Dental interventions in oral antithrombotic therapy.

Dentists commonly encounter patients taking oral antithrombotic agents who require invasive dental procedures. Although antithrombotics can cause an increase in bleeding, there is consensus that treatment regimens with antiplatelet agents, older anticoagulants (warfarin) and direct oral anticoagulants should not be altered before routine dental procedures when the risk of bleeding is low. Thromboembolic risk of their discontinuing likely outweighs potential bleeding complications associated with surgery. Therefore, the risks of stopping or reducing these medications must be weighed against the potential consequences of prolonged bleeding, which can be controlled with local measures such as mechanical pressure, suturing, haemostatic agents or antifibrinolytics. Some patients who are taking antithrombotic medications may have additional comorbid conditions or receive other therapy that can increase the risk of prolonged bleeding after dental treatment. Where a patient is believed to be at high bleeding risk, the dentist should consider a consultation with the patient's physician to discuss temporarily discontinuing the antithrombotic therapy.

May warfarin prevent cancer?

Animal and epidemiologic studies suggest that the use of warfarin might reduce cancer incidence. The antitumor potential of warfarin is demonstrated in different experimental cancer models. Specifically, studies in murine cancer models have shown that warfarin blocks AXL receptor tyrosine kinase by inhibiting a vitamin K-dependent protein called GAS6, thereby may halt the spread of cancer cells. An off-target effect of the anticoagulant warfarin is inhibition of GAS6-AXL signaling, which enhances antitumor immunity and blocks tumorigenesis independently of anticoagulation. Hence, the observed association between warfarin use and lower cancer incidence is likely due to an enhanced antitumor immune surveillance of early cancer. The large observational study also showed a reduction in cancer incidence among regular warfarin users. The study data indicate that warfarin provides a possible cancer protection. Despite some limitations, the results of this study give further support for the hypothesis that warfarin use decreases cancer incidence, which warrants continued investigation. This finding may have important implications for choosing medications in patients who need anticoagulant therapy.

A Comparative Study of Molecular Structure, pKa, Lipophilicity, Solubility, Absorption and Polar Surface Area of Some Antiplatelet Drugs.

Theoretical chemistry methods have been used to study the molecular properties of antiplatelet agents (ticlopidine, clopidogrel, prasugrel, elinogrel, ticagrelor and cangrelor) and several thiol-containing active metabolites. The geometries and energies of most stable conformers of these drugs have been computed at the Becke3LYP/6-311++G(d,p) level of density functional theory. Computed dissociation constants show that the active metabolites of prodrugs (ticlopidine, clopidogrel and prasugrel) and drugs elinogrel and cangrelor are completely ionized at pH 7.4. Both ticagrelor and its active metabolite are present at pH = 7.4 in neutral undissociated form. The thienopyridine prodrugs ticlopidine, clopidogrel and prasugrel are lipophilic and insoluble in water. Their lipophilicity is very high (about 2.5-3.5 logP values). The polar surface area, with regard to the structurally-heterogeneous character of these antiplatelet drugs, is from very large interval of values of 3-255 Ų. Thienopyridine prodrugs, like ticlopidine, clopidogrel and prasugrel, with the lowest polar surface area (PSA) values, exhibit the largest absorption. A high value of polar surface area (PSA) of cangrelor (255 Ų) results in substantial worsening of the absorption in comparison with thienopyridine drugs.

Theoretical Study of Molecular Structure and Physicochemical Properties of Novel Factor Xa Inhibitors and Dual Factor Xa and Factor IIa Inhibitors.

The geometries and energies of factor Xa inhibitors edoxaban, eribaxaban, fidexaban, darexaban, letaxaban, and the dual factor Xa and thrombin inhibitors tanogitran and SAR107375 in both the gas-phase and aqueous solution were studied using the Becke3LYP/6-31++G(d,p) or Grimme's B97D/6-31++G(d,p) method. The fully optimized conformers of these anticoagulants show a characteristic l-shape structure, and the water had a remarkable effect on the equilibrium geometry. According to the calculated pKa values eribaxaban and letaxaban are in neutral undissociated form at pH 7.4, while fidexaban and tanogitran exist as zwitterionic structures. The lipophilicity of the inhibitors studied lies within a large range of log P between 1 and 4. The dual inhibitor SAR107375 represents an improvement in structural, physicochemical and pharmacokinetic characteristics over tanogitran. At blood pH, SAR107375 predominantly exists in neutral form. In contrast with tanogitran, it is better absorbed and more lipophilic and active after oral application.

Platelet abnormalities in adults with severe pulmonary arterial hypertension related to congenital heart defects (Eisenmenger syndrome).

Patients with severe pulmonary arterial hypertension suffer from life-threatening thrombotic and bleeding complications. The aim of this study was to compare selected platelet, endothelial, and coagulation parameters in healthy volunteers and patients with severe pulmonary arterial hypertension because of congenital heart defects. The study included healthy volunteers (n = 50) and patients with cyanotic congenital heart defects classified as Eisenmenger syndrome (n = 41). We investigated platelet count, mean platelet volume, and platelet aggregation - spontaneous and induced by various concentrations of five agonists. Von Willebrand factor (vWF), fibrinogen, factor VIII and XII, plasminogen activator inhibitor, antithrombin, D-dimer, and antiphospholipid antibodies were also investigated. We found a decreased platelet count [190 (147-225) vs. 248 (205-295) 10 l, P < 0.0001], higher mean platelet volume [10.9 (10.1-12.0) vs. 10.2 (9.4-10.4) fl, P < 0.0001], and significantly decreased platelet aggregation (induced by five agonists, in various concentrations) in patients with Eisenmenger syndrome compared with controls. These changes were accompanied by an increase of plasma vWF antigen [141.6 (108.9-179.1) vs. 117.4 (9.2-140.7) IU/dl, P = 0.022] and serum anti-ß2-glycoprotein [2.07 (0.71-3.41) vs. 0.47 (0.18-0.99) U/ml, P < 0.0001]. Eisenmenger syndrome is accompanied by platelet abnormalities. Thrombocytopenia with increased platelet size is probably due to a higher platelet turnover associated with platelet activation. Impaired platelet aggregation can reflect specific platelet behaviour in patients with Eisenmenger syndrome. These changes can be related both to bleeding and to thrombotic events. A higher vWF antigen may be a consequence of endothelial damage in Eisenmenger syndrome, but the cause for an increase of anti-ß2-glycoprotein is unknown.

Platelet abnormalities in chronic thromboembolic pulmonary hypertension.

The reasons for non-resolving thrombosis in chronic thromboembolic pulmonary hypertension (CTEPH) have not been fully elucidated. Despite platelets being implied in its pathogenesis, they have been poorly studied. We hypothesized that platelets would be altered in CTEPH. The aim of our study was to compare selected platelet parameters in CTEPH patients with healthy subjects. The study included healthy subjects (n = 50) and patients with CTEPH (n = 47). We investigated platelet count, mean platelet volume (MPV), and platelet aggregation-spontaneous (SPA) and induced by various concentrations of five agonists. In addition, some other hemostatic parameters were also investigated to provide a comprehensive view on hemostasis. We found a decreased platelet count [212 (171-251) versus 248 (205-408) 10(9) L(-1), P<0.01], higher MPV [11.3 (10.5-11.7) versus 10.1 fL (9.4-10.4), P<0.001] and higher SPA [9.5 (7.1-12.4) versus 5 (1.3-9) %, P<0.001], but a decrease of induced platelet aggregation (only by maximal agonist concentrations) in CTEPH patients compared to controls. These changes were accompanied by a significant increase of plasma fibrinogen, factor VIII, von Willebrand factor (antigen and activity), and plasminogen activator inhibitor. Thus, we can conclude that CTEPH is accompanied by a prothrombotic state, including platelet abnormalities. They reflect a higher platelet turnover/reactivity and specific platelet behavior (impaired aggregation) in these patients. Our findings imply that platelet disorders can contribute to the pathogenesis of CTEPH. However, further research would be desirable to better understand the reason for this finding.

[Are we to pay attention to factor XII deficiency?]. / Máme venovat pozornost defektu koagulacného faktora XII?

UNLABELLED: Severe coagulation factor XII (FXII) deficiency is a very rare, mysterious and not well known inherited condition. Unlike other coagulation factor deficiencies, it is totally asymptomatic. Surprisingly, it does not lead to abnormal bleeding, even with major surgical procedures. The explanation for the lack of bleeding manifestations is unknown. It is suggested, but unproven, that patients are not sufficiently protected from thrombosis. FXII deficiency is usually discovered by accident through a routine coagulation testing done prior to surgery. Since FXII plays an important role in clot formation during in vitro measurements, its deficiency causes a marked prolongation of the activated partial thromboplastin time in the laboratory examination. The main concern related to FXII deficiency is the unnecessary testing, delay in health care and worry of surgical interventions that may be prompted by the abnormal laboratory result. KEY WORDS: activated partial thromboplastin time - bleeding - blood coagulation - factor XII.

[Are we to pay attention to factor XII deficiency?]. / Máme venovat' pozornost' defektu koagulacného faktora XII?

Severe coagulation factor XII (FXII) deficiency is a very rare, mysterious and not well known inherited condition. Unlike other coagulation factor deficiencies, it is totally asymptomatic. Surprisingly, it does not lead to abnormal bleeding, even with major surgical procedures. The explanation for the lack of bleeding manifestations is unknown. It is suggested, but unproven, that patients are not sufficiently protected from thrombosis. FXII deficiency is usually discovered by accident through a routine coagulation testing done prior to surgery. Since FXII plays an important role in clot formation during in vitro measurements, its deficiency causes a marked prolongation of the activated partial thromboplastin time in the laboratory examination. The main concern related to FXII deficiency is the unnecessary testing, delay in health care and worry of surgical interventions that may be prompted by the abnormal laboratory result.

El sistema renina-angiotensina-aldosterona y el estado protrombótico en la hipertensión arterial / The renin-angiotensin-aldosterone system and prothrombotic state in arterial hypertension

La hipertensión arterial se asocia con un incremento en el riesgo de eventos trombóticos oclusivos, como consecuencia de un estado protrombótico presente en los pacientes hipertensos. Una serie de anomalías de la hemostasia parecen desempeñar un papel en las complicaciones trombóticas de la hipertensión. Sistemáticamente se ha informado acerca de disfunción endotelial, incremento de la activación plaquetaria, aumento de la actividad del sistema de la coagulación y reducción de la función del sistema fibrinolítico en los pacientes hipertensos. Estas alteraciones pueden inducirse por la activación del sistema renina- angiotensina-aldosterona (SRAA) y contribuir a un mayor riesgo y gravedad del daño de los órganos blanco. El tratamiento antihipertensivo con antagonistas del SRAA podría revertir estas alteraciones protrombóticas. Dado que los inhibidores de la enzima convertidora de angiotensina (IECA) y los antagonistas del receptor de angiotensina II (ARA-II) tienen dos mecanismos diferentes de interrupción del SRAA, cada terapia podría tener repercusiones distintas sobre el estado protrombótico de los pacientes hipertensos. En algunos estudios se demostró un efecto beneficioso sobre el estado protrombótico de los IECA en particular y también de algunos ARA-II de forma parcial. El potencial efecto antitrombótico de los inhibidores del SRAA podría contribuir a la preservación de la función cardiovascular. Los datos disponibles pueden ofrecer una explicación adicional de la eficacia de los inhibidores del SRAA en la prevención de los eventos cardiovasculares en pacientes con enfermedad vascular aterosclerótica.

A severe renal bleeding as a complication of coumarin therapy in Behçet's disease.

Behçet's disease is a systemic inflammatory disease, which predisposes patients to venous or arterial thrombosis. We report a case of 41-year-old patient who presented for several years with recurrent fevers, arthralgias, episodes of skin eruptions and recurrent bilateral deep venous ileofemoral thromboses, extending into the inferior vena cava, despite the oral anticoagulant therapy. Additionally, he also reported recurrent aphthous oral and genital lesions, and eye problems. A laboratory picture of chronic inflammation, normocytic anaemia and a finding of lupus anticoagulant/antiphospholipid antibodies were observed. PET raised a high suspicion of vasculitic PTT-lupus anticoagulant process, involving the large vessels. During an anticoagulant therapy by warfarin (dose in upper limit of therapeutic range), the left kidney had to be removed because of acute retroperitoneal haemorrhage. On histologic examination, the picture of nephritis was described. A detailed retrospective reevaluation of complex history as well as other clinical findings strongly raised the suspicion of a systemic vasculitic syndrome, such as Behçet's disease, accompanied by antiphospholipid syndrome. The patient responded well to the combination of colchicine and anticoagulant therapy by low-molecular-weight heparin. The episodes of fever, skin eruptions and other symptoms disappeared. We assume that this is a case of an unusual course of Behçet's disease presenting with a rare kidney involvement. Kidney disorder complicated the oral anticoagulant therapy for recurrent venous thromboses and led to the excessive renal bleeding, requiring nephrectomy. Recognition that nephritis is associated with Behçet's disease may be useful to prevent severe renal bleeding in relation to anticoagulant therapy.

Homocysteine and endothelial markers are increased in patients with chronic liver diseases.

BACKGROUND: Hyperhomocysteinaemia is a disorder of methionine metabolism, in which a liver plays a role. It may be frequently due to nutritional deficiencies, particularly low folate status. The aim of the study was to evaluate the serum concentration of homocysteine (Hcy) in patients with chronic liver diseases (CLD), and to assess the relation between Hcy, folate levels, and endothelial markers. METHODS: Seventy-one patients with CLD and 51 healthy subjects of similar sex and age were investigated. There were 19 patients with steatosis and 52 patients with fibrosis/cirrhosis, classified by the Child-Pugh score as groups A, B and C. Fasting serum Hcy and folate levels were measured by the IMx diagnostic system (ABBOTT, USA). Plasma thrombomodulin (TM) and von Willebrand factor (vWF) as markers of endothelial dysfunction/damage were determined by ELISA methods. RESULTS: A significant increase of Hcy in all groups of patients with CLD was found: steatosis (P=0.0036), fibrosis/cirrhosis - groups A, B and C (P=0.0067, P<0.0001, P=0.0005, respectively). No significant changes of serum folate in CLD patients were observed, but there was an inverse correlation between Hcy and folate concentrations (r(2)=0.1076, P=0.0003). A significant increase of endothelial markers in CLD patients was found: TM in steatosis (P=0.029), fibrosis/cirrhosis - group A (P=0.0010), groups B and C (P<0.0001, respectively), vWF in fibrosis/cirrhosis - group A (P=0.0003), groups B and C (P<0.0001, respectively). No significant correlation between serum Hcy and endothelial markers was observed. CONCLUSION: Hyperhomocysteinaemia and abnormalities of endothelial function are demonstrated in CLD patients. The impairment of liver metabolism and local changes in vessel integrity are supposed to play a main role.

Acute vasculitis as a first manifestation of hairy cell leukemia.

Hairy cell leukemia (HCL) is a lymphoproliferative malignancy characterized by bone marrow, spleen, liver, and occasionally lymph node infiltration with hairy cells, usually accompanied by splenomegaly and pancytopenia. We report an unusual case of HCL in a 53-year-old woman with leukopenia and sudden onset of fever of unknown origin, arthritis, and generalized maculopapular exanthem. Skin biopsy revealed perivascular and/or vessel wall lymphocytic infiltration in the dermis. On the basis of bone marrow biopsy and flow cytometry, the diagnosis of HCL was established. A detailed, retrospective re-evaluation of the skin biopsy helped to identify hairy cells among the cells of the perivascular infiltrations. Small-vessel vasculitis, as an atypical presentation, was found to predate a diagnosis of HCL. Recognition that vasculitis can reflect or antedate lymphoid malignancy may permit early diagnosis and aggressive treatment. A rapid response was obtained with a single course of cladribine.

B cell chronic lymphocytic leukemia with meningeal infiltration by T lymphocytes.

Chronic lymphocytic leukemia (CLL) is a generalized malignancy of the lymphoid tissue characterized by an accumulation of monoclonal lymphocytes, usually of the B cell type. Involvement of the central nervous system is a rare complication, usually seen in T cell leukemias. We report a case of a 78-year-old woman with B cell CLL and meningeal infiltration by both B and T lymphocytes, although predominantly T lymphocytes. Neurological symptoms were the first manifestation of this disease. Computed tomography of the brain was negative. The diagnosis of leukemic meningitis was made on the basis of the examination of the cerebrospinal fluid, and which included cytological and flow cytometry analysis. The patient was given systemic chemotherapy in the form of chlorambucil and intrathecal administration of methotrexate and dexamethasone. After recovery, she had regular follow-up. We assume that this rare case of CLL might have been biclonal, with both B and T cell types.