The clinical relevance and significance of new diagnostic options in patients with unexplained bleeding |
|- candidate number||25508|
|- NTR Number||NTR6201|
|- ISRCTN||ISRCTN no longer applicable|
|- Date ISRCTN created|
|- date ISRCTN requested|
|- Date Registered NTR||4-nov-2016|
|- Secondary IDs||NL55101.07818 ABR MEC-2016-218 Erasmus MC|
|- Public Title||The clinical relevance and significance of new diagnostic options in patients with unexplained bleeding |
|- Scientific Title||The clinical relevance and significance of new diagnostic options in patients with unexplained bleeding |
|- ACRONYM||The Crescendo-study|
|- hypothesis||Unexplained bleeding is defined as disproportionate bleeding after trauma, surgery, and minor injuries; easy bruising; mucosal bleeding, and / or menorrhagia without any routine laboratory abnormalities, based on known laboratory definitions for known bleeding disorders. Analysis of retrospective data in the Erasmus MC and Erasmus MC – Sophia Children’s Hospital (unpublished) and a review of literature shows that, despite extensive history taking combined with the routine laboratory tests, it is often not possible to diagnose a bleeding disorder. Strikingly, percentages amount to an impressive 50-60% of patients in which the bleeding tendency remains unexplained and no diagnosis can be made (47% to 69%, Matthews 2013; ~60%, Favaloro 2007). Several explanations are possible for this high percentage of individuals with an unexplained bleeding tendency:
• Routine testing is not sensitive enough to demonstrate minor abnormalities.
• Rare deficiencies (for example PAI-1 deficiency) are not part of routine testing.
• Abnormalities may be subtle and dependent on time point of testing, for example as may be the case with regard to hormonal influences on hemostatic variables in women or a diurnal rhythm of fibrinolytic inhibitors (for example PAI-1).
• More than one abnormality may be present in different domains of the coagulation cascade. For example, it is increasingly evident that individuals with a significant bleeding tendency and low VWF levels may have several risk other undiagnosed factors for bleeding.
• Several mild hemostatic abnormalities that cumulatively lead to clinical symptoms.
|- Healt Condition(s) or Problem(s) studied||Bleeding|
|- Inclusion criteria||In order to be eligible to participate in this study, a subject must meet all of the following criteria:|
- Patients aged ≥12 years at day of presentation at outpatient clinic;
- Patients with a significant history of bleeding tendency according to physician opinion or abnormal bleeding score based on a BAT
o with no definate diagnosis after routine testing (see appendix 5 – Diagnostic criteria according to the CPO guideline for specific laboratory diagnostic criteria),
o with a heterozygous factor deficiency or low Von Willebrand Factor levels that do not match bleeding tendency,
o with aberrant laboratory results that do not lead to a diagnosis;
- (Parental) informed consent should be provided prior to any study specific procedure.
|- Exclusion criteria||A potential subject who meets any of the following criteria will be excluded from participation in this study:|
- Patients ‹ 12 years of age on day of presentation at outpatient clinic;
- Patients with a clearly defined bleeding disorder after routine testing (see appendix 4 – Diagnostic criteria according to the CPO guideline for specific laboratory diagnostic criteria);
- Patients under therapy with anticoagulants and / or antiplatelet and / or anti-inflammatory agents and cannot discontinue medication during diagnostic work-up;
- Patients with thrombocytopenia < 80 x 109/L;
- Patients with a bleeding tendency due to an acquired platelet function disorder (e.g. idiopathic thrombocytopenic purpura – ITP);
- Patients with impaired liver function, e.g. a documented liver cirrhosis or signs of acute liver failure;
- Women that are pregnant or up to three months postpartum;
- Patients who are unable to give (parental) informed consent.
|- mec approval received||yes|
|- multicenter trial||no|
|- planned startdate ||1-jul-2016|
|- planned closingdate||30-nov-2018|
|- Target number of participants||150|
|- Interventions||We will perform a single-center prospective case-control study to determine the value of the introduction of the ISTH-BAT and novel diagnostic tests in patients, both adults as well as children aged 12 to 18 years, with unexplained bleeding symptoms. |
The setting is the outpatient (Pediatric) Hematology clinic of the Erasmus MC and Erasmus MC – Sophia Children’s Hospital where patients present with bleeding symptoms, a positive family history for bleeding disorder and / or aberrant laboratory results.
Patients are eligible if the routine diagnostic tests do not lead to a clear diagnosis of a bleeding disorder.
Patients will be prospectively followed for one year after first visit to the outpatient clinic.
|- Primary outcome||To investigate the additive value of new diagnostic tools in patients with unexplained bleeding and to refine therapeutic interventions. |
|- Secondary outcome||1. To identify abnormalities in primary, secondary or fibrinolytic phase of coagulation in patients with unexplained bleeding. |
o To identify patients with subtle / minor abnormalities in primary, secondary and / or fibrinolytic phase;
o To identify a possible second hemostatic defect in patients with low Von Willebrand diagnosed with a mild Von Willebrand Disease type 1, with a significant bleeding tendency;
o To identify a possible second hemostatic defect in patients with a heterozygous deficiency of a single coagulation factor (e.g. FVII or FXI) and a significant bleeding tendency not explained by the antigen concentration level of this deficiency;
o To identify patients with a fibrinolytic defect;
o To identify patients with an abnormal platelet specific proteomic pattern.
2. To prospectively register bleeding events for a period of one year, treatment advice, actual treatment given and outcome of treatment, by means of:
o The number of bleeding events, defined according to definitions of bleeding by the International Society of Thrombosis and Hemostasis*;
According to the International Society of Thrombosis and Hemostasis definitions of bleeding: Major bleeding: 1. Fatal bleeding, and / or 2. Symptomatic bleeding in a critical area of organ, and / or 3. Bleeding causing a fall in hemoglobin level of 2 g/dL (1.24 mmol/L) or more, or leading to transfusion of two or more units of whole blood or red cells.* Minor bleeding: all non-major bleedings.
o Medication, blood products or coagulation factor concentrates administered perioperatively or after trauma and outcome of treatment;
o The number of treatment related complications.
3. To validate the menorrhagia screeningtool in women with a suspected bleeding disorder.
4. To investigate the cyclic variation of hemostatic variable in premenopausal women with unexplained bleeding, in order to establish an optimal time window for diagnostic testing.
|- Timepoints||Primary endpoint: To determine the association between the bleeding phenotype (normal versus abnormal bleeding phenotype) based on medical history and / or bleeding score – abnormal when scored ≥ 4 for male, ≥ 6 for female and ≥ 3 for children), new diagnostic tests and bleeding complications during a one year follow-up period.|
1. The abnormalities identified by new diagnostic tools and possibly associated with platelet function, primary or secondary hemostasis, and fibrinolysis affecting the individual patients coagulation potential. These abnormalities may be:
o Abnormalities in ROTEM® pattern
o Abnormalities in thrombin generation pattern
o Abnormalities in clot lysis pattern
o Combined abnormalities in global hemostatic assays
o Abnormalities in platelet proteomics
o Secondary abnormalities in patients with low VWF-levels
o Secondary abnormalities in patients with heterozygous factor deficiencies
o Abnormalities in fibrinolytic activators or inhibitors
2. Evaluation of bleeding and treatment advice during one year follow-up, by means of:
o Type of bleeding symptoms
o Frequency of bleeding symptoms
o Treatment advice given in patients with unexplained bleeding
o Treatment advice followed during (dental) surgical procedures or after trauma
o Management of bleeding
o Local treatment
o Antifibrinolytic agents or DDAVP
o Transfusion of red blood cells (RBC), platelets, plasma, prothrombin complex concentrate (PCC) or other factor concentrates
o Surgical, endoscopic or radiologic interventions to control bleeding
o Thromboembolic complications within 30 days after treatment of bleeding
3. Most optimal timing of diagnostic evaluation in premenopausal women with unexplained bleeding based on the cyclic variation of hemostatic variables.
|- Trial web site|
|- status||open: patient inclusion|
|- CONTACT FOR PUBLIC QUERIES||MSc Caroline Veen|
|- CONTACT for SCIENTIFIC QUERIES||Dr. M.J.H.A. Kruip|
|- Sponsor/Initiator ||Erasmus Medical Center, Sophia Children's Hospital|
(Source(s) of Monetary or Material Support)
|- Publications||- |
|- Brief summary||Rationale: Each year approximately 100-150 patients, both adults and children (aged ≥ 12 years), are referred to the Erasmus University Medical Center and the Erasmus MC – Sophia Children’s Hospital due to an experienced subjective or objective bleeding tendency. Retrospective data analysis (unpublished) shows that, despite extensive history taking combined with routine laboratory tests, in approximately 60% of these patients a bleeding disorder cannot be confirmed. This is unfortunate as a diagnosis is of great significance with regard to preferred treatment in case of trauma, (dental) surgery or other situations requiring medical intervention. Currently, if a bleeding tendency is regarded significant and no bleeding disorder is diagnosed, general treatment guidelines are followed.|
In this study, we intend to evaluate the role of novel diagnostic tools and tests in all patients with a currently unexplained bleeding tendency. Furthermore, we aim to establish the effect of hormonal influences on hemostasis in women with bleeding symptoms. Novel diagnostic tools will include a validated as well as a novel international (pediatric) bleeding assessment tool. Novel diagnostic tests will include tests that assess the global hemostatic potential e.g. Thromboelastometry (ROTEM®) and Thrombin Generation Assay (TGA) as well as test that aim to quantify fibrinolytic potential of the individual e.g. plasma clot lysis assay (CLA). In addition a third category of tests will be performed that aims to explore and quantify the proteomic constellation of the platelet, in order to identify potential platelet disorders. As hemostatic testing is currently a developing field, informed consent will be obtained for blood sample storage in order to perform novel techniques in the near future currently under development (e.g. whole exome sequencing, other platelet specific techniques).
Objective: The primary objective of this study is to investigate the additive value of new diagnostic tests to categorize patients with currently unexplained bleeding in order to refine therapeutic interventions.
Study design: Prospective case-control study
Study population: 150 patients, male or female, ≥ 12 years of age, referred to the outpatient (Pediatric) Hematology clinic of the Erasmus MC or Erasmus MC – Sophia Children’s Hospital for evaluation of bleeding symptoms, and 75 healthy control individuals.
Main study parameters/endpoints: The diagnostic utility of novel tests by comparison of the results in patients with a currently unexplained bleeding tendency with results in healthy controls.
Secondary study parameters/endpoints
1. The (number and type of) abnormalities identified and categorized (platelet related, primary or secondary hemostasis, fibrinolysis) by novel diagnostic tests in individual patients.
2. Evaluation of bleeding events during a period of one year (type, frequency), as well as evaluation of treatment advice and actual treatment given.
3. Evaluation of most optimal time point for diagnostic evaluation in premenopausal women with unexplained bleeding based on the cyclic variation of hemostatic variables.
Nature and extent of the burden and risks associated with participation, benefit and group relatedness:
Burden: After obtaining informed consent by the patient and also by his parents or caregivers when the patient is 12-18 years of age, bleeding symptoms will be quantified by both a validated adult and pediatric bleeding assessment tool (BAT). As well as a recently developed novel pediatric bleeding assessment tool. Blood samples will obtained in combination with routine laboratory tests. A maximum of eight (eleven for evaluating the cyclic variation of hemostatic variables) extra tubes will be taken (see appendix 5 – Blood sampling CRESCENDO study).
Risks: The risks associated with study participation are considered negligible and the extra burden is minimal. Patients participating in the study will receive the same routine diagnostic tests and treatment advice as patients not included in the study, according to current clinical practice guidelines. In the patients participating in the study, additional diagnostic tests will be performed in a small amount of extra blood extracted from the patient during blood sampling moments required for the standard diagnostic work up.
Benefits: In current practice, patients (and parents) experience a burden of uncertainty when a bleeding tendency cannot be specified and only general treatment can be recommended. We aim to increase knowledge with regard to the \etiology of the bleeding tendency in patients with currently unexplained bleeding by systematic documentation of the bleeding symptoms by bleeding assessment tools and by performance of novel tests that investigate global hemostatic potential or focus on a defect in part of the coagulation cascade which is not tested in routine laboratory testing. In the future this approach may lead to more targeted therapy of bleeding complications and protect patients from event unnecessary treatment, avoidable medical interventions and/or (prolonged) hospitalization.
|- Main changes (audit trail)|
|- RECORD||4-nov-2016 - 19-feb-2017|
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