Please select the eligibility criteria that correspond to the clinical trial below.
Title: An Open-label, Randomized, Multicenter Phase IIIb Study to Assess the Efficacy, Safety and Tolerance of BERIPLEX® P/N Compared With Plasma for Rapid Reversal of Coagulopathy Induced by Vitamin K Antagonists in Subjects Requiring an Urgent Surgical Procedure
Brief Summary: The purpose of this study is to evaluate efficacy, safety and tolerance of Beriplex® P/N (Kcentra) compared with plasma in regard to rapid reversal of coagulopathy induced by vitamin K antagonists in subjects who require immediate correction of international normalized ratio (INR) because of emergency surgery.


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:

* Male and female subjects greater than or equal to 18 years,
* Subjects currently on oral vitamin K antagonist (VKA) therapy,
* An urgent surgical procedure is required within 24 hours of the start of investigational medicinal product (IMP),
* Due to the nature of the procedure, withdrawal of oral VKA therapy and infusion of plasma are also indicated to reverse the VKA effect,
* INR greater than or equal to 2 within 3 hours before start of IMP,
* Informed consent has been obtained.

Exclusion Criteria:

* Subjects requiring urgent surgical procedures where according to the surgeon's clinical judgment, an accurate estimate of blood loss is not possible (e.g., ruptured aneurysm),
* Subjects for whom administration of intravenous vitamin K and vitamin K antagonists withdrawal alone can adequately correct the subject's coagulopathy before initiation of the urgent surgical procedure,
* Administration of intravenous vitamin K more than 3 hours or administration of oral vitamin K more than 6 hours prior to infusion of IMP,
* Subjects in whom lowering INR within normal range may present an unacceptable risk for a thromboembolic complication where the INR goal is to lower but not normalize the INR because of risk of a procedure-associated stroke,
* Subjects, who despite medical management that includes close monitoring and diuretics, may not, by investigator assessment, tolerate the total volume of IMP required by the protocol,
* Expected need for additional non-study blood products before infusion of IMP (Note: Administration of packed red blood cells is not an exclusion criterion),
* Expected need for platelet transfusions or desmopressin before Day 10,
* Acute trauma for which reversal of vitamin K antagonists alone would not be expected to control or resolve an acute bleeding complication and/or control the acute bleeding event,
* Unfractionated or low molecular weight heparin use within 24 hours before randomization or potential need before completion of the procedure,
* History of thromboembolic event, myocardial infarction, unstable angina pectoris, critical aortic stenosis, cerebral vascular accident, transient ischemic attack, severe peripheral vascular disease, disseminated intravascular coagulation within 3 months of enrollment,
* Reversal of VKA therapy alone may not resolve the coagulopathy (eg, receiving a potent anti-platelet agent, i.e., clopidogrel or prasugrel, or advanced liver disease),
* Known history of antiphospholipid antibody syndrome or lupus anticoagulant antibodies,
* Suspected or confirmed serious viral or bacterial infection, e.g., meningitis, or sepsis at time of enrollment,
* Administration of whole blood, plasma, plasma fractions or platelets within 2 weeks prior to inclusion into the study (Note: Administration of packed red blood cells is not an exclusion criterion),
* 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,
* For subjects with intracranial hemorrhage with:

  * Glasgow Coma Score \<10 (see Appendix 8)
  * Modified Rankin Score \> 3 prior to ICH (see Appendix 9)
  * Intracerebral hemorrhage
  * Epidural hematomas
  * Infratentorial hemorrhage
  * Subarachnoid hemorrhage (SAH) subjects with a Hunt and Hess Scale \>2
  * Subdural hematomas that:

    * are judged to be an acute subdural hematoma (based on neurosurgeon review)
    * have a concurrent SAH or parenchymal contusion
C: Inclusion Criteria:

1. Male and female subjects =/\> 18 years and =/\< 80 years
2. Major trauma (ISS \> 15)
3. Clinical signs of ongoing bleeding or patients who are at risk for significant haemorrhage assessed and judged by the ED team in charge of patient
4. Presence of coagulopathy defined by ROTEM assays as follows,

   * Patients with concomitant decreased fibrinogen polymerisation (ROTEM® FibTEM A10 of \< 7 mm after 10 min)
   * Patients with concomitant decreased coagulation factor levels (ROTEM® ExTEM CT of \> 90 sec)

Exclusion Criteria:

1. Lethal injury
2. CPR on the scene,
3. Isolated brain injury, burn injury
4. Avalanche injury
5. Administration of FFP or coagulation factor concentrates before ED admission
6. Delayed (\> 6hours after trauma) admittance to ED
7. Known use of oral anticoagulants, or platelet aggregation inhibitors within 5 days before injury
8. Known history of severe allergic reaction to plasma products
9. Known history of congenital hemostasis disturbance, IgA or Protein C deficiency
10. Patients with a history of thromboembolic events or heparin induced thrombocytopenia (HIT) type 2 within the last year
11. Patients with a body weight \< 45kg and \> 150kg
12. Patients that are known to be pregnant
13. Jehova's Witness
14. Known participation in another clinical trial
15. Patient with known refusal of a participation in this clinical trial
D: Inclusion Criteria:

* - Planned coronary artery bypass grafting (CABG) or CABG plus single heart valve replacement/repair or planned replacement/repair of a single heart valve

Exclusion Criteria:

* Known intolerance to protamine
* Known or suspected allergy to the used antifibrinolytic agent
* Refusal to receive blood or blood product
* Planned surgery including the aortic arch and/or descending aorta
* Planned surgery including any implantable ventricular assist device
* Adult congenital heart diseases
* Two or more previous cardiac surgery procedures
* Any known autoimmune diseases: Collagen vascular disease (Systemic lupus erythematosus, Rheumatoid arthritis, Sjögrens syndrome) - Endocrine: hyperthyroidism (Graves disease), adrenal insufficiency, Hashimoto's thyroiditis - Neurologic: Multiple sclerosis, myasthenia gravis - Skin: pemphigous vulgaris Hematologic: Pernicious anaemia, Autoimmune haemolytic anaemia - Vasculitis - Primary or secondary antiphospholipid syndrome
* Weight above 140 kg

Answer: B