Polymorphism of platelet glycoprotein IIb and risk of thrombosis and restenosis after coronary stent placement

Both glycoprotein (GP) IIb and IIIa of platelet fibrinogen receptor are polymorphic proteins. Unlike GPIIIa, there is little information about the clinical significance of the GPIIb polymorphism. We designed this prospective study to assess whether patients with the human platelet antigen (HPA)-3 polymorphism of GPIIb are more susceptible to developing thrombosis and restenosis after coronary stent placement. We included 2,178 consecutive patients with coronary artery disease who underwent intracoronary stent implantation, 789 (36.2%) with HPA-3a/a, 1,023 (47.0%) with HPA-3a/b, and 366 (16.8%) with HPA-3b/b genotype. The incidence of stent thrombosis was 1.7% in HPA-3a/a, 1.7% in HPA-3a/b, and 1.6% in HPA-3b/b patients (p = 0.999). The incidence of stent restenosis was 37.3% in HPA-3a/a, 36.2% in HPA-3a/b, and 34.6% in HPA-3b/b patients (p = 0.724). Event-free survival 1 year after stent placement was 76.1% for HPA-3a/a, 76.5% for HPA-3a/b, and 76.4% for HPA-3b/b patients (p = 0.968). We conclude that the HPA-3 polymorphism of platelet GPIIb is not associated with an increase in the risk of thrombosis and restenosis over 1 year after coronary stent placement. These data indicate that unlike the HPA-1 polymorphism of GPIIIa, the HPA-3 polymorphism of GPIIb may not serve as a useful genetic marker for the risk assessment of patients treated with intracoronary stenting.     

The platelet P2 receptors in arterial thrombosis

ADP and ATP play a crucial role in hemostasis and thrombosis and their receptors are potential targets for antithrombotic drugs. The ATP-gated channel P2X1 and the two G protein-coupled P2Y1 and P2Y12 ADP receptors selectively contribute to platelet aggregation. Due to its central role in the formation and stabilization of a thrombus, the P2Y12 receptor is a well established target of antithrombotic drugs like clopidogrel which has proved efficacious in many clinical trials and experimental models of thrombosis. Competitive P2Y12 antagonists have also been shown to be effective in experimental thrombosis as well as in several clinical trials. Studies in P2Y1 and P2X1 knock-out mice and experimental thrombosis models using selective P2Y1 and P2X1 antagonists have shown that, depending on the conditions, these receptors could also be potential targets for new antithrombotic drugs. Since both P2X1 and P2Y1 receptor inhibition result in milder prolongation of the bleeding time as compared to P2Y12 inhibition, the idea is put forward that combination of P2 receptor antagonists could improve efficacy with diminished hemorrhagic risk. However, further studies are required to validate such a point of view.     

von Willebrand factor and factor VIII as risk factors for arterial and venous thrombosis

Since the early 1990s attempts have been made to elucidate whether high concentrations of von Willebrand factor (VWF) and factor VIII (FVIII) in plasma are associated with an increased risk of thrombosis. Several prospective studies on the role of VWF in arterial thrombosis, mainly coronary heart disease, were performed in healthy individuals and patients with previous cardiovascular disease. Although the majority showed an association between high VWF levels and arterial thrombosis, others failed to confirm such findings. A smaller number of studies have evaluated FVIII, mainly for its association with venous thrombosis. Two prospective observations, together with several case-control studies, provided solid evidence of an association between high FVIII levels and a first or recurrent episode of venous thrombosis. On the whole, high levels of VWF and FVIII in plasma confer a moderately high risk of arterial and venous thrombosis, respectively. These findings have no therapeutic implication, but they should be taken into account in the assessment of the individual risk profile.     

Platelet glycoprotein polymorphisms as risk factors for thrombosis

Both blood platelets and genetics contribute to the development of acute ischemic arterial diseases. A careful analysis of the various clinical association studies supports a modest increased risk for coronary artery disease events in carriers of the PIA2 polymorphism of GPIIIa. Investigations with both platelets and stable cells lines have shown the PIA2 polymorphism is prothrombotic. Only a handful of studies have been performed for platelet GPla (integrin alpha2) and GPIb-IX-V, but there is support for the 807 T/C polymorphism of GPIa and the met145 and VNTR B/C genotype of GPIbalpha as risk factors in younger age groups. And isolated reports suggest other platelet polymorphisms (GPIIb, FcgammaRIIa, P-selectin, alpha2 adrenergic receptor, transforming growth factor [TGF]beta) are risk factors for arterial disease or produce a prothrombotic phenotype. Platelet glycoprotein polymorphisms should be added to the list of genetic risk factors for arterial thrombosis, particularly in younger patients and women.     

Hypofibrinolysis is a risk factor for arterial thrombosis at young age

The relationship between defective fibrinolysis and arterial thrombosis is uncertain. The evaluation of the plasma fibrinolytic potential might provide stronger evidence linking fibrinolysis to arterial thrombosis than the evaluation of the individual fibrinolytic factors. We determined the plasma fibrinolytic potential of 335 young survivors of a first arterial thrombosis, including coronary artery disease ( n  = 198), ischaemic stroke ( n  = 103) and peripheral artery disease ( n  = 34), enrolled in a population-based case–control study and of 330 healthy individuals. Patients had significantly higher clot lysis times (CLTs) than the controls. Odds ratios (ORs) were calculated as a measure of relative risk. The OR for arterial thrombosis was determined in these subjects who had a CLT above the 60th, 70th, 80th, 90th and 95th percentiles of the values found in the control subjects. We found a progressive increase in risk of arterial thrombosis in subjects with hypofibrinolysis (OR: 1·7, 2·0, 2·3, 2·3 and 2·9, respectively). Relative risk estimates obtained in the whole group were comparable those obtained in the event-subgroups. In conclusion, a low plasma fibrinolytic potential, found in 10% of the population, increases the relative risk of arterial thrombosis twofold. This points to an important contribution of hypofibrinolysis to the burden of arterial thrombosis.     

Hyperhomocysteinemia: a risk factor for arterial and venous thrombosis]

Homocysteine is a sulfur-containing amino acid intermediate involved in two metabolic pathways, in the remethylation to methionine and in the transsulfuration to cysteine. Severe hyperhomocysteinemia (> 100 mumol/l) is found in congenital homocystinuria. Moderate (15-30 mumol/l) or intermediate (> 30-100 mumol/l) hyperhomocysteinemia is caused by defects in genes encoding for enzymes of homocysteine metabolism or by inadequate intake of those vitamins that are involved in homocysteine metabolism (folic acid, cobalmin, and vitamin B6). Today, hyperhomocysteinemia should be considered an important risk factor for atherosclerotic vascular and venous thromboembolic diseases. Homocysteine-plasma levels above the 95th percentile were found to be associated with a 2 to 3-fold elevated relative risk for deep-vein thrombosis and pulmonary embolism. Moreover, mild hyperhomocysteinemia has been shown to be associated with a 2 to 4-fold increased relative risk for coronary artery disease, cerebrovascular disease, and peripheral arterial occlusive disease. Several mechanisms have been proposed by which hyperhomocysteinemia contributes to atherogenesis and thrombogenesis. Several studies have shown that hyperhomocysteinemia can be corrected by supplementation of folic acid, cobalamin and vitamin B6. Clinical trials are urgently needed which investigate the preventive effect of supplementation of these vitamins on thrombotic diseases.     

Minor injuries as a risk factor for venous thrombosis

BACKGROUND: Injuries increase the risk of venous thrombosis. So far, most research has focused on major injuries that are accompanied by other risk factors for venous thrombosis, such as plaster casts and surgery. We studied the association of venous thrombosis with common minor injuries, such as minor sural muscle ruptures and ankle sprains. METHODS: We performed a large, population-based, case-control study (the Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis [MEGA] study), including consecutive patients with a first deep venous thrombosis of the leg or pulmonary embolism and control subjects. Participants with malignant neoplasms, those who underwent surgery, and those who had a plaster cast or extended bed rest were excluded. RESULTS: Of 2471 patients, 289 (11.7%), and of 3534 controls, 154 (4.4%) had a minor injury in the 3 months preceding the venous thrombosis (patients) or completion of the questionnaire (controls). Venous thrombosis was associated with previous minor injury (odds ratio adjusted for sex and age, 3.1; 95% confidence interval, 2.5-3.8). The association was strongest for injuries that occurred in the 4 weeks before thrombosis and was not apparent before 10 weeks. Thrombosis was more strongly associated with minor injuries located in the leg (odds ratio adjusted for sex and age, 5.1; 95% confidence interval, 3.9-6.7), while those located in other body parts were not associated. A 50-fold increased risk was found in factor V Leiden carriers with a leg injury compared with noncarriers without injury (odds ratio, 49.7; 95% confidence interval, 6.8-362.7). CONCLUSIONS: Minor injuries in the leg are associated with greater risk of venous thrombosis. Because minor injuries are common, they could be major contributors to the occurrence of venous thrombosis.     

The influence of platelet glycoprotein polymorphisms on receptor function and risk for thrombosis

With regard to hemostasis and thrombosis, collagens are among the most important physiologic components of the extracellular matrix in their role as platelet activators. Differences in the rate of platelet activation markedly influence normal hemostasis and the pathological outcome of thrombosis. Thus, collagen receptors, such as the integrin alpha2beta1 and indirectly, GPIb alpha, represent a relatively unexploited target of pharmacological control and are only recently becoming appreciated as potential factors in the generic risk for thrombosis. In general, the importance platelet glycoprotein polymorphisms as genetic risk factors for arterial thrombosis is a new area of human genomics that needs to be carefully addressed. Discrepancies in the degree to which they are reported to contribute to risk for clinical thrombosis will only be resolved once there is a universal standard for clinical study design. Most of the clinical studies differ by patient population size, ethnicity, bias in the selection of patients and controls, plurality in clinical endpoints and variation of environmental factors. Despite these differences, there is substantial evidence that the integrin beta3 PlA2 haplotype, the GPIb alpha Met145 haplotype, the GPIb alpha -5C haplotype and the integrin alpha2 haplotype 1 (807T) each contribute to the risk for and morbidity of thrombotic disease. There may remain dispute as to the extent of their contribution. However, well-designed, large, prospective, genetic and epidemiologic studies are needed to clarify the role of these and other platelet receptor polymorphisms. Most importantly, the cumulative effects of multiple platelet and plasma glycoproteins SNPs to thrombotic risk must be evaluated concurrently. Additional in vitro studies of the functional relevance underlying these polymorphisms are needed to provide a sound biological explanation for the results of clinical correlations. The opportunity now exists to make significant inroads into the development of strategies for the prevention of thrombotic disease.     

Role of Kozak sequence polymorphism of platelet glycoprotein Ibalpha as a risk factor for coronary artery disease and catheter interventions

OBJECTIVES: We sought to determine the role of the -5T/C polymorphism of the platelet glycoprotein (GP) Ibalpha as a potential risk factor for coronary artery disease (CAD) and adverse events complicating a coronary catheter intervention. BACKGROUND: The platelet GP Ib-IX-V receptor complex plays a crucial role in arterial thrombus formation. The -5T/C polymorphism of GP Ibalpha is associated with increased receptor density. METHODS: We genotyped 1,000 patients with angiographically confirmed CAD, as well as 1,000 age- and gender-matched control subjects, for this polymorphism by polymerase chain reaction/restriction fragment length polymorphism. Among the patients with CAD, 269 underwent percutaneous transluminal coronary angioplasty (PTCA), 103 underwent directional coronary atherectomy and 278 underwent stenting. This intervention group was followed for a 30-day composite end point of target vessel revascularization, myocardial infarction or death. RESULTS: Carriers of the -5C allele were significantly over-represented in the group of patients developing acute coronary syndromes (relative risk [RR] 1.43, 95% confidence interval [CI] 1.05 to 1.95, p = 0.02). The -5C allele furthermore predicted an increased risk for developing complications after PTCA (RR 3.75, 95% CI 1.15 to 12.27, p = 0.029). CONCLUSIONS: The -5C allele of the GP Ibalpha Kozak polymorphism may represent a risk factor in clinical conditions in which thrombosis plays an important role, such as in acute coronary syndromes and in complications after PTCA.     

Acute arterial thrombosis due to platelet aggregation in a patient receiving granulocyte colony-stimulating factor

We describe a 44-year-old man with non-Hodgkin's lymphoma receiving granulocyte colony-stimulating factor (G-CSF) who developed an acute arterial thrombosis. The removed thrombus contained large amounts of platelet aggregation. A rapid increase of platelets and increased adenosine diphosphate (ADP)- and collagen-induced platelet aggregation were observed at the time of the thrombotic event. A challenge test of G-CSF showed an increase in the platelet count and an augmentation of ADP- and collagen-induced platelet aggregation. In the use of G-CSF, patients who produce a rapid increase in platelet levels could be at greater risk for thrombotic events and need to be followed-up carefully.     

Acute arterial thrombosis due to platelet aggregation in a patient receiving granulocyte colony-stimulating factor

We describe a 44-year-old man with non-Hodgkin's lymphoma receiving granulocyte colony-stimulating factor (G-CSF) who developed an acute arterial thrombosis. The removed thrombus contained large amounts of platelet aggregation. A rapid increase of platelets and increased adenosine diphosphate (ADP)- and collagen-induced platelet aggregation were observed at the time of the thrombotic event. A challenge test of G-CSF showed an increase in the platelet count and an augmentation of ADP- and collagen-induced platelet aggregation. In the use of G-CSF, patients who produce a rapid increase in platelet levels could be at greater risk for thrombotic events and need to be followed-up carefully.     

Von Willebrand factor (VWF) as a risk factor for bleeding and thrombosis

The von Willebrand factor (VWF) is analysed as a bleeding and thrombotic risk marker. When the VWF level is increased, it predicts a thrombotic phenotype and when VWF level is low in plasma, the phenotype varies to bleeding disorder. But it is quite challenging to define when the level is low, normal or high taking into account that these values are capricious and overlap. This matter should be solved by extensive epidemiologic studies. VWD is a hereditary disorder with several described mutations. VWF is a major acute-phase reactant, besides the physiological conditions such as blood group and pregnancy that affect plasmatic VWF levels. Subjects with O blood group have 25% less VWF than those of non O blood groups, and the latter show higher thrombus burden. VWF would be sensitive though not specific diagnostic marker of myocardial infarction. For the assessment of bleeding severity there are special surveys, scores and pictorial charts. The identification of VWF as a thrombotic risk marker has not been clearly established yet, but it has been involved in stroke and coronary disease. We only have the specific replacement therapy for the bleeding phenotype and we can speculate that enoxaparin and PEG-hirudin are able to blunt the VWF rise in patients with unstable angina pectoris and it is associated with a more favourable clinical outcome. Only two questions remain: does VWF as a bleeding risk marker have the same value as a thrombotic risk marker? Will successful treatments like those achieved for bleeding be also possible in the future for thrombosis?     

Deep venous thrombosis and previous myocardial infarction in mild factor XII deficiency: a risk factor for both venous and arterial thrombosis

Factor XII deficiency is associated with increased risk for both arterial and venous thrombosis. We describe a case of DVT involving superficial femoral and popliteal vein occurred following total hip replacement and despite prophylaxis with low molecular weight heparin in a subject with previous acute myocardial infarction (AMI). Tests of haemostasis documented a slightly prolonged activated partial thromboplastin time (APTT) (45′′) due to mild factor XII deficiency (clotting activity 32%). A therapeutic dose of enoxaparin was started, together with warfarin therapy. The patient was advised to continue oral anticoagulation indefinitely. Although cases of both venous and arterial thrombosis in carriers of severe factor XII deficiency have been already reported, to our knowledge this is the first case in the literature occurred in a carrier of partial factor XII deficiency. In conclusion, factor XII deficiency should be suspected if a patient presents with recurrent arterial and/or venous thrombosis and prolonged APTT. If this defect is diagnosed, in the presence of a history of thrombotic events, lifelong anticoagulation could be considered.     

The venous thrombosis risk factor 20210 A allele of the prothrombin gene is not a major risk factor for arterial thrombotic disease

A nucleotide change (G to A transition) at position 20210 has recently been demonstrated to be a risk factor for venous thrombosis. The relevance of this polymorphism to thrombotic disease was investigated by genotypic identification in three prospective case–control studies: 101 case patients with acute coronary heart disease (CHD), 104 patients with acute cerebrovascular disease (CVD), 82 patients with a confirmed diagnosis of deep venous thrombosis (DVT), and one control age- and sex-matched for each patient. The prevalence of the genetic variation was significantly associated with the occurrence of DVT, but did not differ in patients with CHD or CVD from that in controls, suggesting that this allele should not be considered a major risk factor for arterial thrombotic disease.