Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Large Randomised Placebo Controlled Trial Among Trauma Patients With, or at Risk of, Significant Haemorrhage, of the Effects of Antifibrinolytic Treatment on Death and Transfusion Requirement
Brief Summary: CRASH 2 is a large pragmatic randomised placebo controlled trial of the effects of the early administration of the antifibrinolytic agent tranexamic acid on death, vascular events and transfusion requirements. Adults with trauma who are within 8 hours of injury and have either significant haemorrhage, or who are considered to be at risk of significant haemorrhage, are eligible if the responsible doctor is for any reason substantially uncertain whether or not to use an antifibrinolytic agent. Numbered drug or placebo packs will be available in each participating emergency department. Randomisation will involve calling a 24-hour freecall randomisation service. The call should last only a minute or two and at the end of it the randomisation service will specify which numbered treatment pack to use. For hospitals where telephone randomisation is not feasible, randomisation will be by taking the next consecutively numbered treatment pack. No extra tests are required but a short form must be completed one month later or on discharge or on death (whichever occurs first).


Options:
A: Inclusion Criteria:

* Male and female subjects ≥ 18 years
* Subjects who have received oral vitamin K-antagonist therapy
* Subjects who have acute major bleeding, defined as one of the following: life-threatening or potentially life-threatening, acute bleeding associated with a fall in hemoglobin (Hb) level ≥ 2g/dL, bleeding requiring blood product transfusion
* INR ≥ 2 within 3 hours before start of study treatment
* Informed consent has been obtained

Exclusion Criteria:

* Expected survival of less than 3 days, or expected surgery in less than 1 day
* Acute trauma for which reversal of vitamin K antagonists alone would not be expected to control the acute bleeding event
* Use of unfractionated or low molecular weight heparin use from 24 hours prior to enrollment or expected need within 24 hours after start of infusion
* For patients with ICH: Glasgow coma score (GCS) \< 7; intracerebral hematoma volume \> 30cc as assessed by ABC/21; for subdural hematomas: maximum thickness ≥ 10 mm, midline shift ≥ 5 mm; for subarachnoid hemorrhage: any evidence of hydrocephalus; infratentorial ICH location; epidural hematomas; intraventricular extension of hemorrhage; modified Rankin score (mRS) of \>3 prior to ICH
* History of thrombotic event, myocardial infarction, disseminated intravascular coagulation, cerebral vascular accident, transient ischemic attack, unstable angina pectoris, or severe peripheral vascular disease within 3 months of enrollment
* Known history of antiphospholipid antibody syndrome or lupus anticoagulant antibodies
* Suspected or confirmed sepsis at time of enrollment
* Administration of whole blood, plasma, plasma fractions or platelets within 2 weeks prior to inclusion into the study
* Large blood vessel rupture (e.g. in advanced cancer patient)
* Pre-existing progressive fatal disease with a life expectancy of less than 2 months
* Known inhibitors to coagulation factors II, VII, IX, or X; or hereditary protein C or protein S deficiency; or heparin-induced, type II thrombocytopenia
* Treatment with any other investigational medicinal product within 30 days prior to inclusion into the study
* Presence or history of hypersensitivity to components of the study medication
* Pregnant or breast-feeding women
* Prior inclusion in this study or any other CSL Behring-sponsored Beriplex study
B: Inclusion Criteria:

All trauma patients with ongoing significant haemorrhage (systolic blood pressure less than 90 mmHg and/or heart rate more than 110 beats per minute), or who are considered to be at risk of significant haemorrhage, and are within 8 hours of the injury, are eligible for trial entry if they appear to be at least 16 years old. Although entry is allowed up to 8 hours from injury, the earlier that patients can be treated the better.

Exclusion Criteria:

The fundamental eligibility criterion is the responsible doctor's 'uncertainty' as to whether or not to use an antifibrinolytic agent in a particular adult with traumatic haemorrhage. Patients for whom the responsible doctor considers there is a clear indication for antifibrinolytic therapy should not be randomised. Likewise, patients for whom there is considered to be a clear contraindication to antifibrinolytic therapy (such as, perhaps, those who have clinical evidence of a thrombotic disseminated intravascular coagulation) should not be randomised. Where the responsible doctor is substantially uncertain as to whether or not to use an antifibrinolytic, all these patients are eligible for randomisation and should be considered for the trial. There are no other pre-specified exclusion criteria
C: Inclusion Criteria:

* Eighteen years of age or older
* Undergoing elective thoracoabdominal aortic replacement surgery (TAAA) or thoracic aortic replacement surgery (TAA)
* Understood and willingly given written informed consent (German language) to participate following an explanation of study background, restrictions, and procedures
* Experience clinically relevant bleeding of the microvasculature following removal of CPB during surgery

Exclusion Criteria:

* Positive pregnancy test, pregnancy or lactation
* Women of child bearing age not using a medically approved method of contraception during the study
* Previous aortic replacement at the same aortic site (redo surgeries)
* Undergoing an emergency operation
* Proof or suspicion of a congenital or acquired coagulation disorder (e.g. VWD or via severe liver disease)
* Myocardial Infarction (MI) or apoplexy in the 2 months preceding study surgery
* ASA administration in the 3 days preceding study surgery, and a pathological (\<74.5 U) ASPI Multiplate® test immediately preceding surgery begin
* Clopidogrel administration in the 5 days preceding study surgery, and a pathological (\<31.1 U) ADP/PG Multiplate® test immediately preceding surgery begin
* Tirofiban administration in the 2 days preceding study surgery, and a pathological (\<94.1 U) TRAP Multiplate® test immediately preceding surgery begin
* Phenprocoumon administration in the 5 days preceding study surgery, and an INR \> 1.28 immediately preceding surgery begin
* Participation in another clinical study in the 4 weeks preceding aortic replacement
* Sensitivity to any of the components of study medication, or to MPs with a similar chemical structure to any of the components of study medication
* Any indication that the restrictions or procedures of the study may not be adhered to (e.g. an uncooperative attitude)
* Any indication that the study restrictions, procedures, or consequences therein have not been considered or understood, such that informed consent cannot be convincingly given
* Multiple morbidities, with a notably constrained remaining length of life
D: All legally adult women with postpartum haemorrhage following vaginal or caesarean section delivery who have a clinical diagnosis of postpartum haemorrhage. The clinical diagnosis of PPH may be based on any of the following:

* Blood loss after vaginal delivery \> 500 mL OR
* \> 1,000 mL after caesarean section OR blood loss sufficient to compromise the haemodynamic status of the woman The fundamental eligibility criterion is the responsible clinician's 'uncertainty' as to whether or not to use an antifibrinolytic agent in a particular woman with postpartum haemorrhage.
* Women for whom the responsible doctor considers there is a clear indication for antifibrinolytic therapy should not be randomised.
* Women for whom there is considered to be a clear contraindication to antifibrinolytic therapy should not be randomised.

Where the responsible clinician is substantially uncertain as to whether or not to use an antifibrinolytic, all these women are eligible for randomisation and should be considered for the trial.

There are no other pre-specified exclusion criteria.

Answer: B