Heparin: Action as an Anticoagulant and Information

Heparin is a sulfated polysaccharide chain with anticoagulant action. Derived from the mucosa of porcine intestines or bovine lungs, it has been used therapeutically since the 1930s. In Germany, two main forms are distinguished: unfractionated heparin (UFH, for example Liquemin, Heparin Natrium) and low molecular weight heparin (LMWH, for example Enoxaparin (Clexane), Dalteparin (Fragmin), Tinzaparin (Innohep), Nadroparin (Fraxiparin), Certoparin (Mono Embolex)). Both differ in pharmacokinetics, controllability, and field of application, but are based on the same fundamental mechanism.

Heparin remains indispensable in acute situations. In intensive care patients, during use of extracorporeal procedures such as dialysis or ECMO, in the early phase of acute coronary syndromes, and in pregnancy, it is the drug of choice because its action is short-acting and controllable or well-planned before delivery. In outpatient thrombosis prophylaxis and thrombosis therapy, low molecular weight heparins have increasingly been replaced by oral anticoagulants (DOACs), though they have not lost their importance.

Mechanism of Action

Heparin exerts its anticoagulatory effect indirectly: it binds to antithrombin III, an endogenous inhibitor of coagulation factors. This binding changes the conformation of antithrombin and accelerates its inhibition of factors Xa and IIa (thrombin) approximately a thousandfold. This stops fibrin formation and inhibits thrombus formation.

Unfractionated heparin inhibits both factor Xa and thrombin in a ratio close to 1 to 1. Low molecular weight heparins are created from the breakdown of UFH and contain shorter polysaccharide chains. They preferentially inhibit factor Xa because a longer chain is required for simultaneous binding of antithrombin and thrombin. This selectivity leads to more predictable action, longer half-life, and the possibility of subcutaneous administration in fixed doses without routine monitoring.

Heparin does not cross the placenta and hardly enters breast milk, making it the preferred anticoagulation in pregnancy and lactation. UFH is eliminated primarily hepatically and through the reticuloendothelial system, while LMWH is eliminated renally. These differences have consequences in renal insufficiency.

Indications

• Treatment of deep vein thrombosis and pulmonary embolism, initially LMWH or UFH, then transition to oral anticoagulation
• Acute coronary syndrome, LMWH or UFH supplementing antiplatelet therapy
• Atrial fibrillation as bridging when pausing oral anticoagulants around surgery
• Thrombosis prophylaxis after surgery, in acutely ill patients, in pregnancy with risk
• Anticoagulation for extracorporeal procedures, hemodialysis, hemofiltration, heart-lung machine, ECMO
• Pregnancy-associated thrombophilia, established therapy due to lack of placental passage

Important: Heparin is not a thrombolytic agent; it does not dissolve existing thrombi but prevents their growth and new formation. In acute pulmonary embolism or acute stroke requiring thrombolysis, other substances such as alteplase or tenecteplase are used.

Dosage and Administration

Unfractionated heparin therapeutically: Bolus 80 units per kg body weight intravenously, followed by continuous infusion 18 units per kg per hour. Control via aPTT (1.5 to 2.5 times prolongation) or anti-Xa (0.3 to 0.7 IU per ml).

UFH prophylactically: 5000 units subcutaneously two to three times daily in hospital risk situations.

Low molecular weight heparin therapeutically: Enoxaparin 1 mg per kg body weight every twelve hours subcutaneously or 1.5 mg per kg once daily. Dalteparin 200 IU per kg daily, Tinzaparin 175 IU per kg daily. In acutely hospitalized patients often fixed dose.

LMWH prophylactically: Enoxaparin 40 mg subcutaneously once daily, higher in obesity, lower in renal insufficiency.

Renal insufficiency: With eGFR below 30 ml per minute, accumulation of LMWH is relevant. UFH is often the safer choice then. Alternatively, enoxaparin in reduced dose (20 or 30 mg) with anti-Xa level, or tinzaparin, which accumulates less due to intermediate chain length.

Obesity: Dose adjustment according to actual body weight or weight-adjusted schedule. With very high body weight additional anti-Xa control.

Side Effects

Very common: Hematomas at injection site, pain, sensation of tension.

Common: Bleeding of all localizations (skin, gastrointestinal tract, urogenital tract), increase in liver transaminases, allergic skin reactions.

Rare but relevant: Heparin-induced thrombocytopenia (HIT), particularly type II, a severe immune-mediated complication. It typically occurs between the fifth and fourteenth day of therapy; antibodies against heparin-platelet factor 4 complexes cause platelet activation and paradoxically venous or arterial thromboses. Immediate discontinuation of all heparin forms and switching to alternative anticoagulants such as argatroban or fondaparinux is mandatory.

With long-term use: Osteoporosis with increased fracture risk, especially with UFH.

Antidote: Protamine sulfate neutralizes heparin through electrostatic binding. With UFH practically completely effective, with LMWH only partially (approximately 60 percent of anti-Xa activity). Use in acute bleeding situations, cautious dosing, and slow infusion due to risk of hypotension and anaphylaxis.

Drug Interactions

• Other anticoagulants (DOACs, vitamin K antagonists, fondaparinux, bivalirudin, argatroban): additive bleeding risk, combination only with clearly defined indication and short bridging.
• Platelet aggregation inhibitors (ASA, clopidogrel, ticagrelor, prasugrel, glycoprotein IIb/IIIa antagonists): increased bleeding risk, but frequently required combination in acute cardiology.
• NSAIDs and steroids: increased gastrointestinal bleeding risk, gastric protection and strict indication setting appropriate.
• Thrombolytics (alteplase, tenecteplase): standard use together with heparin in acute coronary syndrome or pulmonary embolism, but increased bleeding risk, careful patient selection.
• SSRIs: moderate increase in bleeding risk, especially gastrointestinal.
• ACE inhibitors and potassium-sparing diuretics: in combination with UFH increased tendency toward hyperkalemia, especially in renal insufficiency.

Special Information

Pregnancy: Heparin does not cross the placenta and is the drug of choice when anticoagulation is needed in pregnancy. LMWH is preferred over UFH because HIT occurs less frequently. Lactation: no clinically relevant transfer into breast milk, breastfeeding possible with heparin.

Surgery: LMWH 24 hours before planned procedure (prophylactic dose 12 hours), with spinal anesthesia strictly at least twelve hours apart with prophylactic dosing and 24 hours with therapeutic dose. UFH can be stopped four to six hours before procedure.

Spinal puncture and epidural anesthesia: exact timing relative to heparin administration due to risk of epidural hematoma. Clear anesthesia protocols are mandatory.

Platelet monitoring: with UFH and prophylactic LMWH every three to four days in the first two weeks, then individually. Sudden platelet drop of more than 50 percent or new thromboembolic events during heparin are alarm signs for HIT.

Allergies and intolerance: consider porcine products; in rare cases religious or ethically motivated refusal. Alternatives are synthetic pentasaccharides such as fondaparinux.

Self-injection: careful training, rotation of injection sites on abdomen, lift skin fold, inject slowly. Hematomas are common and harmless, but should be documented if they become unusually large.

You Might Also Be Interested In

• Warfarin, vitamin K antagonist for oral anticoagulation
• Clopidogrel, platelet aggregation inhibitor in secondary prevention
• Prasugrel, P2Y12 inhibitor in acute coronary intervention
• Creatinine, marker for dose adjustment of LMWH
• Sufentanil, anesthetic opioid with its own information on anticoagulation planning

Frequently Asked Questions

Sources

• Gelbe Liste, Heparin active substance profile
• BfArM, Federal Institute for Drugs and Medical Devices
• AWMF, Guidelines on Thromboembolism Prophylaxis and Therapy
• EMA, European Medicines Agency