Abstract Platelets react immediately in response to traumatic vascular injury by adhesion, activation, aggregation and subsequent haemostatic plug formation. While this reaction pattern is essential for haemostasis, platelet responses can also cause occlusive thrombi in diseased arteries, leading to myocardial infarction or stroke. Initially, flowing platelets are captured from the circulation to vascular lesions. This step is mediated by glycoprotein (GP) Ib-IX-V interacting with immobilized von Willebrand factor (VWF) on exposed subendothelial components. Tethered platelets can now bind to collagen through GPVI and integrin α2β1. Outside-in signals from the adhesion receptors act synergistically with inside-out signals from soluble stimuli and induce platelet activation. These mediators operate through G protein–coupled receptors and reinforce adhesion and activation. Typical manifestations of activated platelets include calcium mobilization, procoagulant activity, cytoskeletal reorganization, granule secretion and aggregation. This requires activation of integrin αIIbβ3 with shifting into a high-affinity state and is indispensable to bind soluble fibrinogen, VWF and fibronectin. The multiple interactions and the impact of thrombin result in firm adhesion and recruitment of circulating platelets into growing aggregates. A fibrin meshwork supports stabilization of haemostatic thrombi and prevents detachment by the flowing blood. This two-part review provides an overview of platelet activation and signal transduction mechanisms with a focus on αIIbβ3-mediated outside-in signaling in integrin variants. In the first part, a three-stage model of platelet recruitment and activation in vivo is presented. Along with that, platelet responses upon exposure to thrombogenic surfaces followed by platelet-to-platelet interactions and formation of haemostatic thrombi are discussed. Moreover, several determinants involved in pathological thrombosis will be reviewed.

Venöse Thromboembolien (VTE) gehen mit hoher Morbidität und Mortalität einher. Die demographische Entwicklung und die Zunahme ausgedehnter Eingriffe tragen dazu bei, das Risiko für thromboembolische Komplikationen zu erhöhen. Die Identifikation genetisch bedingter thrombophiler Varianten und die Beurteilung erworbener Gefährdungspotenziale erlauben es heute, das individuelle VTE-Risikoprofil einzuschätzen und eine risikoadaptierte VTE-Prophylaxe vorzunehmen. Auf der Grundlage aktualisierter Leitlinien werden in Teil I dieser Beitragsserie Prinzipien und Strategien zur Thromboembolieprophylaxe dargestellt und dazu allgemeine und physikalische Maßnahmen erörtert.

Haemostatic disorders can lead to bleeds or thrombosis. Acquired platelet dysfunction is the most common cause of haemorrhagic diathesis and is induced by pharmacological agents in >80%. Apart from antiplatelet drugs, non steroidal anti-inflammatory agents and serotonin reuptake inhibitors etc. can also impair platelet function and cause or aggravate haemorrhages. About 40% of intensive care unit patients suffer from thrombocytopenia which, at plate, let counts <100.000/mu l, is responsible for manifest bleeding. Coagulation disorders are significantly less frequent. Congenital platelet disorders and hereditary deficiencies of haemostatic plasma components are extremely rare, except for von Willebrand disease, representing a congenital or acquired disorder. Venous thromboembolism is considered a multicausal and multifactorial disease. Virchow's triad, including alterations in blood flow (stasis), vessel wall (trauma, inflammation) and blood composition (with subsequent hypercoagulability), is still an up-to-date concept of patho-genesis. Hypercoagulability can result from acquired and/or congenital risks, specifically when genetic thrombophilic defects are present in combination. For example, distinct gain-of-function mutations have been identified in the genes of coagulation factors II and V. Hereditary deficiencies of antithrombin, protein C, or protein S are associated with a high risk of venous thromboembolism (VTE), but are infrequent (<1%). Arterial thrombotic occlusion is mediated by platelets and can cause myocardial infarction, stroke, or peripheral ischaemia. Recently, genetically determined platelet receptor variants are thought to cause increased thrombogenicity in response to atherosclerotic lesions.

For prevention and treatment of thromboembolic events, a number of different potent antiplatelet agents and anticoagulants are avaible for a pharmacological intervention of haemostasis. Despite the proven benefit, the risk of bleeding is one major adverse effect. Therefore, the parallel use of antiplatelet agents such as acetyl salicylic acid, NSAID or ADP receptor antagonists such as clopidogrel may cause pharmacodynamic interactions. Special caution is necessary when further drugs that cause an additional inhibition of platelet function are prescribed, e.g. selective serotonin reuptake inhibitors. After the development of low-molecular-weight heparins, which are associated with a lower risk of thrombocytopenia, the introduction of direct oral anticoagulants (DOAC) provided further options in the prophylaxis of thromoboembolic events. Some DOACs have already gained priority over vitamin K antagonists in cardiology guidelines. However, these drugs also bear/harbour the risk of drug-drug interactions and, to some extent, require a close monitoring of renal function. First antidots have already been approved or are awaiting approval.

SummaryThrombocytosis (defined as platelets >450 × 109/l) has several aetiologies. After having excluded spurious thrombocytosis (e. g., due to microspherocytes, schistocytes, cryoglobulins, or bacteria), the differential diagnosis of true thrombocytosis encompasses secondary causes (as diverse as inflammation, infection, malignancy, iron deficiency, or asplenia), primary hereditary (rare forms of familial thrombocytosis) and primary acquired entities (either in the context of a myelodys-plastic syndrome or more frequently a myeloproliferative neoplasia). This manuscript addresses the following aspects: 1) diagnostic approach to thrombocytosis; 2) various mechanisms leading to a high platelet count; 3) potential of some of these mechanisms to modulate platelet function, producing hyper-reactive platelets and thus exerting a direct impact on the thrombotic risk; 4) indication of anti-thrombotic treatment in patients with thrombocytosis. There is a single prospective randomized clinical trial showing the benefit of acetyl-salicylic acid in polycythaemia vera. For other types of primary thrombocytosis and for secondary forms, treatment decisions have to be individualized according to the patient thrombotic and bleeding risks, taking into account the mechanism causing thrombocytosis. This manuscript discusses experimental and clinical data suggesting that besides patients with essential thrombocythaemia and other forms of primary thrombocytosis also those with thrombocytosis in the context of chronic inflammation, malignancy, or exposure to high altitude might benefit from anti-platelet treatment.

Clinically relevant influential factors on haemostasis are acidosis, hypothermia, hypocalcaemia and haemodilution, whereas the relevance of poisons is very limited. Each infusion therapy for fluid or volume replacement has potentially negative effects on haemostasis. While the effects of crystalloids (such as physiological saline and plasma-adapted solutions) or human albumin are mainly restricted to the dilutional effect, artificial colloids elicit additional specific effects. Here, dextran produces the strongest, gelatine the least negative effects on haemostasis. Negative haemostatic effects of HES have lost relevance, as becomes obvious when HES 130/0.4 is compared with older preparations.

SummaryNon-arteritic anterior ischaemic optic neuropathy (NAION) is caused by ischaemia of the optic nerve head. The pathophysiology of NAION is unclear, and no proven effective treatment exists. Patients, methods: We analyzed thrombophilic risk factors and determinants of atherosclerosis and inflammation in 109 consecutive patients and 109 age- and sex-matched volunteers using a case-control design. Results: High levels of fibrinogen (>384 mg/dl; OR 3.2, p = 0.003), factors VIII:C (>183%; OR 2.6, p = 0.02), IX (>153%; OR 2.6, p = 0.026), XI (>142%; OR 3.4, p = 0.006), von Willebrand factor (activity >205%; OR 3.1, p = 0.005; antigen >194%; OR 3.5, p = 0.002), and triglycerides (>228 mg/dl; OR 2.8, p = 0.026), higher platelet counts (>294 000/[uni03BC]l; OR 2.5, p = 0.04), low levels of HDL cholesterol (<40 mg/dl; OR 2.7, p = 0.032), and an accelerated erythrocyte sedimentation rate (>20 mm/h; OR 4.4, p = 0.003) were associated with NAION. Conclusion: Our findings support the contention of a complex pathogenesis of NAION resulting from the coincidence of proatherogenic, prothrombotic and proinflammatory processes. The alterations described could be causative, side effects, or just coincidental findings.

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