COAgulation Disorders in Ischaemic and Haemorrhagic Stroke

Study Overview
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Brief Summary
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In this study the investigators will assess both procoagulant and anticoagulant pathways using thrombin generation and platelet function tests; as well as neuronal ischemia using cell free DNA in all patients presenting with ischaemic and haemorrhagic stroke (including aneurysmal subarachnoid haemorraghe). Also the cross-talk between inflammation and thrombosis, so-called thrombo-inflammation is further investigated. As such the investigators aim to characterise the patient's coagulation profile before administration of any treatment. By assessing these pathways the investigators strive to detect specific markers to predict vital and functional outcome at 3 months in these patients. Finally the investigators may provide new pathophysiological insights in the course of disease following these events that can possibly improve future therapeutic strategies.

Detailed Description
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In the COADIHS trial the main objective is to map the coagulation profile, both procoagulant and anticoagulant pathways, in patients presenting with acute ischaemic or haemorrhagic stroke. By assessing these different pathways the investigators aim to detect possible biomarkers of coagulation with predictive value for functional and vital outcome at 3 months. In different subgroup analyses the investigators try to answer additional research questions as posed by the specific pathophysiology. Primary Objective: Mapping the coagulation profile of both procoagulant and anticoagulant pathways together with markers of inflammation and ischemia in patients presenting with all types of acute ischaemic or haemorrhagic stroke, at presentation and during first 7 days of clinical course in order to detect biochemical markers with predictive value of vital and functional outcome at 3 months. Secondary Objective: Detection of culprit underlying thrombophilia in cryptogenic stroke and evaluation of their effect on clinical course and outcome (recurrent stroke). Evaluating the interaction between the coagulation profile and pre-stroke medication that works on coagulation pathways. To investigate the role of platelets and platelet activation in different pathophysiological mechanisms described in development of delayed cerebral ischemia following aneurysmal subarachnoid haemorrhage (aSAH)(microvessel constriction, thromboinflammation, large artery vasospasm, cortical spreading depolarization) To evaluate the role of haemostatic derangements following aSAH as biomarker to predict delayed cerebral ischemia.

Official Title
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COAgulation Disorders in Ischaemic and Haemorrhagic Stroke

Conditions
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Ischemic Stroke, Haemorrhagic Stroke, Aneurysmal Subarachnoid Hemorrhage

Intervention / Treatment
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* Diagnostic Test: blood sampling


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Presenting at the hospital with ischaemic stroke, haemorrhagic stroke, aneurysmal subarachnoid haemorrhage or any other type of non-traumatic, intracranial bleeding In patients with minor ischemic stroke (NIHSS <= 4) only baseline lab sampling will be performed (T0 and T0B). Exclusion Criteria: Refusal of participation by patient or legal representative Traumatic intracranial (subdural, subarachnoid, epidural haematoma) bleeding Patients receiving treatment with interference on coagulation (pro / anti) before first sampling: in this group of patients the coagulation assessment at presentation will be excluded, further lab sampling is performed according to protocol. Patients categorized as having stroke mimic will be excluded from analysis afterwards

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Ischemic Stroke<br>Patients presenting at emergency department / Intensive Care unit with ischemic stroke registration of baseline clinical data registration of baseline blood parameters (in context of standard of clinical care) additional blood sampling at 5 time points during 1st week with the purpose of full coagulation testing and cell free DNA methylation | Diagnostic Test: blood sampling<br>* At 5 time points (D0 (T0),morning after (T0B),D3 (T1),D5 (T2),D7(T3)) blood samples will be drawn next to blood sampling in context of standard of clinical care. A full coagulation and inflammation profile will be obtained as well as cell free DNA methylation<br>|
| Haemorrhagic stroke<br>Patients presenting at emergency department / Intensive Care unit with haemorraghic stroke (spontaneous intracranial bleeding, no trauma) registration of baseline clinical data registration of baseline blood parameters (in context of standard of clinical care) additional blood sampling at 5 time points during 1st week with the purpose of full coagulation testing and cell free DNA methylation | Diagnostic Test: blood sampling<br>* At 5 time points (D0 (T0),morning after (T0B),D3 (T1),D5 (T2),D7(T3)) blood samples will be drawn next to blood sampling in context of standard of clinical care. A full coagulation and inflammation profile will be obtained as well as cell free DNA methylation<br>|
| Aneursmal Subarachnoid Haemorrhage<br>Patients presenting at emergency department / Intensive Care unit with aneurysmal subarachnoid haemorrhage registration of baseline clinical data registration of baseline blood parameters (in context of standard of clinical care) additional blood sampling at 5 time points during 1st week with the purpose of full coagulation testing and cell free DNA methylation | Diagnostic Test: blood sampling<br>* At 5 time points (D0 (T0),morning after (T0B),D3 (T1),D5 (T2),D7(T3)) blood samples will be drawn next to blood sampling in context of standard of clinical care. A full coagulation and inflammation profile will be obtained as well as cell free DNA methylation<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Functional Outcome Modified rankin scale | Modified Rankin Scale as defined by: score 0: no symptoms score 1: No significant disability despite symptoms; able to carry out all usual duties and activities Score 2:Slight disability; unable to carry out all previous activities, but able to look after own affairs without assistance Score 3: Moderate disability; requiring some help, but able to walk without assistance Score 4:Moderately severe disability; unable to walk and attend to bodily needs without assistance Score 5: Severe disability; bedridden, incontinent and requiring constant nursing care and attention Score 6:Dead With Score 3-6 defined as poor outcome and score 0-2 defined as good outcome | 3 months | 
| Functional Outcome recurrent stroke | Recurrent stroke during first 3 months | 3 months | 
| Vital Outcome - all cause mortality | Mortality rate in the participants of all cause at 3 months | 3 months | 
| Functional Outcome EQ5D | EQ5D questionnaire scoring different aspects of functionality mobility self-care usual activities pain/discomfort anxiety / depression a global health score will be assessed | 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ICU Length of stay | duration (days) | 3 months | 
| Hospital Length of stay | duration (days) | 3 months | 
| Need for mechanical ventilation in ICU | Yes/No and duration (days) | 3 months | 
| Need for renal replacement therapy in ICU | YES / NO and duration (days) | 3 months | 
| Deep vein thrombosis | Yes/No | 3 months | 
| Need for ventriculo-external drain / ventriculo-peritoneal drain | Yes / No | 3 months | 
| Rate of delayed cerebral ischemia participants with aneurysmal subarachnoid haemorrhage | Rate of delayed cerebral ischemia in participants with aneurysmal subarachnoid haemorrhage vasospasm: clinical / radiological (transcranial doppler, CT perfusion, MRI) Delayed cerebral ischemia as diagnosed with MRI | 3 months | 
| Need for decompressive craniectomy | Yes / no | 3 months | 
| Haemorrhagic transformation of infarction | yes / No | 3 months | 
| Rebleeding aneurysm in aneurysmal subarachnoid haemorrhage | yes /no | 3 months | 
| Rate of epilepsy | Both convulsive epileptic episode as non-convulsive epileptic episode. Both clinical diagnosis and elektro-encephalogram | 3 months | 
| Rate of infection in participants | CNS infection, Pulmonary infection, genito-urinary infection, catheter related blood stream infection,gastro-intestinal infection, skin infection, other infection, bacteriemia, fungaemia | 3 months | 
| Rate of Intensive Care Aquired weakness (ICUAW) | critical illness myopathy, critical illness polyneuropathy or icu-AW | 3 months | 
| Rate of diabetes insipidus during first week | Diabetes insipidus | 7days | 
| Rate of cardiovascular compromise during first week | As defined by use of vasopressors and inotropes / acute heart failure / acute myocardial infarction / cardiac arrest / new arrythmia / use of VA-ECMO | 7 days | 
| Rate of acute respiratory failure during first week | acute respiratory failure (intubation + mechanical ventilation / non-invasive ventilation / ARDS), need for VV-ECMO / neurogenic pulmonary edema | 7 days | 
| Rate of Acute kidney injury during first week | acute kidney injury (KDIGO classification) | 7 days | 
| Rate of enteral feeding (oral/nasograstic) or Total parenteral nutrition during first week | TPN / enteral feeding (oral/nastrogastric) | 7 days | 
| Rate of Acute liver failure during first week | Acute liver failure INR > 1.5 Any grade of hepatic encefalopathy No prior evidence of liver disease | 7 days | 
| Rate of infection during first week | CNS infection / pulmonary infection / endocarditis / UTI / GI infection /skin infection / blood stream infection | 7 days | 
| Rate of antiplatelet / anticoagulant therapy during first week | Rate of antiplatelet therapy or anticoagulant therapy in participants | 7 days |