Thrombolysis Following Heparin Reversal With Protamine Sulfate in Acute Ischemic Stroke: Case Series and Literature Review

J Stroke Cerebrovasc Dis. 2019 Oct;28(10):104283. doi: 10.1016/j.jstrokecerebrovasdis.2019.06.041. Epub 2019 Jul 17.


Introduction: Administering intravenous IV tissue plasminogen activator (tPA) is the recommended standard of care in acute ischemic stroke (AIS), although it is not recommended to administer intravenous thrombolysis with tPA following heparin reversal with protamine sulfate in patients with AIS.

Methods: We describe a case series of three patients and the most comprehensive literature review published to date in this specific subset of AIS patients undergoing thrombolysis following heparin reversal with protamine sulfate. The literature review was based on a scoping review methodology performed on four databases; PubMed, CINAHL, Web of Science, and Cochrane Library. All sources were searched from the inauguration of the database until February 2019. A total of six articles involving eight patients were identified.

Results: The primary safety outcome of no symptomatic intracranial hemorrhage (sICH) was met in all eleven patients, although only seven cases had a good functional outcome at 3 months.

Conclusions: In appropriately selected AIS patients, coagulopathy correction appears to be safe from an sICH standpoint and may be beneficial. However, given the potential for bias with observational databases, case reports and case series, extreme caution is warranted in applying these results to routine clinical practice.

Keywords: Acute ischemic stroke; IV tPA; case series; heparin reversal; literature review; protamine sulfate; symptomatic intracranial hemorrhage; thrombolysis.

Publication types

  • Case Reports
  • Systematic Review

MeSH terms

  • Administration, Intravenous
  • Aged
  • Aged, 80 and over
  • Anticoagulants / adverse effects
  • Anticoagulants / therapeutic use*
  • Blood Coagulation / drug effects*
  • Brain Ischemia / blood
  • Brain Ischemia / diagnosis
  • Brain Ischemia / drug therapy*
  • Female
  • Fibrinolytic Agents / administration & dosage*
  • Fibrinolytic Agents / adverse effects
  • Heparin / adverse effects
  • Heparin / therapeutic use*
  • Heparin Antagonists / adverse effects
  • Heparin Antagonists / therapeutic use*
  • Humans
  • Male
  • Middle Aged
  • Protamines / adverse effects
  • Protamines / therapeutic use*
  • Stroke / blood
  • Stroke / diagnosis
  • Stroke / drug therapy*
  • Thrombolytic Therapy* / adverse effects
  • Tissue Plasminogen Activator / administration & dosage*
  • Tissue Plasminogen Activator / adverse effects
  • Treatment Outcome


  • Anticoagulants
  • Fibrinolytic Agents
  • Heparin Antagonists
  • Protamines
  • Heparin
  • Tissue Plasminogen Activator