What are the considerations for the use of heparin, low molecular weight heparin (LMWH), and proteins sulphate in anticoagulation therapy?

Mechanism of Action and Clinical Applications of Heparin, LMWH, and Protein Sulfate

Heparin and low molecular weight heparin (LMWH) exert their anticoagulant effects primarily by activating antithrombin (AT), with LMWH having more predictable pharmacokinetics and a better safety profile than unfractionated heparin (UFH) for most clinical applications. 1

Mechanisms of Action

Unfractionated Heparin (UFH)

• Binds to antithrombin via a unique pentasaccharide sequence
• Forms ternary complexes between heparin chains, AT, and thrombin
• Inactivates multiple coagulation factors, especially thrombin (factor IIa) and factor Xa
• Has significant non-specific binding to plasma proteins, endothelial cells, and platelets 1

Low Molecular Weight Heparin (LMWH)

• Derived from UFH through chemical or enzymatic depolymerization
• Mean molecular weight of 4,500-5,000 Da (vs. 15,000 Da for UFH)
• More selective anti-factor Xa activity relative to anti-thrombin activity
• Only 25-50% of LMWH molecules have chain length sufficient to inactivate thrombin
• All LMWH molecules containing the pentasaccharide sequence can inactivate factor Xa 1

Protein Sulfate Components

• Danaparoid sodium (Orgaran) is a heparinoid containing:
  • Heparin sulfate (84%)
  • Dermatan sulfate (12%)
  • Chondroitin sulfate (4%) 1
• These sulfated glycosaminoglycans have varying anticoagulant properties

Pharmacokinetic Differences

Property	UFH	LMWH
Administration	IV or SC	SC (primarily)
Bioavailability	Variable (30-70%)	>90%
Half-life	1-2 hours	4-6 hours
Clearance	Reticuloendothelial system and renal	Primarily renal
Monitoring	aPTT required	Generally not required (anti-Xa if needed)
Dosing	Weight-based, frequent	Weight-based, once or twice daily

Clinical Applications

Venous Thromboembolism (VTE) Prophylaxis

• LMWH is preferred over UFH for:
  • Major orthopedic surgery (70-79% risk reduction for all thrombi) 1
  • High-risk surgical patients
  • Medical patients at risk of thrombosis 1
• UFH remains an option when:
  • Severe renal impairment is present (CrCl <15 mL/min) 2
  • Rapid reversal may be needed

VTE Treatment

• LMWH has largely replaced UFH due to:
  • Similar efficacy with better safety profile
  • Once-daily dosing
  • Reduced need for monitoring
  • Lower risk of heparin-induced thrombocytopenia (HIT) 1

Special Populations

Cancer Patients

• LMWH is preferred over vitamin K antagonists for cancer-associated thrombosis
• Lower risk of fatal bleeding (0% vs 8% with vitamin K antagonists) 1
• Cancer patients have higher bleeding risk regardless of anticoagulation intensity 1

Renal Impairment

• For severe renal impairment (CrCl <15 mL/min):
  • UFH is preferred over LMWH
  • LMWH has prolonged half-life due to renal clearance 2
  • If LMWH is used, anti-Xa monitoring is recommended 2

Sepsis

• Strong recommendation for VTE prophylaxis with LMWH over UFH in sepsis patients 1
• Mechanical prophylaxis when pharmacological prophylaxis is contraindicated 1

Safety Considerations

Bleeding Risk

• Major bleeding risk factors:
  • Active or chronic bleeding
  • Recent CNS bleeding or high-risk lesions
  • Recent surgery with high bleeding risk
  • Spinal anesthesia/lumbar puncture
  • High fall risk
  • Thrombocytopenia or platelet dysfunction
  • Systemic coagulopathy 1

Heparin-Induced Thrombocytopenia (HIT)

• Lower incidence with LMWH compared to UFH
• Due to reduced binding to platelets and platelet factor 4 (PF4) 1
• Alternative anticoagulants for HIT include:
  • Danaparoid sodium
  • Direct thrombin inhibitors (e.g., argatroban, bivalirudin) 1

Monitoring Requirements

• UFH: aPTT monitoring required, target 1.5-2.5 times control
• LMWH: Generally no monitoring needed except in:
  • Severe obesity (>150 kg)
  • Renal impairment
  • Pregnancy
  • Children 1, 3

Practical Considerations

Reversal

• UFH: Fully reversible with protamine sulfate
• LMWH: Partially reversible with protamine (anti-Xa activity not fully normalized) 3

Transitioning Between Anticoagulants

• When switching from heparin to oral anticoagulants:
  • Start oral anticoagulant on day 1-2 of heparin treatment
  • Continue heparin until therapeutic INR is achieved (if using warfarin) 1
• Avoid rapid transitions in elderly or renally impaired patients 2

Contraindications

• History of HIT or HITTS
• Known hypersensitivity to heparin or pork products
• Inability to monitor coagulation tests appropriately
• Uncontrolled bleeding (except in DIC) 4

In conclusion, understanding the mechanisms of action and pharmacokinetic differences between UFH, LMWH, and protein sulfate components is essential for appropriate anticoagulant selection. LMWH offers significant advantages over UFH in most clinical scenarios, but individual patient factors including renal function, bleeding risk, and need for reversibility should guide therapeutic decisions.