**2.3.3.3 Apixaban**

Apixaban inhibits both free and clot-bound factor Xa Apixaban is rapidly absorved in the stomach and small intestine, reaching peaks concentrations approximately 1 to 3 hours after oral administration. The elimination includes renal and biliary excretion, and the drug has a mean elimination half life of 8 to 15 hours. ( Shantsila, 2008;Frost,2007)

There are limited data about the clearance of apixaban in patients with renal impairment.

In presence of heparin induced thrombocytopenia or antithrombin deficiency directs thrombin inhibitors may be options for anticoagulation. They are argatroban, bivalidurin and lepirudin, avalaible only by continous venous infusion or subcutaneous injection.

#### **2.3.3.4 Argatroban**

Argatroban is eliminated in liver and no adjustment in dosing is required for renal insufficiency or hemodyalisis, the mean dose in heparin induced thrombocytopenia was 1.6 μg/kg/min, targeting activated partial thromboplastin time 1.5 to 3.0 times control. In patients with renal failure it has been suggest lower dosing requirements with dose reduction of approximately 0.1 to 0.6 μg/kg/min for each 30 ml/min decrease in the creatinine clearance. (Hursting, 2008; Arpino, 2004)

#### **2.3.3.5 Lepirudin**

Lepirudin is the agent most dependent of renal elimination and requires significant dose reductions as renal function declines.

#### **2.3.3.6 Bivalirudin**

Bivalirudin is eliminated independent of renal function, with 80% removed enzimatically, it has also been observed to be removed by ultrafiltration. For patients with renal dysfunction and heparin induced thrombocytopenia, dose reductions has been suggested. The extend depends on the degree of renal dysfunction and form of renal replacement therapy. The target activated partial thromboplastin time for both lepirudin and bivalirudin is 1.5 to 2.5 times baseline and argatroban 1.5 to 3 times baseline, which may be different from the range specified for unfractionated heparin.(Dager, 2007; Kiser,2008).

In conclusion the unfractionated heparin continues been the anticoagulant of choice for chronic kidney disease patients, because it's short half life, reliable monitoring, reversibility and independence of renal function. Of the oral anticoagulants, warfarine is a safe alternative to unfractionated heparin, easy to monitor and does not requires dose alteration in chronic kidney disease.


CrCl: creatinine clearance

Pathophysiology and Clinical Aspects of 48 Venous Thromboembolism in Neonates, Renal Disease and Cancer Patients

Rivaroxaban inhibits both free and clot-bound Factor Xa, this oral anticoagulant has been approved for the prevention of venous thromboembolism after elective hip or knee

Rivaroxaban has a dual mode of elimination hepatic and renal and the inhibition of factor Xa activityalso increased with the reduce renal function. Rivaroxaban is not recommended for patients with a Creatine clearance of less than 15 mil/min. (Kubitza, 2010). To the date there are not reported studies for rivaroxaban in patients with renal impairment for venous

Apixaban inhibits both free and clot-bound factor Xa Apixaban is rapidly absorved in the stomach and small intestine, reaching peaks concentrations approximately 1 to 3 hours after oral administration. The elimination includes renal and biliary excretion, and the drug has a

There are limited data about the clearance of apixaban in patients with renal impairment. In presence of heparin induced thrombocytopenia or antithrombin deficiency directs thrombin inhibitors may be options for anticoagulation. They are argatroban, bivalidurin and lepirudin, avalaible only by continous venous infusion or subcutaneous injection.

Argatroban is eliminated in liver and no adjustment in dosing is required for renal insufficiency or hemodyalisis, the mean dose in heparin induced thrombocytopenia was 1.6 μg/kg/min, targeting activated partial thromboplastin time 1.5 to 3.0 times control. In patients with renal failure it has been suggest lower dosing requirements with dose reduction of approximately 0.1 to 0.6 μg/kg/min for each 30 ml/min decrease in the

Lepirudin is the agent most dependent of renal elimination and requires significant dose

Bivalirudin is eliminated independent of renal function, with 80% removed enzimatically, it has also been observed to be removed by ultrafiltration. For patients with renal dysfunction and heparin induced thrombocytopenia, dose reductions has been suggested. The extend depends on the degree of renal dysfunction and form of renal replacement therapy. The target activated partial thromboplastin time for both lepirudin and bivalirudin is 1.5 to 2.5 times baseline and argatroban 1.5 to 3 times baseline, which may be different from the range

In conclusion the unfractionated heparin continues been the anticoagulant of choice for chronic kidney disease patients, because it's short half life, reliable monitoring, reversibility and independence of renal function. Of the oral anticoagulants, warfarine is a safe alternative to unfractionated heparin, easy to monitor and does not requires dose alteration

mean elimination half life of 8 to 15 hours. ( Shantsila, 2008;Frost,2007)

creatinine clearance. (Hursting, 2008; Arpino, 2004)

specified for unfractionated heparin.(Dager, 2007; Kiser,2008).

reductions as renal function declines.

**2.3.3.2 Rivaroxaban** 

thromboembolism. **2.3.3.3 Apixaban** 

**2.3.3.4 Argatroban** 

**2.3.3.5 Lepirudin** 

**2.3.3.6 Bivalirudin** 

in chronic kidney disease.

replacement surgery in adults (Bauer, 2008)

a Clasification by National Kidney Foundation. Chronic kidney disease is defined as either kidney damage or GFR of <60 mL/min/1.73m2 for ≥ 3 months. Kidney damage is defined as pathological abnormalities or markers of damage, including abnormalities in blood or urine test or imaging studies.GFR reported by the National Kidney Foundation, using the modification of Diet in Renal Disease Study equation based on age, gender, race, and serum creatinine

[Reference: Harder, 2011]

Table 1. Clasification of Renal impairment


ACT =Activated clotting time; aPTT=activated partial thromboplastin time; CYP= cytochrome p450 ECT = ecarin clotting time; INR= International normalized ratio; IV =Intravenous; LMWH= low molecular weight heparin; RES= reticuloendothelial system; SC= subcutaneous; UFH= unfractionated heparin. {Reference: Grand'Maison A, Charest A,Geerts W, 2005 ; Harder S,2011]

Table 2. Anticoagulants characteristics and dose adjustment in severe renal impairment

Venous Thromboembolism in Neonates, Children and

females.(Kuhle et al, 2004; Stein et al, 2004).

women, obesity and smoking.(Stein et al, 2004).

**3.2 Diagnosis** 

**3.2.1 Clinical presentation** 

**3.2.2 Laboratory parameters** 

absolute thrombotic risk of children with thrombophilia.

sepsis, or prominent collateral circulation over chest, neck and head.

Patients with Chronic Renal Disease – Special Considerations 51

The reasons for the lower incidences of TE in children compared to adults are not completely understood; an intact vascular endothelium, the lower capacity of thrombin generation (Haidi et al, 2006) and elevated levels of -2-macroglobulin, an inhibitor of thrombin, are possible age-dependent modifying factors in children. There are two agerelated peaks in the frequency of thromboembolic disorders in children and adolescents: the first peak corresponds to the perinatal/neonatal period, with the highest relative incidence, and the second is observed post puberty in adolescents, with a higher frequency in

The relatively higher incidence in neonates as compared to older children may be due to higher hematocrit, and the greater lability of the hemostatic system in neonates due to the generally decreased levels of both coagulation factors and their inhibitors in this age group, except factor VIII (FVIII) and von Willebrand factor (VWF) which are normal or even elevated.(Monagle et al, 2006) In adolescents the incidence equals that of young adults, probably due to the hormonal status, the use of contraceptives or pregnancy in young

Clearly, these epidemiological data have to be considered when assessing the individual

Pain, swelling and discoloration of extremities are acute symptoms of deep vein thrombosis (DVT). Vena cava inferior thrombosis manifests with prominent cutaneous veins and possibly liver or renal dysfunction depending on the site and extension of the thrombus. Superior vena cava thrombosis leads to cyanosis and swelling of the head and upper thorax with prominent collateral veins and may finally result in acute cardiac failure. Portal vein thrombosis, in most cases due to central catheters, and renal vein thrombosis with hematuria as a frequent sign may result in functional impairment or even failure of liver and renal function, respectively. Acute chest pain and dyspnea could suggest pulmonary embolism. Acute headache, visual impairment, cerebral convulsions and signs of venous congestion may indicate sinus venous thrombosis. Signs and symptoms of central venous catheter (CVC)-associated DVT are loss of CVC patency, the need for local thrombolytic therapy or CVC replacement, CVC-related

Childhood arterial ischemic stroke (AIS) manifests in neonates preferentially with seizures and abnormalities of muscle tone, whereas in elder children hemiparesis is the most frequent neurologic sign.(Steinlin et al, 2005) Acquired or inherited severe deficiencies of protein S and protein C are disorders involving both the microcirculation and arterial vessels and may manifest with characteristic symptoms such as deep skin necrosis (purpura fulminans), blindness due to retinal vessel occlusion and arterial embolism followed by necrosis of distal extremities or whole limbs. Thrombotic thrombocytopenic purpura (TTP), a severe microangiopathic disorder is characterized by nonimmunologic hemolytic anemia and thrombocytopenia, neurologic symptoms, and renal, pulmonary and cardial involvement.

Every thrombotic event initiates a particular response to re-establish the balance of the hemostatic system, e.g., by fibrinolysis. Subsequently markers of fibrinolysis such as D-

While low molecular weight heparins, fondaparinux and direct thrombin inhibitors may offer alternatives to unfractionated heparin in patients with chronic kidney disease, more evidence are needed to determine the safe dose and monitoring strategy.
