generation combined oral contraceptives.Oral hormonal therapy is the preferred method of contraception, especially among young women. In the United States in 2002, 12 million women were using “the pill.”¹ In a survey of households in Great Britain conducted in 2005 and 2006, one-quarter of women aged 16 to 49 years of age were using this form of contraception.² A large variety of combined oral contraceptive preparations are available, differing in terms of estrogen dose and in terms of the dose and type of the progestin component. Among preparations currently in use, the estrogen dose ranges from 15 to 35 μg, and the progestins are second-generation, third-generation or newer. The second-generation progestins (levonorgestrel and norgestrel), which are derivatives of testosterone, have differing degrees of androgenic and estrogenic activities. The structure of these agents was modified to reduce the androgenic activity, thus producing the third-generation progestins (desogestrel, gestodene and norgestimate). Newer progestins are chlormadinone acetate, a derivative of progesterone, and drospirenone, an analogue of the aldosterone antagonist spironolactone having antimineralo-corticoid and antiandrogenic activities. Drospirenone is promoted as causing less weight gain and edema than other forms of oral contraceptives, but few well-designed studies have compared the minor adverse effects of these drugs.³The use of oral contraceptives has been reported to confer an increased risk of venous and arterial thrombotic events,^4–7 specifically an absolute risk of venous thrombosis of 6.29 per 10 000 woman-years, compared with 3.01 per 10 000 woman-years among nonusers.⁸ It has long been accepted that there is a dose–response relationship between estrogen and the risk of venous thrombotic events. Reducing the estrogen dose from 50 μg to 20–30 μg has reduced the risk.⁹ Studies published since the mid-1990s have suggested a greater risk of venous thrombotic events with third-generation oral contraceptives than with second-generation formulations,^10–13 indicating that the risk is also progestin-dependent. The pathophysiological mechanism of the risk with different progestins is unknown. A twofold increase in the risk of arterial events (specifically ischemic stroke^6,14 and myocardial infarction⁷) has been observed in case–control studies for users of second-generation pills and possibly also third-generation preparations.^7,14Conflicting information is available regarding the risk of venous and arterial thrombotic events associated with drospirenone. An increased risk of venous thromboembolism, relative to second-generation pills, has been reported recently,^8,15,16 whereas two manufacturer-sponsored studies claimed no increase in risk.^17,18 In the study reported here, we investigated the risk of venous and arterial thrombotic events among users of various oral contraceptives in a large population-based cohort.     

Computational modeling of blood component transport related to coronary artery thrombosis in Kawasaki disease

Coronary artery thrombosis is the major risk associated with Kawasaki disease (KD). Long-term management of KD patients with persistent aneurysms requires a thrombotic risk assessment and clinical decisions regarding the administration of anticoagulation therapy. Computational fluid dynamics has demonstrated that abnormal KD coronary artery hemodynamics can be associated with thrombosis. However, the underlying mechanisms of clot formation are not yet fully understood. Here we present a new model incorporating data from patient-specific simulated velocity fields to track platelet activation and accumulation. We use a system of Reaction-Advection-Diffusion equations solved with a stabilized finite element method to describe the evolution of non-activated platelets and activated platelet concentrations [AP], local concentrations of adenosine diphosphate (ADP) and poly-phosphate (PolyP). The activation of platelets is modeled as a function of shear-rate exposure and local concentration of agonists. We compared the distribution of activated platelets in a healthy coronary case and six cases with coronary artery aneurysms caused by KD, including three with confirmed thrombosis. Results show spatial correlation between regions of higher concentration of activated platelets and the reported location of the clot, suggesting predictive capabilities of this model towards identifying regions at high risk for thrombosis. Also, the concentration levels of ADP and PolyP in cases with confirmed thrombosis are higher than the reported critical values associated with platelet aggregation (ADP) and activation of the intrinsic coagulation pathway (PolyP). These findings suggest the potential initiation of a coagulation pathway even in the absence of an extrinsic factor. Finally, computational simulations show that in regions of flow stagnation, biochemical activation, as a result of local agonist concentration, is dominant. Identifying the leading factors to a pro-coagulant environment in each case—mechanical or biochemical—could help define improved strategies for thrombosis prevention tailored for each patient.     

Genetics of arterial prothrombotic risk states

Coronary artery disease is a leading cause of death worldwide and the largest killer of men and women in the United States. The pathophysiology of myocardial infarction is multifactorial, and numerous physiologic systems converge to dictate the formation of the two fundamental lesions, thrombosis and atherosclerosis. In this review we address genetic aspects of arterial thrombosis and the key thrombotic factors that have been associated with the increased risk for its development. Specifically, we consider components of coagulation, fibrinolysis, and platelet adhesive receptors, and we review the genetic epidemiology and in vitro laboratory data regarding their risk for the acute coronary syndromes. In combination with traditional risk factor assessment, in the near future these inherited markers can be used to manage patients with vascular disease through a better utilization of invasive or expensive diagnostic testing, as well as pharmacologic intervention.     

24-Hour Assessment of Performance on a Palmtop Computer: Validating a Self-Constructed Test Battery

Serious adverse cardiovascular events, including myocardial infarction, sudden cardiac death, and stroke, frequently result from rupture of atherosclerotic plaques with superimposed thrombosis and exhibit a pronounced circadian rhythmicity, peaking in the morning hours. Two potentially synergistic mechanisms play a pathogenic role in the circadian variation of arterial thrombotic events. A morning surge in sympathetic activity alters hemodynamic forces and predisposes vulnerable coronary atherosclerotic plaques to rupture. Day–night variations of hemostatic and fibrinolytic factors result in morning hypercoagulability and hypofibrinolysis, promoting intraluminal thrombus formation at the same time when the risk for plaque rupture is highest. Diabetic patients have a very high cardiac event rate but fail to show normal circadian fluctuations in the occurrence of myocardial infarction. Alterations in the circadian variation autonomic tone, blood pressure, and the thrombotic–thrombolytic equilibrium have been documented in diabetic patients. These include reduced or absent 24-h periodicity in autonomic tone, fibrinolytic activity, and thrombotic tendency, and a blunted decline in nocturnal blood pressure. Disruption of these circadian rhythms explains the lack of significant circadian distribution of cardiac events in diabetic patients. Moreover, the loss of these normal biorhythms results in a continuous susceptibility to thrombotic events throughout the day and may contribute to the excess cardiovascular mortality and morbidity in these patients. (Chronobiology International, 18(1), 109–121, 2001)