Table S1 Etiology of Spontaneous Intracerebral Hemorrhage (ICH)

Table S1 – Etiology of Spontaneous Intracerebral Hemorrhage (ICH)

Primary Secondary

 Hypertension (most common cause)  Vascular malformations

 Cerebral amyloid angiopathy (most common cause - Arteriovenous malformation of lobar ICH, especially in the elderly) - Cavernous malformation  Sympathomimetic drugs (e.g cocaine, - Cerebral aneurysms methamphetamine)  Dural arteriovenous fistula  Coagulopathy (bleeding disorders, antithrombotic agents, thrombolytic therapy, anticoagulants)  Hemorrhagic transformation

- Ischemic stroke

- Post-tPA

 Dural venous sinus thrombosis (hemorrhagic venous infarction)

 Primary intracranial tumours - Glioblastoma multiforme

- Oligodendroglioma

 Metastases of primary extracranial tumours

- Malignant melanoma

- Bronchial carcinoma

- Thyroid carcinoma

- Hypernephroma

- Breast

 Infections (especially “mycotic” aneurysms – endocarditis-related septic cerebral emboli –, aspergillosis, and herpes simplex encephalitis)

 Primary or secondary CNS vasculitis (rare cause)

 Moyamoya (rare cause) Table S2 – Initial Management

1. ABC. Initial assessment and stabilization of airway, breathing, and circulation.

2. Rapid Neuroimaging. CT or MRI can be used to differentiate ICH from an ischemic stroke.

3. Neurologic assessment to determine baseline severity. (i.e. Glasgow Coma Scale (GCS), NIHSS and /or

ICH score calculation).

4. Blood pressure management (AHA/ASA guidelines for Blood Pressure Management after ICH - NEW

Guidelines 2015). For ICH patients presenting with SBP between 150 and 220 mmHg and without contraindication to acute BP treatment, acute lowering of SBP to 140 mm Hg is safe and can be effective

for improving functional outcome. For ICH patients presenting with SBP > 220 mm Hg, it may be

reasonable to consider aggressive reduction of BP to < 140 mmHg with a continuous intravenous

infusion and frequent BP monitoring.

5. Clinical history and laboratory evaluation of coagulopathy. Evaluate the use of anticoagulants or history

of bleeding disorder. Measure platelets count, partial thromboplastin time (PTT), and international

normalized ratio (INR).

6. Aggressive correction of coagulation derangements. If coagulation abnormalities are detect, they should

be quickly and aggressively correct.

7. Admission to Neurointensive Care Unit (NICU) and frequent neurological assessment. Ideally, neuro

checks every hour in a NICU environment, what would allow for timely detection of early neurological

deterioration.

8. Management of increased intracranial pressure. Table S3 – Factor composition of some of the available commercial preparations of 4PCC

Name Beriplex 500 Octaplex 500 Cofact 500 Confidex 500 (Kcentra) Manufacturer CSL Behring Octapharma Sanquin CSL Behring

Factor II 380–800 280-760 IU 280 – 700 400 – 960

Factor IX 400–620 500 IU 500 400 – 620

Factor X 500–1020 360-600 IU 280 – 700 440 – 1200

Factor VII 200–500 180-480 IU 140 – 400 200 – 500

Protein C and S Yes Yes Yes Yes

Heparin Yes No No No Table S4 – Evidenced based summary of ICH management

ClinicalTrial Country Current Population Intervention Primary Sample s.gov Status outcome size (study name) Blood pressure control

NCT0228183 Canada Recruiting SBP <180 Diffusion- 270 8 mmHg versus weighted SBP <140 imaging (ICH- mmHg within (DWI) lesion ADAPT II) one hour after frequency ranzomization

Temperature Control

NCT0158416 Germany Recruiting Stroke Cold infusions Brain 20 7 (including versus temperature hemorrhagic) EMCOOLS (iCOOL 2 ) Flex.Pads

NCT0075163 United States Completed, Neurological Gaymar Rapr- Core 20 4 not patients Round Temperature published

NCT0160715 United States Recruiting Intracerebral Normothermia Severe 50 1 Hemorrhage (36-37°C) adverse versus events (TTM-ICH) hypothermia (32-34°C)

NCT0207803 United States Ongoing, Intracerebral Arctic Sun® MRI 100 7 not Hemorrhage 5000 (target measurement recruiting 35.5 - 37.5oC) of relative SNICH versus perihematom Acetaminophe al edema n + cooling blanket (target < 38.5oC)

Transfusion/Coagulation NCT0092891 Germany Unknown Intracerebral Prothrombin INR ≤ 1.2 74 5 Haemorrhag complex within 3 e concentrate hours after (INCH) versus fresh start of drug frozen plasma infusion

NCT0069962 Finland Unknown Intracerebral Standard care Hematoma 100 1 Hemorrhage versus growth using platelets within 24 h Platelet measured as Inhibitors increase in hematoma volume observed by head CT

NCT0022262 Italy Unknown Intracerebral Factor VIIa + Change in 32 5 Hemorrhage (vit K in ICH volume using anticoagulated from prior to Platelet patients) dosing to 24 Inhibitors or versus plasma hours anticoagulan or ts prothrombin complex concentrate

NCT0135920 Canada Recruiting Intracranial Factor VIIa ICH size in 110 2 hemorrhage versus placebo 24h with spot (SPOTLIGH sign present T)

Surgical Management

NCT0213578 China Recruiting Intracranial Decompressiv Mortality 200 3 hemorrhage e versus non- and disability in the first decompressive (CARICH) 72h, volume craniectomy 30-100 mL, lobar or basal ganglia location

NCT0182704 United States Recruiting Intracranial Surgical Modified 500 6 hemorrhage, drainage with Rankin Scale supratentoria local rt-PA score at 180 (MISTIE l volume ≥ 30 infusion versus days III) mL Clinical Management

NCT0225891 Germany Recruiting Intracranial Decompressiv Modified 300 9 hemorrhage, e craniectomy Rankin Scale volume of versus clinical score at 180 (SWITCH) ≥30 ml and management days ≤100 ml Table S5 – Hematoma expansion scores - CTA indicates computed tomography angiography; GCS, Glasgow Coma Scale; ICH, intracerebral hemorrhage; INR, international normalized ratio; IVH, intraventricular hemorrhage; NIHSS, National Institutes of Health Stroke Scale; and PREDICT, Predicting Hematoma Growth and Outcome in Intracerebral Hemorrhage Using Contrast Bolus Computed Tomography. 9-Point Score 24-Point Score (Brain) PREDICT A Score Predict B Score

Component Points Component Points Component Points Component Points

Baseline ICH volume, ml Baseline ICH volume, ml GCS NIHSS

< 30 0 ≤ 10 0 14-15 0 0-4 0

30-60 1 10-20 5 ≤ 13 4 5-14 4 > 60 2 > 20 7 ≥ 15 7

Hours from onset to CT Hours from onset to CT Hours from onset to CT Hours from onset to CT

≤ 6 2 ≤ 1 5 ≤ 1 5 ≤ 1 5

> 6 0 > 1-2 4 > 1-2 4 > 1-2 4

> 2-3 3 > 2-3 3 > 2-3 3

> 3-4 2 > 3-4 2 > 3-4 2

> 4-5 1 > 4-5 1 > 4-5 1

> 5 0 > 5 0 > 5 0

Warfarin use Warfarin use Warfarin use or INR > 1.5 Warfarin use or INR > 1.5

Yes 2 Yes 6 Yes 6 Yes 7

No 0 No 0 No 0 No 0

CTA spot sign CTA spot sign number CTA spot sign number

Present 3 0 spots 0 0 spots 0

Absent 0 1 spot 4 1 spot 4 Unavailable 1 ≥ 2 spots 8 ≥ 2 spots 9

IVH extension

Recurrent ICH

Total 0-9 0-24 0-23 0-28