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Economizing health care systems has led to industrialized hospitals. The consequences and side effects are substantial and rather promote costs explosion due to the dictated increase in cases and efficiency. Hence, position sensing and change in direction are required. Effective ways to find out of the current crisis are discussed.

Venous thromboembolism (VTE) is associated with high morbidity and mortality. Therefore, effective methods for safe thromboprophylaxis remain an ongoing challenge in daily clinical practice. This is especially true for pregnant women and patients with gynaecological malignancies. Low-molecular weight heparins continue to be agents of choice for pharmacological thromboprophylaxis postoperatively, in pregnant patients at risk, and during the puerperium. However, these drugs can cause bleeds or heparin-induced thrombocytopenia (type II). Based on recent revisions of corresponding guidelines, this article provides an overview of the current state of pharmacological thromboprophylaxis and discusses prevailing problems and unresolved issues.

Given the high consumption of pharmacological agents in western societies, it is not surprising at all that drugs represent the most common cause of acquired platelet dysfunction. While acetylsalicylic acid, clopigogrel and integrin alphaIIbbeta3 (GPIIb-IIIa) receptor antagonists are well-known as prototypes of antiplatelet drugs, other widely used agents including non-steroidal anti-inflammatory drugs, antibiotics, serotonin reuptake inhibitors, and volume expanders can also impair platelet function and cause or aggravate haemorrhages. Besides pharmacological agents, certain clinical conditions are often associated with qualitative platelet disorders and bleeding diathesis. Consequently, in contrast to inherited platelet disorders, acquired platelet function defects are much more frequent in clinical practice and deserve special attention. Their pathogenesis is widespread and heterogeneous with various, sometimes overlapping abnormalities. Moreover, acquired platelet dysfunctions can occur at any age and range in severity from mild to life-threatening haemorrhages. Due to their heterogeneity, acquired platelet function disorders will be classified and discussed according to the underlying clinical setting or disease.

Apart from on-label indications, recombinant factor VIIa (rFVIIa) is increasingly administered for treatment of life threatening bleeding events when appropriate standard therapy fails. Case reports and short treatment series document the efficacy and safety of rFVIIa to achieve haemostasis in patients with platelet function disorders and thrombocytopenias of various origin. An established on-label indication for the use of rFVIIa is given in patients with Glanzmann thrombasthenia with refractoriness to transfusions of platelet concentrates. Bolus applications of rFVIIa at dosages between 80 and 120 microg/kg body weight every 1.5 to 3 h are also administered successfully in patients with Bernard-Soulier syndrome, platelet storage pool defects, and other acquired platelet function disorders. In patients with Glanzmann thrombasthenia, at least three bolus injections are required to achieve effective haemostasis. In approximately half of the patients with thrombocytopenias, a single bolus of rFVIIa has been shown to be sufficient in managing otherwise untreatable bleeding complications. In these patients, haemostasis was achieved even at platelet counts20,000/microl, although the efficacy of rFVIIa increases at higher platelet concentrations.

Thromboembolic disease remains a leading cause of maternal mortality during pregnancy and the puerperium. Rational and risk-adapted administration of heparin prophylaxis depends on 1. the identification of those women who have an increased risk of thrombosis and 2. the accurate quantification of this risk. In women without prior thrombosis, the presence of a heterozygous factor V Leiden or heterozygous G20210A mutation in the prothrombin gene is associated with a pregnancy-associated thrombotic risk of approximately 1 in 400. Thus, in pregnant carriers of either one of these mutations the risk of venous thromboembolism is low. Therefore, no heparin prophylaxis is recommended. A combination of the two genetic risk factors can increase the risk to a modest level of 1 in 25. In women with a single episode of prior thrombosis associated with a transient risk factor, e.g. surgery or trauma, and no additional genetic risk factor, the probability of a pregnancy-associated thrombosis appears also to be low. However, data are sparse and conflicting. In contrast, in women with a prior idiopathic venous thrombosis who carry an additional hereditary risk factor or who have a positive family history of thrombosis, a high risk (10%) can be expected supporting the indication for active antepartum and postpartum heparin prophylaxis. Despite the remarkable progress in risk stratification, the absolute magnitude of risk and the optimal management in many cases is an issue of ongoing debate.

The association of cancer with thromboembolic events has been established for more than hundred years. While the thrombophilic diathesis of tumor patients and the neoplastic thrombogenesis have been elucidated pathophysiologically, at least in part, there is growing experimental and clinical evidence that factors of plasmic hemostasis promote tumor growth, angiogenesis, and metastasis. Thus, the rationale for antithrombotic prophylaxis and therapy of tumor patients might not only be based on the prevention of thromboembolic complications but also on the potentially antineoplastic and antimetastatic effects of pharmacological anticoagulation. Encouraging results of clinical studies indicate that prophylactic and therapeutic anticoagulation might improve the survival of selected patients with cancer.

A survey is given on congenital and acquired platelet functional disorders. Congenital platelet functional disorders are extremely rare. Acquired platelet functional disorders are probably the most frequent disturbances of haemostasis. The knowledge of the defects leading to inherited platelet function disorders much improved our understanding of platelet function in general. Acquired platelet functional disorders are due to various diseases and drugs.

An overview is given on congenital and acquired thrombocytopenias, their pathophysiology, symptoms, diagnosis and therapy with emphasizing heparin-induced thrombocytopenia (HIT) and the thrombotic thrombocytopenic purpura (TTP).

Complex interactions among constituents of blood, components of the subendothelial extracellular matrix, and artificial surfaces of cardiovascular devices are involved in the thrombogenesis following heart valve replacement. Recently, the molecular basis of some of these interactions has been studied in detail. These insights have extended our understanding of interactive processes between platelet receptors, adhesive macromolecules, and abnormal flow conditions during platelet adhesion and aggregation. On the basis of new experimental data, it is concluded that circulating nonactivated platelets are capable of recognizing surface-bound fibrinogen via their glycoprotein receptor GPIIb-IIIa and become activated as a consequence of this specific interaction. In addition, a molecular mechanism has been proposed indicating that high-shear stress created by prosthetic heart valves can induce platelet aggregation. For this platelet reaction, multimeric von Willebrand factor is essential; its structure function relationship and its interaction with the platelet membrane GPIb receptor have been elucidated. The progress made provides specific targets for selective antithrombotic strategies. Moreover, new molecular activation markers have become available which permit appropriate control of established and experimental antithrombotic regimens. This paper reviews some aspects of recent advances in this area.

Transfusion of whole blood is the most common and successful organ transplantation world wide. It is in use longer than any other transplantation procedure. With the exception of uses in situations of crisis, treatment with whole blood is nowadays obsolete. This is due to enormous progress in preparation technologies. As a result blood from volunteer donors is separated before therapeutic use into its cellular and plasmatic components. The latter may be further processed into subfractions or secondary products. The advantages of this strategy are evident: a) the crude pharmaceutic material blood is used optimally, b) the isolated components may be stored over periods appropriate for their stability be it in a cryopreserved state or after biochemical, immunologic or biological modification, c) the patient receives only the blood components he needs, d) the transfusion of unnecessary fractions of blood is avoided, e) the rate of transfusion-associated adverse events is reduced, f) the physician has a basis for customized hematotherapy. Important implications concern logistics, economy, differentiated therapy and drug safety consideration. This contribution gives an overview on progress made in therapy of hematologic and oncologic patients with blood products and concentrates of coagulation factors. It demonstrates selected aspects of actual interest for optimal hemotherapy.

Deep venous thromboses, in particular when recurrent, can be associated with chronic venous leg ulcers. Such complications are often seen in dermatology departments and frequently represent a therapeutic problem. Resistance to activated protein C (APCR) has recently been identified as the most frequent coagulation defect associated with an increased risk of venous thrombosis. In most cases, APCR is caused by a point mutation in the factor V gene which results in an impaired inactivation of activated factor V (Va). As a consequence of this, an important anti-coagulant mechanism in the physiological balance of the hemostatic system is abolished. This autosomal dominantly inherited genetic defects affects about 5% of the general population. In this article we draw attention to the existence of this recently identified, genetically determined risk factor for venous thrombosis, describe recent diagnostic developments and discuss therapeutic options.

Fetal alloimmune thrombocytopenia is caused by maternal immunization against a fetal platelet antigen and transplacental transfer of the antibody into the fetal circulation. Since 10-20% of the fetuses or newborns are threatened by intracranial hemorrhages, early management is required. Fetal blood sampling should be started between the 20th and 22nd week of gestation to assess fetal phenotype and platelet count. Different concepts to elevate the fetal platelet count have been discussed: maternal intravenous immunoglobulins, fetal intravenous immunoglobulins, or only repeated fetal platelet transfusions. Our investigations suggested that platelet transfusions in short intervals appear to be the only effective regimen to increase platelet counts in thrombocytopenic fetuses at risk.

Fetal alloimmune thrombocytopenia is caused by materno-fetal transfer of platelet antibodies. Since the thrombocytopenic fetus is threatened by intracranial hemorrhage, prenatal observation and, if necessary, treatment is required. However, the benefit of therapeutic options, including intravenous IgG (ivIgG), platelet transfusions or fetal IgG transfusions is still controversial. In this study we have evaluated the effect of intrauterine IgG and intraumbilical platelet transfusions on fetal platelet counts. All patients were multiparous women who were immunized against the Zwa antigen during previous pregnancies and had given birth to at least one severely thrombocytopenic infant. First umbilical blood was sampled at the 20th week of gestation. Fetal treatment of IgG was given, on av erage, over 9 weeks. In all cases, fetal IgG levels rose significantly whereas platelet counts did not increase following fetal IgG treatment. We conclude that fetal IgG infusions have no detectable effect on fetal allo-immune thrombocytopenia. Since platelet counts can be very low as early as 20 weeks of gestation, careful fetal monitoring by umbilical blood sampling is essential. Platelet transfusions in short intervals appear to be the only effective regimen to increase platelet counts in thrombocytopenic fetuses at risk.

Fetal alloimmune thrombocytopenia is caused by maternofetal transfer of platelet antibodies. Since the thrombocytopenic fetus is threatened by intracranial hemorrhage, prenatal observation and, if necessary, treatment is required. However, the benefit of therapeutic options, including intravenous IgG (ivIgG) or platelet transfusions, is still controversial. In this study we have evaluated the effect of maternal ivIgG and intraumbilical platelet transfusions on fetal platelet counts in 7 cases. All patients were multiparous women who were immunized against the Zwa antigen during previous pregnancies and had given birth to at least one severely thrombocytopenic infant. First umbilical blood was sampled at the 26th week of gestation. Maternal treatment of ivIgG was given over 7 weeks, the mean number of intrauterine platelet transfusions was 5.9. In 6 of 7 cases the basal platelet count before transfusion did not rise or even further decreased during maternal ivIgG treatment. In one case the baseline platelet count increased from 18,000/microliter to 60,000/microliter during ivIgG. We conclude that, in general, ivIgG alone has no detectable effect on fetal alloimmune thrombocytopenia. Since platelet counts can be very low as early as 20 weeks of gestation, careful fetal monitoring by umbilical blood sampling is required. Platelet transfusions in short intervals appear to be the only effective regimen to increase platelet counts in extremely thrombocytopenic fetuses.

Alcohol has a variety of pathologic effects on hematopoiesis. It directly damages erythroid precursors, thereby contributing to macrocytosis and the anemic state of chronic alcoholics. Megaloblastic anemia in chronic alcoholism results from a combination of nutritional deficiency and the effect of ethanol as a folate antagonist. Experimental studies suggest that alcohol may disturb hepatic folate metabolism. Ethanol induces sideroblastic anemia, perhaps by direct interference with heme synthesis. Further, chronic ingestion of alcohol can lead to various types of hemolytic anemia caused by alterations in the erythrocyte membrane lipids which occur in association with alcoholic liver disease. Alcohol directly suppresses platelet formation and decreases the platelet life span. These two mechanisms contribute to thrombocytopenia which is a common complication to chronic alcoholism. Since ethanol also interferes with platelet function, prolongation of bleeding the time is common at all stages of alcoholism. Chronic ingestion of alcohol is associated with a diminished marrow granulocyte reserve and may lead to neutrocytopenia. Ethanol-induced dysfunction of granulocytes, monocyte-macrophages and T-lymphocytes undoubtedly contributes to the predisposition to infection observed in alcoholics. In contrast to alcohol-induced changes in liver, heart and central nervous system, hematopoietic disorders are reversible after alcohol withdrawal.

Severe aplastic anaemia was diagnosed in a 24-year-old woman in the 16th week of her pregnancy. She was delivered by cesarean section in the 35th week of a healthy boy, treatment in the intervening period having been exclusively by supportive measures. Allogenic bone marrow transplantation, planned after delivery, had to be cancelled owing to the sudden death of the female donor. Immunosuppressive treatment with antithymocyte globulin, corticosteroids and cyclosporin A failed to improve the haematological picture and the patient died one year after the delivery of intracerebral haemorrhage.

Thrombotic thrombocytopenic purpura (TTP) is an uncommon disorder which usually occurs in young adults. It is characterized by a pentad of clinical findings: fever, neurological abnormalities, renal dysfunction, microangiopathic hemolytic anemia and thrombocytopenia. The histological hallmark is the presence of platelet thrombi occluding the microcirculation of multiple organs. The etiology and pathogenesis of disseminated platelet aggregation are uncertain and obviously not uniform in individual patients. Experimental findings suggest that microthrombi may result from intravascular platelet activation or form secondarily at sites of vessel wall damage. The differential diagnosis of TTP includes the hemolytic uremic syndrome in which the microangiopathic changes are exclusively found in the kidneys. When untreated, TTP invariably runs a progressive and fatal course. In recent years, prognosis has been improved by new forms of therapy such as plasmapheresis or infusions of fresh frozen plasma which may lead to recovery in about 80% of patients.

In a comparative study on the pathomechanism of myocardial hypoxia we determined a parameter each of platelet activity and thrombin activity in 46 patients with angina pectoris, i.e., 15 patients with dilatative cardiomyopathy (DCM), 15 patients with latent cardiomyopathy (LCM) and 16 patients with coronary heart disease (CHD) compared to 15 normal subjects (N). beta-thromboglobulin (beta TG) and fibrinopeptide A (FPA) were measured both at rest (I) and after symptom-limited maximal exercise (II) in plasma. In N, beta TG was not increased in any case, neither at rest nor on exertion (I: 20.5 +/- 6.1 ng/ml, II: 22.4 +/- 6.7 ng/ml). Patients with LCM did not differ significantly from N (I: 20.9 +/- 6.1 ng/ml, II: 22.7 +/- 7.9 ng/ml). beta TG values of some patients with DCM and CHD were increased at rest and especially under exercise (DCM I: 27.9 +/- 9.6 ng/ml, vs. N p less than 0.025; II: 49.9 +/- 45.5 ng/ml, vs. N p less than 0.01; CHD I: 25.2 +/- 7.7 ng/ml, vs. N p less than 0.05; II: 38.6 +/- 34.3 ng/ml, vs. N p less than 0.01). Patients with DCM developing significant angina under exercise showed a higher beta TG under these exercise conditions than those with mild or no angina (p less than 0.01). In patients with coronary heart disease, this correlation was not to be found. With regard to FPA the four investigated groups differed in an analogous way, as they did with regard to beta TG; but only a weak correlation within both values was shown.(ABSTRACT TRUNCATED AT 250 WORDS)

In a 29-year-old man with primary thrombotic-thrombocytopenic purpura a significantly increased plasma concentration of platelet-specific proteins was demonstrated as an expression of increased intravascular platelet activation and destruction during the acute phase of the disease. There was also abnormally elevated IgG loading of platelets. During administration of fresh plasma alone (total of six litres over one week) the clinical state deteriorated further into coma and failure of spontaneous ventilation. The marked thrombocytopenia and microangiopathic haemolytic anaemia remained unchanged. Only after repeated plasmapheresis was it possible to break through the acute disease process. Remission (restoration of vital functions, normalization of platelet count and haemolysis signs) was achieved after five courses of plasmapheresis with a total exchange volume of 20 litres. At least in this case, the therapeutic success of plasmapheresis argues for an immunological-toxic genesis of thrombotic-thrombocytopenic purpura.