Thrombotic Predisposition Research Articles

A Genetical approach to deep venous thrombosis

Deep venous thrombosis (DVT) is a common disorder that frequently occurs after surgical procedures and trauma and in the presence of cancer or immobilization conditions. However, it can also develop without any of these predisposing factors. This condition directs the researcher's enquiry to investigating the basis of organismal thrombotic predisposition. The common prothrombotic genetic mutations include factor V Leiden, factor II G20210 A, plasminogen activator inhibitor-1, prothrombin A20210, and factor XIII - VIII. Nevertheless, current studies suggest that the thrombotic events are not connected with single gene deletion or homeostatic regulation is also affected by other genetic risk factors. Complex interactions of genetic mutations can be affects different levels of thrombotic system or reinforce each other's effects on homeostatic mechanisms. The analysis of literature, together with the action mechanisms of the classic genetical factors and new suggestions, may contribute significantly to our understanding of the genetic predisposition to venous thrombosis.

The surgical application of point-of-care haemostasis and platelet function testing

Disordered coagulation complicates many diseases and their treatments, often predisposing to haemorrhage. Conversely, patients with cardiovascular disease who demonstrate antiplatelet resistance may be at increased thromboembolic risk. Prompt identification of these patients facilitates optimization of haemostatic dysfunction. Point-of-care (POC) tests are performed 'near patient' to provide a rapid assessment of haemostasis and platelet function. This article reviews situations in which POC tests may guide surgical practice. Their limitations and potential developments are discussed. The paper is based on a Medline and PubMed search for English language articles on POC haemostasis and platelet function testing in surgical practice. POC tests identifying perioperative bleeding tendency are already widely used in cardiovascular and hepatic surgery. They are associated with reduced blood loss and transfusion requirements. POC tests to identify thrombotic predisposition are able to determine antiplatelet resistance, predicting thromboembolic risk. So far, however, these tests remain research tools. POC haemostasis testing is a growing field in surgical practice. Such testing can be correlated with improved clinical outcome.

Phenylephrine-Induced Microvascular Occlusion Syndrome in a Patient With a Heterozygous Factor V Leiden Mutation

Cutaneous microvascular occlusion syndromes (MOS) present with noninflammatory retiform purpura with variable outcomes that are dependent on the severity, duration, and specific underlying cause. Transient cases are often associated with few sequelae, while severe forms such as symmetrical peripheral gangrene may be associated with amputation and death. A middle-aged man developed MOS after exposure to phenylephrine hydrochloride and experienced complete resolution when treatment with the vasopressor was discontinued. Further evaluation detected a previously subclinical heterozygous factor V Leiden mutation. We propose that phenylephrine-mediated vasoconstriction superimposed on an underlying thrombotic predisposition precipitated the transient MOS. The role of vasopressors in the development of cutaneous MOS is well documented in the critical care literature; however, it is underrepresented in the dermatologic literature, and, to our knowledge, there are no reports of phenylephrine use inducing MOS. We hope to raise awareness of the potential role of vasopressor medications in causing MOS.

P-selectin glycoprotein ligand-1 VNTR polymorphisms and risk of thrombosis in the antiphospholipid syndrome

Objectives:Antiphospholipid antibodies (aPLA) have been shown to enhance thrombus formation by increasing the expression of adhesive receptors such as P-selectin on endothelial cells. The P-selectin counter-receptor on leucocytes is P-selectin...

Inflammation and coagulation

Inflammation is associated with thrombotic predisposition in patients. The mechanisms by which inflammation contributes to the thrombosis involve both humoral and cellular changes. Inflammation impacts all phases of blood coagulation: initiation, propagation and the inhibition. Inflammatory mediators like endotoxin and tumor necrosis factor alpha induce expression of tissue factor on blood cells, particularly monocytes. Tissue factor then triggers the initiation of coagulation. Normally, negatively charged membrane surfaces are limiting so that even if some activated coagulation factors are generated, they fail to propagate coagulation. C reactive protein, an acute phase reactant, levels increase in response to inflammation. The C reactive protein can then induce tissue factor formation. Complement membrane attack complex provides a potent stimulus for cells to express negatively charged phospholipid on their out membrane leaflet. Alternatively, exposure to collagen in combination with thrombin provides a potent stimulus to platelets eliciting the formation of microparticles and the subsequent exposure of negatively charged phospholipid membrane surfaces that can propagate coagulation. Even when these two events both occur to augment coagulation, potent natural anticoagulant mechanisms limit the thrombotic response. Inflammatory mediators, however, can depress these potent natural anticoagulant mechanisms. Of the natural anticoagulants, the protein C pathway is one of the systems down regulated by inflammation. Thrombomodulin and the endothelial cell protein C receptor are both required for optimal protein C activation in response to thrombin generation. In severe inflammatory situations, both proteins are down regulated resulting in a decreased anticoagulant response. Furthermore, free protein S levels often decrease, further impairing the pathway. In immune mediated inflammatory disease, the pathway may also be down regulated. Some anti-phospholipid antibodies severely impair the protein C pathway. Clinically relevant thrombosis is minimized naturally either by inhibiting the blood clotting or by rapid lysis of the blood clot or both. In addition to shifting the hemostatic balance in favor of clot formation, inflammation elevates plasminogen activator inhibitor levels resulting in decreased fibrinolytic activity. Procoagulant impacts of inflammation are also expressed at the cellular level. Interleukin 6 can increase platelet numbers and their responsiveness to agonists like thrombin. All of these events tend to shift the hemostatic balance in favor of clot formation.

P0574 LONG TERM FOLLOW UP OF CONGENITAL DISORDERS OF GLYCOSYLATION TYPE I OR CDG I SYNDROME

Introduction: Congenital disoders of glycosylation (CDG), or carbohydrate deficient glycoprotein syndromes, form a rapidly growing group of autosomal recessive inherited disorders characterised by defects affecting the glycosylation of proteins. Fourteen CDG are identified, the most frequent is CDG Ia due to a defect in phosphomannomutase. Most CDG Ia are multisystem diseases that include severe brain involvement, early failure to thrive and feeding difficulties. Methods: We report the clinical, biological and molecular analysis of a CDG Ia patient detected by western blotting of serum glycoproteins at age 19. He was the first child of unrelated parents and was born in 1980. At age 1 month, he presented with generalised oedema, diarrhoea which started at the first feeding and anorexia. Neonatal hypotonia, nystagmus, psychomotor retardation were also present as well as inverted nipples, facial dysmorphia and lipodystrophia. Weight was 4.9kg and height 62 cm at age 7 months. Seizures started during the second year of life. At age 16, he developed a thrombosis of the left external iliac artery and the left lower limb. At age 23, he is on anormal diet, has no diarrhoea and his liver function is normal. He is unable to walk without support and receives daily heparin, phenobarbital and valproic acid. Results: Hypoproteinemia <45g/l and hypoalbuminemia were attributed to protein losing enteropathy and lymphangiectasy at 1 month of age and persisted during the first 2 years. Transaminases were elevated and severe portal fibrosis was seen on a liver biopsy at age 1. Thrombocytopenia is permanent. Coagulopathy was noted at 2 months and 10 years: PTT 25%, TCK 180, factor IX 7%. The level of antithrombin III is <5%. Cerebellar atrophy was detected on CT scan at age 2 years. Phosphomannose activity is severely decreased: 0.5 U/g prot (N>3.4). Mutation analysis of the PMM gene identified 2 mutations on the maternal allele (P20S and IVS1 + 1G->T) and a different mutation on the paternal allele (I132T). Conclusion: It is concluded that CDG Ia is a multisystem disease with severe gastrointestinal and hepatic manifestations during the first years of life. After childhood, CDG Ia has no longer digestive symptoms and becomes a non-progressive neurologic disease with peripheral neuropathy, mental retardation and seizures and a thrombotic predisposition due to decreased levels of major coagulation inhibitors, particularly as a result of impaired glycosylation of antithrombin III. A study of ten French adolescents and adult patients with CDG I is ongoing in Paris and coordinated by N Seta.

Prothrombin Gene Variants in Non-Caucasians with Fetal Loss and Intrauterine Growth Retardation

Thrombotic predisposition may affect pregnancy outcome, but in non-Caucasians the contributing genetic factors are poorly characterized. Two recently identified prothrombin gene mutations (20209C>T and 20221C>T) have been observed in non-Caucasian patients with thrombosis. The mutations are located near the commonly identified variant 20210G>A and have not been reported in Caucasian patients. The authors report a novel connection with pregnancy complications. The identification of sequence variants other than 20210G>A in the 3'-untranslated region of the prothrombin gene suggests that additional nucleotide substitutions may contribute to the development of thrombotic events and adverse pregnancy outcomes, especially in less well-characterized populations.

Preanalytical Variables in the Coagulation Laboratory

Though cardiovascular disease remains the most common cause of death in Western countries, significant progress has been made in the management of it during the past 2 decades. Increased use of anticoagulant therapy has played an important role in the improved outlook for patients with occlusive arterial or venous thromboembolic disease. However, while anticoagulant drugs reduce a patient’s risk of heart attack and stroke by making the blood less clottable, this same effect increases the patient’s risk of hemorrhage. This necessitates laboratory monitoring of the patient’s response to these drugs on an ongoing basis. For instance, of the approximately 300 million coagulation tests performed annually in the United States, more than 40 million are prothrombin times (PT) performed for monitoring of warfarin therapy. While monitoring of anticoagulant therapy may have the most immediate impact on patient management and outcome, clinicians also rely heavily on the accuracy of screening and diagnostic PT and activated partial thromboplastin time (APTT) tests; platelet function studies; work-ups to identify inherited thrombotic predisposition; and measurement of coagulation factors and inhibitors, D-dimer, and other coagulation analytes. Because of the significantly improved instrumentation and highly sensitive reagents available in modern coagulation laboratories, preanalytical variability now represents the most important source of errors that can lead to inaccurate patient results, patient mismanagement, and preventable hemorrhagic or thrombotic complications. This article will review the importance of the quality and integrity of the coagulation sample for the accuracy and precision of patient test results, and discuss approaches to improve coagulation laboratory performance by controlling preanalytical variability.

Increased Fragmentation of von Willebrand Factor, Due to Abnormal Cleavage of the Subunit, Parallels Disease Activity in Recurrent Hemolytic Uremic Syndrome and Thrombotic Thrombocytopenic Purpura and Discloses Predisposition in Families

We investigated here the changes in von Willebrand factor (vWF) multimers in recurrent, sporadic and familial forms of hemolytic uremic syndrome (HUS)/thrombotic thrombocytopenic purpura (TTP) to see whether they are actually proteolyzed in vivo in these patients. Molecular determinants of fragments in vWF were also characterized to identify possible sites of cleavage of the subunit. Unusually large vWF multimers were found in blood of 8 of 10 patients with recurrent HUS/TTP, both in the acute phase and in remission, but never in familial and sporadic cases. Instead, all of the groups showed evidence of enhanced fragmentation of vWF multimers during the acute phase. Increased fragmentation was also shown by decrease in native 225-kD vWF subunit. In recurrent and sporadic HUS/TTP, enhanced fragmentation normalized at remission, but the abnormality persisted in familial HUS/TTP patients. The latter findings suggest that patients with familial HUS/TTP may have a congenital abnormality in vWF processing. Analysis with specific monoclonal antibodies showed the presence of the normal vWF fragments with apparent molecular mass of 189, 176, and 140 kD in all patients; however, in 6 recurrent and in 5 familial cases, novel fragments that differed in size from normal ones were found. The size of these abnormal fragments differed from one patient to another and none of them was ever found in normal plasma. These results documented, for the first time in HUS/TTP, an abnormal cleavage of the vWF subunit that might account for the increased fragmentation observed in these patients.

Association of osteonecrosis in systemic lupus erythematosus with abnormalities of fibrinolysis.

Patients with systemic lupus erythematosus (SLE) are at an increased risk of developing osteonecrosis (ON). Twenty-six patients with SLE were studied. Fifteen of these had ON and 11 did not. The latter were used as control subjects. Various coagulation analytes including antithrombin III (ATIII) activity, protein C activity, protein S activity, alpha 2-antiplasmin activity, anticardiolipin antibodies (aCL), plasminogen activator inhibitor (PAI-1) activity and tissue type plasminogen activator (tPA) antigen were measured using citrated plasma samples from the patients. A significant proportion (80%) of patients had at least one laboratory abnormality that has been associated with a thrombotic predisposition. ON was significantly associated with elevated levels of PAI-1 activity; it was also associated with elevated PAI-1/tPA ratio. There was no association between ON of SLE and abnormalities of the other measured coagulation analytes. These results suggest that defective fibrinolysis seems to be operative in the pathogenesis of ON associated with SLE. The defect appears to involve an imbalance between tPA and its inhibitor, PAI-1. This imbalance could represent an important risk factor in the pathogenesis of ON.

2 Congenital thrombophilia

The heritable defects which are at present accepted as proven to be associated with familial venous thrombosis are deficiency of antithrombin (AT), protein C (PC) or protein S (PS) and the FV Leiden mutation. In women from symptomatic kindred each of these defects is associated with increased risk of pregnancy-associated venous thrombosis and increased risk of fetal loss and other vascular complications of pregnancy. The risks appear to be greatest for some types of AT deficiency. These defects are very common but there is growing evidence that congenital thrombophilia is a multigene defect and abnormalities of AT or of the PC-PS system represent only part of the genetic thrombotic predisposition in symptomatic families. Currently it seems reasonable to focus resources on women with AT or PC-PS system abnormalities who are themselves already symptomatic or who come from symptomatic families rather than screen whole populations for these defects. In symptomatic families screening of females around the time of puberty allows time for education and counselling. Pregnancies should be planned, and each pregnancy in each patient managed individually. In general though, women with AT deficiency from symptomatic families require anticoagulant prophylaxis throughout pregnancy and for at least 3 months post-partum, whereas those with PC-PS system defects may require third-trimester plus post-partum prophylaxis or post-partum anticoagulant prophylaxis only.

Thrombotic tendencies and correlation with clinical status in patients infected with HIV.

Previous publications have described thrombotic events with unclear causes in individuals infected with the human immunodeficiency virus (HIV). We stratified the cases of 52 individuals infected with HIV by degree of immunosuppression and the presence of complicating illnesses. Plasma from these individuals was screened for abnormalities that might predispose to thromboses. We found statistically significant differences between patients with CD4 counts < 200/mm3 and those whose CD4 counts were > 400/mm3 in the following: d-dimers, functional protein C, antigenic protein C, total protein S antigen, free protein S antigen, C4b-binding protein (C4b-BP), and von Willebrand antigen (vWD). Free protein S correlated inversely with C4b-BP; vWD directly with total protein S; and protein C inversely with d-dimers. D-dimers were significantly elevated only in immunosuppressed patients with complicating neoplastic/inflammatory disease. We propose that low-grade disseminated intravascular coagulopathy in severely immunosuppressed individuals with HIV and infectious, inflammatory, or neoplastic complications is responsible for depressed protein C, which, together with elevations in total protein S and vWD (markers of endothelial injury), indicates a thrombotic predisposition.

Hemostatic studies in patients with carbohydrate-deficient glycoprotein syndrome

The carbohydrate deficient glycoprotein(CDG) syndrome is a newly described disorder characterized by impaired glycosylated molecules. It has been reported that transient stroke-like episodes appear in half of the patients. We performed hemostatic studies on three CDG syndrome patients belonging to two unrelated families. The most characteristic findings were decreases in antithrombin III(AT III), protein C and α 2 plasmin inhibitor to nearly half normal levels. Protein S was reduced in two(siblings) patients. Isoelectric focusing of AT III in native plasma revealed decreased intensity of the major band and increased intensity of a minor cathodal band. These minor AT III molecules were considered to lack an oligosaccharide sidechain. A 12-year-old girl defective not only for AT III but also protein C and protein S developed disseminated intravascular coagulation accompanied by arterial thrombosis in her left hand following dyspnea associated with bronchial asthma. These findings suggest that thrombotic predisposition in patients with CDG syndrome is due to decreased levels of major coagulation inhibitors, particularly as a result of impaired glycosylation of AT III.

Antiphospholipid Antibodies and Thrombotic Predisposition: Underlying Pathogenetic Mechanisms

Antiphospholipid Antibodies and Thrombotic Predisposition: Underlying Pathogenetic Mechanisms

Antiphospholipid antibodies and thrombotic predisposition: underlying pathogenetic mechanisms [editorial; comment

Antiphospholipid antibodies and thrombotic predisposition: underlying pathogenetic mechanisms [editorial; comment

Catastrophic thrombosis of porcine aortic bioprostheses

Hemodynamically critical thrombotic stenosis of porcine bioprosthetic valves in the aortic position without thrombotic predisposition is rare. Two patients at our institution abruptly manifested thrombotic stenosis of porcine bioprosthetic valves in the aortic position within 3 months of implantation without apparent predisposing factors. Clinicians should consider this rare but catastrophic complication in the appropriate setting.