Heparin

Heparin is an anticoagulant agent belonging to unfractionated Heparin.

Heparin is an anticoagulant indicated for thromboprophylaxis and to treat thrombosis associated with a variety of conditions such as pulmonary embolism and atrial fibrillation.

Heparin is not absorbed through the gastrointestinal tract and is therefore administered via the parenteral route. Peak plasma concentration and the onset of action are achieved immediately after intravenous administration. Heparin is highly bound to antithrombin, fibrinogens, globulins, serum proteases, and lipoproteins. The volume of distribution is 0.07 L/kg. Heparin does not undergo enzymatic degradation. The plasma half-life is dose-dependent, and it ranges from 0.5 to 2 h.

Heparin shows common side effects like Redness, pain, bruising, or sores at the spot where heparin was injected and hair loss.

Heparin is available in the form Injectable Solution.

Heparin is available in India, the US, the UK, Zealand, Canada, China, Japan, Spain, and Australia.

Heparin belonging to the unfractionated heparin acts as an anticoagulant agent.

Heparin interacts with the naturally occurring plasma protein, Antithrombin III, to induce a conformational change, which markedly enhances the serine protease activity of Antithrombin III, thereby inhibiting the activated coagulation factors involved in the clotting sequence, particularly Xa and IIa. Small amounts of heparin inhibit Factor Xa, and larger amounts inhibit thrombin (Factor IIa). Heparin also prevents the formation of a stable fibrin clot by inhibiting the activation of the fibrin-stabilizing factor. Heparin does not have fibrinolytic activity; therefore, it will not lyse existing clots.

The Onset of action of Heparin is about immediate (IV) and 20-30 minutes (Subcutaneously).

The data on the duration of Action of Heparin is not available.

The Tmax was found to be immediate (IV) and 2-4 hours (Subcutaneously) following the administration of Heparin.

Heparin is available in the form of Injectable solutions.

Heparin injectable solution is given intravenously and subcutaneously.

Heparin is a prescription medicine used to treat and prevent the symptoms of blood clots caused by medical conditions or medical procedures. Heparin may be used alone or with other medications.

Heparin is an anticoagulant agent belonging to unfractionated Heparin.

Heparin potentiates the action of antithrombin III, thereby inactivating thrombin as well as activated coagulation factors IX, X, XI, XII, and plasmin, and inhibits the conversion of fibrinogen to fibrin. It also stimulates the release of lipoprotein lipase which hydrolyses triglycerides to glycerol and free fatty acids.

Heparin is approved for use in the following clinical indications

●  Atrial fibrillation

●  Hemodialysis, anticoagulation of circuit

●  Venous thromboembolism prophylaxis

●  Venous thromboembolism treatment, deep vein thrombosis, and/or pulmonary embolism

Although not approved, there have been certain off-label indications. These include

●  Ischemic heart disease

●   Antibiotic lock technique, adjunctive therapy

●  Frostbite

●  Mechanical heart valve, bridging anticoagulation

●  Mechanical heart valve, postsurgical management

●  Peripheral arterial occlusion, acute

● Atrial fibrillation

IV: Initial bolus of 60 to 80 units/kg (maximum: 5,000 units), followed by a continuous infusion of 12 to 18 units/kg/hour (maximum: 1,000 units/hour). Institutional dosing protocols may vary; adjust infusion rate to maintain anticoagulation target.

● Hemodialysis, anticoagulation of circuit

Standard risk for bleeding:

IV: Initial: Bolus 1,000 units or 2,000 units at the beginning of hemodialysis, followed by a continuous infusion of 500 units/hour; stop the infusion 60 minutes before the end of hemodialysis.

High risk for bleeding:

IV: Initial: Bolus 1,000 units at the beginning of hemodialysis; do not administer a continuous infusion during the procedure.

● Venous thromboembolism prophylaxis

• Medical patients with acute illness at moderate to high risk for venous thromboembolism

Subcutaneously: 5,000 units every 8 to 12 hours; continue for the length of hospitalization or until fully ambulatory; extended prophylaxis beyond acute hospital stay is not routinely recommended.

• Nonorthopedic surgery

Patients with active cancer:

Subcutaneously: 5,000 units 2 to 4 hours prior to surgery, then 5,000 units every 8 hours thereafter or 5,000 units every 8 to 12 hours started ~6 to 24 hours after surgery.

Patients without cancer:

Subcutaneously: 5,000 units every 8 to 12 hours, with the initial dose given ≥2 hours prior to surgery. Alternatively, may postpone pharmacologic prophylaxis until after surgery (eg, high bleeding risk) when it is safe to initiate. Continue until fully ambulatory and the risk of VTE has diminished (typically up to 10 days).

Orthopedic surgery (eg, hip fracture surgery, total hip arthroplasty, total knee arthroplasty):

Subcutaneously: 5,000 units every 8 to 12 hours, with the initial dose administered ≥12 hours preoperatively or ≥12 hours postoperatively once hemostasis is achieved; optimal duration of prophylaxis is unknown, but it is usually given for a minimum of 10 to 14 days and can be extended for up to 35 days; some experts suggest a duration in the lower end of the range (10 to 14 days) for total knee arthroplasty or higher end of the range (~30 days) for total hip arthroplasty. For the extended duration of prophylaxis, may transition to an oral anticoagulant or alternative Subcutaneously anticoagulant with less frequent dosing.

Pregnancy:

• First trimester:

Subcutaneously: 5,000 to 7,500 units every 12 hours.

• Second trimester:
  

Subcutaneously: 7,500 to 10,000 units every 12 hours.

• Third trimester:
  

Subcutaneously: 10,000 units every 12 hours (reduce dose if the aPTT becomes elevated).

Adjusted dose (therapeutic):

Subcutaneously: 10,000 units every 12 hours; adjust the dose to target an aPTT of 1.5 to 2.5 times control, measured 6 hours after injection; monitor aPTT once daily until stable and within the therapeutic range, then monitor every 1 to 2 weeks.

● Venous thromboembolism treatment, deep vein thrombosis, and/or pulmonary embolism

Inpatient treatment:

IV: Initial: 80 units/kg bolus followed by a continuous infusion of 18 units/kg/hour, or 5,000-unit bolus followed by 1,333 units/hour; adjust infusion rate to maintain target laboratory values based on institutional protocol.

Ischemic heart disease (off-label use)

Acute coronary syndromes:

ST-elevation myocardial infarction

• Adjunct to percutaneous coronary intervention:

See Percutaneous coronary intervention for dosing guidance.

• Adjunct to fibrinolysis:

IV: Bolus 60 units/kg (maximum: 4,000 units), followed by 12 units/kg/hour (maximum: 1,000 units/hour); adjust infusion rate to maintain anticoagulation target based on institutional protocol; continue for ≥48 hours or until revascularization (if performed).

• No planned reperfusion:

IV: Bolus 50 to 70 units/kg (maximum: 5,000 units), followed by 12 units/kg/hour; adjust infusion rate to maintain anticoagulation target based on institutional protocol; continue for ≥48 hours.

Non-ST-elevation acute coronary syndromes

• Ischemia-guided (conservative) approach (alternative agent):

IV: Bolus 60 units/kg (maximum: 5,000 units), followed by 12 units/kg/hour (maximum: 1,000 units/hour); adjust infusion rate to maintain anticoagulation target based on institutional protocol; continue for ≥48 hours or until management changes to an invasive strategy (eg, percutaneous coronary intervention [PCI]); if PCI is performed, see Percutaneous coronary intervention for dosing guidance.

• Invasive approach (adjunct to percutaneous coronary intervention):

See Percutaneous coronary intervention for dosing guidance.

• Percutaneous coronary intervention
• No prior anticoagulant therapy:

No planned glycoprotein IIb/IIIa inhibitor use:

IV: Initial bolus of 70 to 100 units/kg (maximum: 10,000 units) to achieve activated clotting time (ACT) of 250 to 300 seconds (goal ACT may vary depending on point-of-care device); repeat bolus as needed to maintain goal ACT throughout the procedure.

Planned glycoprotein IIb/IIIa inhibitor use:

IV: Initial bolus of 50 to 70 units/kg (maximum: 7,000 units) to achieve an ACT of 200 to 250 seconds (regardless of point-of-care device); repeat bolus as needed to maintain goal ACT throughout the procedure.

• Prior anticoagulant therapy (with Heparin):

No planned glycoprotein IIb/IIIa inhibitor use:

IV: Check ACT prior to PCI and administer heparin bolus as needed (eg, 2,000 to 5,000 units) to achieve an ACT of 250 to 300 seconds (goal ACT may vary depending on point-of-care device); repeat bolus (maximum: 10,000 units) as needed to maintain goal ACT throughout the procedure.

Planned glycoprotein IIb/IIIa inhibitor use:

IV: Check ACT prior to PCI and administer heparin bolus as needed (eg, 2,000 to 5,000 units) to achieve an ACT of 200 to 250 seconds (regardless of point-of-care device); repeat bolus (maximum 7,000 units) as needed to maintain goal ACT throughout the procedure.

● Antibiotic lock technique, adjunctive therapy (off-label use)

Intracatheter: 100 to 5,000 units/mL in combination with an appropriate antibiotic. Heparin concentration depends on compatibility with the selected antibiotic, antibiotic concentration, and catheter type, which may vary by institution. For patients with an end-stage renal disease requiring hemodialysis, the maximum final heparin concentration should not exceed 1,000 units/mL due to the increased risk of bleeding. Instill into each lumen of the catheter access port using a sufficient volume to fill the catheter (eg, 2 to 5 mL) with a maximum dwell time of ≤72 hours, depending on the frequency of catheter use. Withdraw the lock solution prior to catheter use; replace it with fresh lock solution after catheter use.

● Frostbite (off-label use)

• When thrombolytic is administered IV:

IV: 500 to 1,000 units/hour as a fixed dose or targeted to an aPTT 2× control for up to 6 hours; some centers extend the duration to up to 5 days or transition to therapeutic low-molecular-weight heparin (LMWH) (eg, enoxaparin).

• When thrombolytic is administered intra-arterial:

Intra-arterial: 500 units/hour administered through the intra-arterial catheter; targeted to a goal aPTT 50 to 70 seconds; after discontinuation of thrombolytic therapy, continue anticoagulation for 72 to 96 hours or transition to therapeutic LMWH (eg, enoxaparin). Instead of intra-arterial heparin, some suggest the use of IV heparin after intra-arterial thrombolytic.

● Mechanical heart valve, bridging anticoagulation (off-label use)

IV: Initial: 12 to 18 units/kg/hour (no bolus) starting when INR falls below the therapeutic range; adjust infusion rate to maintain anticoagulation target based on institutional protocol. If the patient is to undergo an invasive procedure, discontinue heparin 4 to 6 hours prior to the procedure; reinitiate heparin infusion as soon as possible after the procedure when bleeding risk is acceptable. Continue heparin until warfarin has been reinitiated and INR is within the therapeutic range for 2 consecutive days.

● Mechanical heart valve, postsurgical management (off-label use)

IV: Initial: 12 to 18 units/kg/hour (no bolus); adjust infusion rate to maintain anticoagulation target based on institutional protocol. Overlap with warfarin until INR is stable and within the therapeutic range for ≥2 consecutive days.

● Peripheral arterial occlusion, acute (off-label use)

IV: Initial bolus of 60 to 80 units/kg, followed by an initial continuous infusion of 12 to 18 units/kg/hour; adjust infusion rate to maintain anticoagulation target based on institutional protocol.

Heparin is available in various strengths as 10000 units/mL; 1000 units/mL; 20000 units/mL; 5000 units/0.5 mL; 5000 units/mL; 7500 units/mL; 2500 units/mL; 2000 units/mL; 25000 units/mL; 100 units/mL-D5%; 50 units/mL-D5%; 100 units/mL-NaCl 0.45%; 50 units/mL-NaCl 0.45%; 40 units/mL-D5%; 40000 units/mL; 500 units/mL-NaCl 0.9%; 2000 units/mL-NaCl 0.9%; 10 units/mL-NaCl 0.9%; 50 units/mL-NaCl 0.9%; 30 units/mL-NaCl 0.9%.

Heparin is available in the form of Injectable solutions.

• Dosage Adjustment in Kidney Patient

Altered kidney function

IV, subcutaneously: Mild to severe impairment: No initial dosage adjustment necessary; adjust to maintain anticoagulation target based on institutional protocol.

Renal replacement therapies: Poorly dialyzed

IV, subcutaneously: No supplemental dose or initial dosage adjustment is necessary for patients receiving renal replacement therapies (eg, hemodialysis, peritoneal dialysis, CRRT, PIRRT); adjust to maintain anticoagulation target based on institutional protocol.

• Dosage Adjustment in Hepatic impairment Patient

No dosage adjustment is required; adjust therapeutic heparin according to aPTT or anti-Factor Xa activity.

Avoid herbs and supplements with anticoagulant/antiplatelet activity. Examples include garlic, ginger, bilberry, danshen, piracetam, and ginkgo Biloba.

Heparin is contraindicated in patients with

• History of Heparin-Induced Thrombocytopenia (HIT) and Heparin-Induced Thrombocytopenia and Thrombosis (HITT).
• Known hypersensitivity to heparin or pork products (e.g., anaphylactoid reactions).
• In whom suitable blood coagulation tests e.g., the whole blood clotting time, partial thromboplastin time, etc., cannot be performed at appropriate intervals (this contraindication refers to full-dose heparin; there is usually no need to monitor coagulation parameters in patients receiving low-dose heparin).
• An uncontrolled bleeding state, except when this is due to disseminated intravascular coagulation.

• Bleeding

May occur, including fatal events. Use with caution in patients with an increased risk of bleeding, including subacute bacterial endocarditis; congenital or acquired bleeding disorders; active ulcerative or angiodysplasia GI diseases; continuous GI tube drainage; severe uncontrolled hypertension; history of hemorrhagic stroke; use shortly after brain, spinal, or ophthalmologic surgery or other invasive procedures including spinal tap or spinal anesthesia; concomitant treatment with platelet inhibitors; recent GI bleeding; impaired hemostasis; thrombocytopenia or platelet defects; patients with hereditary antithrombin deficiency receiving concurrent antithrombin replacement therapy; severe liver disease; hypertensive or diabetic retinopathy; renal failure; or in patients (especially women) >60 years of age. Discontinue if bleeding occurs; severe hemorrhage or overdosage may require protamine (consult Protamine monograph for dosing recommendations).

• Heparin resistance

Dose requirements >35,000 units/24 hours to maintain a therapeutic aPTT may occur in patients with antithrombin deficiency, increased heparin clearance, elevations in heparin-binding proteins, and elevations in factor VIII and/or fibrinogen; frequently encountered in patients with fever, thrombosis, thrombophlebitis, infections with thrombosing tendencies, myocardial infarction, cancer, and in postsurgical patients; measurement of anticoagulant effects using anti-Factor Xa levels may be of benefit.

• Hepatic effects

Elevations in serum aminotransferases have been observed during therapy. These elevations should be evaluated with caution as they may occur and resolve in the setting of the underlying condition for which heparin is being used.

• Hyperkalemia

Hyperkalemia may occur, especially in patients with diabetes, renal impairment, history of metabolic acidosis, history of hyperkalemia, or taking concomitant potassium-sparing medication; may suppress aldosterone production.

• Hypersensitivity reactions

Hypersensitivity reactions, including fever, chills, urticaria, asthma, rhinitis, lacrimation, and anaphylaxis, have been reported. In patients with a documented hypersensitivity reaction, heparin should only be considered in life-threatening situations when use of an alternative anticoagulant is not possible. Some products are derived from animal tissue and may be contraindicated in patients with animal allergies (ie, pork); consult individual prescribing information.

• Osteoporosis

May occur with prolonged use (>6 months) due to a reduction in bone mineral density.

• Thrombocytopenia

Mild thrombocytopenia (platelet count >100,000/m³) may occur during therapy. Heparin-induced thrombocytopenia (HIT), a serious antibody-mediated reaction resulting from irreversible aggregation of platelets, may occur. Patients who develop HIT may be at risk of developing a new thrombus (heparin-induced thrombocytopenia with thrombosis [HITT]). Discontinue therapy and consider alternatives if the platelet count falls below 100,000/mm³, there is a >50% reduction in platelet count from baseline, and/or thrombosis develops while on heparin therapy. The onset of HIT or HITT is usually delayed (5 to 10 days after exposure in heparin-naive individuals) and can occur up to several weeks after discontinuation of heparin. “Rapid onset” HIT can occur within 24 hours of heparin initiation, especially in patients with recent heparin exposure within the previous 100 days. Use with extreme caution (for a limited duration) or avoid use in patients with a history of HIT, especially if administered within 100 days of a HIT episode.

Heparin is not present in breast milk. Heparin is considered acceptable for use in patients who are breastfeeding. However, some products contain benzyl alcohol as a preservative; their use in breastfeeding patients is contraindicated due to the association with the gasping syndrome in premature infants.

Due to pregnancy-induced physiologic changes, the risk of thromboembolism is increased during pregnancy and the immediate postpartum period. Heparin may be used for anticoagulation in pregnancy. Due to a better safety profile and ease of administration, the use of low molecular weight heparin (LMWH) is generally preferred over heparin (unfractionated heparin [UFH]) in pregnancy. Anticoagulant therapy for the prevention and treatment of thromboembolism in pregnant patients can be discontinued prior to induction of labor or a planned cesarean delivery or LMWH can be converted to UFH in higher-risk patients. Consult current recommendations for appropriate use in pregnancy.

Avoid herbs and supplements with anticoagulant/antiplatelet activity. Examples include garlic, ginger, bilberry, danshen, piracetam, and ginkgo Biloba.

• Vasospasm (including cyanotic extremities, limb ischemia, and limb pain), Skin ulceration at the injections site, alopecia, acute adrenocortical insufficiency, adrenal hemorrhage, hyperkalemia, ovarian hemorrhage, suppression of aldosterone synthesis, priapism, bruise, hemorrhage, heparin-induced thrombocytopenia retroperitoneal hemorrhage, thrombocytopenia, thrombosis in heparin-induced thrombocytopenia (including acute myocardial infarction, cerebrovascular accident, deep vein thrombosis, gangrene of the extremities, pulmonary embolism, skin necrosis), increased serum alanine aminotransferase, increased serum aspartate aminotransferase, anaphylactic shock, hypersensitivity reaction, nonimmune anaphylaxis, severe infusion-related reaction (skin necrosis), erythema at the injection site, hematoma at the injection site, irritation at the injection site, pain at the injection site, tissue necrosis at the injection site, osteoporosis.

• Oral Anticoagulants

Heparin sodium may prolong the one-stage prothrombin time. Therefore, when heparin sodium is given with dicumarol or warfarin sodium, a period of at least 5 hours after the last intravenous dose or 24 hours after the last subcutaneous dose should elapse before blood is drawn if a valid prothrombin time is to be obtained.

• Platelet Inhibitors

Drugs such as NSAIDS (including salicylic acid, ibuprofen, indomethacin, and celecoxib), dextran, phenylbutazone, thienopyridines, dipyridamole, hydroxychloroquine, glycoprotein IIb/IIIa antagonists (including abciximab, eptifibatide, and tirofiban), and others that interfere with platelet-aggregation reactions (the main hemostatic defense of heparinized patients) may induce bleeding and should be used with caution in patients receiving heparin sodium. To reduce the risk of bleeding, a reduction in the dose of an antiplatelet agent or heparin is recommended.

• Other Interactions

Digitalis, tetracyclines, nicotine, antihistamines, or intravenous nitroglycerin may partially counteract the anticoagulant action of heparin sodium.

• Heparin Sodium In 5% Dextrose Injection

Intravenous nitroglycerin administered to heparinized patients may result in a decrease of the partial thromboplastin time with subsequent rebound effect upon discontinuation of nitroglycerin. Careful monitoring of partial thromboplastin time and adjustment of heparin dosage is recommended during coadministration of heparin and intravenous nitroglycerin.

Antithrombin III (human) - The anticoagulant effect of heparin is enhanced by concurrent treatment with antithrombin III (human) in patients with hereditary antithrombin III deficiency. To reduce the risk of bleeding, a reduced dosage of heparin is recommended during treatment with antithrombin III (human).

The common side effects of Heparin include the following

• Common

Redness, pain, bruising, or sores at the spot where heparin was injected, hair loss.

• Rare

Unusual bruising or bleeding, vomit that is bloody or looks like coffee grounds, stool that contains bright red blood or is black and tarry, blood in urine, excessive tiredness, nausea, vomiting, chest pain, pressure, or squeezing discomfort, discomfort in the arms, shoulder, jaw, neck, or back, coughing up blood, excessive sweating, sudden severe headache, light-headedness or fainting, sudden loss of balance or coordination, sudden trouble walking, sudden numbness or weakness of the face, arm or leg, especially on one side of the body, sudden confusion, or difficulty speaking or understanding speech, difficulty seeing in one or both eyes, purple or black skin discoloration, pain and blue or dark discoloration in the arms or legs, itching and burning, especially on the bottoms of the feet, chills, fever, hives, rash, wheezing, shortness of breath, difficulty breathing or swallowing, hoarseness, painful erection that lasts for hours.

• Pregnancy

Pregnancy Category C

There are no available data on heparin sodium use in pregnant women to inform a drug-associated risk of major birth defects and miscarriage. In published reports, heparin exposure during pregnancy did not show evidence of an increased risk of adverse maternal or fetal outcomes in humans. No teratogenicity, but early embryo-fetal death was observed in animal reproduction studies with administration of heparin sodium to pregnant rats and rabbits during organogenesis at doses approximately 10 times the maximum recommended human dose (MRHD) of 40,000 units/24 hours infusion. Consider the benefits and risks of Heparin Sodium in 0.45% Sodium Chloride Injection or Heparin Sodium in 5% Dextrose Injection to a pregnant woman and possible risks to the fetus when prescribing Heparin Sodium in 0.45% Sodium Chloride Injection or Heparin Sodium in 5% Dextrose Injection to a pregnant woman.

• Nursing Mothers

Heparin is not present in breast milk. Heparin is considered acceptable for use in patients who are breastfeeding. However, some products contain benzyl alcohol as a preservative; their use in breastfeeding patients is contraindicated due to the association with the gasping syndrome in premature infants.

• Pediatric Use

There are no adequate and well-controlled studies on heparin use in pediatric patients. Pediatric dosing recommendations are based on clinical experience.

• Geriatric Use

There are limited adequate and well-controlled studies in patients 65 years and older. However, a higher incidence of bleeding has been reported in patients over 60 years of age, especially women. Lower doses of heparin may be indicated in these patients.

• Bleeding may result from heparin overdosage.
• Neutralization of Heparin Effect

When circumstances (e.g., bleeding) require reversal of heparinization, protamine sulfate (1% solution) by slow infusion will neutralize heparin sodium.

• No more than 50 mg should be administered, very slowly, in any 10-minute period. Each mg of protamine sulfate neutralizes approximately 100 USP units. The amount of protamine required decreases over time as heparin is metabolized. Although the metabolism of heparin is complex, it may, for the purpose of choosing a protamine dose, be assumed to have a half-life of about 1/2 hour after intravenous injection.
• Because fatal reactions often resembling anaphylaxis have been reported, the drug should be given only when resuscitation techniques and treatment of anaphylactoid shock are readily available.

Pharmacodynamic

Bleeding time is usually unaffected by heparin. Various times (activated clotting time, activated partial thromboplastin time, prothrombin time, whole blood clotting time) are prolonged by full therapeutic doses of heparin; in most cases, it is not measurably affected by low doses of heparin.

Pharmacokinetics

• Absorption

Heparin is not absorbed through the gastrointestinal tract and is therefore administered via the parenteral route. Peak plasma concentration and the onset of action are achieved immediately after intravenous administration.

• Distribution

Heparin is highly bound to antithrombin, fibrinogens, globulins, serum proteases, and lipoproteins. The volume of distribution is 0.07 L/kg.

• Metabolism

Heparin does not undergo enzymatic degradation.

• Excretion

Heparin is mainly cleared from the circulation by the liver and reticuloendothelial cells mediated uptake into extravascular space. Heparin undergoes biphasic clearance, a) rapid saturable clearance (zero-order process due to binding to proteins, endothelial cells, and macrophage), and b) slower first-order elimination. The plasma half-life is dose-dependent and it ranges from 0.5 to 2 h.

• https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/017029s140lbl.pdf
• https://www.rxlist.com/heparin-drug.htm#description
• https://reference.medscape.com/drug/calciparine-monoparin-heparin-342169#11
• https://www.mims.com/india/drug/info/heparin?type=full&mtype=generic
• https://medlineplus.gov/druginfo/meds/a682826.html#precautions
• https://go.drugbank.com/drugs/DB01109
• https://www.drugs.com/dosage/heparin.html
• https://www.uptodate.com/contents/heparin-unfractionated-drug-information#F178776