Heparin (Unfractionated Heparin)

Indications for Unfractionated Heparin Anticoagulation

Anticoagulation During Extracorporeal Life Support (ECLS)

Cardiopulmonary Bypass (CPB) (see Cardiopulmonary Bypass)
Extracorporeal Membrane Oxygenation (ECMO)
- Venoarterial Extracorporeal Membrane Oxygenation (VA-ECMO) (see Venoarterial Extracorporeal Membrane Oxygenation)
- Venovenous Extracorporeal Membrane Oxygenation (VV-ECMO) (see Venovenous Extracorporeal Membrane Oxygenation)

Cardiac

Acute Coronary Syndrome (ACS) (see Coronary Artery Disease)

xxx

Atrial Fibrillation (AF) (see Atrial Fibrillation)

Rationale
- Heparin Anticoagulation Decreases the Risk of Embolic Ischemic Ischemic Cerebrovascular Accident (CVA)/Transient Ischemic Attack (TIA) (see Ischemic Cerebrovascular Accident and Transient Ischemic Attack)

Pulmonary

Venous Thromboembolism Prophylaxis and/or Treatment

Clinical
- Deep Venous Thrombosis (DVT) Prophylaxis (see Deep Venous Thrombosis)
- Deep Venous Thrombosis (DVT) Treatment (see Deep Venous Thrombosis)
- Acute Pulmonary Embolism (PE) (see Acute Pulmonary Embolism)

Other Indications for Unfractionated Heparin Anticoagulation

Cerebral Venous Thrombosis (see Cerebral Venous Thrombosis)

XXXXXX

Coronavirus Disease 2019 (see Coronavirus Disease 2019)

Trial of Heparin in Non-Critically Ill Patients with SARS-CoV2 (COVID-19)
- In Noncritically Ill Patients with SARS-CoV2, an Initial Strategy of Therapeutic-dose anticoagulation with heparin increased the probability of survival to hospital discharge with reduced use of cardiovascular or respiratory organ support as compared with usual-care thromboprophylaxis (NEJM, 2021) [MEDLINE]
Trial of Heparin in Critically Ill Patients with SARS-CoV2 (COVID-19)
- In Critically Ill Patients with SARS-CoV2, an Initial Strategy of therapeutic-dose anticoagulation with heparin did not result in a greater probability of survival to hospital discharge or a greater number of days free of cardiovascular or respiratory organ support than did usual-care pharmacologic thromboprophylaxis (NEJM, 2021) [MEDLINE]

Contraindications

Heparin-Induced Thrombocytopenia (HIT) (see Heparin-Induced Thrombocytopenia)

Pharmacology

Heparin Binds to Antithrombin (aka Antithrombin III or Heparin Cofactor I)

Heparin Binding Results in a Conformational Change in Antithrombin, Converting Antithrombin from a Slow to a Rapid Inactivator of Thrombin, Factor Xa, and to a Lesser Extent Factor XIIa, Factor XIa, and Factor IXa
- Inactivation of Thrombin (But Not Factor Xa) Requires the Formation of a Complex in Which Heparin Binds to Both Antithrombin and a Binding Site on Thrombin
  - This Requires Pentasaccharide-Containing Chains of at Least 18 Saccharide Units Long (Which are Present on Unfractionated Heparin, Less Commonly in Low Molecular Weight Heparins, and Not at All in Fondaparinux)
  - Consequently, Low Molecular Weight Heparins and Fondaparinux Have Less Antithrombin Activity than Unfractionated Heparin
Heparin Also Directly Binds to Platelets
At High Concentrations, Heparin Binds to Heparin Cofactor II

Metabolism

XXXXXX

Administration

Subcutaneous (SQ)

DVT Prophylaxis
- 5000 Units BID-q8hrs
Full-Dose Anticoagulation
- XXXXX Units XXXXX

Intravenous (IV)

Full-Dose Anticoagulation

XXXXXXX bolus, then XXXXXXX drip

Monitor PTT to Achieve Adequate Anticoagulation

Aim for PTT equal to 1.5-2x control PTT (or 1.5-2x upper limit of normal PTT for the specific laboratory): generally, target PTT is 60-80
- Relationship to Heparin Blood Level: this target PTT corresponds to a heparin blood level of at least 0.2 U/mL (as assessed by protamine titration assay)
- PTT Monitoring: check PTT 4-6 hrs after initiation of heparin drip and/or a change in heparin drip rate

Utility of PTT Monitoring in Setting of Elevated Baseline PTT

In the Presence of an Elevated Baseline PTT, Monitoring the PTT for Heparin Dosing is Unreliable and the Following Options May Be Considered
- Option #1: If PTT is elevated due to unclear etiology, use unfractionated heparin -> monitor with anti-factor Xa assay or specific heparin assay
- Option #2: If PTT is elevated due to lupus anticoagulant, use unfractionated heparin -> laboratory can use an alternate PTT assay which is not affected by the presence of the lupus anticoagulant
- Option #3: Use low molecular weight heparin
  - If Therapeutic Effect is Uncertain (Due to Conditions Such as Renal Failure, Obesity, or Pregnancy), Low Molecular Weight-Specific Anti-Factor Xa Assays are Available for Monitoring
  - Note: Anti-Factor Xa Levels are Different for Low Molecular Weight Heparins Than They are for Unfractionated Heparin

Heparin Dosing in Morbid Obesity (see Obesity)

Clinical Efficacy

Study of Heparin Dosing in Morbidly Obese Patients (J Crit Care, 2015) [MEDLINE]
- Patients ≥130 kg Have Lower Weight-Based Heparin Requirements, as Compared to Patients 95-104 kg
  - This Difference Appears to Be Driven Mostly by Patients >165 kg
  - Patients >165 kg Have Lower Weight-Based Heparin Requirements, Whereas Patients 105-164 kg Have Weight-Based Heparin Requirements Similar to a Normal-Weight Patient Populations

Recommendations

Proposed Dose Adjustment Formulas (Pharmacotherapy, 2010) [MEDLINE]
- Dosing Weight = Ideal Body Weight + 0.3 (Actual Body Weight – Ideal Body Weight)
- Dosing weight = Ideal Body Weight + 0.4 (Actual Body Weight – Ideal Body Weight)

Heparin Dosing in Pregnancy (see Pregnancy)

Heparin Does Not Cross the Placenta (Making it Safer to Use in Pregnancy than Coumadin)

Effect of Heparin on Anticoagulation Tests

Prothrombin Time (PT)/International Normalized Ratio (INR) (see Prothrombin Time): no effect
- Heparin is an Indirect Thrombin Inhibitor and Should Theoretically Prolong the INR
  - However, Most INR Assay Reagents Contain Heparin-Binders Which Block the Effect of Heparin (or Similar Agents) at Concentrations <1 unit/mL
  - Therefore, at Heparin Concentrations >1 unit/mL, the INR May Be Prolonged
Prolonged Partial Thromboplastin Time (PTT) (see Partial Thromboplastin Time)
Prolonged Anti-Factor Xa Activity (see Anti-Factor Xa Activity)

Periprocedural/Perioperative Management of Full-Dose Intravenous Unfractionated Heparin Anticoagulation

Recommendations for Periprocedural/Perioperative Management of Coumadin (American College of Chest Physicians Clinical Practice Guideline for the Perioperative Management of Antithrombotic Therapy) (Chest, 2022) [MEDLINE]

In Patients Receiving Therapeutic-Dose Unfractionated Heparin IV Bridging for an Elective Procedure/Surgery, Stop Unfractionated Heparin ≥4 hrs Before the Procedure/Surgery (as Opposed to Stopping Unfractionated Heparin <4 hrs Before a Procedure/Surgery) (Conditional Recommendation, Very Low Certainty of Evidence)
In Patients Receiving Therapeutic-Dose Unfractionated Heparin IV Bridging for an Elective Procedure/Surgery, Resume Unfractionated Heparin ≥24 hrs After a Procedure/Surgery (as Opposed to Resuming Unfractionated Heparin <24 hrs After Procedure/Surgery (Conditional Recommendation, Very Low Certainty of Evidence)
- When Resuming Postprocedure/Postoperative Unfractionated Heparin, Avoid Using a Bolus Dose and Start with a Lower-Intensity Infusion that is Associated with a Lower Target Activated Partial Thromboplastin Time (PTT) Than That Used for Initiation of Full-Dose Unfractionated Heparin Administration

Reversal of Unfractionated Heparin Anticoagulation

Protamine Sulfate (see Protamine)

Indications

xxxx

Adverse Effects

xxxx

Adverse Effects

Allergic/Immunologic Adverse Effects

Anaphylaxis/Anaphylactoid Reaction (see Anaphylaxis)

Epidemiology
- Heparin-Associated Anaphylaxis/Anaphylactoid Reactions are Rare
- Occurrence Should Raise Clinical Suspicion for Heparin-Induced Thrombocytopenia (HIT), Since Anaphylaxis is a Clinical Manifestation of HIT

Dermatologic Adverse Effects

Heparin-Induced Skin Necrosis

Epidemiology
- Rare
Clinical
- May Appear Similar to the Lesions of Coumadin Skin Necrosis
- Occurrence at heparin injection sites should raise the suspicion of heparin-induced thrombocytopenia (HIT) (see Heparin-Induced Thrombocytopenia)
Treatment
- Withdrawal of Heparin

Hematologic Adverse Effects

Hemorrhagic Adverse Effects

Adrenal Hemorrhage (see Adrenal Insufficiency)
Diffuse Alveolar Hemorrhage (DAH) (see Diffuse Alveolar Hemorrhage)
Epistaxis (see Epistaxis)
Gastrointestinal Hemorrhage (see Gastrointestinal Hemorrhage)
Hematuria (see Hematuria)
Intracerebral Hemorrhage (Hemorrhagic Cerebrovascular Accident) (see Intracerebral Hemorrhage)
Intracranial Epidural Hematoma (see Intracranial Epidural Hematoma)
Retroperitoneal Hemorrhage (see Retroperitoneal Hemorrhage)
Spinal Epidural Hematoma (see Spinal Epidural Hematoma)
Subarachnoid Hemorrhage (SAH) (see Subarachnoid Hemorrhage)
Subdural Hematoma (SDH) (see Subdural Hematoma)

Heparin-Induced Thrombocytopenia (HIT) (see Heparin-Induced Thrombocytopenia)

Epidemiology
- XXXX

Heparin Resistance

Heparin Resistance is Defined as Using More Heparin than Usual to Achieve a Therapeutic Activated Partial Thromboplastin Time (PTT) (NEJM, 2021) [MEDLINE]
- Management
  - Increasing the Heparin Dose
  - Supplementing Antithrombin Levels
  - Alternate Use of a Direct Thrombin Inhibitor

Renal Adverse Effects

Hyperkalemia (see Hyperkalemia)

Potential Mechanisms
- Adrenal Hemorrhage (see Adrenal Hemorrhage)
- Atrophy of Adrenocortical Zona Glomerulosa
- Decreased Aldosterone Synthesis
- Decreased in Number and Affinity of Aldosterone II Receptors

References

General

Heparin-induced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin. N Engl J Med 1995; 332:1330-1335 [MEDLINE]
Heparin-induced skin necrosis and low molecular weight heparins. Ann R Coll Surg Engl. 1999 Jul;81(4):266-9 [MEDLINE]
Fludrocortisone for the treatment of heparin-induced hyperkalemia. Ann Pharmacother. 2000 May;34(5):606-10 [MEDLINE]
Heparin and low-molecular-weight heparin: mechanisms of action, pharmacokinetics, dosing, monitoring, efficacy, and safety. Chest 2001; 119:64S-94S
Heparin-induced thrombocytopenia: pathogenesis and management. Br J Haematol 2003; 121:535-555
Argatroban anticoagulation in patients with heparin-induced thrombocytopenia. Arch Intern Med 2003; 163:1849-1856
Treatment and prevention of heparin-induced thrombocytopenia: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133:340S-380S
Unfractionated heparin dosing for venous thromboembolism in morbidly obese patients: case report and review of the literature. Pharmacotherapy. 2010 Mar;30(3):324. doi: 10.1592/phco.30.3.324 [MEDLINE]
Executive summary: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012 Feb;141(2 Suppl):7S-47S. doi: 10.1378/chest.1412S3 [MEDLINE]
Allergic anaphylaxis due to subcutaneously injected heparin. Allergy Asthma Clin Immunol. 2013 Jan 10;9(1):1. doi: 10.1186/1710-1492-9-1 [MEDLINE]
Unfractionated heparin dosing for therapeutic anticoagulation in critically ill obese adults. J Crit Care 2015;30:395–399 [MEDLINE]
Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report. Chest. 2016 Feb;149(2):315-52. doi: 10.1016/j.chest.2015.11.026. Epub 2016 Jan 7 [MEDLINE]
Perioperative Management of Antithrombotic Therapy: An American College of Chest Physicians Clinical Practice Guideline. Chest. 2022 Aug 11;S0012-3692(22)01359-9. doi: 10.1016/j.chest.2022.07.025 [MEDLINE]

Indications

Therapeutic Anticoagulation with Heparin in Noncritically Ill Patients with Covid-19. N Engl J Med. 2021 Aug 26;385(9):790-802. doi: 10.1056/NEJMoa2105911 [MEDLINE]
Therapeutic Anticoagulation with Heparin in Critically Ill Patients with Covid-19. N Engl J Med. 2021 Aug 26;385(9):777-789. doi: 10.1056/NEJMoa2103417 [MEDLINE]
Surviving Covid-19 with Heparin? N Engl J Med. 2021 Aug 26;385(9):845-846. doi: 10.1056/NEJMe2111151 [MEDLINE]

Administration

Heparin Resistance – Clinical Perspectives and Management Strategies. N Engl J Med. 2021 Aug 26;385(9):826-832. doi: 10.1056/NEJMra2104091 [MEDLINE]

Adverse Effects

XXXX