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Wir berichten uber einen schweren Morbus haemolyticus neonatalis eines rhesusnegativen Kindes (Ccddee). Das Neugeborene wurde 2 Tage nach zeitgerechter vaginaler Entbindung der Mutter (G2, P2; Rhesusformel ccddee) notfallmasig aus einem peripheren Haus in das Universitatsklinikum Dusseldorf verlegt. Bei Ubernahme bot das Kind einen Icterus gravis (Ges.-Bilirubin > 30 mg/dl) bei Hamolyse (LDH > 1500 U/l), aber noch normwertigem Hamoglobin (13,7 g/dl). Unter Austauschtransfusion mit dem 3-fachen kindlichen Blutvolumen fiel das Ges.-Bilirubin auf 18 mg/dl, bei weitergefuhrter intensiver Phototherapie innerhalb von 24 h auf 12 mg/dl. Nach erfolgreicher Behandlung einer bereits bei Aufnahme bestehenden Sepsis konnte das Kind in gutem Allgemeinzustand entlassen werden. Ursache des Morbus haemolyticus neonatalis war eine erst postpartal diagnostizierte Alloimmunisierung durch antierythrozytare Antikorper der Spezifitaten Anti-C und Anti-G in Kombination. Zwar wurde bei der Mutter auswarts ein als Anti-D fehlinterpretierter Alloantikorper ab der 8. SSW mit steigendem Titer gefunden, aber keine erneute Rhesusprophylaxe durchgefuhrt. Diese Entscheidung stutzte sich offenbar auf den molekulargenetischen Befund „keine fetalen D-spezifischen Nukleinsaurepolymorphismen“ und fehlende indirekte Hinweise einer fetalen Hamolyse im weiteren Schwangerschaftsverlauf. Unsere immunhamatologischen Untersuchungen ergaben, dass die Mutter vermutlich bereits in ihrer Erstschwangerschaft (Rhesusformel von P1 Ccddee) immunisiert worden war und nun einen weiteren irregularen Antikorper der Spezifitat Anti-G entwickelt hatte. Die Besonderheit des G-Antigens liegt darin, dass es auf Erythrozyten exprimiert wird, welche das C- und/oder D-Antigen tragen. Durch diese Assoziation kann ein Anti-G-Antikorper wie eine Kombination aus Anti-C und Anti-D erscheinen und verkannt werden. Bei dem Reaktionsmuster „Anti-C und Anti-D“ sind unterschiedliche Kombinationen von Anti-C, Anti-D und Anti-G in Betracht zu ziehen. Die genaue Differenzierung der Antikorperspezifitaten erfolgt durch Absorptions- und Elutionsuntersuchungen mit spezifischen Testerythrozyten. Bei Ausschluss eines Antikorpers der Spezifitat Anti-D ist bei rhesusnegativen Schwangeren mit einem rhesuspositiven Feten unbedingt eine Rhesusprophylaxe indiziert.

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.

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.

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.

ZusammenfassungRekombinanter Faktor VIIa (rFVIIa) wird über die zugelassenen Indikationen hinaus zunehmend zur Behandlung lebensbedrohlicher Blutungsereignissen bei Versagen der jeweiligen Standardtherapien eingesetzt. Kasuistiken und Fallserien dokumentieren die Wirksamkeit und Sicherheit von rFVIIa zur Blutstillung bei Patienten mit Thrombozytopathien und Thrombozytopenien verschiedener Ursache. Eine Zulassung zur Anwendung von rFVIIa liegt bei Patienten mit Thrombasthenie Glanzmann im Falle eines Refraktärzustandes auf die Transfusion von Thrombozytenkonzentraten vor. rFVIIa-Bolusapplikationen mit Dosierungen zwischen 80 und 120 μg/kg Körpergewicht alle 1,5 bis 3 Stunden werden auch bei Bernard-Soulier-Syndrom, Plättchen- Storage-Pool-Defekten und verschiedenen erworbenen Thrombozytopathien erfolgreich eingesetzt. Bei Thrombasthenie Glanzmann sind zur Gewährleistung einer effektiven Hämostase mindestens drei Bolusgaben notwendig. Bei Thrombozytopenie hat sich bei annähernd der Hälfte der Patienten ein einzelner rFVIIa-Bolus zur Beherrschung sonst unstillbarer Blutungen als ausreichend erwiesen. Dabei kann eine Blutstillung unter rFVIIa auch bei Thrombozytenwerten unter 20 000/μl erreicht werden, wenngleich bei höheren Thrombozytenkonzentrationen eine bessere Wirksamkeit erzielbar ist.

SummaryAcquired haemophilia A (AHA) is caused by autoantibody inhibitors of coagulation factor VIII (FVIII : C). Recent onset of bleeds and isolated prolongation of the activated partial thromboplastin time (aPTT) are characteristic features of the disorder. Reduced FVIII : C activity and a detectable FVIII : C inhibitor in the Bethesda assay confirm the diagnosis. Patients should be referred to expert centres, whenever possible, and invasive procedures with a high risk of bleeding must be avoided, until haemostasis has been secured by adequate therapy.Bypassing agents capable of inducing sufficient thrombin formation in the presence of FVIII : C inhibitors are treatment of choice, including currently available recombinant factor VIIa (NovoSeven™) and activated prothrombin complex concentrate (FEIBA™). These agents represent first line therapy to control acute or severe bleeds. To eradicate inhibitors, immunosuppressive treatment (IST) is indicated in patients with AHA. Glucocorticoids, cytotoxic agents and rituximab are most widely used. However, an ideal IST regimen has not been established so far. Adverse events of IST, including infections as the foremost cause death, are frequent complications in AHA.

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.

ZusammenfassungEs wird ein Überblick über angeborene und erworbene Thrombozytenfunktionsstörungen und ihre Therapiemöglichkeiten gegeben. Angeborene Thrombozytenfunktionsstörungen kommen extrem selten vor, erworbene Störungen hingegen dürften die häufigsten Störungen der Blutstillung sein. Die Aufklärung der den angeborenen Störungen zugrunde liegenden Defekte hat unser Verständnis der Plättchenfunktionen wesentlich verbessert. Erworbene Plättchenfunktionsstörungen werden durch unterschiedlichste Erkrankungen oder Arzneimittel hervorgerufen.

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.

For many decades, hemostatic and immune defense mechanisms were thought to act independently. More recently, this concept has been revised largely. Thus, it is becoming apparent that platelets, like leukocytes, have multiple functions in innate and adaptive immunity, changing their role from “innocent bystanders” to integral players in inflammatory or infectious processes and immunity (1, 2). For example, platelets express and secrete a variety of pro-inflammatory molecules that can trigger or modulate immune responses (3). Apart from that, up-regulation of plasma components such as distinct adhesive proteins and several coagulation factors in response to inflammatory processes (commonly designated “acute phase reaction”) is a frequent and well-known but less wellunderstood phenomenon. The multiple functions of tissue factor also illustrate the extensive cross talk between inflammation and coagulation. For example, apart from its crucial role in initiating coagulation by activating FVII (4), membrane-bound tissue factor is also capable of signal transduction, thus mediating inflammatory pathways (5). A brief look at the evolution reveals that hemostasis and immune defense have emerged from a “common trunk”. Thus, invertebrates possess circulating cells termed hemocytes that have a dual role: hemocytes protect the host from invading microbes, prevent loss of hemolymph by initiating coagulation upon injury, and mediate wound healing (1, 6). Only at the level of lower vertebrates, immune defense and hemostatic mechanisms are carried out through distinct cell populations, i. e. leukocytes and nucleated thrombocytes, while anucleated platelets are only found in mammals. Recently proposed concepts and designations such as “immuno-thrombosis” (7) or “thrombo-inflammation” (8) are reflecting both the evolutionary nexus and the up-to-date contention of a multifunctional link between hemostasis and the immune system. This theme issue of Hamostaseologie presents several highlights of the GTH Congress 2015 (9, 10) and offers the opportunity to reflect and strengthen a central topic, which was covered in various stateof-the-art lectures at the Dusseldorf conference. Ruggeri and Mendolicchio provide a comprehensive review on the key role of plasma von Willebrand factor (VWF) and its interaction with platelet and endothelial cell receptors or extracellular matrix components during physiological hemostasis and abnormal thrombus formation (11). Specifically, the impact of flow dynamic conditions on the action of VWF after traumatic injury or atherosclerotic plaque rupture is discussed in detail. Complementary to this contribution, Reininger reports on the function of ultra-large VWF multimers that are being formed under abnormally high shear stress and modulated by ADAMTS13-induced proteolytic cleavage. This interaction appears to provide an effective regulatory mechanism to control highly reactive ultra-large VWF multimers (12) . Vogtle et al. summarize recent insights into platelet receptors, including the C-type lectin-like (CLEC) receptor 2, and their role as potential pharmacological tarProf. Rudiger E. Scharf Institut fur Hamostaseologie, Hamo therapie und Transfusionsmedizin, Universitatsklinikum, Heinrich-Heine-Universitat Dusseldorf Fo to : D an ie l S ch um an n

For clinicians, who are not experienced in hemostasis and thrombosis, coagulation and coagulation disorders remain a ‘book of seven seals’ (1). This may be due, at least in part, to the complexity of the hemostatic apparatus and its interaction with inflammatory processes and immune mechanisms, all of which require detailed theoretical knowledge, practical experience, and continuous medical education (CME). More recently, the use of direct oral anticoagulants, which have specific pharmacological targets and pharmacodynamics distinct from those of vitamin K antagonists, heparins, or the pentasaccharide fondaparinux, has created insecurities and concerns among clinicians. Some of these concerns result from the fact that these novel agents with their superior safety profile impact on standard coagulation screening tests (such as prothrombin time and activated partial thromboplastin time) in a way that is different from conventional anticoagulants. This theme issue of Hamostaseologie should facilitate the readers’ access to several acquired coagulation disorders and assist to overcome fundamental problems of understanding hemostasis or, metaphorically spoken, to ‘break some of the seals’ of hemostasis and thrombosis textbooks. As third part in a series of reviews, the current edition also reflects several highlights of the GTH Congress 2015 (2, 3, 4). In his article, Medcalf provides an upto-date view on fibrinolysis, demonstrating that tissue-type plasminogen activator (t-PA)-mediated conversion of plasminogen into plasmin is not solely designed to remove fibrin deposits and blood clots in a self-regulated proteolytic process (5). Importantly, it is shown that t-PA and plasmin have pleotrophic effects and other substrates than fibrin such as prion proteins, amyloid-β, and misfolded or aggregated proteins. Thus, t-PA can act in a nonfibrinolytic (i.e., plasmin-independent) manner and have multiple effects on cerebral functions (e.g., synaptic plasticity, neurotransmission, visual processing, learning and memory). The author therefore concludes that the “original concept for the fibrinolytic system, being focused on fibrin, is a massive understatement” (5). Tiede et al. report on recent advances in the management of acquired hemophilia A (AHA) (6). At an incidence of about 1.3 cases per million people (7), AHA is a rare but challenging bleeding disorder caused by inhibitory autoantibodies against coagulation factor (F) VIII. Apart from hemostatic management to control active bleeding, immunosuppressive treatment is mandatory in AHA to achieve remission. However, the outcome of AHA remains highly variable. Therefore, clinically valid prognostic factors for remission are urgently required. Recently, the GTH-AH (01/2010) study, a multicenter trial conducted under the leadership of Andreas Tiede, has demonstrated for the first time that residual FVIII activity and inhibitor

SummarySpecific membrane glycoproteins (GP) expressed by the megakaryocyte-platelet system, including GPIa-lla, GPIb-V-IX, GPIIb-llla, and GPIV are involved in mediat-ing platelet adhesion to the subendothelial matrix. Among these glycoproteins, GPIIb-llla plays a pivotal role since platelet aggregation is exclusively mediated by this receptor and its interaction with soluble macromolecular proteins. Inherited defects of the GPIIb-llla or GPIb-V-IX receptor complexes are associated with bleeding disorders, known as Glanzmann's thrombasthenia, Bernard-Soulier syndrome, or platelet-type von Willebrand's disease, respectively. Using immuno-chemical and molecular biology techniques, rapid advances in our understanding of the molecular genetic basis of these disorders have been made during the last few years. Moreover, analyses of patients with congenital platelet membrane glycoprotein abnormalities have provided valuable insights into molecular mechanisms that are required for structural and functional integrity, normal biosynthesis of the glycoprotein complexes and coordinated membrane expression of their constituents. The present article reviews the current state of knowledge of the major membrane glycoproteins in health and disease. The spectrum of clinical bleeding manifestations and established diagnostic criteria for each of these dis-orders are summarized. In particular, the variety of molecular defects that have been identified so far and their genetic basis will be discussed.

We have performed a monocenter study on 29 consecutive patients with acquired haemophilia A who were referred for diagnosis and treatment to the Düsseldorf Haemophilia Comprehensive Care Center between March 2001 and February 2010.18 men (age: 44-86 years) and 11 women (age: 20-83 years). For laboratory evaluation, a standardized staged protocol of aPTT, FVIII:C activity and concentration, mixing studies with patient and normal plasma, and quantification of inhibitor titers (Bethesda assay) was used. Diagnostic work-up included elaborate examinations for any underlying disease.In 18 (62%) of the 29 patients with acquired haemophilia A, an underlying disorder was identified, including 9 patients with respiratory diseases (31%), 7 patients with autoimmune disorders (24%), one with malignancy, and one with postpartum state, while in 11 patients (38%) acquired haemophilia A remained idiopathic. Haemotherapy of bleeding, suppression or elimination of the inhibitor, and induction of immunotolerance to endogenous FVIII:C were performed according to a treatment algorithm. Predefined clinical endpoints were control of bleeding, eradication of the inhibitor, complete or partial remission (CR, PR), relapse, or early death (or =30 days). Of the 29 patients in total, 22 individuals achieved CR (76%), three had PR, one relapsed, and three died within 30 days (one of acute myocardial infarction while on antihaemorrhagic treatment, one of sepsis while on immunosuppression due to active acquired haemophilia A, one of lung bleeding in association with pre-existing pulmonary sarcoidosis).This monocenter study demonstrates that control of life-threatening bleeding, eradication of the inhibitor, and induction of tolerance to endogenous FVIII have significantly improved the clinical outcome of acquired haemophilia A. Our data also suggest a shift in underlying disorders associated with acquired haemophilia A, whereby, in comparison to published studies, a relative increase in the proportion of patients with respiratory diseases is present.

Antiplatelet agents and anticoagulants are effective in the prevention and treatment of a variety of thrombotic disorders. Several clinical settings require more intense antithrombotic regimens. These can be provided by combining (i) two antiplatelet drugs, (ii) antiplatelet monotherapy with an anticoagulant, or (iii) anticoagulation with dual antiplatelet treatment (triple therapy). A major side effect of all antithrombotic regimens, however, is the induction of a bleeding diathesis. This is especially true in patients with preexisting haemostatic defects of any kind that may remain compensated, unless platelet function and/or coagulation are not inhibited pharmacologically. To address the dilemma of the "double-edged sword" between thrombosis and bleeding, several strategies are currently under study, including (i) identification of high-risk patients, (ii) stratification of patient subgroups, (iii) individualized decision making, and (iv) administration of "tailor-made" risk-adapted regimens. Nonetheless, prevention and protection from bleeding in patients using antithrombotic agents remain an enduring challenge. For high-risk patients on antiplatelet agents with urgent need of surgery, an algorithm is discussed that allows short-term interruption of oral antithrombotic therapy and i.v. administration of a GPIIb-IIIa receptor antagonist for bridging without increasing perioperative bleeding. When individual patients, using antiplatelet or anticoagulant agents, experience serious or even life-threatening haemorrhages, haemotherapy with platelet units or prothrombin complex concentrates remains an integral part of the clinical management.

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.

Preliminary results are presented of an ongoing, prospective, randomized, study comparing ofloxacin, ciprofloxacin and co-trimoxazole/colistin for the prevention of infection in patients with acute leukaemia. The results for 59 patients (median age 47 years, range 21-72) included 88 episodes of neutropenia, each associated with a course of cytotoxic therapy. The main factor measured was the time elapsed from the beginning of neutropenia (neutrophils less than 500/microliter) until the first infectious febrile episode. The median time for the period was 12 days (range 1-56) for the cotrimoxazole/colistin group, 15 days (range 1-38) for the ofloxacin group and 20 days (range 1-36) for the ciprofloxacin group (differences not significant). Microbiologically proven major infections occurred in 10/27 treatment courses with co-trimoxazole/colistin 7/31 courses with ofloxacin and 7/30 courses with ciprofloxacin (P not significant). These were mostly due to Gram-positive cocci. There were no Gram-negative infections in the quinolone groups compared with one major Pseudomonas aeruginosa infection in the co-trimoxazole/colistin group. No Pneumocystis carinii infections were encountered. Adverse reactions associated with co-trimoxazole/colistin required discontinuation of medication in 11/27 treatment courses because of compliance problems, skin reactions or gastrointestinal intolerance. There were significantly fewer discontinuations in the ofloxacin (n = 2) and in the ciprofloxacin groups (n = 3). Major side effects of the quinolones included persistent icterus in one patient receiving ofloxacin and psychiatric symptoms in one patient receiving ciprofloxacin. It is concluded from these data that there were no statistically significant differences between the three treatment groups in respect of the prevention of infection.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Conflicting results of an association of the human platelet antigen 1b (HPA-1b/PlA2), localized on the beta-subunit of the integrin alpha(IIb)beta3, and the alpha(2)807TT genotype of the integrin alpha2beta1 with coronary atherosclerosis and myocardial infarction have been reported. Both platelet receptor polymorphisms were genotyped in 3261 patients who had undergone coronary angiography, including 1175 survivors of a myocardial infarction, 1211 individuals with coronary artery disease but no history of myocardial infarction, and 571 control patients without angiographic coronary artery disease, and in 793 blood donors. In a case-control design, the prevalence of HPA-1b and alpha(2)807TT genotypes did not differ significantly between the patient groups with coronary artery disease or myocardial infarction and patient controls or blood donors. By contrast, using a multivariate case-only design, it was found that the median age of onset of myocardial infarction was 5.2 years earlier (P = 0.006) in carriers of the HPA-1b allele and 6.3 years earlier (P = 0.006) in carriers of the alpha(2)807TT genotype in the 264 survivors of myocardial infarction of recent onset with one- or two-vessel coronary artery disease. A significant interaction with the conventional risk factors hypercholesterolemia, smoking, diabetes, hypertension, and hyperfibrinogenemia was excluded. Human platelet antigen 1b and alpha(2)807TT are associated with premature myocardial infarction but not with coronary artery disease, suggesting a role of distinct integrin genotypes for increased platelet thrombogenicity. This association requires confirmation in follow-up studies.

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).

Thrombozytare Funktionen konnen unter pathologischen Bedingungen entweder abnorm gesteigert oder defizitar sein. Die mit einer herabgesetzten Plattchenfunktion einhergehenden Storungen werden als Thrombozytopathien im engeren Sinne bezeichnet. Sie lassen sich einteilen in Storungen der Aktivierung, Adhasion, Aggregation sowie Sekretion und verminderte prokoagulatorische Aktivitat.

Venose Thrombosen und ihre embolischen Komplikationen, insbesondere die Lungenarterienembolie, tragen weltweit wesentlich zu Morbiditat und Mortalitat in der Schwangerschaft und Postpartalphase bei [1–5]. Bereits wahrend einer normalen Schwangerschaft besteht ein 5–6fach erhohtes Risiko gegenuber nichtgraviden Frauen gleichen Alters, ein thromboembolisches Ereignis zu erleiden Die in der Literatur berichteten Angaben zur Haufigkeit einer Thromboembolie liegen bei 1 auf 1000 bis 1 auf 2000 Schwangerschaften [1–3].

Recently, we have demonstrated that human platelet antigen 1b (HPA-1b or P1A2) is a hereditary risk factor for platelet thrombogenicity leading to premature myocardial infarction in preexisting coronary artery disease. However, HPA-lb does not represent a risk factor for coronary artery disease itself. The aim of our present study was to evaluate the role of HPA-lb on the outcome in patients after coronary-artery bypass surgery. We prospectively determined the HPA-1 genotype in 261 consecutive patients prior to saphenous-vein coronary-artery bypass grafting. The patients were followed for one year. Among patients with bypass occlusion, myocardial infarction, or death more than 30 days after surgery, the prevalence of HPA-lb was significantly higher than among patients without postoperative complications (60 percent, 6/10, vs. 24 percent, 58/241, p0.05, odds ratio 4.7). Using a stepwise logistic regression analysis with the variables HPA-1b, age, sex, body mass index, smoking (pack-years), hypertension, diabetes, cholesterol and triglyceride concentration, only HPA-lb had a significant association with bypass occlusion, myocardial infarction, or death after bypass surgery (p = 0.019, odds ratio 4.7). This study shows that HPA-1b is a hereditary risk factor for bypass occlusion, myocardial infarction, or death in patients after coronary-artery bypass surgery.

Das Bernard-Soulier-Syndrom (BSS) ist eine seltene, autosomal rezessiv vererbte Thrombozyto-pathie und durch das Vorkommen von morphologisch veranderten, ungewohnlich grosen, sogenannten „Riesenplattchen“ bei gleichzeitig bestehender Thrombozytopenie charakterisiert. Betroffene Patienten leiden unter einer lebenslangen Blutungsneigung. Molekulare Ursache des BSS ist ein quantitativer und/oder qualitativer Synthesedefekt des Glykoprotein-Ib-V-IX (GP Ib-V-IX)-Komplexes. Da der GP Ib-V-IX-Komplex den primaren Rezeptor fur das Adhasivprotein Von-Willebrand-Faktor (VWF) darstellt, konnen BSS-Thrombozyten VWF nur unzureichend binden. Dadurch ist die Adhasionsreaktion an das nach einer Verletzung der Gefaswand freigelegte subendotheliale Gewebe gestort. In vitro last sich bei BSS-Patienten nach Zugabe von Ristocetin oder Botrocetin keine VWF-abhangige Thrombozytenaggregation auslosen. Blutungskomplikationen konnen durch die Transfusion von Thrombozyten effektiv behandelt werden. Wegen der Gefahr einer Immunisierung gegen die GPIb-V-IX-Komplexe der Spenderthrombozyten sollte die Indikation zur Thrombozytengabe jedoch so restriktiv wie moglich gestellt werden. Bei einer Reihe von BSS-Patienten konnten Blutungskomplikationen durch die Gabe des Vasopressinanalogons DDAVP (1-Desamino-8-D-ar-ginin-vasopressin) und durch eine lokale antifi-brinolytische Therapie erfolgreich behandelt werden.

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.

Conflicting results of an association between the human platelet antigen 1b (HPA-1b or PlA2) allele and the risk of myocardial infarction and coronary artery disease have been reported. To assess the reason for this discrepancy, we determined the HPA-1 genotype in 298 men who had undergone coronary angiography, including 124 individuals with myocardial infarction, 83 individuals with coronary artery disease but no history of myocardial infarction, and 91 control patients. Among patients with acute or recent onset myocardial infarction (1 year), the prevalence of HPA-1b was higher than among patients with coronary artery disease but without myocardial infarction (33 percent vs. 14 percent, p = 0.016). In patients under 60 years of age this difference was even more pronounced (45 percent vs. 15 percent, p = 0.003). Unlike conventional risk factors HPA-1b does not represent a risk factor for coronary artery disease itself but appears to be associated with increased platelet thrombogenicity.

Neuere durchfluszytometrische Verfahren gestatten eine Multiparameteranalyse von Thrombozyten hinsichtlich Grose, Granulagehalts, Aktivierungszustands und qualitativer oder quantitativer Anderungen ihres Membranglykoproteinmusters (GP). Die Hauptanwendungsgebiete der Plattchendurchfluszytometrie sind gegenwartig: Identifizierung und Quantifizierung spezifischer Glykoproteindefekte bei angeborenen oder erworbenen Thrombozytopathien, Bestimmung der Plattchenaktivierung in vitro bei der Praparation und Lagerung von Thrombozytenkonzentraten fur Transfusionszwecke, Nachweis und Charakterisierung aktivierter Plattchen ex vivo bei arteriosklerotischen oder thromboembolischen Gefaskomplikationen und Bestimmung zirkulierender Plattchen-Leukozyten-Konjugate bei extrakorporalen Kreislaufverfahren.

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.

Resistance of coagulation factor Va to inactivation by activated protein C (APCR) is associated with a point mutation in which adenine is substituted for guanine at nucleotide 1691 in the gene coding for factor V (FV Leiden). To date, this mutation of factor V is the most frequent genetic risk factor for venous thrombophilia. In this report, we describe the adaptation of an automatable oligonucleotide ligation assay (OLA) to detect the mutation in polymerase chain reaction-amplified DNA samples from 40 normal, 20 affected heterozygous, and 3 affected homozygous individuals. The genotypes determined by conventional allele-specific restriction enzyme site analysis were in complete concordance with the results obtained by ELISA-based oligonucleotide-ligation assay. The automated oligonucleotide ligation assay provides a rapid, reliable, nonisotopic method to detect the mutation responsible for APCR that can rapidly be applied to large population screening.

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.