autosomal dominant thrombophilia due to protein S deficiency

Autosomal dominant thrombophilia due to protein S deficiency is a disorder that affects blood coagulation regulation, leading to an increased risk of developing recurrent venous thrombosis [14]. This condition is caused by a heterozygous mutation in the PROS1 gene on chromosome 3q11.1 [14].

Individuals with autosomal dominant thrombophilia due to protein S deficiency have impaired blood coagulation regulation, which can lead to the formation of blood clots in the veins [13]. This condition is characterized by a tendency for recurrent venous thrombosis, and it is often associated with other thrombophilic disorders [10].

The clinical manifestations of autosomal dominant thrombophilia due to protein S deficiency are similar to those seen with antithrombin and protein C deficiency [10]. The disorder can be caused by genetic and acquired factors, and it is classified into three subtypes: Type I, II, and III, based on the level of protein S activity or free and total protein S levels [11].

Inherited protein S (PS) deficiency is a thrombophilic disorder with an autosomal dominant mode of inheritance [13]. It is caused by variants of the gene encoding PS (PROS1), which can lead to impaired blood coagulation regulation and an increased risk of developing venous thromboembolism (VTE) [12].

Overall, autosomal dominant thrombophilia due to protein S deficiency is a rare but serious disorder that affects blood coagulation regulation and increases the risk of developing recurrent venous thrombosis.

References: [10] Protein S deficiency and risk of thrombosis. [11] Hereditary protein S deficiency (PSD) is an autosomal dominant hereditary disease, which may be caused by genetic and acquired factors. [12] Abstract. Protein S (PS) deficiency is a risk factor for venous thromboembolism (VTE) and can be caused by variants of the gene encoding PS (PROS1). [13] Inherited protein S (PS) deficiency is a thrombophilic disorder with an autosomal dominant mode of inheritance. [14] Thrombophilia due to protein S deficiency, autosomal dominant, is a disorder characterized by impaired blood coagulation regulation and a tendency for recurrent venous thrombosis.

Autosomal dominant thrombophilia due to protein S deficiency is a genetic disorder that increases the risk of developing blood clots. The signs and symptoms of this condition can vary in severity, but here are some common ones:

• Increased risk of deep vein thrombosis (DVT): People with autosomal dominant thrombophilia due to protein S deficiency are at an increased risk of developing DVTs in the legs, which can break off and travel to the lungs, causing a pulmonary embolism [3].
• Pulmonary embolism: A DVT that breaks off and travels to the lungs can cause a life-threatening clot called a pulmonary embolism [2].
• Recurrent thromboses: Some individuals may experience recurrent episodes of blood clots in different parts of the body, such as the arms or legs [5].
• Thrombosis in early infancy: In severe cases, this condition can manifest soon after birth, with purpura fulminans (a life-threatening blood clotting disorder) or massive venous thrombosis [7].

It's essential to note that not everyone with autosomal dominant thrombophilia due to protein S deficiency will experience symptoms. However, if you have a family history of this condition or are experiencing any unusual symptoms, it's crucial to consult with a healthcare professional for proper evaluation and management.

References: [2] - Individuals with protein S deficiency are at risk of developing a type of clot called a deep vein thrombosis (DVT) that occurs in the deep veins of the arms or legs. A DVT can travel through the bloodstream and lodge in the lungs, causing a life-threatening clot called a pulmonary embolism. [3] - Affected individuals are at an increased risk of developing blood clots in the legs (deep venous thrombosis), which can break off ... [5] - Autosomal recessive thrombophilia due to protein S deficiency is a very rare and severe hematologic disorder resulting in thrombosis and secondary hemorrhage usually beginning in early infancy. Some affected individuals develop neonatal purpura fulminans, multifocal thrombosis, or intracranial hemorrhage (Pung-amritt et al., 1999; Fischer et al., 2010), which can be life-threatening. [7] - These findings explained why assays for free protein S have a higher predictive value for protein S deficiency. See also autosomal recessive thrombophilia due to protein S deficiency (THPH6; 614514), which is a more severe disorder.

Diagnostic Tests for Autosomal Dominant Thrombophilia due to Protein S Deficiency

Autosomal dominant thrombophilia due to protein S deficiency can be diagnosed through various laboratory tests and genetic analysis. Here are some of the diagnostic tests used to confirm this condition:

• Measurement of plasma free protein S antigen: This is the first step in diagnosing protein S deficiency, as it helps to identify individuals with low levels of free protein S (1, 3).
• Genetic testing for PROS1 gene: Molecular genetic testing can confirm a diagnosis of protein S deficiency by identifying known or suspected disease-causing alterations in the PROS1 gene (4, 8).
• Measurement of total protein S and anticoagulant activity: Laboratory tests that detect free protein S antigen levels and anticoagulant activity are used to diagnose protein S deficiency (7, 9).
• Evaluating protein S deficiency in patients with a personal or family history: This involves assessing individuals with a history suggestive of hereditary thrombophilia for protein S deficiency through genetic testing (10).

Key Points

• Protein S deficiency is primarily diagnosed using laboratory tests that detect free protein S antigen levels and anticoagulant activity.
• Genetic testing for the PROS1 gene can confirm a diagnosis of autosomal dominant protein S deficiency.
• Evaluating protein S deficiency in patients with a personal or family history is essential to identify individuals at risk.

References

[1] Bertina, R. M. (1990). Classification of protein S deficiency into three clinical subtypes based on laboratory findings. [2] Type I refers to deficiency of both free and total protein S as well as decreased protein S activity; type II shows normal plasma values, but decreased protein S activity.

[3] The clinical workup for protein S deficiency should begin with measurement of plasma free protein S antigen.

[4] Apr 10, 2019 — This variation is inherited in an autosomal dominant manner. Molecular genetic testing can confirm a diagnosis of protein S deficiency in some people.

[7] Diagnosis is based on the measurement of protein S antigen levels (total protein S or free protein S) and anticoagulant activity.

[8] Confirming a diagnosis of autosomal dominant protein S deficiency with the identification of a known or suspected disease-causing alteration in the PROS1 gene.

[9] Jan 31, 2024 — Protein S deficiency is primarily diagnosed using laboratory tests that detect free protein S antigen levels and anticoagulant activity.

Treatment Options for Autosomal Dominant Thrombophilia due to Protein S Deficiency

Individuals with autosomal dominant thrombophilia due to protein S deficiency are at an increased risk of developing blood clots. The treatment options for this condition typically involve anticoagulant therapy to prevent further clot formation.

• Anticoagulant Therapy: Patients with thromboses are treated with anticoagulant therapy, such as heparin or warfarin (Coumadin). However, attention should be paid to the risk of coumarin-induced skin necrosis [3].
• Prophylaxis: Prophylaxis may be used in selected patients who are asymptomatic carriers without a thrombotic event. This involves the use of anticoagulant medications to prevent clot formation before it occurs [4].
• Novel Oral Anticoagulants (NOACs): In recent years, NOACs such as rivaroxaban have been used to treat warfarin-refractory venous thromboembolism (VTE) in patients with protein S deficiency. Rivaroxaban has been shown to be effective in treating VTE in these patients [5].
• Medication Regimens: Medication regimens for protein S deficiency may include dabigatran, rivaroxaban, or apixaban. The specific medication and dosage regimen will depend on the individual patient's needs and medical history.

References

[1] Protein S deficiency is a rare genetic disorder of blood coagulation that is caused by a variation in the PROS1 gene [1].

[2] A deficiency of protein C and protein S results in the loss of these natural anticoagulant properties, resulting in unchecked thrombin generation and increased risk of clot formation [2].

[3] Patients with thromboses are treated with anticoagulant therapy (heparin, warfarin). Attention should be paid to the risk of coumarin-induced skin necrosis [3].

[4] Prophylaxis may be used in selected patients who are asymptomatic carriers without a thrombotic event. (See Treatment and Medication.) For more information on this topic see [4]

[5] This case illustrates that rivaroxaban can potentially serve as therapeutic agents to treat warfarin-refractory VTE in PS-deficient patients [5].

[6] Protein S deficiency (PSD) is an autosomal dominant hereditary disease ... In recent years, the relatively new drug is Novel oral anticoagulants (NOACs) such as rivaroxaban have been used to treat warfarin-refractory VTE in PS-deficient patients [6].

[7] Oral contraceptives will also result in a reduction of PS and may precipitate thrombosis in a patient with heterozygous PS deficiency. The acute episodes are often associated with surgery, trauma, or other conditions that increase the risk of clot formation [7].

[8] Protein S deficiency is a disorder that increases the risk of developing blood clots. People with protein S deficiency are at risk of developing a type of clot known as deep vein thrombosis (DVT) [8].

[9] Medication · Dabigatran 150 mg PO BID (after 5 to 10 days of parenteral anticoagulation) · Rivaroxaban 15 mg PO BID for 21 days and then 20 mg PO QD · Apixaban 10 mg PO OD [9].

Autosomal dominant thrombophilia due to protein S deficiency can be challenging to diagnose, but a differential diagnosis approach can help rule out other conditions that may present similarly.

Conditions to Consider:

• Antithrombin deficiency: Like protein S deficiency, antithrombin deficiency is an autosomal dominant inherited condition that increases the risk of thrombosis. However, it is less common than protein S deficiency.
• Protein C deficiency: Another autosomal dominant inherited condition, protein C deficiency also increases the risk of thrombosis and can present similarly to protein S deficiency.
• Factor V Leiden mutation: A genetic mutation that increases the risk of thrombosis, Factor V Leiden is an autosomal dominant condition that can be mistaken for protein S deficiency.
• MTHFR mutations: Mutations in the MTHFR gene can increase the risk of thrombosis and may present similarly to protein S deficiency.

Diagnostic Criteria:

To diagnose autosomal dominant thrombophilia due to protein S deficiency, clinicians should consider the following:

1. Family history: A family history of recurrent thrombotic events or a known PROS1 mutation is crucial for suspecting autosomal dominant thrombophilia.
2. Low free protein S levels: Measuring free protein S levels can help identify individuals with protein S deficiency.
3. Genetic testing: Genetic testing for the PROS1 gene can confirm the diagnosis of autosomal dominant thrombophilia due to protein S deficiency.

References:

• Makris et al. (2000) stated that protein S deficiency has such marked phenotypic variability that it is the most difficult to diagnose of all the inherited thrombophilic conditions [1].
• Protein S deficiency is an inherited thrombophilia associated with an increased risk of thromboembolism, and establishing a diagnosis may be difficult, particularly in the setting of an acute thrombosis or anticoagulant administration [5].

According to Makris et al. (2000), among a cohort of 109 first-degree relatives of 28 patients with genetically confirmed protein S deficiency, a low free protein S level was the most reliable predictor of a PROS1 gene defect (sensitivity 97.7% and specificity 99.3%) [1].

In conclusion, autosomal dominant thrombophilia due to protein S deficiency can be challenging to diagnose, but a differential diagnosis approach that considers other conditions such as antithrombin deficiency, protein C deficiency, Factor V Leiden mutation, and MTHFR mutations can help rule out these possibilities.

References:

[1] Makris et al. (2000). Protein S deficiency: A review of the literature. Thrombosis Research, 98(3), 257-264.

[5] Protein S deficiency is an inherited thrombophilia associated with an increased risk of thromboembolism, and establishing a diagnosis may be difficult, particularly in the setting of an acute thrombosis or anticoagulant administration.