Blood Coagulation & Fibrinolysis最新文献

Cancer-associated thrombosis (CAT) is a common complication and a major cause of morbidity and mortality in patients with active cancers. CAT is common in various malignancies, particularly pancreatic, ovarian, gastric, colorectal, and hematologic cancers. In fact, CAT is a complicated multifactorial complication that may be influenced by the type of cancer as well as by the genetic background and inheritance of thrombophilic variants and elevated concentrations of coagulation factors. Several studies have shown the prominent role of inherited thrombophilias, such as prothrombin 20210, factor V Leiden, factor XIII Val34Leu, MTHFR C677T, in the occurrence of CAT, while others have found no correlation between them and CAT. In the present review, we have attempted to investigate the possible role of inherited thrombophilia in the occurrence of CAT.

Thrombotic thrombocytopenic purpura (TTP) is one of the rare group disorders classified as thrombotic microangiopathies (TMAs). Approximately 90% of TTP developed immune-mediation by the formation of antibodies against the enzyme ADAMTS-13. The exact cause is unknown. To establish an association between human leukocyte antigen (HLA) and autoimmune basis, as susceptibility or protection against the disease, we contributed a study aiming to evaluate the role of HLA in immune-mediated TTP (iTTP). Considering epidemiological factors such as age, sex, ethnicity, and geographical origins, we contributed the study in our country, Turkey, which consist of a very heterogeneous population. Patients' data collection was retrospectively from electronic database on two University hospitals having big therapeutic apheresis service. Control arm was healthy people registered as stem cell donors matched in terms of age and sex. The frequency of HLA-DRB1 and HLA-DQB1 alleles between acquired TTP and the control group was compared using the chi-square method. Yates correction and logistic regression were performed on these results. A total of 75 iTTP patients and 150 healthy individuals enrolled to the study. HLA-DRB1∗11, HLA-DQB1∗03, HLA-DRB1∗11:01, HLA-DRB1∗14:01, HLA-DRB1∗13:05, HLA-DRB1∗11 + HLA-DQB1∗03 allele pair and HLA-DRB1∗15 + HLA- DQB1∗06 were proved to be susceptibility allele pairs for iTTP. HLA-DRB1∗15, HLA-DRB1∗01:01, HLA-DRB1∗07:01, HLA-DRB1∗13:01, HLA-DRB1∗14:54, HLA-DQB1∗05:01, HLA-DQB1∗02:02 and HLA-DRB1∗07 + HLA-DQB1∗02 allele pair were found to be protective against iTTP. Our findings support an association with iTTP across very heterogenous populations in Turkey.

D-dimer is a fibrin degradation product and its measurement is affected by hemolysis. This study was designed to reveal the value of hemolysis affecting D-dimer in our laboratory. In this study, hemolysate samples obtained by both mechanical and freezing methods were used. D-dimer levels of all plasmas were measured with Improgen Diagnostic kit by immune-turbidimetric method. Numerical change in hemolyzed samples was evaluated by calculating the percentage difference, and clinically significant differences were evaluated by calculating the maximum acceptable bias (MAB). In the hemolysate study prepared by both freeze-thaw and mechanical methods, it was observed that low D-dimer levels did not exceed the total allowable error (TAE) (30%) up to +2 hemolysis (corresponds to hemoglobin = 1.01-2 g/l) and did not exceed the MAB (65%) even at +4 hemolysis (corresponds to hemoglobin = 1.01-2 g/l). High D-dimer levels did not exceed the limit values of both TAE (30%) and MAB (68%) even in +4 hemolysis. The D-dimer test was affected by lower levels of hemolysis compared to both other studies and the values in the kit insert (hemoglobin >5 g/l corresponds to +4 hemolysis index). We verified the hemolysis interference in the D-dimer test, which we thought was not compatible with the kit insert, under our own laboratory conditions. This is the first hemolysis interference study performed with the Improgen brand d-dimer kit. In samples with a hemolysis rate of +2 and above, it would be more accurate to reject the D-dimer result as a 'hemolyzed sample'.

The diagnostic and therapeutic approach for an unusual clinical situation is presented. Twenty-three-year-old female patient is evaluated for hematuria and metrorrhagia. She reported irregular follow-up with hematology because of bleeding in childhood. She has also been receiving factor VII for 2 years, denying hospitalizations because of bleeding. Laboratory reported hb: 5.2 g/dl; platelets: 234 000/mm 3 ; PT: 100 s; PTT: 112 s, fibrinogen: 90 mg/dl without other alterations. Abdominal ultrasound reported uterine myoma, urinalysis was pathological. The gynecology indicated oral progesterone. She started antibiotic therapy, transfusion of red-blood cells, plasma, and cryoprecipitates and subsequently reported: factor VII: 2%, IX: 1% and VIII: 70%. She received factor VII-recombinant (rFVII), achieving resolution of bleeding. She was prescribed prophylactic rFVII and hematology monitoring. Readmission due to acute abdomen with Hb 5 g/dl, prolonged prothrombin time (PT)/partial thromboplastin time (PTT) and abdominal tomography reported hemoperitoneum. She received rFVII and required laparotomy and left oophorectomy. Then readmission to metrorrhagia, hb6 g/dl, prolonged PT/PTT and factor VII-IX of two coagulation factors were reported, without reports found in the literature consulted.

Fostamatinib is a spleen tyrosine kinase inhibitor indicated for the treatment of chronic immune thrombocytopenia (ITP) unresponsive to a previous treatment. Real-world studies evaluating the utilization and effectiveness of fostamatinib outside the context of a clinical trial are lacking. The objective of this analysis was to evaluate the effectiveness of fostamatinib for the treatment of ITP in a real-world cohort. We conducted a single-center, retrospective, observational study to evaluate the effectiveness of fostamatinib for the treatment of ITP. The primary endpoint was durable response as defined by the American Society of Hematology ITP response criteria. Secondary endpoints included overall response rate, time to response, and safety. Subgroup analysis was performed to assess frequency of durable response in key subgroups of patients based on prior therapies. Thirty-one patients treated with fostamatinib for ITP were included in our analysis. Patients had received a median of four prior lines of therapy. Ten patients (32%) achieved a durable response. Most durable responders maintained their response at 24 months ( n  = 7; 70%). The median time to response was 9 days. Four patients (13%) discontinued fostamatinib due to an adverse event. Subgroups who had higher rates of durable responses included those who had received two to three prior lines of therapy (40%), splenectomized patients (50%), and those who had not received prior rituximab (55%). Fostamatinib therapy in a real-world population of patients with heavily pretreated ITP led to a durable response in a third of patients, which was maintained for most responders.

Objective: We aimed to evaluate the effect of hyperbilirubinemia and phototherapy on total apoptotic, platelet-derived, endothelial-derived, and tissue factor (TF)-positive apoptotic microparticle (MP) levels in neonates with nonhemolytic pathologic hyperbilirubinemia.

Methods: Thirty-three term neonates with nonhemolytic pathologic hyperbilirubinemia and 25 healthy term neonates were included. MP levels were analyzed by flow cytometry using peripheral blood samples only once for the neonates in the control group and twice for the neonates in the study group (before and after phototherapy). Annexin V-positive MPs were defined as apoptotic MPs. Platelet-derived MPs were defined as those containing CD31. MPs containing CD144 were defined as endothelial-derived MPs, and MPs expressing TF were identified as those containing CD142.

Results: The rates of total apoptotic and endothelial-derived apoptotic MPs were significantly higher in the study group than the control group before phototherapy (P = 0.012 and P = 0.003, respectively) and after phototherapy (P = 0.046 and P = 0.001, respectively). Total apoptotic, platelet-derived, endothelial-derived, and TF-positive apoptotic MPs did not show any significant differences before and after phototherapy in the study group (P = 0.908, P = 0.823, P = 0.748, and P = 0.437, respectively).

Conclusions: Our study demonstrated that total apoptotic and endothelial-derived apoptotic MPs are increased in cases of nonhemolytic pathologic hyperbilirubinemia. We showed that phototherapy does not have a significant effect on apoptotic MP levels. Further studies are needed to evaluate the risk of elevated apoptotic MPs on the development of thromboembolism in neonates with nonhemolytic pathologic hyperbilirubinemia.

The aim of this study is to characterize zebrafish coagulation cofactors fviii and fv mutant fish and assess if they phenocopy classical hemophilia A and factor V deficiency in humans. The embryos from fviii and fv zebrafish heterozygote mutants generated by ENU mutagenesis were purchased from the ZIRC repository. They were reared to adulthood and genotyped. The heterozygote male and female were crossed to get homozygote, heterozygote, and wild-type fish. Functional kinetic coagulation assays and bleeding assays were performed on normal and mutant adult fish, and venous laser injury assays were performed on the larvae. The DNA from fviii and fv mutants were sequenced to confirm if they have a premature stop codon in exon 19, and in exon 2, respectively, and in both mutants, the amino acid glutamine is replaced with a stop codon. Homozygous and heterozygous 5 days post fertilization (dpf) larvae for fviii and fv deficient mutants exhibited prolonged time to occlusion after venous laser injury compared to wild-type controls. The homozygous and heterozygous fviii adult mutants showed modest bleeding and delayed fibrin formation in the kinetic partial thromboplastin time (kPTT) assay with their plasma. fv homozygous larvae had poor survival beyond 12 dpf. However, heterozygous fv mutants exhibited heavy bleeding and prolonged fibrin formation in the kPTT and kPT assay compared with wild-type siblings. Our characterization showed fviii and fv mutants from ZIRC phenocopied to a considerable extent classical hemophilia A and factor V deficiency in humans, respectively. These models should be useful in studying and developing novel drugs that reverse the phenotype and in generating suppressor mutations to identify novel factors that compensate for these deficiencies.

Normally, von Willebrand factor (VWF) remains inactive unless its A1A2 domains undergo a shear stress-triggered conformational change. We demonstrated the capacity of a recombinant A2 domain of VWF to bind and to affect fibrin formation, altering the fibrin clot structure. The data indicated that VWF contains an additional binding site for fibrin in the A2 domain that plays a role in the incorporation of VWF to the polymerizing fibrin. This study is to examine the hypothesis that active plasma VWF directly influence fibrin polymerization and the structure of fibrin clots. The study used healthy and type 3 von Willebrand disease (VWD) plasma, purified plasma VWF, fibrin polymerization assays, confocal microscopy and scanning electron microscopy. The exposed A2 domain in active VWF harbors additional binding sites for fibrinogen, and significantly potentiates fibrin formation (P < 0.02). Antibody against the A2 domain of VWF significantly decreased the initial rate of change of fibrin formation (P < 0.002). Clot analyses revealed a significant difference in porosity between normal and type 3 VWD plasma (P < 0.008), further supported by scanning electron microscopy, which demonstrated thicker fibrin fibers in the presence of plasma VWF (P < 0.0003). Confocal immunofluorescence microscopy showed punctate VWF staining along fibrin fibrils, providing visual evidence of the integration of plasma VWF into the fibrin matrix. The study with type 3 VWD plasma supports the hypothesis that plasma VWF directly influences fibrin polymerization and clot structure. In addition, a conformational change in the A1A2 domains exposes a hidden fibrin(ogen) binding site, indicating that plasma VWF determines the fibrin clot structure.

Immune-mediated thrombotic thrombocytopenia purpura (iTTP) is a rare microvascular disease characterized by severe disseminated microvascular thrombose-bleeding syndrome. Caplacizumab has been approved for the treatment of iTTP in combination with Plasma Exchange (PE) and immunosuppressive therapy, but its role in iTTP therapy remains uncertain. Therefore, we conducted a meta-analysis to investigate the safety and efficacy of caplacizumab for the treatment of patients with iTTP. We searched electronic databases (PubMed, Embase, Cochrane Library, and Scopus) and reference lists of relevant articles to find articles published from 2015 to 2022. The time to normalization of the platelet count of the group caplacizumab is shorter than the group placebo (SMD = -0.72; 95% CI -0.88 to -0.56; P  < 0.05). Caplacizumab reduced the incidence of mortality (OR = 0.41; 95% CI 0.18-0.92; P  < 0.05), exacerbations (OR = 0.10; 95% CI 0.05-0.18; P  < 0.05), and recurrence (OR = 0.17; 95% CI 0.06-0.50; P  < 0.05). However, the bleeding events in the caplacizumab group were higher than those in the placebo group, especially severe bleeding events. There was no difference in ADAMTS13 activity and thromboembolic events between the two groups. Our analysis indicated that caplacizumab is effective and well tolerated for the treatment of iTTP.

Systematic review registration: PROSPERO CRD42022362370.