J Gumulec

Alemtuzumab, the humanized monoclonal anti-CD52 antibody, is an effective agent in the treatment of fludarabine-refractory chronic lymphocytic leukemia (CLL). Due to many specific issues associated with alemtuzumab treatment, the Working Committee of Czech CLL Study Group developed these guidelines. (1) The main indication of alemtuzumab is fludarabine-refractory CLL. (2) Further possible indications include first-line treatment (in patients who cannot be treated by fludarabine-containing regimens), therapy of patients with del 17p, treatment of refractory autoimmune cytopenias and management of patients with severe cytopenias due to bone marrow infiltration. (3) The treatment should last 12 weeks and should not be terminated prematurely if there are no signs of CLL progression; bone marrow aspirate/biopsy can be performed after 12 weeks of treatment. (4) Subcutaneous administration of alemtuzumab seems to be equally effective with advantageous reduction of infusion-related adverse events. (5) Patients treated with alemtuzumab must receive combined antimicrobial prophylaxis against Pneumocystis jiroveci and herpetic viruses. Cytomegalovirus viremia should be monitored using weekly PCR from peripheral blood. (6) Use of alemtuzumab in combinations and consolidation/maintenance protocols must be considered experimental and needs optimization within prospective clinical trials. (7) Alemtuzumab treatment should be conducted by an experienced hematologist within a center of intensive hematology care.

Patients with multiple myeloma have a high risk of venous thromboembolism (VTE), especially during the induction chemotherapy. The aim of our observational study was to determine the impact of prophylaxis with low molecular weight heparin (LMWH) on the incidence of thromboembolic complications. We analyzed the incidence of thromboembolic events in 258 patients treated with induction chemotherapy containing vincristin, doxorubicin or idarubicin, and dexamethasone, followed by stimulation chemotherapy with cyclophosphamide and G-CSF, and high-dose chemotherapy with melphalan. Two groups of these patients were compared based on the practice of thromboprophylaxis. Patients in the first group (Control, n = 140) were either not treated or treated with a short duration of anticoagulation therapy while the patients in the second group (Prophylactic, n = 118) underwent standard prophylaxis with LMWH throughout the entire period of induction chemotherapy. A total of 102 patients were selected for a close monitoring of the prophylactic effect of different LMWH doses and to be compared to patients without treatment. Standard prophylaxis with LMWH significantly (p < 0.007) lowered a risk of VTE when compared to patients without such prophylaxis (3.4% versus 12.9%, respectively). Furthermore, analysis of the subgroup of 102 patients revealed that higher LMWH doses (> 70 IU/kg per day) achieved full prophylaxis in 28 patients while lower doses were less effective leading to DVT in 3 (7.7%) out of 39 patients. In contrast, VTE was diagnosed in 5 (14.3%) out of 35 patients without any LMWH prophylaxis. Prophylaxis with LMWH leads to a significant reduction of the risk of thromboembolic complications during the induction chemotherapy in patients suffering from MM. The prophylactic effect of LMWH is dose-dependent.

A total 37 patients suffering from end stage-IV Fontaine (CLI and diabetic foot) with an ulcerated limb in whom all previous therapeutic strategies failed (e.g. surgical revascularization and endovascular repair) were selected and underwent local transplantation of Autologous Bone Marrow Stem Cells (ABMSCs). The efficacy/safety ofthis therapy was assessed by using several endpoints such as (a) prevention of amputation, (b) wound healing and (c) degree of angiogenesis. In order to assess the limb ischemia and hypoxia the several tests and measurements were performed pre- and post transplantation at a variety of time intervals. The measurements include: TP-toe pressure measurements (by Periflux 5000 Laser Doppler and Oxymetry system), SPP-skin perfusion pressure, ABI-ankle brachial index, LDP-Laser Doppler baseline and heat perfusion assessment, TcpO2 without and with O2 provocation inhalation test. In addition, a battery of biochemical and hematological tests of peripheral venous blood samples and bone marrow analysis were performed. Limb salvage was 81% in 30 patients, 7 patients (19%) were amputated for terminal severe ischemia and gangrene progression. In the group of limb salvage patients initial Toe pressure 23.119 (std. error 5.358) increased in 90 days follow-up into 29.888 (std. error 5.99), Toe brachial index increased from 0.1469 (std. 0.0326) to 0.1991(std. 0.401). In LASER doppler and TcpO2, TcpCO2 tissue perfusion examination TcpO2% Increase after O2 provocation inhalation test was elevated from 162.95 (%) to 229.86% which confirmed a very good tissue vasoreactivity after BMSC transplantation.

Traumatology and orthopaedics have undergone substantial progress in the use of new, sophisticated techniques, implants and navigation methods. Nevertheless, these new methods continue to fail in some instances. Regenerative medicine using the growth potential of stem cells that posses the ability to regenerate damaged tissues represent one of the possible ways forward. There is a potential for more comprehensive utilization of bone marrow stem cells that had for many years been used in transplant medicine. Traumatology and orthopaedics could utilise stem cells in the treatment of bone defects, i.e. in the treatment of pseudarthrosis, delayed fracture healing, defect fractures and aseptic bone necroses. Bone formation and growth is a complex, predominantly anabolic, process with a range of feedbacks. Nevertheless, it is the bone marrow where the necessary progenitors of bone growth are located. These are mesenchymal stem cells (MSCs), haematopoietic stem cells (HSCs) as well as thrombocytes containing a range of necessary growth factors. A number of studies showed positive results for stem cells treatment of pseudarthrosis, with only a fraction, however, being statistically significant in human medicine. This method was used in 11 patients of the Traumatology Centre of the Faculty Hospital in Ostrava, Czech Republic in 2008. The researched patients were treated for pseudarthrosis of long bones, delayed multifragmentary fracture haling and defect fractures of long bones. Autologous concentrate of bone marrow stem cells was applied in one session into the area of bone defect in a patient lightly anaesthetised with propofol. The results from this small sample of patients are not yet available. However, we are sharing our first experiences with this treatment option.

Deep venous thrombosis and pulmonary embolism are major health problems with potential serious outcomes. Acutely, pulmonary embolism may be fatal. In the long term, pulmonary hypertension can develop from recurrent pulmonary embolism. Often overlooked is post-thrombotic chronic venous insufficiency occurring as a result of deep venous thrombosis causing deep venous reflux or obstruction with skin changes and ulceration with adverse impact on quality of life and escalation of health care costs. Almost all hospitalized patients have at least one risk factor for venous thrombosis and approximately 40% have three or more risk factors. Without thromboprophylaxis, the incidence of objectively confirmed, hospital-acquired deep venous thrombosis is approximately 10 to 40% among medical or general surgical patients and 40 to 60% following major orthopedic surgery. Abundant data from metaanalysis and blinded, randomized clinical trials have demonstrated strong evidence that primary thromboprophylaxis reduces deep venous thrombosis and pulmonary embolism and little or no increase in the rates of clinically important bleeding with prophylactic doses of low-dose unfractionated heparin, low-molecular-weight heparin or fondaparinuxem.

We present an example of a patient with confirmed cold agglutinin disease who underwent cardiac surgery in hypothermia to illustrate a known fact that, when exposed to cold, cold agglutinins induce haemolysis of erythrocytes and that cryoglobulins and cryofibrinogens may, upon exposition to cold during a surgery under hypothermia, precipitate or gelify and thus increase plasma viscosity and damage microcirculation. Detailed immunological and haematological investigations in all patients awaiting cardiac surgery with a risk of developing hypothermia is not advantageous considering the low number of patients with clinical and laboratory signs of cold agglutinin disease, autoimmune haemolytic anaemia or paroxysmal cold haemoglobinuria and considering that these investigations, in addition, might not detect cryoglobulinaemia and cryofibrinogenemia. Identification of in-risk patients from the warning signs in the medical history, physical or basal laboratory testing who would subsequently undergo confirmatory investigations to verify the presence of these entities and define them accurately might be a potential solution to this clinical issue. Cardiac surgery strategy and peri-operative care should be tailored to the results of these investigations. Well-structured, practiced and functional cooperation between clinicians and laboratory personnel is a prerequisite for success in these circumstances.

The management of warfarin therapy in patients undergoing surgery or other invasive procedures involves a balance between the risk of hemorrhage, and the risk of thrombosis. Risk of hemorrhage and the trombosis depends on the type of procedure and on pre-existing conditions. Procedures with low risk of hemorrhage (dental, dermatologic or ophtalmologic procedures, endoscopy) can be provided with continuing anticoagulant therapy. Surgery with high hemorrhagic risk need stop warfarin and start bridging anticoagulant therapy, such as unfractionated heparin or low molecular weight heparin, prior and after surgery. In patients requiring emergency surgery, vitamin K, prothrombin complex concentrate or fresh frozen plasma can be used to improve coagulation.

Anticoagulant therapy is one of the most common forms of medical intervention. It is the mainstay of prevention and treatment of thrombotic events. Omission of adequate anticoagulant prophylaxis at least for moderate-risk and high-risk patients is a widely recognized medical error. Bleeding is one of the most feared complications of anticoagulant therapy, and is a risk of all anticoagulants. Whereas unfractionated heparin and warfarin, the oldest and most widely used anticoagulants, have specific antidotes for their anticoagulant effect, many of the newer agents (direct and indirect inhibitors of coagulation factors Xa and/or IIa) do not have specific antidotes to reverse their actions. The use of novel anticoagulants is further complicated by a lack of easily available laboratory tests to measure their levels and thereby optimize their benefit and safety in clinical practice. In this review, we evaluate the risk of bleeding associated with current anticoagulants, review the data available on current and experimental agents used for the reversal of anticoagulation, and provide recommendations for the management of major bleeding associated with anticoagulant therapy and for the management of asymptomatic overdosing of the anticoagulants.

Thrombocytopenia--decrease in the blood platelets count below 100 x 10(9)/L--may represent a significant clinical complication--bleeding. A risk of haemorrhagic complications increases with the severity of thrombocytopenia. Even severe thrombocytopenia, however, may be a sign of a condition with predominant symptoms of thrombosis where bleeding is on the background (thrombotic microangiopathy, for example) or where bleeding occurs concurrently with symptoms of thrombosis (so called thrombohaemorrhagic syndromes). It is necessary to exclude pseudothrombocytopenia when thrombocytopenia is first diagnosed. It is then recommended to follow a standardized differential diagnosis algorithm that should be available at each clinical site. We summarize the general rules of thrombocytopenia differential diagnosis with a specific focus on laboratory processes.

The current trend in medicine is to sustain the possibility for necessary procedures to be performed in patients who suffer from haemostatic disorders which complicate eventual surgery. Among such disorders are congenital blood coagulation disorders, haemostatic disorders concomitant with other diseases and also therapies which affect haemostasis either on purpose or as part of adverse effects. Among coagulation disorders are congenital haemorrhagic or thrombotic conditions, acquired blood coagulation disorders--combined in the vast majority of cases-- and associated with pregnancy, severe internal diseases and surgery related diseases, severe injuries, wounds, burns, malignancies, systemic connective tissue diseases, inflammatory bowel disease, and a number of other diseases. A separate issue is that ofanticoagulation therapy--both antiplatelet, used in the treatment or prevention of venous thrombosis, and anticoagulation, predominantly used to manage venous thromboembolism. Also considered should be any therapy which may have a negative impact on coagulation due to its adverse effects.