# Hemostatic Therapy and Anticoagulant Reversal in Spontaneous ICH — AHA/ASA 2022

## General Principle

In patients with anticoagulant-associated spontaneous ICH, **anticoagulation should be discontinued immediately** and **rapid reversal of anticoagulation should be performed as soon as possible** after diagnosis to improve survival (Class I, LOE B-NR).

## Vitamin K Antagonist (VKA)-Associated ICH

### 4-Factor Prothrombin Complex Concentrate (4F-PCC)

- In patients with VKA-associated spontaneous ICH and **INR >= 2.0**, **4-factor PCC** is recommended in preference to fresh-frozen plasma (FFP) to achieve rapid correction of INR and limit hematoma expansion (Class I, LOE B-NR).
  - 4F-PCC provides faster and more complete INR reversal compared with FFP.
  - 4F-PCC does not require blood type matching and has a smaller infusion volume.

**4F-PCC Dosing (by baseline INR):**

| Baseline INR | 4F-PCC Dose | Maximum Dose |
|-------------|-------------|--------------|
| **2.0-3.9** | 25 IU/kg | 2,500 IU |
| **4.0-6.0** | 35 IU/kg | 3,500 IU |
| **> 6.0** | 50 IU/kg | 5,000 IU |

- In patients with VKA-associated ICH and **INR 1.3-1.9**, 4F-PCC at a dose of **10-20 IU/kg** may be considered (Class IIb, LOE C-LD).
- **INR target after reversal:** < 1.3 (recheck INR within 15-30 minutes of 4F-PCC administration).

### Intravenous Vitamin K

- **Intravenous vitamin K (10 mg IV)** should be administered directly after coagulation factor replacement (PCC or other) to prevent later increase in INR and subsequent hematoma expansion (Class I, LOE B-NR).
- Vitamin K alone is insufficient for acute reversal because onset of effect is 2-6 hours.
- Vitamin K ensures sustained correction of INR beyond the duration of PCC effect (approximately 6-8 hours).

### Fresh-Frozen Plasma (FFP) -- Not Preferred

- FFP is less effective than 4F-PCC for rapid INR reversal:
  - Requires blood type matching.
  - Requires larger infusion volumes (10-15 mL/kg).
  - Slower administration time.
  - Associated with volume overload and transfusion reactions.
- FFP should only be used when 4F-PCC is unavailable.

## Dabigatran-Associated ICH

- In patients with dabigatran-associated spontaneous ICH, **idarucizumab** is reasonable to reverse the anticoagulant effect of dabigatran (Class IIa, LOE B-NR).
- **Idarucizumab dosing:** 5 g IV administered as two consecutive infusions of 2.5 g each (each infused over 5-10 minutes, or as bolus injection).
- Idarucizumab is a humanized monoclonal antibody fragment that specifically binds dabigatran.
- If idarucizumab is unavailable, **activated PCC (aPCC, e.g., FEIBA) at 50 IU/kg** may be considered as an alternative.

## Direct Factor Xa Inhibitor-Associated ICH

### Andexanet Alfa

- In patients with direct factor Xa inhibitor-associated spontaneous ICH (e.g., apixaban, rivaroxaban, edoxaban), **andexanet alfa** is reasonable to reverse the anticoagulant effect (Class IIa, LOE B-NR).
- Andexanet alfa is a recombinant modified factor Xa protein that acts as a decoy to sequester factor Xa inhibitors.

**Andexanet Alfa Dosing:**

| Factor Xa Inhibitor | Last Dose Timing | Bolus | Infusion |
|--------------------|--------------------|-------|----------|
| **Apixaban <= 5 mg** or **Rivaroxaban <= 10 mg** | >= 8 hours or unknown | 400 mg IV at 30 mg/min | 4 mg/min for 120 min (480 mg) |
| **Apixaban > 5 mg** or **Rivaroxaban > 10 mg** | < 8 hours | 800 mg IV at 30 mg/min | 8 mg/min for 120 min (960 mg) |

### 4F-PCC or aPCC as Alternative

- In patients with direct factor Xa inhibitor-associated spontaneous ICH, **4F-PCC (50 IU/kg) or activated PCC (aPCC)** may be considered to improve hemostasis when andexanet alfa is unavailable (Class IIb, LOE C-LD).
- PCC does not directly reverse factor Xa inhibitors but can augment thrombin generation.

## Antiplatelet-Associated ICH

### Platelet Transfusion -- NOT Recommended

- In patients with spontaneous ICH being treated with antiplatelet agents and **not scheduled for emergency surgery**, platelet transfusions **should not be administered** (Class III: Harm, LOE B-R).
- Evidence from the **PATCH trial** demonstrated that platelet transfusion was associated with worse functional outcomes and increased mortality in patients with antiplatelet-associated ICH.

### Desmopressin

- In patients with spontaneous ICH being treated with antiplatelet agents, the effectiveness of **desmopressin (DDAVP) 0.3 mcg/kg IV** with or without platelet transfusions to reduce hematoma expansion is uncertain (Class IIb, LOE C-LD).
- Desmopressin may enhance platelet adhesion by releasing von Willebrand factor from endothelial stores.

## Hematoma Expansion Prevention -- General Population

### Tranexamic Acid

- In patients with spontaneous ICH who are **not on anticoagulants**, the usefulness of hemostatic therapies (e.g., tranexamic acid, recombinant factor VIIa) to improve functional outcomes is not well established (Class IIb, LOE B-R).
- The **TICH-2 trial** showed that tranexamic acid (1 g loading dose IV, then 1 g over 8 hours) reduced early hematoma expansion but did not improve functional outcomes at 90 days.
- Recombinant factor VIIa is not recommended for unselected ICH patients due to increased thromboembolic risk without functional outcome benefit.

## Anticoagulant Reversal Decision Algorithm

```
Patient with anticoagulant-associated spontaneous ICH
  --> Discontinue anticoagulant IMMEDIATELY
  --> Identify anticoagulant type:
      --> VKA (warfarin)?
          --> Check INR
              --> INR >= 2.0:
                  --> 4F-PCC 25-50 IU/kg IV (dose by INR) [Class I]
                  --> Vitamin K 10 mg IV [Class I]
                  --> Recheck INR in 15-30 min; target < 1.3
              --> INR 1.3-1.9:
                  --> Consider 4F-PCC 10-20 IU/kg [Class IIb]
                  --> Vitamin K 10 mg IV
      --> Dabigatran?
          --> Idarucizumab 5 g IV [Class IIa]
          --> If unavailable: aPCC (FEIBA) 50 IU/kg
      --> Factor Xa inhibitor (apixaban, rivaroxaban, edoxaban)?
          --> Andexanet alfa (dose based on drug, dose, and timing) [Class IIa]
          --> If unavailable: 4F-PCC 50 IU/kg or aPCC [Class IIb]
      --> Antiplatelet agent?
          --> Do NOT transfuse platelets (unless emergency surgery planned) [Class III: Harm]
          --> Consider desmopressin 0.3 mcg/kg IV [Class IIb]
  --> Repeat imaging to assess for hematoma expansion
```

## Resumption of Anticoagulation After ICH

- The optimal timing for resumption of anticoagulation after ICH is not firmly established and requires individualized risk-benefit assessment.
- In patients with a strong indication for anticoagulation (e.g., mechanical heart valve, high-risk atrial fibrillation), resumption may be considered after at least 4 weeks, depending on the etiology of the ICH and risk of recurrence.
- The decision involves balancing the risk of thromboembolic events against the risk of recurrent ICH.

## Limitations

- Andexanet alfa dosing recommendations are based on the ANNEXA-4 trial; prospective randomized data comparing andexanet alfa to 4F-PCC in ICH are limited.
- The PATCH trial established harm from platelet transfusion in antiplatelet-associated ICH, but sample sizes were modest and the study was stopped early.
- Optimal timing and safety of anticoagulation resumption after ICH remain uncertain, with ongoing clinical trials expected to inform future guidelines.
- Idarucizumab data are from the RE-VERSE AD study, which was a single-arm open-label study without a control group.
