**2.3.1 Indirect thrombin Inhibitors**

#### **2.3.1.1 Unfractionated Heparin (UFH)**

Heparin is a large, heterogeneous compound of approximately 45 saccharide units that indirectly binds to and increases the enzymatic activity of antithrombin III, against activated Factors II, and X. Unfractionated Heparin clearance is the result of a combination of rapid, saturable mechanism via the endothelium and the reticuloendothelial system in liver, and a slower, non saturable mechanism through the kidneys (Follea, 1987) However UFH remain the anticoagulant choice for in-hospital treatment of patients with thromboembolic disorders who also have renal dysfunction.

There are no recommendations from the American College of Chest Physicians (ACCP) Consensus Conference on Antithrombotic Therapy and from the manufacturers for dose reduction of UFH in patients with chronic renal impairment (Kearon, 2008). The monitoring of the activated partial thromboplastin time is recommended while UFH are administered to renal impairment patients.

In acute thromboembolic events, an intravenous bolus dose up to 80 units/kg may be administered, but in the absence of an emergent need for anticoagulation or high risk situations, the bolus dose could be omitted and just a continuous infusion may be initiated with the advantage of gradually establishing of the anticoagulation and limiting the risk of bleeding. Initial continuous infusion of unfractionated heparin do not require special adjustments because of chronic kidney disease alone and goal activated partial time of thromboplastin should be targeted to the indication for anticoagulant therapy. Another option is subcutaneous weight adjusted dosing. (Dager, 2010)

#### **2.3.1.2 Low molecular weight heparin (LMWH)**

Low molecular weight heparins may not be considered as the preferred option for initial parenteral anticoagulation in chronic kidney disease patients, but they could be considered in special situations because these agents are primarily eliminated on kidneys and dosing adjustments are needed as renal failure progresses (Kearon, 2006).

A meta analysis was performed to study the incidence of bleeding in chronic kidney disease patients treated with low molecular weight heparins like enoxaparin, dalteparin and tinzaparin. Enoxaparin has elevated levels of anti-factor Xa and an increased risk for mayor bleeding, suggesting empirical dose adjustment of enoxaparin in patients with severe renal impairment. In patients with mild to moderate renal impairment there are not required dose adjustment of enoxaparin [ Lim, 2006 ]

For venous tromboembolism prophylactic doses of enoxaparin the American College of Chest Physicians (ACCP) recommendations for patients with severe renal impairment is to lower or halve the standard dose. For the treatment of venous thromboembolism in patients with severe renal impairment the ACCP guidelines recommended either using unfractionated heparin instead of low molecular weight heparins. No especific dose recommendations are made in this guidelines for other low molecular weight heparins in venous thromboembolism. For tinzaparin and dalteparin monitoring of anticoagulant activity in patients with renal failure should be considered.

#### **2.3.1.3 Fondaparinux**

Pathophysiology and Clinical Aspects of 46 Venous Thromboembolism in Neonates, Renal Disease and Cancer Patients

Decisions for anticoagulation therapy respect the agent selected, dose, duration of treatment, and approaches to monitoring should balance the risks between bleeding and

Heparin is a large, heterogeneous compound of approximately 45 saccharide units that indirectly binds to and increases the enzymatic activity of antithrombin III, against activated Factors II, and X. Unfractionated Heparin clearance is the result of a combination of rapid, saturable mechanism via the endothelium and the reticuloendothelial system in liver, and a slower, non saturable mechanism through the kidneys (Follea, 1987) However UFH remain the anticoagulant choice for in-hospital treatment of patients with thromboembolic

There are no recommendations from the American College of Chest Physicians (ACCP) Consensus Conference on Antithrombotic Therapy and from the manufacturers for dose reduction of UFH in patients with chronic renal impairment (Kearon, 2008). The monitoring of the activated partial thromboplastin time is recommended while UFH are administered

In acute thromboembolic events, an intravenous bolus dose up to 80 units/kg may be administered, but in the absence of an emergent need for anticoagulation or high risk situations, the bolus dose could be omitted and just a continuous infusion may be initiated with the advantage of gradually establishing of the anticoagulation and limiting the risk of bleeding. Initial continuous infusion of unfractionated heparin do not require special adjustments because of chronic kidney disease alone and goal activated partial time of thromboplastin should be targeted to the indication for anticoagulant therapy. Another

Low molecular weight heparins may not be considered as the preferred option for initial parenteral anticoagulation in chronic kidney disease patients, but they could be considered in special situations because these agents are primarily eliminated on kidneys and dosing

A meta analysis was performed to study the incidence of bleeding in chronic kidney disease patients treated with low molecular weight heparins like enoxaparin, dalteparin and tinzaparin. Enoxaparin has elevated levels of anti-factor Xa and an increased risk for mayor bleeding, suggesting empirical dose adjustment of enoxaparin in patients with severe renal impairment. In patients with mild to moderate renal impairment there are not required dose

For venous tromboembolism prophylactic doses of enoxaparin the American College of Chest Physicians (ACCP) recommendations for patients with severe renal impairment is to lower or halve the standard dose. For the treatment of venous thromboembolism in patients with severe renal impairment the ACCP guidelines recommended either using unfractionated heparin instead of low molecular weight heparins. No especific dose recommendations are made in this guidelines for other low molecular weight heparins in

thrombosis.

**2.3.1 Indirect thrombin Inhibitors 2.3.1.1 Unfractionated Heparin (UFH)** 

disorders who also have renal dysfunction.

option is subcutaneous weight adjusted dosing. (Dager, 2010)

adjustments are needed as renal failure progresses (Kearon, 2006).

**2.3.1.2 Low molecular weight heparin (LMWH)** 

adjustment of enoxaparin [ Lim, 2006 ]

to renal impairment patients.

Fondaparinux is a synthetic pentasaccharide, that inhibits factor Xa by binding to antithrombin. After subcutaneous administration the peak plasma concentration is achieved within 2 hours, the half life is 17 hours in young healthy subjects and 21 hours in the elderly. Up to 80% of fondaparinux is eliminated as unchanged drug via the kidneys.

However the ACCP guidelines for VTE prevention do not recommend specific doses adjustments for fondaparinux in renal impaired patients, depending of the circumstances the guidelines recommended avoiding the anticoagulant, lowering dose or monitoring anticoagulant activity [Hirsh,2008]

The summary of manufacturers insert states contraindicated of fondaparinux in patients with severe renal impairment (clearance of creatinine ‹20 ml/min) and use with caution in patients with moderate renal impairment (creatinine clearance 30 a 50 ml/min)[ Harder 2011]
