Purpose
To provide details about unfractionated heparin (UFH) use

Indication
UFH is used for the treatment of thrombosis.

USE

Initiating Therapy

• Prior to initiation of therapy, but no longer than 48 hours before, the following labs should be checked: CBC, coagulation profile (PT, PTT, fibrinogen activity), hepatic function panel, creatinine, urine pregnancy if applicable.
• Prior to starting, a brain ultrasound is recommended for neonates less than 44 weeks corrected gestational age. It is also suggested that other high risk patients (i.e., patients < 1 year old, trauma patients, infants with recent history of cardiac surgery) undergo a brain ultrasound/imaging prior to starting UFH.
• Patients with chylous drainage via pleural catheter may have AT3 losses that effect UFH dosing
• In obese patients (BMI >95% for age), treatment dosing should be based on adjusted body weight for starting dosing.

Pharmacokinetics

Half-life	~30-90 min.
Time to peak	immediate
Excretion	RES, liver

Therapeutic initial loading dose 

heparin 75 units/kg/dose IV once infused over 10 minutes.

Do NOT give loading dose in neonates less than 44 weeks corrected gestational age, children with stroke, or when risk of bleeding is perceived to be high. A suggested maximum dose of 10,000 units/dose for some indications (excluding ECMO).

Therapeutic initial maintenance infusion

< 1 year: heparin 28 units/kg/hr IV

1-17 years: heparin 20 units/kg/hr IV

≥ 18 years: heparin 18 units/kg/hr IV

Prophylactic dosing

heparin 10 units/kg/hr IV

• heparin ≤ 15 units/kg/hr can be considered prophylactic dosing

Monitoring Therapy

• Anti-factor Xa and aPTT are used to monitor heparin activity.
• Anti-factor Xa and aPTT levels are drawn from fresh venipuncture when possible and ideally not drawn from an extremity or line through which heparin is infusing. If drawn from heparinized line, waste should be drawn to avoid heparin contamination.
• Obtain anti-factor Xa and aPTT levels are checked 4 hours after the initial dose (not earlier), or 6 hours after start of infusion (if no bolus is administered).
• Goal anti-factor Xa is 0.35-0.7 U/mL correlates in general with aPTT of 60-85 seconds. If using aPTT, then target 1.5-2x times baseline aPTT.
• Adjust infusion to maintain therapeutic goal. aPTTs will be drawn simultaneously with all anti-factor Xa levels to ensure aPTTs are not greater than 150 seconds. If aPTT is greater than 150 seconds, consider repeating the anti-FXa and APTT by venipuncture STAT to rule out sample contamination. Monitor closely for bleeding and ensure remaining coagulation parameters (platelet count, prothrombin time, fibrinogen) are optimized.
  • Note: Anti-Xa levels may be underestimated in patients with very high levels of bilirubin or hemolysis.
  • Note: aPTT may not always be a reliable measure of heparin effect, especially in setting of nflammation or coagulopathy.
  • Note that all heparin monitoring labs should be sent STAT.

aPTT (sec)	Anti-factor Xa (units/mL)	Bolus (units/kg)	Hold (min.)	Dose change (u/kg/hr)	Repeat aPTT and anti-Xa
<50	<0.2	50*	0	Increase 20%	4 hours
50-59	0.2-0.34	0	0	Increase 10%	4 hours
60-85	0.35-0.7	0	0	0	12-24 hours When 2 consecutive anti-Xa results obtained 4 hours apart are therapeutic, obtain anti-Xa and aPTT qAM
96-120	0.71-0.8	0	0	Decrease 10%	4 hours
	0.81-0.99	0	30	Decrease 10%	4 hours
>120	>1	0	60	Decrease 15% and notify IHTC	4 hours

*Do not give bolus doses in neonates less than 44 weeks corrected gestational age

• Obtain anti-factor Xa and aPTT 4 hours after any change in infusion rate
• Once 2 consecutive anti-factor Xa obtained 4 hours apart are therapeutic, obtain anti-factor Xa and aPTT once daily.
• Other labs: CBC should be monitored daily for the first 10 days, then every 72 hours. A sudden decrease in platelet counts > 50% below baseline or below 100k should raise suspicion for heparin induced thrombocytopenia (HIT). The risk of HIT is greatest after 5 days of therapy. Maintain platelet count ≥50K to prevent excess bleeding. Heparin use is contraindicated in patients who have a history of laboratory confirmed heparin induced thrombocytopenia (HIT)
• UFH infusions should be continued without interruption through a dedicated catheter. If the maintenance infusion is interrupted for > 30 minutes, obtain anti-factor Xa and aPTT level and adjust the infusion rate as indicated above (see above Table)

Safety Precautions

• Renal impairment: No dosage adjustment requirement; adjust therapeutic heparin according to aPTT or anti-Xa activity.
• Hepatic impairment: No dosage adjustment requirement; adjust therapeutic heparin according to aPTT or anti-Xa activity.
• Drug-Drug interactions:
  • Agents with Antiplatelet Properties (e.g., P2Y12 inhibitors, NSAIDs, SSRIs, etc.) may enhance the anticoagulant effect of Anticoagulants.
• Drug-Food Interactions: None
• Long term use (≥1 year) of heparin or LMWH may increase the risk of osteoporosis.
• Heparin Induced Thrombocytopenia (HIT) – Though rare, HIT does occur in children. This should be suspected in any patient on heparin, UFH or LMWH, with unexplained drop in platelet count > 50% from baseline or with thrombocytopenia.

Bleeding Precautions & Warnings

• While on anticoagulation avoid aspirin, ibuprofen, or other anti-platelet drugs unless specifically indicated as anti-platelet therapy.
• Avoid IM injections or lumbar punctures except in cases where benefits outweigh the risks. Avoid arterial punctures except in cases of emergencies. Apply pressure after venipuncture until bleeding has ceased.

Perioperative Management

• Decision making regarding whether UFH needs to be held depends on type of surgery and balance of bleeding versus thrombosis risk. If it is indicated, heparin should be held 4-6 hours procedure for complete reversal.
• Restart heparin infusions after the procedure as soon as adequate hemostasis has been established and once cleared by the surgeon or interventionalist.

Reversal Information

• Protamine sulfate can be used in the event that heparin reversal is required
• Protamine combines with the strongly acidic heparin to form a stable salt complex neutralizing the anticoagulant activity
• Protamine requires a high level of caution when being prescribed and administered. Protamine should be administered IV in a concentration of 10 mg/mL at a rate not to exceed 5 mg/minute (slowly over 10 minutes). If administered too quickly it may cause cardiovascular collapse/hypotension. Patients with known hypersensitivity reactions to fish, and those who have received protamine containing insulin or previous protamine therapy may be at risk of hypersensitivity reactions to protamine sulfate
• The dosage of protamine sulfate is based on the both the amount of heparin and the time since the last dose in the previous 2 hours, up to maximum dose of 50 mg/dose, as follows:

Time Since Last Heparin Dose (minutes)	Protamine Dose per 1 mg Heparin Received
<30 minutes	1 mg per 1 mg (100 units) heparin received
30-60 minutes	0.5-0.75 mg per 1 mg (100 units) heparin received
61-120 minutes	0.375-0.5 mg per 1 mg (100 units) heparin received
>120 minutes	0.25-0.375 mg per 1 mg (100 units) heparin received

Example protamine calculation for a heparin infusion discontinued in previous 30 minutes: Multiply hourly rate (units/kg/hr) by patient weight (kg) to result in hourly heparin rate (units/hr). Multiply hourly heparin rate (units/hr) by 2 hours to result in heparin dose (units). Based on above table, 1 mg protamine is required to neutralize every 100 units of heparin if < 30 minutes since last heparin, therefore divide heparin dose (units) by 100 to result in protamine dose (mg). Do not exceed maximum 50 mg protamine per dose.

• Anti-Xa, aPTT, PT may be obtained 15 minutes after administration of protamine sulfate.
• Critical site bleeds: Intracranial hemorrhage, including intraparenchymal, subdural, epidural, and subarachnoid hemorrhages; Other CNS hemorrhage, including intraocular, intra- or extra-axial spinal hemorrhages; Pericardial tamponade; Airway, including posterior epistaxis; Hemothorax, intraabdominal bleeding, and retroperitoneal hemorrhage; Extremity bleeds, including intramuscular and intraarticular bleeding concerning for compartment syndrome, bleeding associated with hemodynamic instability, bleeding in a noncompressible vessel (e.g., subclavian)

Transition Information

• See separate anticoagulant-specific Clinical Case Manual for transitioning from another specific anticoagulant to heparin.
• See table for switching from enoxaparin to another anticoagulant

From	To	Action
UFH	Argatroban/ Bivalirudin/ Dalteparin/	Initiate parenteral anticoagulant within 2 hours after discontinuing heparin infusion. Can stop UFH 0-4 hours after 1st enoxaparin dose.
	Enoxaparin/ Fondaparinux/ Apixaban, Betrixaban Dabigatran, Edoxaban, or Rivaroxaban	Initiate within 2 hours after discontinuation of heparin infusion. Can start DOAC concurrently with UFH discontinuation.
	Warfarin	Overlap therapeutic heparin dose with warfarin for at least 5 days AND until INR is in therapeutic range for 2 consecutive days in a row.

Pregnancy
Currently, only Lovenox (enoxaparin) and unfractionated heparin are advised for use in pregnant women.

Patient Education & Ongoing Management
Discharging IHTC physician/APP is responsible for ensuring adequate follow-up for anticoagulation management has been scheduled prior to patient leaving the hospital.

References

1.     Heparin sodium injection [Prescribing Information]. Baxter Healthcare Corporation, Deerfield, IL, Baxter International Inc.; January 2022.

2.     Monagle, P.; Chan, A.K.C.; Goldenberg, N.A.; Ichord, R.N.; Journeycake, J.M.; Nowak-Gottl, U.; and Vesely, S.K. Antithrombotic therapy in neonates and children: antithrombobotic therapy and prevention of thrombosis, 9 th ed: American College of Chest Physicians Evidence Based Clinical Practice Guidelines. Chest, 2012: 141(2)(Suppl): e737se801s

3.     Protamine. Lexi-Drugs AHFS Drug Information [Internet database]. Lexi-Comp, Inc.; Accessed September 18, 2023.

4.     Ignjatovic V et al. Therapeutic range for unfractionated heparin therapy: age related differences in response in children. J Thromb Haemostasis 2006; 4:2280–2282.

5.     Douketis, J.D.; Spyropoulos, A.C.; Spencer, F.A.; Mayr, M.; Jaffer, A.K.; Eckman, M.H.; Dunn, A.S.; and Kunz, R. Perioperative management of antithrombotic therapy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence Based Clinical Practice Guidelines. Chest, 2012: 141 (2)(Suppl): e326Se350S

6.     Chan A et al. Utility of aPTT in monitoring unfractionated heparin in children. Thrombosis Res 2007; 122:135–136.

7.     Garcia, D.A.; Baglin, T.P.; Weitz, J.I.; and Samama, M.M. Parenteral anticoagulants: antithrombotic therapy and prevention of thrombosis, 9 th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest, 2012: 141(2)(Suppl): e24S-e43S.

8.     Newall F et al. Clinical use of unfractionated heparin therapy in children: time for change? Br J Hematol 2010; 150(6):674-8.

9.     Linkins, L.A.; Dans, A.L.; Moores, L.K.; Bona, R.; Davidson, B.L.; Schulman, S.; and Crowther, M. Treatment and prevention of heparininduced thrombocytopenia: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence Based Clinical Practice Guidelines. Chest,2012: 141(2)(Suppl): e495Se530S

10.  Riney, J.N.; Hollands, J.M.; Smith, J.R.; and Deal, E.N. Identifying optimal initial infusion rates for unfractionated heparin in morbidly obese patients. Ann Pharmacother, 2010: 44: 1141-11

11.  Liveris et al. Anti-factor Xa assay is a superior correlate of heparin dose than activated partial thromboplastin time or activated clotting time in pediatric ECMO. Pediatr Crit Care Med 2014; 15(2):e72-79.