The in vitro effect of the new antithrombotic drug candidate ALX-0081 on blood samples of patients undergoing percutaneous coronary intervention.

Compound ALX-0081 is a bivalent humanised Nanobody® that binds the A1-domain of von Willebrand factor (VWF) with high affinity. Consequently, it can block the interaction between VWF and its platelet-receptor-glycoprotein Ib, which leads inevitably to formation of arterial thrombi. It was the objective of this study to assess the in vitro effects of ALX-0081 on platelet adhesion and aggregation in coronary artery disease (CAD) patients to determine the optimal concentration of ALX-0081 and the effect of co-medication.

Managing patients with von Willebrand disease type 1, 2 and 3 with desmopressin and von Willebrand factor-factor VIII concentrate in surgical settings.

Guidelines and recommendations for the acute and prophylactic treatment of bleeding in von Willebrand disease (VWD) patients with von Willebrand factor (VWF)/factor VIII (FVIII) concentrates should be based on the analysis of the content of VWF/FVIII concentrates and on pharmacokinetic studies in patients with different severity of VWD (type 1, type 2 or type 3). The VW/FVIII concentrates should be assessed using the parameters FVIII:coagulant activity (C), VWF:ristocetin cofactor activity (RCo), VWF:collagen binding and VWF multimeric patterns for the presence of large multimers to determine their predicted efficacy and safety in prospective management studies. As the bleeding tendency is moderate in VWD type 2 and severe in type 3 and because the FVIII:C levels are subnormal in type 2 but very low in type 3 VWD patients, new guidelines using VWF:RCo unit dosing for the acute and prophylactic treatment of bleeding episodes are proposed.

Dominant von Willebrand disease type 2A groups I and II due to missense mutations in the A2 domain of the von Willebrand factor gene: diagnosis and management.

Pertinent findings in patients with von Willebrand disease (VWD) type 2A include prolonged bleeding time (BT), consistently low von Willebrand factor (VWF):ristocetin cofactor activity (RCo)/antigen concentration (Ag) and VWF:collagen binding (CB)/Ag ratios, absence of high, and (depending on severity) intermediate and large VWF multimers, the presence of pronounced triplet structure of individual bands and increased VWF degradation products due to increased proteolysis caused by mutations in the A2 domain of VWF. Two categories of VWD type 2A can be distinguished: group I with severe and group II with mild VWD. A minority of VWD type 2A have mild VWD characterized by near normal to prolonged BT, normal factor VIII coagulant activity and VWF:Ag, low VWF:RCo and VWF:CB, a normal ristocetin-induced platelet aggregation and complete but transient correction of BT and functional VWF parameters to normal levels for only a few hours due to short half-lives for VWF:RCo and CWF:CB.

Laboratory diagnosis and molecular basis of mild von Willebrand disease type 1.

Mild type 1 von Willebrand disease (VWD) is characterized by low to variable penetrance of bleeding, a high (increased) prevalence of blood group O, von Willebrand factor (VWF) values around and above 30% with normal ratios of VWF:ristocetin cofactor activity (RCo)/VWF:antigen (Ag), VWF:collagen binding (CB)/VWF:Ag and factor VIII (FVIII):coagulant activity (C)/VWF:Ag. Within this group of patients, the combination of the C1584 mutation and blood group O is rather frequent. Patients with mild VWD type 1 present good/normal responses of FVIII:C and VWF parameters to desmopressin (DDAVP).

PFA-100 monitoring of von Willebrand factor (VWF) responses to desmopressin (DDAVP) and factor VIII/VWF concentrate substitution in von Willebrand disease type 1 and 2.

Dose-response relationship was studied between PFA-100 closure times (PFA CTs) and factor (F)VIII-von Willebrand factor (VWF) parameters in patients with von Willebrand disease (VWD) type 1 and type 2 before and after treatment with DDAVP (n=84) or FVIII/VWF concentrate (n=38). DDAVP treatment of patients with VWD type 1 normalised the PFA CTs by increasing VWF levels to normal. Of the 14 patients with VWD type 2, PFA CTs did not normalize in eight.

Intravenous DDAVP and factor VIII-von Willebrand factor concentrate for the treatment and prophylaxis of bleedings in patients With von Willebrand disease type 1, 2 and 3.

The current standard set of von Willebrand factor (VWF) parameters used to differentiate type 1 from type 2 VWD include bleeding times (BTs), factor VIII coagulant activity (FVIII:C), VWF antigen (VWF:Ag), VWF ristocetine cofactor activity (VWF:RCo), VWF collagen binding activity (VWF:CB), ristocetine induced platelet aggregation (RIPA), and analysis of VWF multimers in low and high resolution agarose gels and the response to DDAVP. The BTs and RIPA are normal in asymptomatic carriers of a mutant VWF allele, in dominant type 1, and in recessive type 2N VWD, and this category has a normal response of VWF parameters to DDAVP. The response of FVIII:C is compromised in type 2N VWD.

Platelet-mediated erythromelalgic, cerebral, ocular and coronary microvascular ischemic and thrombotic manifestations in patients with essential thrombocythemia and polycythemia vera: a distinct aspirin-responsive and coumadin-resistant arterial thrombophilia.

Microvascular circulation disturbances including erythromelalgia, its microvascular ischemic complications, and migraine-like atypical or typical transient ischemic cerebral, ocular, and coronary ischemic attacks are specific clinical manifestations in patients with essential thrombocythemia (ET), and polycythemia vera (PV) associated with thrombocythemia. Thrombocythemia (ET and PV) patients with microvascular disturbances have shortened platelet survival, increased beta-thromboglobulin (beta-tg), platelet factor 4 (PF4), and thrombomoduline (TM) levels, and increased urinary thromboxane B2 (TxB2) excretion indicating platelet-mediated processes in vivo. Inhibition of platelet cyclooxygenase (COX 1) by aspirin is followed by relief of microvascular disturbances, correction of shortened platelet survival, and return of plasma levels of beta-tg, PF4, TM levels and TxB2 excretion to normal.

High von Willebrand factor levels increase the risk of first ischemic stroke: influence of ADAMTS13, inflammation, and genetic variability.

Background And Purpose: Elevated von Willebrand factor (vWF) concentrations are associated with an increased risk of ischemic heart disease. Several factors influence vWF antigen levels and activity, including blood group, genetic variability, acute-phase response, and proteolysis by A Disintegrin and Metalloprotease with ThromboSpondin motif (ADAMTS13), a determinant of proteolytic cleavage of vWF. We assessed how these factors affect the relation between vWF and the occurrence of stroke to understand the underlying mechanism.

The paradox of platelet activation and impaired function: platelet-von Willebrand factor interactions, and the etiology of thrombotic and hemorrhagic manifestations in essential thrombocythemia and polycythemia vera.

Patients with essential thrombocythemia (ET) and polycythemia vera (PV), complicated by microvascular ischemic or thrombotic events, have shortened platelet survival, increased beta-thromboglobulin, platelet factor 4, and thrombomodulin levels, and increased urinary thromboxane B2 excretion. These are all reversible by inhibition of platelet cyclooxygenase 1 with aspirin, and are therefore indicative of platelet activation and platelet-mediated thrombotic processes. The thrombotic tendency persists as long as platelet counts are above the upper limit of normal (400 x 10 (9)/L).

Immune-mediated etiology of acquired von Willebrand syndrome in systemic lupus erythematosus and in benign monoclonal gammopathy: therapeutic implications.

The most common nonimmune etiology of acquired von Willebrand syndrome (AvWS) includes hypothyroidism, Wilms' tumor, thrombocythemia, or congenital heart defects, and the use of various drugs. AvWS type 1 in patients with hypothyroidism is due to decreased Willebrand factor (vWF) synthesis and is reversible by treatment with thyroxin. AvWS type 1 or 3 in children with Wilms' tumor disappears after successful chemotherapy or tumor resection but the mechanism of the vWF deficiency is unknown.

Platelet-mediated thrombotic complications in patients with ET: Reversal by aspirin, platelet reduction, and not by coumadin.

The broad spectrum of aspirin-sensitive erythromelalgia, its microvascular ischemic complications, migraine-like atypical or typical transient ischemic attacks (cerebral and ocular) as well as acute coronary syndromes in thrombocythemia vera (essential thrombocythemia and thrombocythemia associated with polycythemia vera in maintained remission by phlebotomy) is caused by platelet cyclo-oxygenase-mediated arteriolar inflammation, fibromuscular intimal proliferation without and with occlusive thrombosis by platelet-rich thrombi in the end-arterial microvasculature of the peripheral, cerebral, ocular and coronary circulation. These microvascular ischemic and thrombotic complications does not respond to Coumadin, but are immediately relieved by a loading dose of 500 mg aspirin, and does not recur when the patient is maintained on low dose aspirin (50 mg per day) or after reduction of platelet counts to normal (<400.000/microl).

Bleeding prophylaxis for major surgery in patients with type 2 von Willebrand disease with an intermediate purity factor VIII-von Willebrand factor concentrate (Haemate-P).

The parameters to diagnose von Willebrand disease (vWD) include factor VIII coagulant activity (FVIII:C), von Willebrand factor antigen (vWF:Ag), von Willebrand factor ristocetin cofactor activity (vWF:RCo), and von Willebrand factor collagen binding activity (vWF:CB). Type 2 vWD is associated with a moderate bleeding diathesis due to low levels of vWF:RCo and vWF:CB as compared with near normal or normal values for FVIII:C and vWF:Ag. As the factor VIII/von Willebrand factor (vWF) concentrate, Haemate-P, is featured by a vWF:RCo/FVIII:C ratio of about 2.

Pathophysiology and treatment of platelet-mediated microvascular disturbances, major thrombosis and bleeding complications in essential thrombocythaemia and polycythaemia vera.

Essential thrombocythaemia (ET) is associated with a broad spectrum of microvascular circulation disturbances including erythromelalgia and its ischaemic complications, episodic neurological symptoms of atypical and typical transient ischaemic attacks (TIAs), transient ocular ischaemic attacks, acute coronary syndromes, and superficial 'thrombophlebitis'. The microvascular circulation disturbances are caused by spontaneous activation and aggregation of hypersensitive thrombocythaemic platelets at high shear stress in the endarterial microcirculation involving the peripheral, cerebral and coronary circulation. As this microvascular syndrome is a pathognomonic feature of essential thrombocythaemia and of thrombocythaemia associated with polycythaemia vera (PV) in complete remission with normal haematocrit, we have labelled these two variants of thrombocythaemia as thrombocythaemia vera.

What is the lowest dose of aspirin for maximum suppression of in vivo thromboxane production after a transient ischemic attack or ischemic stroke?

Background: There is still worldwide disagreement about the optimal lowest dose of aspirin to be used in patients after a transient ischemic attack (TIA) or nondisabling stroke. We measured the urinary 11-dehydro-thromboxane-B(2) (uTXB(2)) excretion to compare the degree of suppression of in vivo platelet activation by various low doses of aspirin.

Methods: 60 patients were randomly allocated to treatment with either 30, 50, 75 or 325 mg of aspirin.

Functional characteristics of photochemically treated platelets.

Background: A photochemical treatment (PCT) process using the psoralen compound amotosalen HCL (S59) and long wavelength UVA light was developed for inactivation of infectious pathogens and WBCs. In this study the effect of PCT on functional characteristics of the platelets was evaluated in vitro.

Study Design And Methods: Platelet concentrates were treated photochemically using the experimental clinical processing system T-bag S59 Reduction Device (SRD) (n = 4) or the commercially available integral processing system Wafer SRD (n = 4) and compared with control platelet concentrates in plasma/PAS III alone (n = 4).

The value of alloantibody detection in predicting response to HLA-matched platelet transfusions.

Alloantibody tests demonstrate immunological causes of insufficient increments in random platelet transfusions. The value of a positive or negative test result in predicting the outcome of human leucocyte antigen (HLA)-matched transfusions in patients refractory to leucodepleted random platelet transfusions has not been assessed. We retrospectively evaluated the outcome of the first HLA-matched platelet transfusion in 72 patients with haematological diseases in two ways: first, the strategy according to which the patient was selected for HLA-matched platelet transfusions was analysed.

New TPO treatment schedules of increased safety and efficacy: pre-clinical validation of a thrombopoiesis simulation model.

Thrombopoietin (TPO) immunogenicity hampers its development as a therapeutic agent for attenuating thrombocytopenia and improving platelet harvest in donors. This work was aimed at validating, in mouse and in monkey experiments, a thrombopoiesis computer-model prediction that platelet counts, similar to those obtained with accepted TPO dose scheduling, can also be achieved by new and safer schedules of significantly reduced doses. To this end we compared, in a two-arm mouse experiment, platelet increases obtained with a single intraperitoneal dosing of recombinant mouse TPO (17.

Response of von Willebrand factor parameters to desmopressin in patients with type 1 and type 2 congenital von Willebrand disease: diagnostic and therapeutic implications.

In the present study, we prospectively evaluated the contribution of the von Willebrand factor collagen-binding activity (vWF:CBA) assay, vWF multimeric analysis, and the response to intravenous desmopressin (DDAVP) to correctly diagnose and classify congenital von Willebrand disease (CvWD) in 24 probands with mild to moderate type 1 vWD, 6 probands with severe CvWD type 1, and 12 probands with type 2 CvWD. CvWD type 1 of mild to moderate severity is featured by proportionally decreased levels of vWF antigen (vWF:Ag), vWF ristocetin cofactor activity (vWF:RCof), and vWF:CBA between 0.20 and 0.

Fibrinolysis during liver transplantation is enhanced by using solvent/detergent virus-inactivated plasma (ESDEP).

Unlabelled: After the introduction of solvent/detergent-treated plasma (ESDEP) in our hospital, an increased incidence of hyperfibrinolysis was observed (75% vs 29%; P = 0.005) compared with the use of fresh frozen plasma for liver transplantation. To clarify this increased incidence, intraoperative plasma samples of patients treated with fresh frozen plasma or ESDEP were analyzed in a retrospective observational study.