Recurrent jejunal bleeding due to angiodysplasia in a Bernard-Soulier patient.

Angiodysplasia of the gastrointestinal tract consists of ectasia of the submucosal vessels of the bowels and may lead to acute or chronic bleeding. The presence of a coagulopathy will increase the frequency and the severity of gastrointestinal bleeding, whether spontaneously or medically. In literature, few cases of Bernard-Soulier syndrome associated with gastrointestinal angiodysplasia have been reported. We hereby present a female patient known to have Bernard-Soulier syndrome presenting with persistent bleeding due to jejunal angiodysplasia, which, to our knowledge, is the eighth reported case in the medical literature. The patient responded to tranexamic acid (antifibrinolytic agent) with gradual reduction in required transfusions until cessation of bleeding.

Targeting von Willebrand factor and platelet glycoprotein Ib receptor.

Atherothrombotic events, such as acute coronary syndrome or stroke, are the result of platelet activation. Von Willebrand factor (vWF), a multimeric glycoprotein, plays a key role in aggregation of platelets, especially under high-shear conditions. Acting as bridging element or ligand between damaged endothelial sites and the glycoprotein Ib (GPIb) receptor on platelets, vWF is responsible for platelet adhesion and aggregation. This vWF activation and further platelet aggregation mainly occurs under high shear stress present in small arterioles or during deficiency of the vWF-cleaving protease ADAMTS13. There are several substances targeting vWF itself or its binding receptor GPIb on platelets. Two antibodies are directed against vWF: AJW200, an IgG4 humanized monoclonal antibody, and 82D6A3, a monoclonal antibody of the collagen-binding A-3 domain of vWF. ALX-0081 and ALX-0681 are bivalent humanized nanobodies targeting the GPIb binding site of vWF. Aptamers are oligonucleotides with drug-like properties that share some of the attributes of monoclonal antibodies. ARC1779 is a second-generation, nuclease-resistant aptamer, binding to the activated vWF A1 domain and ARC15105 is a chemically advanced follower with an assumed higher affinity to vWF. Antibodies targeting GPIbα are h6B4-Fab, a murine monoclonal antibody; GPG-290, a recombinant, chimeric protein containing the amino-terminal 290 amino acids of GPIbα linked to human IgG1 Fc; and the monoclonal antibody SZ2. There are a number of promising preclinical results and development of some agents (AJW 200, ARC1779 and ALX-0081) has already reached Phase II trials.

Clinical benefit of recombinant factor VIIa in management of bleeds and surgery in two brothers suffering from the Bernard-Soulier syndrome.

Bernard-Soulier syndrome (BSS) is a rare congenital bleeding disorder characterized by thrombocytopenia and giant platelets that display impaired or absent platelet agglutination with ristocetin. The disease is caused by mutations in genes controlling the expression of the platelet glycoprotein Ib-IX complex. The most severely affected patients suffer from profound muco-cutaneous bleeding tendency. Patients suffering from BSS may require platelet transfusion in prevention and management of severe bleeding. However, recent publications have suggested that recombinant factor VIIa (rFVIIa) infusion may support haemostasis in BSS. The present report describes two brothers who received treatment with rFVIIa together with tranexamic acid on a total of six occasions in management of haemostasis in minor surgery and for a serious spontaneous upper gastrointestinal tract bleed. Although platelet transfusion was omitted, haemostasis was regarded excellent in all of these treatment episodes.

Platelet function defects.

Inherited defects of platelet function are a heterogeneous group of disorders that can result in bleeding symptoms ranging from mild bruising to severe mucocutaneous haemorrhage. These defects may be classified according to their effect on the various steps of platelet microthrombi formation including initiation, extension and cohesion, or based on their particular structural or functional deficiency. Platelet membrane receptor deficiencies result in the rare, but well-characterized syndromes of defective clot initiation, such as Bernard-Soulier Syndrome. Platelet storage pool defects are the most common disorders affecting the extension phase of clot formation. Glanzmann thrombasthenia, with absent or dysfunctional alpha IIb beta 3 receptor is the prototypical defect of the cohesion/aggregation phase of microthrombi formation. Many of these disorders share common treatments although some therapies will have greater efficacy for one patient than another and should be individualized so as to provide optimal control of symptoms. Currently much effort is being put into methods to more rapidly and accurately diagnose patients with platelet disorders and to initiate appropriate therapy and prevent life threatening bleeding.

Congenital and acquired platelet disorders: current dilemmas and treatment strategies.

Platelets are important for primary hemostasis. When a blood vessel is damaged, platelets adhere to exposed subendothelial connective tissue and form a hemostatic plug. Formation of the plug is contingent upon a series of processes, with adhesion, activation, and aggregation all being involved. Patients with quantitative platelet disorders have reduced numbers of platelets. Patients with qualitative disorders have platelets that exhibit abnormal functioning. Defects that impair function can affect platelet receptors, secretory responses, or intracellular signaling pathways. Examples of qualitative platelet disorders include Glanzmann's thrombasthenia (GT) and Bernard-Soulier syndrome (BSS). The treatment of platelet disorders is primarily with platelet concentrates. However, in patients with abnormalities of their platelet surface receptors, platelet transfusion may provoke an immune response. Recombinant factor VIIa (rFVIIa) may provide hemostatically effective therapy in such patients.

Gastric angiodysplasia in a child with Bernard-Soulier syndrome: efficacy of octreotide in long-term management.

Gastrointestinal angiodysplasia in association with Bernard-Soulier syndrome has been previously described in adults. The authors report on a 14year-old boy presenting with massive upper gastrointestinal bleeding due to a large gastric angiodysplasia, in whom medical history and laboratory investigations were consistent with Bernard-Soulier syndrome. The vascular lesion was so widespread that surgical or endoscopic therapy was not considered. Therefore, treatment with octreotide, a somatostatin analog, was commenced, following a short course of tranexamic acid and proton pump inhibitor. During the 16-month follow-up with octreotide therapy, no occult or gross bleeding occurred. This case illustrates the utility of using octreotide for the long-term treatment of children with bleeding disorders and angiodysplasia.

The use of recombinant factor VIIa in children with inherited platelet function disorders.

Inherited deficiencies of platelet surface glycoproteins such as Glanzmann's thrombasthenia (GT) or Bernard-Soulier syndrome (BSS) can lead to a severe bleeding diathesis. In the past, bleeding episodes in these patients have often required platelet transfusion to secure haemostasis but recently a number of patient reports have suggested that recombinant factor VIIa (rVIIa) may also be effective. We have used rVIIa on 33 occasions in seven children with inherited platelet function disorders over a 2-year period: five had GT, one had BSS and one had storage pool disease with a severe phenotype. Bleeding ceased with rVIIa alone in 10 of 28 acute bleeding episodes, but recurred in two of these. The two features that predicted response to rVIIa were the severity of the bleeding and the delay from the onset of bleeding to treatment. Five episodes of planned surgical intervention were treated successfully with rVIIa. Eighteen out of the 28 acute episodes and none of the planned surgical episodes required blood product support. We have found variable efficacy of rVIIa for acute bleeding episodes in this small series of children with inherited platelet function defects but larger studies are warranted, particularly as rVIIa is a relatively low-risk treatment approach for these disorders.

Treatment of bleeding in patients with platelet disorders: is there a place for recombinant factor VIIa?

The mechanism of action of recombinant factor VIIa (rFVIIa), i.e. increased thrombin generation on the membrane of activated platelets, as well as the results from in vitro and ex vivo models of thrombocytopenia or inherited thrombocytopathia may support some potential of rFVIIa in thrombocytopenia/thrombocytopathia. rFVIIa was reported as effective to stop or to decrease bleeding in few patients with severe thrombocytopenia resistant to platelet transfusions; however data are still scarce and clinical studies are really needed to define efficacy/safety ratio as well as optimal treatment regimen in this potential indication. Some data in patients with Glanzmann thrombasthenia (GT) may support the use of rFVIIa outside its primary indication in the cases in which there is no real treatment alternative (GT patients with antibodies to GP IIb-IIIa or with platelet refractoriness).

[Constitutional thrombopathies: from the clinical description of rare diseases (Glanzmann thrombasthenia and Bernard-Soulier syndrome) to the development of new antithrombotic agents]. / Les thrombopathies constitutionnelles: de la description clinique d'affections rares (la thrombasthénie de Glanzmann et le syndrome de Bernard-Soulier) au développement de nouveaux agents antithrombotiques.

The study of exceptional thrombocytopathies has led to considerable progress in the understanding of normal and pathologic haemostasis. Thus, precise structure/function relationships were able to be established. The lack or the abnormalities of the glycoprotein IIb/IIIa complex is responsible for the complete defect in platelet aggregation characterizing Glanzmann's Thrombasthenia, while the lack or the abnormalities of the glycoprotein Ib/IX/V complex is responsible for the defect in platelet adhesion to the subendothelium noted in the Bernard-Soulier syndrome. The bases for these abnormalities are now known at the molecular level. Recent data also underline the role of these glycoproteinic complexes as receptors for platelet activation; besides an involvement of the GPIIb/IIIa complex in adhesion and of the GPIb/IX/V complex in platelet aggregation, von Willebrand factor dependent, were newly evidenced. New antithrombotic agents directed against the GPIIb/IIIa complex are currently being tested in large clinical trials, especially in cardiovascular diseases. In the future, the inhibition of the GPIb-IX-V/von Willebrand factor axis should permit the development of a new class of antithrombotics, perhaps even more promising since they will act at the very early phases of primary hemostasis.

A new variant of Bernard-Soulier syndrome characterized by dysfunctional glycoprotein (GP) Ib and severely reduced amounts of GPIX and GPV.

We describe a new variant of Bernard-Soulier syndrome characterized by almost normal amounts of GPIb and severely reduced GPIX and GPV. Despite surface expression, GPIbalpha failed to support ristocetin-induced platelet agglutination and to bind two conformation-dependent monoclonal antibodies, suggesting a qualitative defect. Sequence analysis of the gene coding for GPIX revealed a T-to-C substitution at base 1811, leading to a Leu40Pro conversion, whereas no defects were found in the coding region of the GPIbalpha gene. Allele-specific restriction enzyme analysis showed that the propositus and one of his sisters. both with severe bleeding diathesis. were homozygous for the GPIX mutation: the members of the family with mild bleeding diathesis and/or giant platelets in the peripheral blood were heterozygous, whereas the healthy ones were homozygous for the normal allele. Infusion of 1-desamino-8-D-arginine vasopressin normalized bleeding time in the two severely affected patients, although it did not modify ristocetin-induced platelet agglutination or membrane expression of GPIbalpha, GPIX, GPIIb-IIIa and GMP-140. Moreover, in one patient, normalization of bleeding time and rise of von Willebrand factor plasma concentration did not seem to be directly related.

Utilidad de la desmopresina en cuatro casos de trombocitopatías asociadas a plaquetas gigantes / Utility of desmopressin in four cases of thrombocytopathy with giant platelets

La agresión plaquetaria requiere de complejos glucoproteicos plaquetarios (Gp), del factor de von Willebrand y del ADP. Los síndromes de Bernard-Soulier (BS) y de la plaqueta gris (SPG) son defectos hereditarios de la función plaquetaria caracterizados por ausencia del Gp lb-lX y ausencia de gránulos alfa, respectivamente, con presencia en ambos síndromes de hemorragias mucocutáneas, tiempo de sangrado (TS) prolongado, trombocitopenia moderada y plaquetas gigantes. Existen informes que la desmopresina (DDAVP) acorta el TS en algunos pacientes con defectos de la función plaquetaria. El objetivo de este estudio fue evaluar la respuesta a DDVAP en cuatro mujeres (2 con SPG + enfermedad de marfán y 2 con BS). Todas presentaron hemorragias mucocutáneas de intensidad variable con TS> 10 minutos, cuenta de plaquetas (CP) entre 40 y 88 X 10/L y defectos en la agregación plaquetaria. El DDAVP se administró a dosis de 0.3µg X kg/dosis única en solución salina, por vía intravenosa durante 30 a 45 minutos. Todas las pacientes fueron estudiadas antes y después de la administración del DDAVP (TS, CP, factor 4 plaquetarios volumen plaquetario medio, factores F.VIII:C, FvW:Ag, FvW:RiCof y agregación plaquetarías). El TS se corrigió a < 6 minutos y se incrementaron los niveles de F.VIII:C, FvW:Ag y FvW:RiCof (> 100 UI/dL); las manifestaciones hemorrágicas desaparecieron. Concluímos que hubo una buena respuesta al DDAVP, la cual puede estar relacionada con mejoría de la adhesión plaquetaria e incremento de multínumeros del factor de von Willibrand

[Utility of desmopressin in 4 cases of thrombocytopathies associated with giant platelets]. / Utilidad de la desmopresina en cuatro casos de trombocitopatías asociadas a plaquetas gigantes.

Shear-induced aggregation requires the platelet glycoprotein complexes (Gp), the von Willebrand factor (vWf) and ADP. The Bernard Soulier syndrome (BS) and the gray platelet syndrome (GPS) are platelet function defects characterized by absence of GP Ib/IX and alpha granules, respectively, with mucocutaneous hemorrhages, prolonged bleeding time (BT) and moderate thrombocytopenia in both syndromes. There are reports that desmopressin (DDAVP) shortens the BT in some patients with platelet dysfunction. The purpose of this study was to evaluate the response t(DDAVP) in four female patients (2 with GPS plus Marfan's disease and 2 BS). All had bleeding episodes, BTs > 10 minutes, platelet counts (PC) between 40-88 x 10(9)/L and defects in platelet aggregation. The DDAVP was administered at a dose of 0.3 microgram/kg in 15 to 30 mL of isotonic saline given by slow intravenous drip in 30 to 45 min. All patients were studied before and after DDAVP administration (BT, PC, platelet factor, mean platelet volume, factors F.VIII:C, FvW:Ag, FvW:RiC of, and platelet aggregation). After DDAVP infusion the patients had a BT < 6 min, and increased levels of F. VIII:C, FvW:Ag and FvW:RiC of (> 100 Ul/dL), and the bleeding disappeared. We conclude that there was a good response to DDAVP probably associated with improved platelet adhesion, and increases in the multimers of the von Willebrand factor.

Bernard-Soulier syndrome in two Swedish families: effect of DDAVP on bleeding time.

We present 2 patients with Bernard-Soulier syndrome from two different families. The parents of one of the patients were found to have had common ancestors in the 17th century. The platelet membrane content of glycoprotein (GP)Ib was measured in the patients and their first-degree relatives with an ELISA technique based on monoclonal antibodies. Both patients had very low levels of GPIb. In one of the families the heterozygotes had reduced expression of GPIb but in the other the obligate heterozygotes had normal values, suggesting that the molecular pathology differs between the two families. In both patients, bleeding time was shortened by infusion of DDAVP (1-deamino-8-D-arginine vasopressin), although it was not completely normalised. DDAVP may be of some therapeutic value in cases of Bernard-Soulier syndrome.