Platelets play crucial role in acute vascular atherosclerotic diseases, including myocardial infa... more Platelets play crucial role in acute vascular atherosclerotic diseases, including myocardial infarction and stroke. Additionally, platelet aggregation is a key target of antiplatelet agents, forming the keystone of pharmacotherapy of various atherosclerotic cardiovascular diseases. Thromboelastography and thromboelastometry, representing currently available viscoelastic hemostatic assays (VHA), are designed as whole blood, real-time analyzers of clot formation and clot resolution. These assays could, in theory, overcome some limitations of currently available platelet function testing assays. This article reviews the current experience with the use of VHA for platelet function testing and for monitoring of the response to antiplatelet therapy.
Congenital fibrinogen disorders are diseases associated with a bleeding tendency; however, there ... more Congenital fibrinogen disorders are diseases associated with a bleeding tendency; however, there are also reports of thrombotic events. Fibrinogen plays a role in the pathogenesis of thrombosis due to altered plasma concentrations or modifications to fibrinogen’s structural properties, which affect clot permeability, resistance to lysis, and its stiffness. Several distinct types of genetic change and pathogenetic mechanism have been described in patients with bleeding and a thrombotic phenotype, including mutations affecting synthesis or processing in three fibrinogen genes. In this paper, we focused on familial hypofibrinogenemia, a rare inherited quantitative fibrinogen disorder characterized by decreased fibrinogen levels with a high phenotypic heterogeneity. To begin, we briefly review the basic information regarding fibrinogen’s structure, its function, and the clinical consequences of low fibrinogen levels. Thereafter, we introduce 15 case reports with various gene mutations d...
von Willebrand disease (VWD) is reportedly the most common inherited bleeding disorder. This diso... more von Willebrand disease (VWD) is reportedly the most common inherited bleeding disorder. This disorder develops as a result of defects and/or deficiency of the plasma protein von Willebrand factor (VWF). Laboratory testing for VWF-related disorders requires the assessment of both VWF level and VWF activity, the latter requiring multiple assays. As an additional step, an evaluation of VWF structural features by multimer analysis is useful in selective investigations. Multimer analysis is also important for the selection of a suitable VWF therapy preparation (desmopressin, VWF/FVIII concentrate, recombinant VWF) and the determination of the correct dose for the patient. Based on clinical and laboratory findings, including the analysis of VWF multimers, we classified our patients into individual types of VWD. Our study group included 58 patients. The study group consisted of 66% (38 patients) with VWD type 1, 5% (3 patients) with VWD type 2, 7% (4 patients) with VWD type 3, 5% (3 patien...
Thromboprophylaxis with low-molecular-weight heparin (LMWH) for patients with a history of venous... more Thromboprophylaxis with low-molecular-weight heparin (LMWH) for patients with a history of venous thromboembolism (VTE) is suggested. Rotational thromboelastometry (ROTEM®) represents an innovative point-of-care method enabling the complex and quick evaluation of hemostasis. However, there are only episodic cases of its use for hemostasis assessment and guidance of LMWH in pregnancy. Therefore, we provide the results of unique prospective and longitudinal monitoring of hemostasis in high-risk pregnant women, which we used for the individualized optimalization of secondary thromboprophylaxis. According to the shortening of clot formation time (CFT) in EXTEM (p = 0.0007 from the 26th gestational week vs. controls) and INTEM (p = 0.002 from the 35th gestational week), increase in alpha angle (AA) in EXTEM, INTEM, and HEPTEM, and the persistence of increase in maximum clot firmness (MCF) in EXTEM, INTEM, and HEPTEM (p < 0.001 from the 26th and 35th gestational week vs. controls for E...
Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis, Jan 17, 2015
The immune tolerance induction is the treatment of choice for the eradication of factor VIII inhi... more The immune tolerance induction is the treatment of choice for the eradication of factor VIII inhibitors, a serious complication of inherited haemophilia A. Despite the preferred treatment of patients with good prognosis and testing of different regimens, the immune tolerance is achieved in 70-80%. Several modifications of regimens including the addition of immunomodulatory agents were proposed in order to improve immune tolerance induction (ITI) outcome. Intravenous immunoglobulin has complex immunomodulatory properties and has been used in immune tolerance induction since the introduction of Malmö regimen in the 1980s. The aim of the work is to evaluate the published evidence of its use in ITI in haemophilia A. In addition, the authors' own experience with a high-dose regimen using human plasma-derived factor VIII containing von Willebrand factor and pulsed IVIg is reported. The course of three patients with severe inherited haemophilia A and inhibitor (all high responders, two...
The aim of this study was to compare the activity of coagulation factor XI (FXI) between patients... more The aim of this study was to compare the activity of coagulation factor XI (FXI) between patients with spontaneous miscarriage versus control group with no history of miscarriage and thrombosis, and then we evaluated the occurrence of risk alleles in the relation to miscarriage. FXI activity was determined using a coagulometer (Sysmex, CA 1500, Japan). Single nucleotide polymorphisms (SNPs) of F11 and CYP4V2 genes were evaluated. We examined 55 patients versus 31 control subjects. We found significantly higher activity of FXI (p = 0.04) in patients versus control subjects. The occurrence of two SNPs (rs2289252 and rs2036914) of the F11 gene and SNP (rs13146272) of CYP4V2 gene was not significantly different between both groups. Increased activity of FXI may be a potential risk factor for miscarriage. High activity of FXI diagnosed in women with history of miscarriage is not probably caused by the presence of studied SNPs.
Clinical and applied thrombosis/hemostasis : official journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis, 2015
Dual antiplatelet treatment (DAPT) with clopidogrel and aspirin represents common approach in pre... more Dual antiplatelet treatment (DAPT) with clopidogrel and aspirin represents common approach in prevention of thromboembolic events in patients with acute coronary syndrome undergoing percutaneous coronary intervention (PCI). The drawback of clopidogrel treatment is large interindividual variability in response. Our article aims to suggesting the most convenient method in monitoring the DAPT of post-PCI patients. We analyzed the on-treatment platelet reactivity by light transmission aggregometry and vasodilator-stimulated phosphoprotein (VASP) flow cytometric assay. Samples were obtained in 3 intervals: first prior to PCI, then 1, and 30 days after PCI. Based on VASP-platelet reactivity index (PRI), we observed 100% response rate in prasugrel-treated patients and 62% to 73 % in the clopidogrel group. Overall, only 2 (7%) patients with the VASP-PRI value in therapeutic range had major adverse cardiovascular events. Our results hint VASP-phosphorylation assay as a relevant method for gu...
Background: To our knowledge KFAFH cardiac department is one of the few centers performing aortic... more Background: To our knowledge KFAFH cardiac department is one of the few centers performing aortic arch surgery in Saudi Arabia. The optimal strategy for management of the circulation during aortic arch surgery remains controversial and neurologic dysfunction due to cerebral ischemia remains a significant concern. We report our early experience on aortic arch surgery performed with Deep or Moderate Hypothermic Circulatory Arrest (DHCA or MHCA) and Antegrade Selective brain Perfusion (SAP).
Medical science monitor : international medical journal of experimental and clinical research, 2009
The production of factor VIII (FVIII) inhibitors is a serious problem of replacement therapy with... more The production of factor VIII (FVIII) inhibitors is a serious problem of replacement therapy with FVIII concentrates in hemophiliacs. It affects 10-20% patients and leads to an increased risk of severe bleeding and its complications. Immune tolerance induction (ITI) is considered the appropriate treatment in such cases, despite different regimens without clearly defined effectiveness. ITI eradicates FVIII inhibitors and allows retreatment with FVIII concentrates in 70% of patients. The case of a patient with congenital hemophilia A in whom allo-antibodies against FVIII were identified in a high titer at the age of 5 after 70 exposures to human plasma FVIII concentrates is presented. A spontaneous decrease in inhibitor titer to 14 BU/ml within 6 months after the termination of FVIII administration allowed ITI, consisting of FVIII in high doses and intravenous immunoglobulins. Cessation of bleeding during the treatment was achieved with recombinant activated FVII (rFVIIa). ITI lasted ...
Long-term secondary prophylaxis with recombinant activated factor VII (rFVIIa) in haemophilia A w... more Long-term secondary prophylaxis with recombinant activated factor VII (rFVIIa) in haemophilia A with inhibitors: A case report -
The sticky platelet syndrome (SPS) is a thrombophilic qualitative platelet disorder with familial... more The sticky platelet syndrome (SPS) is a thrombophilic qualitative platelet disorder with familial occurrence and autosomal dominant trait, characterized by increased in vitro platelet aggregation after low concentrations of adenosine diphosphate and/or epinephrine. Its clinical manifestation includes arterial thrombosis, pregnancy complications (fetal growth retardation and fetal loss), and less often venous thromboembolism. SPS was considered to be a rare thrombophilic disorder, but it can be found relatively often as a cause of unexplained thrombosis, particularly among patients with arterial thrombosis such as stroke. The syndrome was recognized as a distinct disorder in 1983 by Holiday and further characterized in the 1980s and 1990s, with Mammen and Bick providing the key findings. Although recognized for more than 30 years, significant issues, namely the syndrome&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s etiology, inheritance, and epidemiology, remain unclear. The aim of the first part of this review is to summarize the previous 35 years of the research into, and to provide a brief historical account of, SPS. The history section is focused particularly on the work of two most prominent investigators: Eberhard F. Mammen and Rodger L. Bick. The second part summarizes the present understanding of the syndrome and outlines unresolved issues and the trends in which the future research is likely to continue.
Introduction: Patients with glioblastoma multiforme (GBM) are at high risk of venous thromboembol... more Introduction: Patients with glioblastoma multiforme (GBM) are at high risk of venous thromboembolism (VTE). Although clinical factors such as immobility, paresis and hypovolemia contribute to this risk, they do not correlate with occurrence of VTE. Indeed, biological factors may be more significant than clinical factors in predicting post-operative thrombosis. Tissue factor (TF), the initiator of coagulation in vivo, is expressed in all gliomas, and correlates with tumor grade. TF is normally expressed extravascularly, but has recently been shown to be present in blood. Whether blood-borne TF is functionally active remains unclear. We report the presence of active TF in cell-free plasma of a 38 year old male patient with GBM. Methods: Pre-and post-operative (day 3) blood samples were collected. Whole blood coagulation analysis was performed by thromboelastography (TEG). Platelet activation was determined by measuring platelet surface P-selectin and monocyte-platelet conjugates. Plasma microparticles (MP) were isolated by high-speed centrifugation of cell-free plasma. Procoagulant activities of MP and particle-free supernatant (SN) were measured by thrombin generation assay. Results: Pre-op TEG revealed a hypercoagulable state as evidenced by a shortened clot time (6.8 mins, normal: 9-27mins), and elevated clot rate and strength values. Post-operatively, the clot time normalized (10 mins), indicating the reduction of a plasmatic procoagulant trigger. Other TEG parameters remained elevated. Platelet counts were normal in both samples, although platelet activation decreased by >50% postoperatively. TF-dependent procoagulant activity was detected in MP (but not in SN). Consistent with the TEG clot times, this TF activity was reduced postoperatively, but remained higher than that of control plasma. Conclusion: In this report we have shown TF activity in the plasma of a patient with GBM. The post-op reduction of this circulating, MP-associated TF activity suggests that the observed hypercoagulability could be at least partially due to TF shed from the tumor.
Background: Thrombophilia play an important role in obstetric complications, especially in cases ... more Background: Thrombophilia play an important role in obstetric complications, especially in cases of multiple pregnancy. Normal is a prothrombotic state because of stasis, venous pressure elevation, increased fibrinogen activity, and decreased protein S activity and associated with profound alterations in the coagulation and fibrinolytic systems. Methods: We examined 25 patients with multiple pregnancy, thrombophilia and complicated obstetric history (fetal loss syndrome, pre-eclampsia, severe pre-eclampsia, IVF failure, thrombosis). All pregnancies were dichorionic. 13 women were after IVF. These patients were compared with group of 53 women examined retrospectively (case-control study) with multiple pregnancy, thrombophilia (75,4%) and obstetric complications (fetal loss syndrome 45%, antenatal fetal death 30%, IUGR 13%, neonatal death 11%, preeclampsia 60%, severe preeclampsia 8%, abruptio placenta 26%, preterm labor 26%) and did not receive antithrombotic therapy. All patients had been examined for the genetic and acquired thrombophilia. Criteria of thrombophilia were: mutation of the factor V Leiden, mutations of prothrombin G20210A, antithrombin III deficiency, protein C deficiency, 3 homozygous thrombophilic polymorphisms, or 5 heterozygotic polymorphisms, moderate or heavy hyperhomocysteinemia and antiphospholipid syndrome. Results: 40% of patients had circulation of antiphospholipid antibodies, 28%-hyperhomocysteinemia. The incidence of factor V Leiden mutation was 8%, prothrombin gene mutation-12%. 80% of patients had combined thrombophilia. Anticoagulant therapy was started after first visit to a doctor: 13 women with IVF were cured from preparing to IVF, 8from the period of pregnancy planning, 5at the beginning of I trimester of pregnancy. Anticoagulant therapy (enoxaparin sodium) was given during all stages of pregnancy. The doses vary from 40 mg to 100 mg depends on blood coagulation potential. All patients received folic acid, vitamins group B, Omega-3, 400-600 mg of micronized progesterone until 16-20 weeks of pregnancy and antianemic therapy. In 2 cases there was fetal reduction in woman pregnant with triplets. Mild preeclampsia was in 5 patients at term 30-34 weeks of pregnancy. There were no cases of placental or chorionic abruption, no cases of fetal loss, thrombosis or severe pre-eclampsia. 6 women were delivered by Cesarean section as planned at 37 weeks, 14 patients were delivered at term 34-36 weeks and 5-at 30-34 weeks. Enoxaparin treatment was stopped shortly (24 hours) before surgery and was resumed 8-10 hours after Cesarean section in dose 40 mg during 10 days depends on initial thrombophilia. Comment: Testing for thrombophilia should be performed in all patients with multiple pregnancy. Since thrombophilia has been diagnosed LMWH therapy and micronized progesterone should be started.
Sticky platelet syndrome (SPS) is a thrombophilic thrombocytopathy with familial occurrence and a... more Sticky platelet syndrome (SPS) is a thrombophilic thrombocytopathy with familial occurrence and autosomal dominant trait, characterized by an increased in vitro platelet aggregation in response to low concentrations of adenosine diphosphate (ADP) and/or epinephrine (EPI). According to aggregation pattern, three types of the syndrome can be identified (hyperresponse after both reagents, Type I; EPI alone, Type II; ADP alone, Type III). Clinically, the syndrome is associated with both venous and arterial thrombosis. In pregnant women, complications such as fetal growth retardation and fetal loss have been reported. The first thrombotic event usually occurs before 40 years of age and without prominent acquired risk factors. Antiplatelet drugs generally represent adequate treatment. The use of other antithrombotics is usually ineffective and may result in the recurrence of thrombosis. In most patients, low doses of antiplatelet drugs (acetylsalicylic acid, 80-100 mg/d) lead to normalization of hyperaggregability. Combination of SPS with other thrombophilic disorders has been described. Despite several studies investigating platelet glycoproteins&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; role in platelets&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; activation and aggregation, the precise defect responsible for the syndrome remains unknown. The aim of this review is to summarize authors&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; own experience about SPS and the clinical data indexed in selected databases of medical literature (PubMed and Scopus).
Singlearm Study of bridging therapy with low-molecular-weight heparin for patients at risk of art... more Singlearm Study of bridging therapy with low-molecular-weight heparin for patients at risk of arterial embolism who require temporary interruption of warfarin.
Introduction: The development of factor VIII inhibitors is a serious complication of replacement ... more Introduction: The development of factor VIII inhibitors is a serious complication of replacement therapy in patients with congenital hemophilia A. Immune tolerance induction has been accepted as the only clinically proven treatment allowing antigen-specific tolerance to factor VIII. However, some of its issues, such as patient selection, timing, factor VIII dosing, use of immunosuppressive or immunomodulatory procedures, still remain the subject of debate. Case presentation: A case of a 3-year-old Caucasian boy with severe congenital hemophilia A, intron 22 inversion of the F8 gene and high-titer inhibitor, who underwent an immune tolerance induction according to the modified Bonn regimen (high doses of plasma-derived factor VIII rich in von Willebrand factor and pulsed intravenous immunoglobulin) is presented. The treatment lasted for 13 months and led to the eradication of inhibitor. Conclusion: Addition of intravenous immunoglobulin did not negatively affect the course of immune tolerance induction and led to the rapid eradication of factor VIII inhibitor.
Currently, recombinant activated factor VII (rFVIIa) (NovoSeven) is indicated for the treatment o... more Currently, recombinant activated factor VII (rFVIIa) (NovoSeven) is indicated for the treatment of spontaneous and surgical bleeding in congenital haemophilia A and B patients with inhibitors to factors VIII (FVIII) and IX (FIX) &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;5 Bethesda units (BU) worldwide, and in patients with acquired haemophilia, congenital FVII deficiency and Glanzmann&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s thrombasthenia in Europe. Until April 2003, almost three-quarters of a milion doses of rFVIIa have been administered proving its efficacy and excellent safety record. According to results from initial clinical trials and a large number of case reports, the rFVIIa may be effective not only in treating haemophilia patients but also in treatment of bleeding in patients on oral anticoagulation or heparin, patients with liver diseases, von Willebrand disease (vWD), thrombocytopenia, various platelet defects, congenital or acquired deficiency of FVII, and in subjects without any pre-existing coagulopathy with diffuse life-threatening bleeding triggered by surgery or trauma. This review will briefly summarize rFVIIa mode of action in haemostasis, the current clinical experience with rFVIIa and focus on the alternative use of rFVIIa in patients at the high risk of bleeding in both spontaneous cases and clinical trials reports.
The aim of the study was to evaluate the genetic variability of the GP6 gene in patients with sti... more The aim of the study was to evaluate the genetic variability of the GP6 gene in patients with sticky platelet syndrome (SPS), a disorder characterized by platelet hyperaggregability, and thus to identify the genetic changes of the glycoprotein VI with possible relation to the platelet hyperaggregability. Patients and methods: Seventy-one patients with SPS, clinically manifested as ischemic stroke, and 77 controls without SPS and with negative personal history of thromboembolic events were involved. SPS was diagnosed by platelet aggregometry (PACKS-4 aggregometer, Helena Laboratories) according to the method and criteria described by Mammen and Bick. Seven single-nucleotide polymorphisms (SNPs) of the GP6 gene (rs1654410, rs1671153, rs1654419, rs11669150, rs1613662, rs12610286, and rs1654431) were evaluated with the use of restriction-fragment-length polymorphism analysis. Results: All allele and genotype frequencies were comparable between both SPS patients and the control group with no statistically significant differences. The haplotype analysis showed a higher occurrence of the one major haplotype (TTGTGA, 0.228 vs. 0.174; odds ratio (OR) 1.421; confidence interval (CI) 0.799-2.526) and two minor haplotypes (CGATAA, 0,026 vs. 0,006; OR 4.117; CI 0.443-38.25; TTGTGG, 0.018 vs. 0.009; OR 2.107; CI 0.259-17.12) in patients with SPS. None of haplotype differences was statistically significant. However, both the allele G of SNP rs12610286 (P = 0.029; OR 2.411; CI 1.134-5.123) and one major haplotype (TTGTGA; P = 0.012; OR 2.749; CI 1.223-6.174) were found significantly more frequent in patients with SPS type I in comparison with controls. Conclusion: Our results, especially higher occurrence of four haplotypes in SPS patients, can support an idea that variability of the GP6 gene may be associated with the platelet hyperaggregability in SPS.
Diabetes & Metabolic Syndrome: Clinical Research & Reviews, 2009
We measured serum VEGF in type 2 diabetes, to correlate VEGF with the degree of albuminuria. Eigh... more We measured serum VEGF in type 2 diabetes, to correlate VEGF with the degree of albuminuria. Eighty-four diabetics were divided in normoalbuminuric (NAU ≤30mg/24h, n=42) and microalbuminuric (MAU &amp;amp;amp;amp;amp;amp;amp;amp;gt;30 and ≤300mg/24h, n=42) subgroup. Forty-two age and sex matched blood donors were in the control group. VEGF levels were measured using VEGF Quantikine, R&amp;amp;amp;amp;amp;amp;amp;amp;amp;D Systems Inc., Minneapolis, MN kits, according to
Platelets play crucial role in acute vascular atherosclerotic diseases, including myocardial infa... more Platelets play crucial role in acute vascular atherosclerotic diseases, including myocardial infarction and stroke. Additionally, platelet aggregation is a key target of antiplatelet agents, forming the keystone of pharmacotherapy of various atherosclerotic cardiovascular diseases. Thromboelastography and thromboelastometry, representing currently available viscoelastic hemostatic assays (VHA), are designed as whole blood, real-time analyzers of clot formation and clot resolution. These assays could, in theory, overcome some limitations of currently available platelet function testing assays. This article reviews the current experience with the use of VHA for platelet function testing and for monitoring of the response to antiplatelet therapy.
Congenital fibrinogen disorders are diseases associated with a bleeding tendency; however, there ... more Congenital fibrinogen disorders are diseases associated with a bleeding tendency; however, there are also reports of thrombotic events. Fibrinogen plays a role in the pathogenesis of thrombosis due to altered plasma concentrations or modifications to fibrinogen’s structural properties, which affect clot permeability, resistance to lysis, and its stiffness. Several distinct types of genetic change and pathogenetic mechanism have been described in patients with bleeding and a thrombotic phenotype, including mutations affecting synthesis or processing in three fibrinogen genes. In this paper, we focused on familial hypofibrinogenemia, a rare inherited quantitative fibrinogen disorder characterized by decreased fibrinogen levels with a high phenotypic heterogeneity. To begin, we briefly review the basic information regarding fibrinogen’s structure, its function, and the clinical consequences of low fibrinogen levels. Thereafter, we introduce 15 case reports with various gene mutations d...
von Willebrand disease (VWD) is reportedly the most common inherited bleeding disorder. This diso... more von Willebrand disease (VWD) is reportedly the most common inherited bleeding disorder. This disorder develops as a result of defects and/or deficiency of the plasma protein von Willebrand factor (VWF). Laboratory testing for VWF-related disorders requires the assessment of both VWF level and VWF activity, the latter requiring multiple assays. As an additional step, an evaluation of VWF structural features by multimer analysis is useful in selective investigations. Multimer analysis is also important for the selection of a suitable VWF therapy preparation (desmopressin, VWF/FVIII concentrate, recombinant VWF) and the determination of the correct dose for the patient. Based on clinical and laboratory findings, including the analysis of VWF multimers, we classified our patients into individual types of VWD. Our study group included 58 patients. The study group consisted of 66% (38 patients) with VWD type 1, 5% (3 patients) with VWD type 2, 7% (4 patients) with VWD type 3, 5% (3 patien...
Thromboprophylaxis with low-molecular-weight heparin (LMWH) for patients with a history of venous... more Thromboprophylaxis with low-molecular-weight heparin (LMWH) for patients with a history of venous thromboembolism (VTE) is suggested. Rotational thromboelastometry (ROTEM®) represents an innovative point-of-care method enabling the complex and quick evaluation of hemostasis. However, there are only episodic cases of its use for hemostasis assessment and guidance of LMWH in pregnancy. Therefore, we provide the results of unique prospective and longitudinal monitoring of hemostasis in high-risk pregnant women, which we used for the individualized optimalization of secondary thromboprophylaxis. According to the shortening of clot formation time (CFT) in EXTEM (p = 0.0007 from the 26th gestational week vs. controls) and INTEM (p = 0.002 from the 35th gestational week), increase in alpha angle (AA) in EXTEM, INTEM, and HEPTEM, and the persistence of increase in maximum clot firmness (MCF) in EXTEM, INTEM, and HEPTEM (p < 0.001 from the 26th and 35th gestational week vs. controls for E...
Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis, Jan 17, 2015
The immune tolerance induction is the treatment of choice for the eradication of factor VIII inhi... more The immune tolerance induction is the treatment of choice for the eradication of factor VIII inhibitors, a serious complication of inherited haemophilia A. Despite the preferred treatment of patients with good prognosis and testing of different regimens, the immune tolerance is achieved in 70-80%. Several modifications of regimens including the addition of immunomodulatory agents were proposed in order to improve immune tolerance induction (ITI) outcome. Intravenous immunoglobulin has complex immunomodulatory properties and has been used in immune tolerance induction since the introduction of Malmö regimen in the 1980s. The aim of the work is to evaluate the published evidence of its use in ITI in haemophilia A. In addition, the authors' own experience with a high-dose regimen using human plasma-derived factor VIII containing von Willebrand factor and pulsed IVIg is reported. The course of three patients with severe inherited haemophilia A and inhibitor (all high responders, two...
The aim of this study was to compare the activity of coagulation factor XI (FXI) between patients... more The aim of this study was to compare the activity of coagulation factor XI (FXI) between patients with spontaneous miscarriage versus control group with no history of miscarriage and thrombosis, and then we evaluated the occurrence of risk alleles in the relation to miscarriage. FXI activity was determined using a coagulometer (Sysmex, CA 1500, Japan). Single nucleotide polymorphisms (SNPs) of F11 and CYP4V2 genes were evaluated. We examined 55 patients versus 31 control subjects. We found significantly higher activity of FXI (p = 0.04) in patients versus control subjects. The occurrence of two SNPs (rs2289252 and rs2036914) of the F11 gene and SNP (rs13146272) of CYP4V2 gene was not significantly different between both groups. Increased activity of FXI may be a potential risk factor for miscarriage. High activity of FXI diagnosed in women with history of miscarriage is not probably caused by the presence of studied SNPs.
Clinical and applied thrombosis/hemostasis : official journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis, 2015
Dual antiplatelet treatment (DAPT) with clopidogrel and aspirin represents common approach in pre... more Dual antiplatelet treatment (DAPT) with clopidogrel and aspirin represents common approach in prevention of thromboembolic events in patients with acute coronary syndrome undergoing percutaneous coronary intervention (PCI). The drawback of clopidogrel treatment is large interindividual variability in response. Our article aims to suggesting the most convenient method in monitoring the DAPT of post-PCI patients. We analyzed the on-treatment platelet reactivity by light transmission aggregometry and vasodilator-stimulated phosphoprotein (VASP) flow cytometric assay. Samples were obtained in 3 intervals: first prior to PCI, then 1, and 30 days after PCI. Based on VASP-platelet reactivity index (PRI), we observed 100% response rate in prasugrel-treated patients and 62% to 73 % in the clopidogrel group. Overall, only 2 (7%) patients with the VASP-PRI value in therapeutic range had major adverse cardiovascular events. Our results hint VASP-phosphorylation assay as a relevant method for gu...
Background: To our knowledge KFAFH cardiac department is one of the few centers performing aortic... more Background: To our knowledge KFAFH cardiac department is one of the few centers performing aortic arch surgery in Saudi Arabia. The optimal strategy for management of the circulation during aortic arch surgery remains controversial and neurologic dysfunction due to cerebral ischemia remains a significant concern. We report our early experience on aortic arch surgery performed with Deep or Moderate Hypothermic Circulatory Arrest (DHCA or MHCA) and Antegrade Selective brain Perfusion (SAP).
Medical science monitor : international medical journal of experimental and clinical research, 2009
The production of factor VIII (FVIII) inhibitors is a serious problem of replacement therapy with... more The production of factor VIII (FVIII) inhibitors is a serious problem of replacement therapy with FVIII concentrates in hemophiliacs. It affects 10-20% patients and leads to an increased risk of severe bleeding and its complications. Immune tolerance induction (ITI) is considered the appropriate treatment in such cases, despite different regimens without clearly defined effectiveness. ITI eradicates FVIII inhibitors and allows retreatment with FVIII concentrates in 70% of patients. The case of a patient with congenital hemophilia A in whom allo-antibodies against FVIII were identified in a high titer at the age of 5 after 70 exposures to human plasma FVIII concentrates is presented. A spontaneous decrease in inhibitor titer to 14 BU/ml within 6 months after the termination of FVIII administration allowed ITI, consisting of FVIII in high doses and intravenous immunoglobulins. Cessation of bleeding during the treatment was achieved with recombinant activated FVII (rFVIIa). ITI lasted ...
Long-term secondary prophylaxis with recombinant activated factor VII (rFVIIa) in haemophilia A w... more Long-term secondary prophylaxis with recombinant activated factor VII (rFVIIa) in haemophilia A with inhibitors: A case report -
The sticky platelet syndrome (SPS) is a thrombophilic qualitative platelet disorder with familial... more The sticky platelet syndrome (SPS) is a thrombophilic qualitative platelet disorder with familial occurrence and autosomal dominant trait, characterized by increased in vitro platelet aggregation after low concentrations of adenosine diphosphate and/or epinephrine. Its clinical manifestation includes arterial thrombosis, pregnancy complications (fetal growth retardation and fetal loss), and less often venous thromboembolism. SPS was considered to be a rare thrombophilic disorder, but it can be found relatively often as a cause of unexplained thrombosis, particularly among patients with arterial thrombosis such as stroke. The syndrome was recognized as a distinct disorder in 1983 by Holiday and further characterized in the 1980s and 1990s, with Mammen and Bick providing the key findings. Although recognized for more than 30 years, significant issues, namely the syndrome&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s etiology, inheritance, and epidemiology, remain unclear. The aim of the first part of this review is to summarize the previous 35 years of the research into, and to provide a brief historical account of, SPS. The history section is focused particularly on the work of two most prominent investigators: Eberhard F. Mammen and Rodger L. Bick. The second part summarizes the present understanding of the syndrome and outlines unresolved issues and the trends in which the future research is likely to continue.
Introduction: Patients with glioblastoma multiforme (GBM) are at high risk of venous thromboembol... more Introduction: Patients with glioblastoma multiforme (GBM) are at high risk of venous thromboembolism (VTE). Although clinical factors such as immobility, paresis and hypovolemia contribute to this risk, they do not correlate with occurrence of VTE. Indeed, biological factors may be more significant than clinical factors in predicting post-operative thrombosis. Tissue factor (TF), the initiator of coagulation in vivo, is expressed in all gliomas, and correlates with tumor grade. TF is normally expressed extravascularly, but has recently been shown to be present in blood. Whether blood-borne TF is functionally active remains unclear. We report the presence of active TF in cell-free plasma of a 38 year old male patient with GBM. Methods: Pre-and post-operative (day 3) blood samples were collected. Whole blood coagulation analysis was performed by thromboelastography (TEG). Platelet activation was determined by measuring platelet surface P-selectin and monocyte-platelet conjugates. Plasma microparticles (MP) were isolated by high-speed centrifugation of cell-free plasma. Procoagulant activities of MP and particle-free supernatant (SN) were measured by thrombin generation assay. Results: Pre-op TEG revealed a hypercoagulable state as evidenced by a shortened clot time (6.8 mins, normal: 9-27mins), and elevated clot rate and strength values. Post-operatively, the clot time normalized (10 mins), indicating the reduction of a plasmatic procoagulant trigger. Other TEG parameters remained elevated. Platelet counts were normal in both samples, although platelet activation decreased by >50% postoperatively. TF-dependent procoagulant activity was detected in MP (but not in SN). Consistent with the TEG clot times, this TF activity was reduced postoperatively, but remained higher than that of control plasma. Conclusion: In this report we have shown TF activity in the plasma of a patient with GBM. The post-op reduction of this circulating, MP-associated TF activity suggests that the observed hypercoagulability could be at least partially due to TF shed from the tumor.
Background: Thrombophilia play an important role in obstetric complications, especially in cases ... more Background: Thrombophilia play an important role in obstetric complications, especially in cases of multiple pregnancy. Normal is a prothrombotic state because of stasis, venous pressure elevation, increased fibrinogen activity, and decreased protein S activity and associated with profound alterations in the coagulation and fibrinolytic systems. Methods: We examined 25 patients with multiple pregnancy, thrombophilia and complicated obstetric history (fetal loss syndrome, pre-eclampsia, severe pre-eclampsia, IVF failure, thrombosis). All pregnancies were dichorionic. 13 women were after IVF. These patients were compared with group of 53 women examined retrospectively (case-control study) with multiple pregnancy, thrombophilia (75,4%) and obstetric complications (fetal loss syndrome 45%, antenatal fetal death 30%, IUGR 13%, neonatal death 11%, preeclampsia 60%, severe preeclampsia 8%, abruptio placenta 26%, preterm labor 26%) and did not receive antithrombotic therapy. All patients had been examined for the genetic and acquired thrombophilia. Criteria of thrombophilia were: mutation of the factor V Leiden, mutations of prothrombin G20210A, antithrombin III deficiency, protein C deficiency, 3 homozygous thrombophilic polymorphisms, or 5 heterozygotic polymorphisms, moderate or heavy hyperhomocysteinemia and antiphospholipid syndrome. Results: 40% of patients had circulation of antiphospholipid antibodies, 28%-hyperhomocysteinemia. The incidence of factor V Leiden mutation was 8%, prothrombin gene mutation-12%. 80% of patients had combined thrombophilia. Anticoagulant therapy was started after first visit to a doctor: 13 women with IVF were cured from preparing to IVF, 8from the period of pregnancy planning, 5at the beginning of I trimester of pregnancy. Anticoagulant therapy (enoxaparin sodium) was given during all stages of pregnancy. The doses vary from 40 mg to 100 mg depends on blood coagulation potential. All patients received folic acid, vitamins group B, Omega-3, 400-600 mg of micronized progesterone until 16-20 weeks of pregnancy and antianemic therapy. In 2 cases there was fetal reduction in woman pregnant with triplets. Mild preeclampsia was in 5 patients at term 30-34 weeks of pregnancy. There were no cases of placental or chorionic abruption, no cases of fetal loss, thrombosis or severe pre-eclampsia. 6 women were delivered by Cesarean section as planned at 37 weeks, 14 patients were delivered at term 34-36 weeks and 5-at 30-34 weeks. Enoxaparin treatment was stopped shortly (24 hours) before surgery and was resumed 8-10 hours after Cesarean section in dose 40 mg during 10 days depends on initial thrombophilia. Comment: Testing for thrombophilia should be performed in all patients with multiple pregnancy. Since thrombophilia has been diagnosed LMWH therapy and micronized progesterone should be started.
Sticky platelet syndrome (SPS) is a thrombophilic thrombocytopathy with familial occurrence and a... more Sticky platelet syndrome (SPS) is a thrombophilic thrombocytopathy with familial occurrence and autosomal dominant trait, characterized by an increased in vitro platelet aggregation in response to low concentrations of adenosine diphosphate (ADP) and/or epinephrine (EPI). According to aggregation pattern, three types of the syndrome can be identified (hyperresponse after both reagents, Type I; EPI alone, Type II; ADP alone, Type III). Clinically, the syndrome is associated with both venous and arterial thrombosis. In pregnant women, complications such as fetal growth retardation and fetal loss have been reported. The first thrombotic event usually occurs before 40 years of age and without prominent acquired risk factors. Antiplatelet drugs generally represent adequate treatment. The use of other antithrombotics is usually ineffective and may result in the recurrence of thrombosis. In most patients, low doses of antiplatelet drugs (acetylsalicylic acid, 80-100 mg/d) lead to normalization of hyperaggregability. Combination of SPS with other thrombophilic disorders has been described. Despite several studies investigating platelet glycoproteins&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; role in platelets&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; activation and aggregation, the precise defect responsible for the syndrome remains unknown. The aim of this review is to summarize authors&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; own experience about SPS and the clinical data indexed in selected databases of medical literature (PubMed and Scopus).
Singlearm Study of bridging therapy with low-molecular-weight heparin for patients at risk of art... more Singlearm Study of bridging therapy with low-molecular-weight heparin for patients at risk of arterial embolism who require temporary interruption of warfarin.
Introduction: The development of factor VIII inhibitors is a serious complication of replacement ... more Introduction: The development of factor VIII inhibitors is a serious complication of replacement therapy in patients with congenital hemophilia A. Immune tolerance induction has been accepted as the only clinically proven treatment allowing antigen-specific tolerance to factor VIII. However, some of its issues, such as patient selection, timing, factor VIII dosing, use of immunosuppressive or immunomodulatory procedures, still remain the subject of debate. Case presentation: A case of a 3-year-old Caucasian boy with severe congenital hemophilia A, intron 22 inversion of the F8 gene and high-titer inhibitor, who underwent an immune tolerance induction according to the modified Bonn regimen (high doses of plasma-derived factor VIII rich in von Willebrand factor and pulsed intravenous immunoglobulin) is presented. The treatment lasted for 13 months and led to the eradication of inhibitor. Conclusion: Addition of intravenous immunoglobulin did not negatively affect the course of immune tolerance induction and led to the rapid eradication of factor VIII inhibitor.
Currently, recombinant activated factor VII (rFVIIa) (NovoSeven) is indicated for the treatment o... more Currently, recombinant activated factor VII (rFVIIa) (NovoSeven) is indicated for the treatment of spontaneous and surgical bleeding in congenital haemophilia A and B patients with inhibitors to factors VIII (FVIII) and IX (FIX) &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;5 Bethesda units (BU) worldwide, and in patients with acquired haemophilia, congenital FVII deficiency and Glanzmann&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s thrombasthenia in Europe. Until April 2003, almost three-quarters of a milion doses of rFVIIa have been administered proving its efficacy and excellent safety record. According to results from initial clinical trials and a large number of case reports, the rFVIIa may be effective not only in treating haemophilia patients but also in treatment of bleeding in patients on oral anticoagulation or heparin, patients with liver diseases, von Willebrand disease (vWD), thrombocytopenia, various platelet defects, congenital or acquired deficiency of FVII, and in subjects without any pre-existing coagulopathy with diffuse life-threatening bleeding triggered by surgery or trauma. This review will briefly summarize rFVIIa mode of action in haemostasis, the current clinical experience with rFVIIa and focus on the alternative use of rFVIIa in patients at the high risk of bleeding in both spontaneous cases and clinical trials reports.
The aim of the study was to evaluate the genetic variability of the GP6 gene in patients with sti... more The aim of the study was to evaluate the genetic variability of the GP6 gene in patients with sticky platelet syndrome (SPS), a disorder characterized by platelet hyperaggregability, and thus to identify the genetic changes of the glycoprotein VI with possible relation to the platelet hyperaggregability. Patients and methods: Seventy-one patients with SPS, clinically manifested as ischemic stroke, and 77 controls without SPS and with negative personal history of thromboembolic events were involved. SPS was diagnosed by platelet aggregometry (PACKS-4 aggregometer, Helena Laboratories) according to the method and criteria described by Mammen and Bick. Seven single-nucleotide polymorphisms (SNPs) of the GP6 gene (rs1654410, rs1671153, rs1654419, rs11669150, rs1613662, rs12610286, and rs1654431) were evaluated with the use of restriction-fragment-length polymorphism analysis. Results: All allele and genotype frequencies were comparable between both SPS patients and the control group with no statistically significant differences. The haplotype analysis showed a higher occurrence of the one major haplotype (TTGTGA, 0.228 vs. 0.174; odds ratio (OR) 1.421; confidence interval (CI) 0.799-2.526) and two minor haplotypes (CGATAA, 0,026 vs. 0,006; OR 4.117; CI 0.443-38.25; TTGTGG, 0.018 vs. 0.009; OR 2.107; CI 0.259-17.12) in patients with SPS. None of haplotype differences was statistically significant. However, both the allele G of SNP rs12610286 (P = 0.029; OR 2.411; CI 1.134-5.123) and one major haplotype (TTGTGA; P = 0.012; OR 2.749; CI 1.223-6.174) were found significantly more frequent in patients with SPS type I in comparison with controls. Conclusion: Our results, especially higher occurrence of four haplotypes in SPS patients, can support an idea that variability of the GP6 gene may be associated with the platelet hyperaggregability in SPS.
Diabetes & Metabolic Syndrome: Clinical Research & Reviews, 2009
We measured serum VEGF in type 2 diabetes, to correlate VEGF with the degree of albuminuria. Eigh... more We measured serum VEGF in type 2 diabetes, to correlate VEGF with the degree of albuminuria. Eighty-four diabetics were divided in normoalbuminuric (NAU ≤30mg/24h, n=42) and microalbuminuric (MAU &amp;amp;amp;amp;amp;amp;amp;amp;gt;30 and ≤300mg/24h, n=42) subgroup. Forty-two age and sex matched blood donors were in the control group. VEGF levels were measured using VEGF Quantikine, R&amp;amp;amp;amp;amp;amp;amp;amp;amp;D Systems Inc., Minneapolis, MN kits, according to
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