Risk factors detection in chronic thromboembolic pulmonary hypertension, a tool for risk quantification?

BACKGROUND: Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by chronic thromboembolic obstruction in the pulmonary bed. The definitive pathogenesis remains incompletely explained, although multiple risk factors of CTEPH have been identified. The purpose of the study was to evaluate the risk profile of patients with CTEPH and the representativeness of risk factors, identify possible new CTEPH risk factors and specify the epidemiology of CTEPH in our country. METHODS: In 81 patients with CTEPH, well known risk factors were analyzed, and a detailed analysis of selected hematological parameters was investigated at a specialized hematology laboratory. RESULTS: CTEPH risk factors were identified as follows: pulmonary embolism (PE), deep vein thrombosis (DVT), thyreopathy, blood type other than "0", inflammatory bowel disease, malignancy, splenectomy, pacemaker. When compared to healthy controls, the following was observed: a significant decrease in platelet count, higher mean platelet volume, higher spontaneous platelet aggregation, increase in von Willebrand factor and fibrinogen. The median of risk factors representativeness was 3 (PE, DVT, blood type other than "0"). The prevalence of CTEPH in adult population in our country is estimated to be 1.8 per 100,000 inhabitants. CONCLUSION: In the study we confirmed multiple established risk factors of CTEPH, set their representativeness, identified some platelet abnormalities which could be a potential new risk marker and specified the prevalence of CTEPH (Tab. 5, Ref. 35).

[Is antiplatelet therapy always effective?]. / Je protidosticková liecba vzdy úcinná?

OBJECTIVE: Acetylsalicylic acid (ASA) and clopidogrel (KLP) therapy is associated with the high degree of variability in response to the drug and some patients are drug-resistant. The aim of our study was to evaluate the individual response to antiplatelet therapy in patients at high risk of cardiovascular events treated with ASA (n = 131), KLP (n = 51) or ASA + KLP (n = 34). SUBJECTS AND METHODS: Investigations were performed in them by light transmission aggregometry and in selected patients by VASP fosforylation. RESULTS: Good response to ASA treatment with arachidonic acid-induced platelet aggregation inhibition < 20% reached 75.0% of patients, partial response with 20-40% inhibition 12.9% of patients and poor response with > 40 % inhibition 12.1 % of patients. Good response to KLP treatment with 20 µmol/l ADP-induced platelet aggregation inhibition < 60% reached 66.1% of patients, partial response with 60-70% inhibition 13.9% of patients and poor response > 70% in 20% of patients. In patients treated by KLP + ADP induced platelet aggregation correlated with VASP fosforylation. We found, that 50% of KLP-treated and 44.4% of ASA-treated patients obtained the adequate response to therapy by compliance improvement. In 80% of patients, which did not respond to KLP therapy in daily dose of 75 mg, the adequate response after the increase to daily dose of 150 mg was observed. The increase of ASA daily dose above 100 mg did not improve in our patients their response to therapy. However, in those patients without a good response to low-dose ASA (< 100 mg daily) the increase to daily dose of 100 mg effectively influenced the aggregatory response. CONCLUSION: Laboratory monitoring of individual response allows the optimalization of the antiplatelet therapy. The patients who could profit from other type of antiplatelet therapy, such as prasugrel and ticagrelor, can be selected by this method.

The role of renin-angiotensin system in prothrombotic state in essential hypertension.

Rheological, haemostatic, endothelial and platelet abnormalities appear to play a role in the thrombotic complications of hypertension. This prothrombotic/hypercoagulable state in hypertension may contribute to the increased risk and severity of target organ damage. It can be induced by the activated renin-angiotensin system (RAS), with abnormalities in endothelial and platelet function, coagulation and fibrinolysis. Treatment of uncomplicated essential hypertension by RAS targeting antihypertensive therapy could result in a reversal of prothrombotic abnormalities, contributing to a reduction of thrombosis-related complications. Since angiotensin converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) have two distinct mechanisms of RAS interruption, it is hypothesized that each therapy might have different impact on the prothrombotic state in hypertensive patients. Some studies demonstrate a beneficial effect of both ACE inhibitors and ARBs on prothrombotic state, in addition to their efficacy to normalize elevated blood pressure. The potentially antithrombotic effect of the RAS inhibiting agents may in turn support the preservation of cardiovascular function. Available data may offer an additional explanation for the efficacy of the RAS targeting agents in the prevention of cardiovascular events in patients with atherosclerotic vascular disease.

[Markers of endothelial function in the early stages of essential hypertension and the effect of antihypertensive therapy]. / Markery funkcie endotelu vo vcasných stádiách esenciálnej hypertenzie a ucinok antihypertenznej terapie.

OBJECTIVE: Endothelial abnormalities appear to play a role in the pathogenesis of atherosclerotic/atherothrombotic complications of hypertension. They may contribute to the increased risk and severity of target organ damage. The aim of the study was to investigate the endothelial markers in patients at the early stages of mild-to-moderate untreated hypertension with low-to-moderate added risk, and the effect of antihypertensive therapy by perindopril, telmisartan or rilmenidine on endothelial function. SUBJECTS AND METHODS: The measurements were carried out in 54 previously untreated hypertensive patients before and after one month of antihypertensive therapy by perindopril-arginine (5 mg once daily, n = 20), telmisartan (40 mg once daily, n = 16), rilmenidine (1 mg once daily, n = 18) or after placebo administration (n = 23). A population of 50 healthy normotensive subjects of similar sex, age and ethnic origin was also examined. Plasma thrombomodulin (TM) and von Willebrand factor (vWF) measurements were used as indicators of endothelial dysfunction. RESULTS: In untreated hypertensive patients compared with a control group of healthy subjects a significant increase of plasma vWF (86.26 +/- 26.18 IU/dl against 69.14 +/- 18.74 IU/dl, P < 0.001) and TM (35.98 +/- 12.98 ng/ml against 29.34 +/- 9.18 ng/ml, P < 0.01) was found. BP was reduced (P < 0.001) or normalized due to each therapy. No significant changes of endothelial markers after placebo administration were found. A decrease of plasma vWF antigen level after 1 month of therapy by perindopril (from 81.93 +/- 22.07 to 72.88 +/- 23.26 IU/dl, P < 0.05) or rilmenidine (from 100.6 +/- 26.09 to 86.07 +/- 27.66 IU/dl, P < 0.05) was observed. No significant changes of vWF antigen levels were found after telmisartan therapy. We failed to find any changes of plasma TM due to any therapy. CONCLUSION: Our results demonstrate that antihypertensive treatment by perindopril or rilmenidine has a favourable affect on some endothelial markers.

General changes in hemostasis in gastric cancer.

Disorders of haemostasis and haemocoagulation are often seen in patients with cancer as a part of paraneoplastic syndrome. Thrombotic and/or haemorrhagic complications are the second most common cause of mortality in patients with cancer. The evaluation of the haemostatic parameters of 67 patients with gastric cancer have indicated tendency to thrombophilia and activation of intravascular coagulation, of which 31.3% showed tendency to hypercoagulation and 47.8% disseminated intravascular coagulation (DIC). Only 7.5% of subjects have yielded normal laboratory findings while 5.9% of patients had DIC with remarkable hypocoagulation. Thrombocytosis, platelet hyperaggregability and elevation of beta-thromboglobulin are the indicators of changes in primary haemostasis and elevation of thrombomodulin indicates vascular wall damage. Lower antithrombin III levels, C-protein and S-protein in plasma have indicated lower antithrombotic potential in patients with gastric cancer. It can be concluded that patients suffering from gastric cancer are at higher risk of thromboembolism as for haemorrhagic diathesis (20.1% thromboembolism, 11.94% fatal thromboembolic events vs 5.9 % haemorrhagic diathesis) (Tab. 5, Ref. 22). Full Text (Free, PDF) www.bmj.sk.

Local changes in hemostasis in patients with gastric cancer.

Disorders of haemostasis and haemocoagulation are often seen in cancer patients as a part of the paraneoplastic syndrome. This study describes a novel compound that activates coagulation and also inhibits fibrinolytic system and fibrin degradation products in the gastric juice of 33 patients with gastric cancer. Similar, but less pronounced changes have been found in gastric juice of patients with gastric precancerosis. Procoagulant activity, induced by pathologically changed cells or monocytes, macrophages from tumor stroma, indicates the activation of local coagulation with the production of fibrin. It can be concluded that the local changes of coagulation and fibrinolysis may precede coagulopathies in cancer patients (Tab. 2, Ref. 15). Full Text (Free, PDF) www.bmj.sk.

Impact of the therapy by renin-angiotensin system targeting antihypertensive agents perindopril versus telmisartan on prothrombotic state in essential hypertension.

The aim of the study was to investigate the effect of therapy by perindopril or telmisartan on endothelial/platelet function and on coagulation/fibrinolysis in 20 and 16 hypertensive patients, respectively. The measurements were carried out before and after 1 month of therapy. Both systolic blood pressure and diastolic blood pressure were reduced (P<0.001) or normalized due to each therapy. Plasma thrombomodulin (TM) and von Willebrand factor (vWF) as indicators of endothelial dysfunction, plasma beta-thromboglobulin (betaTG), platelet factor 4 (PF4), soluble P-selectin (sPsel) and soluble glycoprotein V (sGpV) as indicators of in vivo platelet activation, plasminogen activator inhibitor type 1 (PAI-1) antigen and tissue type plasminogen activator (tPA) antigen as markers of fibrinolytic activity, soluble endothelial protein C receptor (sEPCR) as a new marker of hypercoagulation and fibrinogen level as a known risk factor for vascular changes were investigated. A decrease of plasma vWF, sPsel, sGpV, PAI-1 and tPA antigen level (P<0.05, respectively) after 1 month of therapy by perindopril was observed. On the other hand, a decrease of plasma sEPCR and fibrinogen level (P<0.05, respectively) after 1 month of therapy by telmisartan was found. We failed to find changes of plasma TM, betaTG and PF4 due to any therapy investigated. The additional beneficial 'antithrombotic' effects of the renin-angiotensin system targeting agents (vasculoprotective, anti-platelet and profibrinolytic effects of perindopril and anticoagulant/rheological effects of telmisartan) may be important in terms of the favourable role of antihypertensive drugs in cardiovascular morbidity.

Diagnostic approach to hypercoagulable states.

The primary hypercoagulable states are inherited thrombotic disorders, resulting from mutations in genes encoding a plasma protein component of one of the coagulation mechanisms. The anticoagulant pathways most frequently involved include antithrombin III, protein C, and protein S deficiencies and activated protein C (APC) resistance. Around 80 % of all individuals with APC resistance carry a mutation of the factor V gene. Abnormalities in procoagulant pathways mostly concern elevated levels and/or function of procoagulant factors. Elevation in plasma prothrombin (FII) levels is associated with a FII gene mutation. Hyperhomocysteinemia as a risk factor for thrombosis is determined by genetic or dietary factors. The acquired or secondary hypercoagulable states consist of a heterogeneous group of disorders with an increased risk for developing thrombosis. Many underlying conditions (e.g., malignancies) may induce changes in the coagulation system. The risk of thrombosis is increased in individuals with antiphospholipid antibodies. They are found in about one-half of patients with systemic lupus erythematosus, but also in the course of infections, neoplastic diseases, and sometimes in apparently normal subjects. A definite molecular abnormality of hypercoagulable states can be identified in the special coagulation laboratory, using two types of molecular risk factors for thrombosis (genetic factors and abnormal laboratory phenotypes). Its recognition is useful for a prevention and/or therapy of thrombosis (Tab. 4, Ref. 10).

Effect of the new centrally acting antihypertensive agent rilmenidine on endothelial and platelet function in essential hypertension.

The aim of the study was to investigate the effect of therapy by rilmenidine on endothelial and platelet function in 23 patients with the early stages of untreated essential hypertension. The measurements were carried out before therapy, after 1 week of placebo administration, after 1 week, after 1 month and after 3 months of therapy. After 1 week of therapy both systolic (SBP) and diastolic blood pressure (DBP) were reduced (P < 0.001) all over the study period. Plasma thrombomodulin (TM) and von Willebrand factor (vWF) as indicators of endothelial dysfunction, and plasma beta-thromboglobulin (betaTG) as an indicator of in vivo platelet activation, were investigated. Fibrinogen as a risk factor for vascular changes was also assayed. Platelet aggregation without stimulation (spontaneous, SPA) and induced by adrenaline (APA) was measured. A decrease of plasma vWF level after 1 month (P < 0.05) and after 3 months (P < 0.05) of therapy was observed. We failed to find any changes of plasma TM and fibrinogen level. A reduction of platelet aggregation was evident after 1 week (SPA and APA, P < 0.05, respectively) but mainly after 1 month (SPA P < 0.01, APA P < 0.05) and after 3 months of therapy (SPA and APA, P < 0.01, respectively). It was accompanied by a decrease of plasma betaTG level after 3 months of therapy (P < 0.05). The vasculoprotective and antiplatelet effect of rilmenidine may be important in terms of the favourable role of antihypertensive drugs in cardiovascular morbidity.

Effect of the angiotensin-converting enzyme inhibitor perindopril on haemostasis in essential hypertension.

Endothelial damage, platelet hyperactivity and other changes of blood coagulation may play a role in the vascular complications of essential hypertension. Undesirable changes of haemostasis induced by some anti-hypertensive drugs can encourage the acceleration of atherogenesis. Therefore, the effect of angiotensin-converting enzyme (ACE)-inhibitors on haemostasis is of interest. The therapeutic dose of perindopril was previously shown to reduce platelet aggregation. In the present study, selected parameters of haemostasis were investigated in 23 patients with first and second stage of non-treated essential hypertension. The measurements were carried out before therapy, after 1 week of placebo administration, and after 1 week and after 1 month of ACE-inhibitor perindopril therapy in a once-daily dose of 4 mg. Plasma prothrombin time, activated partial thromboplastin time, fibrinogen level, plasminogen and antithrombin III activities, protein C and free protein S antigens, total fibrinolytic activity as well as fibrin monomers and D-dimers were assayed. There were no significant changes in any haemostasis variables investigated following placebo administration or perindopril therapy. On the basis of this study, no unfavourable effects on haemostasis induced by this therapy were found. The platelet-inhibitory effect of perindopril, without any harmful effects on coagulation or fibrinolytic activity and coagulation inhibitors, is desirable in the new approach to hypertension treatment. These properties of perindopril may be important in terms of the beneficial role of anti-hypertensive drugs in cardiovascular morbidity.

[Perioperative care by internists in splenectomy]. / Perioperacná starostlivost internistu pri splenektómii.

Splenectomy (SE) is one of the surgical interventions requiring an increased internal care. The removal of the spleen which is an organ with an exceptional function can lead to complications even in people who are healthy in all other respects. The complications in coincidence with SE can arise early (up to 30 days after surgery) or later. Early complications can involve infections of the respiratory tract (especially bronchopneumonia), or subphrenic abscess. Thromboembolic complications occur not only in peri-operational period, but also in several weeks or months after SE. A severe complication resides in disseminated intravascular blood coagulation. Late complications represent a lifelong danger for asplenic patients. They include the fulminant sepsis, known as so-called OPSI syndrome (overwhelming postsplenectomy infection). The mortality rate in coincidence with the latter is very high despite intensive antibiotic therapy. The risk is especially high in children, in immuno-deficient states and immunosuppressive therapy. 60% of patients develop OPSI during the first two years, out of whom one third is afflicted in the first half of the year following SE. In more than 30% of patients OPSI manifests itself minimally 5 years later. The prevention of infection in coincidence with SE is performed by means of immunization, antibiotic prophylaxis and via education of patients. Immunization includes the administration of a polyvalent pneumococcus vaccine, in children it includes also the vaccine against Haemophilus inluenzae and Neisseria meningitidis. The appropriate antibiotic prophylaxis is represented especially by penicillin, amoxicillin, or amoxicillin with clavulanic acid. The children or other patients with disturbed immunity functions are administered with antibiotics in low doses per os for a long period. Antibiotics in the therapy of OPSI are administered in full doses together with immunoglobulin, both are applied intravenously. A specific approach is required in patients with autoimmune thrombocytopenia, in whom the increase in the number of thrombocytes prior to operation can be achieved by high intravenous doses of corticoids or immunoglobulin G. In this case, unless explicitly necessary, the transfusion of thrombocytes should not be performed prior to SE. The antithrombotic therapy is appropriate in patients at high risk of post-surgical thrombosis (e.g. hereditary haemolytic anaemias, myeloproliferative diseases, SE in coincidence with polytraumatism.

Serum transferrin receptor in diagnosis of iron deficiency.

OBJECTIVE: The aim of the present study is to assess the diagnostic value of the serum transferrin receptor in distinguishing IDA (iron deficiency anemia) from ACD (anemia of chronic diseases) and combination of IDA and ACD (COMBI anemia) as compared to conventional laboratory tests of iron metabolism. BACKGROUND: Serum iron and serum ferritin are tests most commonly used for the detection of iron deficiency, however their values may be falsely changed. Serum fransferrin receptor (sTfR) has been introduced as a new tool, and its values are not affected by an increase in cytokine production in ACD patients. METHODS: In the retrospective study, 39 patients with IDA, 29 patients with ACD and 25 patients with COMBI, were evaluated using iron status tests including sTfR assay. The control group consisted of 33 healthy adults. RESULTS: Serum iron values in IDA, ACD and COMBI groups were not significantly different. Serum ferritin values distinguished IDA from ACD reliably but the diagnostic usefulness of ferritin measurements in ACD and COMBI patients is limited for their large variation breadth. Serum TfR concentrations were elevated in the vast majority of the IDA and COMBI patients and distinguished them from the ACD group. The distinguishing of IDA from COMBI of the single basis of iron status is still difficult. However, the detection of iron deficiency in COMBI patients is very useful for the initiation of replacement therapy. CONCLUSION: We conclude that sTfR measurement is a valuable non-invasive tool for the diagnosis of iron depletion and an attractive supplement to more conventional laboratory tests in the detection of depleted iron stores. (Tab. 2, Fig. 3, Ref. 25.).

Thrombomodulin as a marker of endothelium damage in some clinical conditions.

Background: Thrombomodulin (TM) is a membrane glycoprotein in the vascular endothelium. It may be cleaved from endothelial cells and released into the circulation. The plasma TM level depends on the integrity of the endothelium and the clearance of the molecule. The physiological role of soluble TM forms is still unclear. The clinical significance of elevated levels of TM in various pathologic conditions is not well established yet. To analyze variations of plasma TM level in different clinical situations, its concentrations in patients with three groups of diseases were measured and compared with those in healthy subjects. Methods: Plasma samples from 23 patients at risk for development of vascular complications [essential hypertension (EH), stages 1 and 2], 31 patients with inflammatory bowel diseases [Crohn's disease (IBD), mostly in the active stage], and 19 patients with malignant tumors [gastric carcinoma (NEO)], were analyzed for soluble TM with an enzyme immunoassay kit. Results: In the group of patients with the early stages of EH and with non-active IBD, no significant changes were found in comparison to the healthy subjects. In the patients with active IBD and mainly with NEO, soluble TM was significantly increased (P<0.05 and P<0.001, respectively). Conclusions: Our TM levels failed to demonstrate increased endothelial damage in the early stage of EH. This suggests that TM is released into the plasma only by true endothelial cell damage during the development of vascular complications. Probably a certain degree of endothelial injury is necessary for an increase in plasma. In the active stage of IBD and in NEO, soluble TM appears to be derived not only from injured endothelial cells, but may also be proteolytically cleaved from membrane TM by proteases. There may also be increased synthesis of TM in activated and/or transformed cells.