HEPARIN FLUSH (Generic for HEPARIN LOCK)

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
-Use extreme caution during the preparation, dispensing, and administration of any heparin-containing products for pediatric patients. Heparin injection is available in various concentrations, and the inadvertent administration of the incorrect concentration could result in devastating consequences. Fatal hemorrhages have occurred in pediatric patients (including neonates) due to medication errors in which concentrated 1 mL heparin injection vials were administered rather than 1 mL 'catheter lock flush' vials.
-Do NOT administer via intramuscular injection due to risk of hematoma at the injection site.
-Updates for coronavirus disease 2019 (COVID-19): The FDA is allowing heparin 1,000 units/mL. 5,000 units/mL, and 10,000 units/mL (NDCs: 0069-0058-01, 0069-0059-01, 0069-0059-03, 0069-0137-03, 0069-0043-01) to be used beyond the labeled in-use time to help ensure access during COVID-related drug shortages. This period should be as short as possible, and for a maximum of 2 hours at room temperature or 4 hours when refrigerated. In-use time is defined as the maximum amount of time allowed to elapse between penetration of a closed-container system or after reconstitution of a lyophilized drug before patient administration.
Intravenous Administration
Continuous IV Infusion

-Administer loading doses over 10 minutes.
-Infuse intravenously via an electronic infusion pump. For systemic anticoagulation, adjust rate based on aPTT or plasma heparin concentration (by protamine titration or anti-factor Xa assay).
-ASHP Recommended Standard Concentrations for Pediatric Continuous Infusions: 50 units/mL or 100 units/mL.

The most serious adverse reaction associated with heparin therapy is bleeding, which can occur at any site. This can involve minor bleeding, such as bleeding from the gums or hematuria, or frank hemorrhage. Repeated flushing of a catheter device with heparin can result in systemic effects, including anticoagulation and bleeding. Withdrawing the drug can usually control an overly prolonged bleeding time or minor bleeding during therapy. Adverse bleeding events include epistaxis, GI bleeding, hematoma, purpura, petechiae, unexplained bruising, heavy menstrual/vaginal bleeding, or prolonged bleeding from cuts or wounds. Back pain, abdominal pain, anemia, hematuria, melena, hematochezia, and hematemesis can indicate internal hemorrhage. If bleeding is serious, heparin therapy should be discontinued, and protamine can be administered as a heparin antagonist. Retroperitoneal bleeding, intracranial bleeding (e.g., subdural hematoma), or ovarian (corpus luteum) hemorrhage can be difficult to detect. Adrenal hemorrhage, with resultant acute adrenocortical insufficiency, has occurred with heparin therapy, including fatal cases. Therefore, discontinue heparin treatment in patients who develop signs and symptoms of acute adrenal hemorrhage and insufficiency. Do not delay initiation of corrective therapy for laboratory confirmation, as any delay in treatment during an acute situation may result in death. Although rare, massive ocular hemorrhage has been reported in patients with pre-existing disciform macular degeneration receiving systemic anticoagulants, such as heparin. Subconjunctival hemorrhage and spontaneous hyphema have also been reported.

Thrombocytopenia is a well-known complication of heparin therapy. The reported incidence of thrombocytopenia during heparin therapy is 30% or less in the general population. Thrombocytopenia can present in 2 forms: an early, benign, reversible, nonimmune thrombocytopenia and a late, more serious IgG-mediated immune thrombocytopenia. Mild nonimmune thrombocytopenia generally occurs about 2 to 4 days after the initiation of therapy. In nonimmune heparin-associated thrombocytopenia, the decrease in platelet count may be mild and of no obvious clinical significance; the platelet count may recover despite continued heparin treatment. In contrast, the immune form of heparin-induced thrombocytopenia (HIT) is characterized by IgG-mediated platelet activation and usually occurs after the fifth day of therapy. Although the precise frequency of immune-mediated HIT is uncertain, reported rates in pediatric patients have ranged from 0% to 2.3%. Data in postoperative adult patients indicate a frequency of about 1% to 5% for unfractionated heparin while rates in adult medical patients range from 0.1% to 1%. In patients previously unexposed to heparin, the platelet count usually begins to decline 5 to 10 days after starting heparin therapy in a patient with immune-mediated HIT. However, thrombocytopenia may occur within 24 hours of initiation of heparin in patients who have been previously exposed to heparin therapy, especially if heparin was administered within the previous 3 months. A platelet decrease of greater than 50% from baseline is considered indicative of HIT. In patients with immune-mediated HIT, platelet aggregation is greatly increased and the patient can develop thrombotic complications (white-clot syndrome or heparin-induced thrombocytopenia and thrombosis [HITT]). Serious thromboembolic events include deep vein thrombosis, pulmonary embolism, cerebral vein thrombosis, limb ischemia, stroke, myocardial infarction, mesenteric thrombosis, renal arterial thrombosis, necrosis of the skin, gangrene of the extremities that may lead to amputation, and possibly death. Thrombosis development shortly after documenting thrombocytopenia is a characteristic finding in approximately half of all patients with HIT. Thrombosis can occur while the platelet count is declining, but before the onset of overt thrombocytopenia, which may occur a few days later. Therefore, thrombosis may be the initial manifestation of HITT and may be accompanied by severe thromboembolic complications. HIT-associated thrombosis occurs in about 1% of patients who receive therapeutic doses of IV heparin for 5 days or more. Venous thromboembolism is more common than arterial (approximate ratio 4:1). Bilateral adrenal hemorrhagic necrosis can occur in patients with HIT; consider in any patient who complains of abdominal pain or unexplained low blood pressure during heparin therapy. If the platelet count falls below 100,000/mm3 or recurrent thrombosis develops, stop all heparin therapy (including heparin flushes), evaluate for HIT and HITT, and, if necessary, institute an alternative anticoagulant. Avoid future heparin use in patients with a diagnosis of HIT or HITT, especially within 3 to 6 months of diagnosis and while patients test positive for antibodies. After discontinuation of heparin, the median time to platelet count recovery to normal is about 4 days; about 90% of patients recover by 1 week, although in rare cases, the platelet count may not return to normal for several weeks. HIT or HITT can occur up to several weeks after the discontinuation of heparin therapy, and patients presenting with thrombocytopenia or thrombosis after heparin discontinuation should also be evaluated for HIT. Because the incidence of thrombosis is high even after discontinuation of heparin, consideration should be given to using an alternate anticoagulant.

Generalized hypersensitivity reactions have been reported with heparin use. Fever, chills, and urticaria are the most common manifestations; however, bronchospasm, rhinitis, lacrimation, headache, nausea, vomiting, and anaphylactoid reactions, including anaphylactic shock, may also occur. Itching and burning, especially on the plantar site of the feet, may occur. Histamine-like reactions have been observed at the site of heparin injection. Also, episodes of painful, ischemic, and cyanosed limbs have been reported and attributed to allergic vasospastic reactions; it is unclear whether these reactions are separate from or related to thrombocytopenia-associated reactions.

Heparin can suppress adrenal secretion of aldosterone leading to hyperkalemia. The risk of hyperkalemia appears to increase with duration of therapy; however, it is usually reversible upon discontinuation of heparin. Measure plasma potassium in persons at risk of hyperkalemia prior to initiation of heparin therapy and periodically in all persons receiving heparin for more than 5 days or sooner if clinically indicated.

Osteoporosis has been reported in patients receiving long-term administration of high doses of heparin ; this is particularly concerning during infancy, childhood, and adolescence, periods of active bone development. When possible, the chronic use of unfractionated heparin should be avoided in pediatric patients. There have been a few reports of heparin-induced osteoporosis in pediatric patients; however, these reports were complicated by additional risk factors. Significant reduction in bone density has been reported in about 30% of adult patients and symptomatic bone fractures occur in 2% to 3% of adult patients receiving heparin for 1 month or more. In animal studies, unfractionated heparin has been found to stimulate bone resorption in addition to decreasing bone formation.

Dermatologic reactions that may develop during heparin therapy include skin ulcer, hematoma, erythema, skin plaques, and skin necrosis. Although skin lesions usually occur at the sites of heparin injection (i.e., injection site reaction), there have been rare reports of necrosis at sites remote from heparin injection. Severe injection site reactions are more commonly associated with intramuscular injections or deep subcutaneous injections. Skin lesions usually develop 5 days or more after subcutaneous heparin administration. The delayed onset is consistent with an immunologic reaction. Some patients with skin lesions have tested positive for HIT-IgG even though they did not develop thrombocytopenia. Patients who develop these delayed-onset skin lesions may be at increased risk for serious systemic reactions or thrombotic events, accompanied by an abrupt fall in platelet count, if they are given IV heparin. Pruritus and burning, especially on the plantar side of the feet may occur. Delayed, transient alopecia has been reported.

Rebound hyperlipidemia on discontinuation of heparin therapy has been reported. Significantly elevated hepatic enzymes (AST and ALT) have occurred in persons receiving heparin. Hepatic enzyme elevations usually resolve upon heparin discontinuation. Elevated hepatic enzymes in persons receiving heparin therapy should be interpreted with caution.

Heparin has been associated with priapism in a few case reports. However, it is unclear if the priapism was related to heparin administration or to the underlying thrombotic condition.

Heparin inhibits the formation of 1,25(0H)2D by the kidneys and may lead to vitamin D deficiency. Monitor vitamin D concentrations and supplement with vitamin D, especially with prolonged therapy (greater than 1 month).

Do not use therapeutic heparin when appropriate blood coagulation tests for monitoring cannot be performed at appropriate intervals. Discontinue heparin immediately if the coagulation test is excessively prolonged or hemorrhage occurs. Monitor platelet counts, hematocrit, and occult blood in stool throughout the course of therapy, regardless of the route of administration.

Use caution when interpreting the clinical implications of elevated hepatic enzymes in patients receiving heparin. Significant elevations in aminotransferases (AST and ALT) have occurred in a high percentage of patients (including healthy subjects) who received heparin.

Heparin may prolong the one-stage prothrombin time. Hence, when given with warfarin, allow at least 5 hours after the last IV dose or 24 hours after the last subcutaneous dose of heparin to elapse before blood is drawn to obtain an accurate prothrombin time.

Heparin is contraindicated in patients with known heparin hypersensitivity; reserve heparin in these patients for clearly life-threatening situations. Heparin is derived from porcine tissue; therefore, use of heparin is contraindicated in patients with porcine protein hypersensitivity. Because heparin is derived from animal tissue, monitor for signs and symptoms of hypersensitivity when it is used in patients with a history of allergy. Heparin solutions containing dextrose may be contraindicated in patients with corn hypersensitivity. Some heparin preparations contain sulfites, which can induce a life-threatening allergic response in some patients. Use such heparin products with extreme caution in patients with known sulfite hypersensitivity; sulfite sensitivity reactions tend to occur more frequently in patients with asthma. Some heparin preparations contain benzyl alcohol as a preservative; avoid these formulations in patients with benzyl alcohol hypersensitivity.

Heparin is contraindicated in patients with severe thrombocytopenia and in those with a history of heparin-induced thrombocytopenia (HIT), heparin-induced thrombocytopenia and thrombosis (HITT), or thrombocytopenia with pentosan polysulfate. Heparin may be used safely in patients with mild nonimmune thrombocytopenia (platelets more than 100,000/mm3), which may remain stable or reverse with continued treatment. However, use an alternative anticoagulant and avoid all sources of heparin in patients with a history of immune-mediated HIT because these patients can develop thrombotic complications during heparin therapy. Because it may not be possible to differentiate asymptomatic, nonimmune thrombocytopenia from immune-mediated thrombocytopenia, monitor the platelet count closely. If the platelet count falls below 100,000/mm3 or recurrent thrombosis develops, promptly discontinue heparin, evaluate for HIT and HITT, and, if necessary, administer an alternative anticoagulant. Thrombosis in association with thrombocytopenia may indicate white-clot syndrome, which can lead to severe thromboembolic complications. HIT or HITT can occur up to several weeks after the discontinuation of heparin therapy; evaluate patients presenting with thrombocytopenia or thrombosis after heparin discontinuation for HIT or HITT. Avoid future heparin use in patients with a diagnosis of HIT or HITT, especially within 3 to 6 months of diagnosis and while patients test positive for antibodies.

Heparin is contraindicated in patients with uncontrollable bleeding (with the exception of bleeding associated with disseminated intravascular coagulation). Avoid use of heparin in the presence of major bleeding, unless the benefits of therapy outweigh the potential risks. Fatal hemorrhages have occurred during anticoagulant therapy with heparin. Hemorrhage can occur at virtually any site in patients receiving heparin. Consider the possibility of a hemorrhagic event with an unexplained fall in hematocrit, hypotension, or any other unexplained symptom. Use heparin with extreme caution in a patient with conditions that might increase the risk of hemorrhage. These may include subacute bacterial endocarditis; dissecting aortic aneurysm; peptic ulcer disease; diverticulitis; inflammatory bowel disease; liver disease; coagulopathy; hemophilia; thrombocytopenia; menstruation; abnormal vaginal bleeding; severe hypertension; head trauma; major surgery or trauma, especially involving eye, brain, or spinal cord; during or immediately after a lumbar puncture or spinal anesthesia; tube drainage of stomach or small intestine; and increased capillary permeability. Patients with hereditary antithrombin III deficiency receiving antithrombin III therapy are also at risk for hemorrhage with concurrent heparin use; reduce the heparin dose during concomitant use to reduce the risk of bleeding. Monitor all patients receiving heparin closely for easy bruising, petechiae, and other signs of hemorrhage such as nosebleed, hematuria, or tarry stools.

Increased resistance to heparin is frequently encountered in patients with fever, thrombosis, thrombophlebitis, infection with thrombosing tendencies, myocardial infarction, neoplastic disease, postsurgical patients, and patients with antithrombin III deficiency. Consider measurement of anti-thrombin concentrations if heparin resistance is suspected. Monitor coagulation tests closely in such patients; heparin dose adjustments based on anti-factor Xa concentrations and/or partial thromboplastin time may be necessary.

Use heparin cautiously in patients with underlying hepatic disease as these patients often have coagulopathies and are at increased risk for anticoagulant-associated bleeding. Patients with inherited antithrombin deficiency usually have antithrombin concentrations 40% to 60% of normal but may have resistance to heparin and require higher doses to achieve the desired therapeutic response. Patients with acquired antithrombin deficiency, as seen with severe hepatic disease (e.g., cirrhosis), renal disease (e.g., nephrotic syndrome), or disseminated intravascular coagulation (DIC), may not respond to heparin.

When using heparin lock flush solutions to maintain catheter patency, the 100 unit/mL concentration should not be used in neonates or in infants who weigh less than 10 kg because of the risk of systemic anticoagulation. While systemic anticoagulation is not common with the use of heparin flushes for line patency in general, clinicians should use caution and carefully monitor small infants and other at risk patients receiving multiple flushes per day regardless of the heparin concentrations used. Extreme caution should be used during the preparation, dispensing, and administration of heparin flushes, heparin-containing fluids, and therapeutic doses of heparin for pediatric patients. Heparin injection is available in a wide range of concentrations. Fatal hemorrhages have occurred in pediatric patients (including neonates) due to medication errors in which concentrated 1 mL heparin injection vials were administered rather than 1 mL 'catheter lock flush' vials. To confirm correct vial choice during preparation and prior to administration, carefully inspect labels of heparin injection vials. Use preservative-free heparin formulations in neonates. Multiple dose vials contain benzyl alcohol as a preservative and should be avoided in this population. A 'gasping syndrome' characterized by CNS depression, metabolic acidosis, and gasping respirations has been associated with benzyl alcohol dosages more than 99 mg/kg/day in neonates. However, the minimum amount of benzyl alcohol at which toxicity may occur is unknown and low-birth-weight and premature neonates may be more likely to develop toxicity. Normal therapeutic heparin doses would deliver benzyl alcohol at amounts lower than those reported with 'gasping syndrome'; however, the clinician should be aware of the toxic potential, especially if other drugs containing benzyl alcohol are administered.

Heparin is not intended for intramuscular administration. Severe large hematomas caused by accidental puncture of an IM vein may occur. Avoid intramuscular injections of other medications to patients receiving heparin. IM injections may cause bleeding, bruising, or hematomas.

Heparin can suppress adrenal secretion of aldosterone leading to hyperkalemia, particularly in persons with diabetes mellitus, chronic renal failure, preexisting metabolic acidosis, a raised plasma potassium (e.g., preexisting hyperkalemia), or taking potassium sparing medications. The risk of hyperkalemia appears to increase with duration of therapy; however, it is usually reversible upon discontinuation of heparin. Measure plasma potassium in persons at risk of hyperkalemia prior to initiation of heparin therapy and periodically in all persons receiving heparin for more than 5 days or sooner if clinically indicated.

Description: Heparin, also referred to as unfractionated heparin, is a parenteral anticoagulant widely used in acute clinical practice for a variety of indications including the treatment of thromboembolic conditions, anticoagulation for extracorporeal treatments such as extracorporeal membrane oxygenation (ECMO), and the maintenance of intravascular line patency. Full therapeutic doses of heparin prolong clotting time; however, bleeding time is usually unaffected. The response to heparin is variable because only about one-third of the molecules have anticoagulant activity, and its activity and clearance are dependent upon the length and size of the heparin molecules. Age-dependent variability in concentrations of coagulation proteins and faster clearance compared to adults contribute to the variable response to heparin by pediatric patients. Heparin is a very large molecule with a molecular weight ranging from 5,000 to 30,000 daltons, with a mean of 15,000 daltons. Compared with low molecular weight heparin, unfractionated heparin produces a less predictable anticoagulant response due primarily to its dose-dependent clearance and differences among patients in the nonspecific binding of heparin to proteins and cells. Therapeutic drug monitoring (e.g., partial thromboplastin time (aPTT), activated clotting time (ACT), or anti-Xa concentrations) is necessary when heparin is administered for the intent of systemic anticoagulation. Heparin is listed on the Institute for Safe Medication Practices list of High-Alert Medications. Numerous medication errors, some fatal, have involved the use of heparin in pediatric patients; clinicians must ensure that the correct heparin concentration is used when preparing doses and set up work practices that minimize the potential for error. Heparin is FDA-approved in pediatric patients as young as neonates.

Converting to Oral Anticoagulants
-When converting from heparin to warfarin, continue therapeutic heparin therapy for several days after warfarin initiation until the patient's INR (prothrombin time) is within a stable therapeutic range. At that point, heparin may be discontinued without tapering. NOTE: Heparin may prolong the one-stage prothrombin time. When heparin is given with warfarin, prothrombin time is most accurate at least 5 hours after the last IV dose or 24 hours after the last subcutaneous dose of heparin.
-When converting from heparin to oral anticoagulants other than warfarin, stop the heparin IV infusion immediately after administering the first dose of oral anticoagulant. If the patient is receiving intermittent IV heparin, discontinue heparin and administer the oral anticoagulant 0 to 2 hours before the time that the next dose of heparin would have been administered.

For systemic anticoagulation for the management of thromboembolic conditions including the treatment of deep venous thrombosis (DVT) or pulmonary embolism, arterial thromboembolism including cerebral thromboembolism, acute and chronic consumptive coagulopathies (disseminated intravascular coagulation (DIC)), and mural thrombosis:
Continuous Intravenous Infusion dosage:
Neonates: 75 to 100 units/kg IV load then 28 units/kg/hour IV as an initial maintenance dose. Adjust dose to maintain aPTT 60 to 85 seconds, assuming this reflects an anti-factor Xa level of 0.3 to 0.7 units/mL.
Infants: 75 to 100 units/kg IV load then 28 units/kg/hour IV as an initial maintenance dose. Adjust dose to maintain aPTT 60 to 85 seconds, assuming this reflects an anti-factor Xa level of 0.3 to 0.7 units/mL.
Children and Adolescents: 75 to 100 units/kg IV load then 20 units/kg/hour IV as an initial maintenance dose. Adjust to maintain aPTT 60 to 85 seconds, assuming this reflects an anti-factor Xa level of 0.3 to 0.7 units/mL. Max: 1,000 units/hour.

For thrombosis prophylaxis during cardiac catheterization:
Intravenous dosage:
Neonates: 100 units/kg IV bolus is recommended for pediatric patients requiring cardiac catheterization via an artery. For prolonged procedures, further doses may be necessary; however, specific recommendations are not available.
Infants, Children, and Adolescents: 100 units/kg IV bolus is recommended for pediatric patients requiring cardiac catheterization via an artery. For prolonged procedures, further doses may be necessary; however, specific recommendations are not available.

For intravascular catheter occlusion prophylaxis*:
NOTE: The amount of heparin solution in each single dose is sufficient to prevent clotting within the lumen of the indwelling catheter for up to 24 hours. If the catheter is used for withdrawal of repeated blood samples for laboratory tests and the presence of heparin is likely to interfere with the test, the in situ heparin flush should be cleared from the catheter by aspirating and discarding a volume of solution equivalent to that of the indwelling catheter before the desired blood sample is drawn. If the drug to be administered is incompatible with heparin, the entire catheter or lumen should be flushed with sterile water or normal saline before and after the medication is administered. Following the second flush, the heparin flush solution may be reinstilled into the set.
-to maintain patency of intravenous single-lumen, multiple-lumen, and peripheral catheters (i.e., heparin locks):
Intravenous catheter:
Neonates: 0.5 units/kg/hour infused through the line is recommended for maintaining central venous access line patency in neonates. Use only preservative free solutions.
Infants and Children weighing less than 10 kg: In general, heparin 10 units/mL is used for infants and small children (e.g., weight less than 10 kg). Instill enough volume to fill the lumen of the catheter. Catheters should be flushed at least daily; certain types of catheters are more prone to clotting and require more frequent flushing. Refer to site-specific guidelines for details. Additional flushes should be administered when stagnant blood is observed in the catheter. This solution should be replaced each time the catheter or lumen is used for drug or blood administration, and after blood withdrawal from the catheter.
Infants, Children, and Adolescents weighing more than 10 kg: In general, heparin 100 units/mL is used for pediatric patients weighing more than 10 kg. Instill enough volume to fill the lumen of the catheter. Catheters should be flushed at least daily; certain types of catheters are more prone to clotting and require more frequent flushing. Refer to site-specific guidelines for details. Additional flushes should be administered when stagnant blood is observed in the catheter. This solution should be replaced each time the catheter or lumen is used for drug or blood administration, and after blood withdrawal from the catheter.
-to maintain patency of arterial lines:
Intra-arterial dosage (continuous infusion):
Neonates: Use a final heparin concentration of 0.5 units/mL running at a rate of 1 mL/hour IV for peripheral arterial catheters. A final heparin concentration of 0.25 to 1 unit/mL with a total heparin dose of 25 to 200 units/kg/day IV is recommended to maintain patency of umbilical artery catheters (UAC). Use only preservative free solutions.
Infants, Children, and Adolescents: Use a final heparin concentration of 0.5 units/mL to run at 1 mL/hour IV.
-to maintain line patency in patients receiving parenteral nutrition (PN):
PN solution additive:
Neonates: A final concentration of heparin of 0.5 to 1 unit/mL added to peripheral or central PN solutions. Lower concentrations may be used in small infants receiving larger PN volumes to avoid systemic heparin effects.
Infants: A final concentration of heparin of 0.5 to 1 unit/mL added to peripheral or central PN solutions. Lower concentrations may be used in small infants receiving larger PN volumes to avoid systemic heparin effects.
Children and Adolescents: A final heparin concentration of 1 unit/mL may be added to PN solutions intended for central or peripheral administration.

Therapeutic Drug Monitoring:
Usual target aPTT for systemic anticoagulation: 60 to 85 seconds (assuming this reflects an anti-factor Xa level of 0.3 to 0.7)
-The American College of Chest Physicians (ACCP) recommends the following dose adjustments for systemic heparin in pediatric patients based on aPTT (seconds) :-aPTT less than 50: bolus 50 units/kg and then increase infusion rate by 10%
-aPTT 50 to 59: increase infusion rate by 10%
-aPTT 60 to 85: no change
-aPTT 86 to 95: decrease infusion rate by 10%
-aPTT 96 to 120: hold infusion for 30 minutes and then decrease infusion rate by 10%
-aPTT more than 120: hold infusion for 1 hour and then decrease infusion rate by 15%

-Check aPTT 4 hours after the initial loading dose and 4 hours after any dosage change until therapeutic then monitor each morning. Monitor CBC daily.
-Alternatively, heparin treatment can be monitored by a chromogenic anti-factor Xa heparin assay with a targeted range of 0.3 to 0.7 units/mL. In patients with a subtherapeutic aPTT response despite high doses of heparin, further increases in heparin dosage may not be necessary if the heparin concentration is therapeutic (i.e., 0.3 to 0.7 units/mL by anti-factor Xa assay).
-The aPTT is sensitive over a heparin range of 0.1 to 1 units/mL. However, in high-risk patients requiring significant anticoagulation (e.g. patients on extracorporeal membrane oxygenation (ECMO) or in patients having cardiac bypass surgery), the aPTT is unsuitable for monitoring heparin dosage because these patients often require heparin concentrations more than 1 units/mL. For these types of procedures, the activated clotting time (ACT) is usually used to monitor heparin therapy because this test shows a graded response to heparin concentrations in the range of 1 to 5 units/mL.

Maximum Dosage Limits:
Titrate to response. Maintain the aPTT below levels that correlate with heparin concentrations of 0.4 units/mL (by protamine titration) or an anti-factor Xa concentration of 0.7 units/mL.

Patients with Hepatic Impairment Dosing
It appears that hepatic impairment does not affect the elimination of heparin; however, patients with hepatic disease may have increased risk of bleeding during heparin therapy.

Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: Heparin exerts its anticoagulant action by accelerating the activity of antithrombin III (ATIII) to inactivate thrombin; however, heparin does not lyse existing clots. Approximately one-third of heparin molecules contain a unique pentasaccharide sequence with high-affinity binding to ATIII. The interaction of heparin with ATIII produces a conformational change in ATIII, which accelerates the ability of ATIII to inactivate thrombin (factor IIa), factor Xa, and factor IXa. Of these enzymes, thrombin is the most sensitive to inhibition by heparin/ATIII. Heparin catalyzes the ATIII inactivation of thrombin by acting as a template to which both thrombin and ATIII bind to form a ternary complex. The inactivation of factor Xa does not require the heparin/ATIII complex formation and occurs via binding of ATIII to factor Xa. Heparin molecules must be more than 18 monosaccharides to bind to thrombin and ATIII simultaneously. Therefore, smaller heparin molecules (i.e., less than 18 monosaccharides) are unable to accelerate the inactivation of thrombin by ATIII, but retain their ability to catalyze the inhibition of factor Xa by ATIII. At doses higher than those required to stimulate the activity of ATIII, heparin catalyzes the inactivation of thrombin by heparin cofactor II, which does not require interaction with ATIII. The actions of heparin in pediatric patients are highly variable. Factors such as reduced levels of antithrombin and prothrombin, reduced capacity to generate thrombin, and a higher anti-Xa to anti-IIa ratio in pediatric patients compared to adults may contribute to this variability; however, the clinical implications of these factors are not clear.

High doses of heparin also interfere with platelet aggregation, which, in turn, prolongs the bleeding time, although commonly used therapeutic doses of heparin do not affect bleeding time. High-molecular-weight heparin fractions have a greater effect on platelet function. It has been shown that the platelet-aggregating activity of heparin can be directly related to its molecular weight.

Fibroblast growth factors (FGF) bind to heparin with high-affinity. Heparin potentiates the effects of FGF by promoting the binding of these factors to their receptors, a transmembrane tyrosine kinase. Fibroblast growth factors stimulate angiogenesis. As opposed to its anticoagulation effects, the activity of heparin on FGF is due to the degree of sulfation and not the size of the molecule.

The variability of anticoagulant response in individuals given fixed doses of heparin is thought to be due to differences between patients in their plasma concentrations of neutralizing plasma proteins and/or heparin-binding proteins (e.g., histidine-rich glycoprotein, vitronectin, lipoproteins, fibronectin, fibrinogen, platelet factor 4, and von Willebrand factor). The response of the aPTT ratio to heparin may be decreased in patients with high levels of factor VIII. These patients may have therapeutic plasma heparin levels at the usual dose of heparin when measured using anti-Xa activity or by protamine sulfate titration, but require very high doses of heparin (more than 50,000 units/day) to achieve an aPTT more than 1.5-times control. Patients with acquired antithrombin deficiency (less than 25% normal concentration) may not respond to heparin.

Pharmacokinetics: Heparin is primarily administered intravenously in pediatric patients; however, it is also given subcutaneously in adults. Heparin is highly bound to antithrombin, fibrinogens, globulins, serum proteases, and lipoproteins. The Vd is 0.07 L/kg. Heparin does not undergo enzymatic degradation. It is primarily cleared from the circulation by liver and reticuloendothelial cells mediated uptake into extravascular space. Heparin undergoes biphasic clearance, first by a rapid, saturable, zero-order process, then via slower first order elimination. In the zero-order phase, heparin is bound to the surface of cells (e.g., proteins, endothelial cells, macrophages) where it is internalized and depolymerized. Low doses of heparin are cleared mostly by a saturable, rapid, zero-order process. Slower first order elimination usually occurs with very high doses of heparin and is dependent on renal function. Plasma half-life is dose-dependent and ranges from 0.5 to 2 hours.

Affected cytochrome P450 isoenzymes and drug transporters: none


-Route-Specific Pharmacokinetics
Intravenous Route
Peak plasma concentration and onset of action are achieved immediately after intravenous administration.

Subcutaneous Route
Administration of low or moderate doses of subcutaneous heparin reduces the plasma recovery. However, plasma recovery is almost complete with use of high therapeutic doses of subcutaneous heparin (more than 35,000 units every 24 hours). After subcutaneous administration, approximately 22% to 40% of the administered dose is absorbed systemically as determined by anti-factor Xa assay. Subcutaneous heparin concentrations reach steady-state between 4 and 10 hours.


-Special Populations
Pediatrics
Neonates
Premature neonates (n = 25, gestational age 25 to 36 weeks) had a significantly shorter plasma half-life (35.5 to 41.6 minutes), larger volume of distribution (57.8 to 81 mL/kg), and faster clearance (1.37 to 1.49 mL/kg/minute) after an IV bolus dose of 100 units/kg compared to adults receiving an IV bolus dose of 75 units/kg (half-life = 63.3 minutes, Vd = 36.6 mL/kg, CL = 0.43 mL/kg/minute).

Hepatic Impairment
The rate of clearance of unfractionated heparin may be decreased in persons with hepatic impairment and plasma heparin concentrations may be higher compared to persons with normal hepatic function.

Renal Impairment
The rate of clearance of unfractionated heparin may be decreased in persons with renal impairment and plasma heparin concentrations may be higher compared to persons with normal renal function.