From the Guidelines
Antithrombin is lost in patients with nephrotic syndrome primarily due to urinary excretion of this important anticoagulant protein, which occurs as a result of damage to the glomerular filtration barrier in the kidneys, leading to increased permeability and allowing antithrombin to leak into the urine. In nephrotic syndrome, the glomerular filtration barrier is damaged, allowing proteins that would normally be retained in the bloodstream to pass through and be excreted in the urine. Antithrombin, with a molecular weight of approximately 58 kDa, is small enough to pass through the damaged glomerular filter and be excreted in urine, as noted in the context of anticoagulant dosing considerations in patients with nephrotic syndrome 1. This urinary loss exceeds the liver's capacity to synthesize replacement antithrombin, resulting in decreased plasma levels.
The reduction in antithrombin contributes significantly to the hypercoagulable state observed in nephrotic syndrome patients, as antithrombin normally inhibits several coagulation factors including thrombin and factor Xa. The severity of antithrombin deficiency often correlates with the degree of proteinuria and hypoalbuminemia. This mechanism explains why nephrotic syndrome patients have an increased risk of thrombotic complications, particularly venous thromboembolism, and may require prophylactic anticoagulation in certain clinical scenarios, such as the use of low-dose anticoagulation or full warfarin anticoagulation for thromboembolic events, as recommended in the kdigo 2021 clinical practice guideline for the management of glomerular diseases 1.
Key points to consider in the management of antithrombin loss in nephrotic syndrome include:
- The use of anticoagulants, such as low-dose molecular-weight heparin or unfractionated heparin, to prevent thrombotic complications
- The potential need for higher than usual heparin dosing due to antithrombin III urinary loss
- The importance of monitoring international normalized ratio frequently in patients on warfarin, as warfarin-protein binding may fluctuate with changing serum albumin levels
- The need for additional study on the pharmacokinetic properties of newer anticoagulants, such as factor Xa inhibitors and direct thrombin inhibitors, in patients with nephrotic syndrome 1.
From the Research
Antithrombin Loss in Nephrotic Syndrome
- Nephrotic syndrome is characterized by the loss of proteins, including antithrombin, in the urine due to severe alteration of the glomerular filtration barrier 2.
- The liver tries to counterbalance these losses by increasing the unselective synthesis of all types of proteins, which can have different clinical consequences 2.
- Antithrombin is a protein that plays a crucial role in regulating blood coagulation, and its deficiency can increase the risk of thromboembolic complications 3, 4.
- Patients with nephrotic syndrome often have low levels of antithrombin, which can make them more susceptible to thromboembolic events 3, 4.
Mechanism of Antithrombin Loss
- The exact mechanism of antithrombin loss in nephrotic syndrome is not fully understood, but it is thought to be related to the increased permeability of the glomerular filtration barrier 2.
- This increased permeability allows proteins, including antithrombin, to be lost in the urine, leading to a deficiency in the blood 2.
- The severity of antithrombin loss can vary depending on the underlying cause of nephrotic syndrome and the level of proteinuria 3.
Clinical Implications
- The loss of antithrombin in nephrotic syndrome can increase the risk of thromboembolic complications, including deep venous thrombosis, renal vein thrombosis, and pulmonary embolism 3, 5.
- Patients with nephrotic syndrome and low antithrombin levels may require prophylactic anticoagulation to prevent thromboembolic events 3, 5.
- Rivaroxaban, a direct oral anticoagulant, has been shown to be effective and safe in patients with nephrotic syndrome and low antithrombin levels 5, 4.