Diagnostic challenges of inherited mild bleeding disorders: a bait for poorly explored clinical and basic research.

The best-known inherited mild bleeding disorders (MBDs), i.e. type 1 von Willebrand disease (VWD), platelet function disorders (PFDs), and mild to moderate clotting factor deficiencies, are characterized clinically by mucocutaneous bleeding, and, although they are highly prevalent, still pose difficult diagnostic problems. These include establishing the pathological nature of bleeding, and the uncertainties surrounding the clinical relevance of laboratory results. Furthermore, the high frequency of bleeding symptoms in the normal population and the subjective appraisal of symptoms by patients or parents makes elucidating the pathological nature of bleeding difficult. Standardized bleeding assessment tools and semiquantitative bleeding scores (BSs) help to discriminate normal from abnormal bleeding. However, as most MBDs have similar bleeding patterns, for example, bleeding sites, frequency, and severity, BSs are of little help for diagnosing specific diseases. Global tests of primary hemostasis (bleeding time; PFA-100/200) lack sensitivity and, like BSs, are not disease-specific. Problems with the diagnosis of type 1 VWD and PFD include assay standardization, uncertain definition of von Willebrand factor cut-off levels, and the lack of universal diagnostic criteria for PFD. Regarding clotting factor deficiencies, the bleeding thresholds of some coagulation factors, such as factor VII and FXI, are highly variable, and may lead to misinterpretation of the clinical relevance of mild to moderate deficiencies. Remarkably, a large proportion of MBDs remain undiagnosed even after comprehensive and repeated laboratory testing. These are tentatively considered to represent bleeding of undefined cause, with clinical features indistinguishable from those of classical MBD; the pathogenesis of this is probably multifactorial, and unveiling these mechanisms should constitute a fertile source of translational research.

Enfermedad de von Willebrand de tipo 1 en un perro de la raza de San Bernardo - presentación clínica y el perfil de la hemostasia / Type 1 von Willebrand disease in St. Bernard dog - clinical presentation and hemostasis profile / Doença de von Willebrand tipo 1 grave em cão da raça São Bernardo - apresentação clínica e perfil de hemostasia

La enfermedad de von Willebrand (EvW) es el resultado de una deficiencia cuantitativa y/o cualitativa del factor de von Willebrand (FvW). Esta clasificado como un defecto extrínseco de las plaquetas, donde el fallo de respuesta hemostática se atribuye a la deficiencia de un factor del plasma necesario para la función normal de las plaquetas. Este estudio tiene como objetivo describir sistemáticamente el diagnóstico de la EvW tipo 1, tomando como ejemplo el reporte de un caso de un perro que presenta intensa epistaxis bilateral tratado en el hospital veterinario.

The von Willebrand disease (vWD) results from a quantitative and / or qualitative deficiency of von Willebrand factor (vWF). It is classified as a platelet- extrinsic defect, wherein the hemostatic response failure is attributed to deficiency of a plasma factor required for normal platelet function. This study aims to describe systematically the diagnosis of vWD type 1 exemplified in a case report of a dog treated at a veterinary teaching hospital due to intense bilateral epistaxis.

A doença de von Willebrand (DvW) resulta de uma deficiência quantitativa e/ou qualitativa do fator de von Willebrand (FvW). É classificada como um defeito extrínseco à plaqueta, em que a falha da resposta hemostática é atribuída à deficiência de um fator plasmático necessário para a função plaquetária normal. Este estudo visa descrever de maneira sistemática o diagnóstico da doença de (DvW) tipo 1 exemplificada em um relato de caso de um cão atendido em hospital veterinário de ensino devido a uma intensa epistaxe bilateral.

Enfermedad de von Willebrand de tipo 1 en un perro de la raza de San Bernardo - presentación clínica y el perfil de la hemostasia / Type 1 von Willebrand disease in St. Bernard dog - clinical presentation and hemostasis profile / Doença de von Willebrand tipo 1 grave em cão da raça São Bernardo - apresentação clínica e perfil de hemostasia

La enfermedad de von Willebrand (EvW) es el resultado de una deficiencia cuantitativa y/o cualitativa del factor de von Willebrand (FvW). Esta clasificado como un defecto extrínseco de las plaquetas, donde el fallo de respuesta hemostática se atribuye a la deficiencia de un factor del plasma necesario para la función normal de las plaquetas. Este estudio tiene como objetivo describir sistemáticamente el diagnóstico de la EvW tipo 1, tomando como ejemplo el reporte de un caso de un perro que presenta intensa epistaxis bilateral tratado en el hospital veterinario.(AU)

The von Willebrand disease (vWD) results from a quantitative and / or qualitative deficiency of von Willebrand factor (vWF). It is classified as a platelet- extrinsic defect, wherein the hemostatic response failure is attributed to deficiency of a plasma factor required for normal platelet function. This study aims to describe systematically the diagnosis of vWD type 1 exemplified in a case report of a dog treated at a veterinary teaching hospital due to intense bilateral epistaxis.(AU)

A doença de von Willebrand (DvW) resulta de uma deficiência quantitativa e/ou qualitativa do fator de von Willebrand (FvW). É classificada como um defeito extrínseco à plaqueta, em que a falha da resposta hemostática é atribuída à deficiência de um fator plasmático necessário para a função plaquetária normal. Este estudo visa descrever de maneira sistemática o diagnóstico da doença de (DvW) tipo 1 exemplificada em um relato de caso de um cão atendido em hospital veterinário de ensino devido a uma intensa epistaxe bilateral.(AU)

Quantitative impact of using different criteria for the laboratory diagnosis of type 1 von Willebrand disease.

INTRODUCTION: Only ± 50% of patients with type 1 von Willebrand disease (VWD) have recognized molecular defects and diagnosis still rests on demonstrating low plasma von Willebrand factor (VWF) protein/function. However, no generalized consensus exists regarding the type and number of VWF variables that should be considered for diagnosis. AIM: To compare the quantitative impact of four different criteria to diagnose type 1 VWD. METHODS: We tested four laboratory criteria on 4298 laboratory studies during a 5-year period. The first was the National Heart, Lung, and Blood Institute recommendation, which diagnoses type 1 VWD with plasma VWF antigen (VWF:Ag) and VWF ristocetin cofactor (VWF:RCo) < 30 IU dL(-1) and possible VWD/'low VWF' with values between 30 and 50 IU dL(-1) . Second, diagnosis was established when two of three variables, VWF:Ag, VWF:RCo, VWF collagen binding assay (VWF:CB), were ≤ 2.5th percentile. Diagnostic criterion for possible VWD/'low VWF' using percentiles was also described. The third criterion (European Group on von Willebrand Disease, EUVWD), uses a plasma level of VWF:RCo (or VWF:CB) ≤ 40 IU dL(-1) for diagnosis. Finally, the Zimmerman Program for the Molecular and Clinical Biology of VWD (ZPMCBVWD) diagnoses VWD if VWF:Ag or VWF:RCo are ≤ 40 IU dL(-1) . RESULTS: The three assays had high correlation and excellent agreement at levels < 120 IU dL(-1) . The National Heart, Lung, and Blood Institute recommendation was followed to diagnose 122 (2.8%) patients with type 1 VWD and 704 (16.4%) with possible VWD/'low VWF.' Using percentiles, the diagnosis of type 1 VWD increased to 280 (6.5%) patients; 169 (3.9%) patients had possible VWD and 180 (4.2%) patients had 'low VWF.' Diagnoses using EUVWD and ZPMCBVWD criteria increased to 339 (7.9%) and 357 (8.3%) patients, respectively. DISCUSSION: Identical data, analyzed using different criteria, led to almost three-fold difference (2.8-8.3%) in diagnostic rate. This increase is mostly explained by increasing the cut-off values of VWF measurements from < 30 to ≈ 40 IU dL(-1) . Further refinement of the laboratory diagnosis of type 1 VWD is a priority.

Fetal surface placental hematomas: the clue in the diagnosis of a bleeding dyscrasia.

Von Willebrand disease (vWD) is the most common inherited bleeding disorder in humans, occurring in about 1% of women and caused by a deficiency or abnormality in the von Willebrand factor (vWF). There are different types of vWD. Type I comprises approximately 80% of the cases, its inheritance is autosomal dominant. Women with vWD have a 10-fold risk of having antepartum bleeding when compared to the general population. We report a case of von Willebrand disease diagnosed due to findings on a routine ultrasound evaluation.