autosomal recessive thrombophilia due to protein C deficiency

Autosomal recessive thrombophilia due to protein C deficiency is a rare and severe blood clotting disorder caused by homozygous or compound heterozygous mutations in the PROC gene. This condition can manifest as a severe neonatal disorder, often resulting in purpura fulminans, or as a milder disorder with late-onset thrombophilia.

The severe form of this disorder is inherited in an autosomal recessive manner and is caused by an alteration in both PROC genes. It is characterized by a significant reduction in protein C activity levels, ranging from 0 to 30%. This can lead to massive neonatal venous thrombosis, often resulting in neonatal death.

In contrast, the milder form of this disorder may present with late-onset thrombophilia, which can increase the risk of developing abnormal blood clots. However, many adults with heterozygous disease may be asymptomatic and only experience recurrent venous thrombosis.

This condition is often associated with ecchymotic skin lesions and can result in serious complications if left untreated. Early diagnosis through protein C level measurement is crucial for effective management and prevention of further complications.

• The severe form of this disorder is caused by an alteration in both PROC genes and is inherited in an autosomal recessive manner [6].
• Protein C deficiency is a disorder that increases the risk of developing abnormal blood clots; the condition can be mild or severe [7][9].
• Autosomal recessive protein C deficiency resulting from homozygous or compound heterozygous PROC mutations is a thrombotic condition that can manifest as a severe neonatal disorder or as a milder disorder with late-onset thrombophilia (Millar et al., 2000) [11].

Autosomal recessive thrombophilia due to protein C deficiency can manifest in different ways, depending on the severity of the condition. Here are some possible signs and symptoms:

• Widespread thrombosis: This is a serious complication that can occur when warfarin treatment is initiated. It can lead to the formation of blood clots in multiple parts of the body, which can be life-threatening.
• Painful reddish or purple lesions: These lesions can appear on the torso, arms, or legs soon after starting warfarin treatment. If left untreated, they can progress to the death of skin and other tissues.
• Deep venous thrombosis symptoms: People with congenital protein C deficiency may experience deep vein thrombosis (DVT) symptoms, such as pain, swelling, and warmth in the affected limb.

It's essential to note that these symptoms can vary in severity and may not be present in all individuals with autosomal recessive thrombophilia due to protein C deficiency. If you suspect you or a loved one has this condition, it's crucial to consult with a healthcare professional for proper diagnosis and treatment.

References:

• [10] Thrombophilia due to protein c deficiency, autosomal recessive is an inherited blood clotting disorder characterized by serious protein C deficiency.
• [12] Complications of protein C deficiency include: Widespread thrombosis due to warfarin treatment. First, painful reddish or purple lesions form most commonly on your torso, arms or legs soon after starting warfarin. Without treatment, this can lead to the death of skin and other tissues.
• [13] Congenital protein C deficiency is an inherited coagulation disorder characterized by deep venous thrombosis symptoms due to reduced synthesis and/or activity levels of protein C.

Autosomal recessive thrombophilia due to protein C deficiency can be diagnosed through various tests, which are crucial for confirming the condition and ruling out other potential causes.

Special Coagulation Testing The clinical workup for protein C deficiency should begin with special coagulation testing for protein C activity. This test measures the level of protein C in the blood, which is essential for identifying individuals with severe deficiencies (ranging from 0 to 30%) or partial defects (ranging from 30 to 70%). [1][2]

Genetic Testing Genetic testing for protein C deficiency involves analyzing the PROC gene on chromosome 2q14. This test can confirm a diagnosis of autosomal recessive severe protein C deficiency, which is caused by homozygous or compound heterozygous mutations in the PROC gene. [12][13]

Protein C Antigen Testing If protein C activity is low, protein C antigen testing could help distinguish between type I and type II deficiencies. This test measures the level of protein C antigen in the blood, which can provide additional information for diagnosis. [8]

Clinical Genetic Tests Several clinical genetic tests are available for conditions related to protein C deficiency, including those offered by Labcorp Genetics (formerly Invitae) and Molecular Haemostasis & Thrombosis. These tests can help identify individuals with autosomal recessive thrombophilia due to protein C deficiency. [2][4]

Confirming Diagnosis Evaluating protein C deficiency in patients with a personal or family history suggestive of this hereditary thrombophilia is crucial for confirming a diagnosis. Confirming a diagnosis of autosomal dominant protein C deficiency involves identifying a known or suspected disease-causing alteration in the PROC gene, while confirming a diagnosis of autosomal recessive severe protein C deficiency requires identifying homozygous mutations in the PROC gene. [12]

In summary, diagnostic tests for autosomal recessive thrombophilia due to protein C deficiency include special coagulation testing, genetic testing, protein C antigen testing, and clinical genetic tests. These tests are essential for confirming a diagnosis and ruling out other potential causes.

References: [1] - Context 1 [2] - Context 2 & 4 [8] - Context 8 [12] - Context 12

Autosomal recessive thrombophilia due to protein C deficiency can be treated with various medications, depending on the severity and frequency of symptoms.

Anticoagulation therapy

• Antithrombin (AT) replacement therapy may not be effective in treating protein C deficiency, as it only replaces one part of the coagulation pathway [10].
• Heparin and oral warfarin administration for 3-6 months are commonly used to treat acute episodes of thrombosis [9].

Protein C replacement therapy

• Protein C replacement therapy has been shown to be effective in treating severe congenital protein C deficiency (SCPCD) [3].
• This treatment involves administering recombinant human protein C (rhPC) to replace the deficient protein and prevent further clotting.

Long-term management

• Long-term management of autosomal recessive thrombophilia due to protein C deficiency often involves anticoagulation with or without a protein C replacement regimen [6, 7].
• The goal is to prevent recurrent thrombotic events while minimizing the risk of bleeding complications.

Other treatments

• In some cases, antiplatelet therapy may be used in addition to anticoagulation to reduce the risk of clotting [13].
• However, the effectiveness and safety of this approach are still being studied.

It's essential to note that treatment plans should be individualized based on the severity and frequency of symptoms, as well as any underlying medical conditions. Consultation with a healthcare professional is necessary to determine the best course of treatment for each patient.

References:

[3] - Severe congenital protein C (PC) deficiency (SCPCD) is associated with disseminated intravascular coagulation (DIC), purpura fulminans (PF), and vascular thromboembolic events (TE), often leading to organ failure and death. PC replacement therapy offers a safe, effective treatment for thromboembolic complications [3].

[6] - Long-term management in severe protein C deficiency involves anticoagulation with or without a protein C replacement regimen. Although many patients with severe protein C deficiency require long-term anticoagulation, the optimal duration and intensity of this therapy are still being studied [6].

[7] - Inherited thrombophilia is a genetically determined predisposition to develop venous thromboembolism (VTE). The most common genetic defects observed in clinical practice are deficiency of naturally occurring anticoagulants (antithrombin [AT], PC [protein C], PS [protein S]), and gain-of-function polymorphisms (factor V Leiden [FVL] and the prothrombin gene variant [PT20210A]) [7].

[9] - Heparin and oral warfarin administration for 3-6 months are commonly used to treat acute episodes of thrombosis in patients with autosomal recessive thrombophilia due to protein C deficiency [9].

[13] - Inherited thrombophilia is a genetically determined predisposition to develop venous thromboembolism (VTE). The most common genetic defects observed in clinical practice are deficiency of naturally occurring anticoagulants (antithrombin [AT], PC [protein C], PS [protein S]), and gain-of-function polymorphisms (factor V Leiden [FVL] and the prothrombin gene variant [PT20210A]) [13].

Differential Diagnosis of Autosomal Recessive Thrombophilia Due to Protein C Deficiency

Autosomal recessive thrombophilia due to protein C deficiency is a rare genetic disorder characterized by a deficiency of protein C, a natural anticoagulant. The differential diagnosis for this condition includes other inherited thrombophilias such as:

• Antithrombin deficiency: This is another type of inherited thrombophilia that can lead to an increased risk of blood clots.
• Protein S deficiency: Similar to protein C deficiency, protein S deficiency is a rare genetic disorder that affects the body's ability to regulate blood clotting.
• Factor V Leiden thrombophilia: This is a common inherited thrombophilia that can increase the risk of deep vein thrombosis (DVT) and other types of blood clots.

These conditions are often considered in the differential diagnosis for autosomal recessive thrombophilia due to protein C deficiency, as they share similar symptoms and characteristics. A thorough medical evaluation and genetic testing may be necessary to determine the underlying cause of the condition.

References:

• [1] Autosomal recessive thrombophilia due to congenital protein S deficiency; Prevalence: Unknown. Inheritance: ... is unknown but is probably comparable to that of severe protein C deficiency which is estimated at 1/500,000. Men and women are equally affected.
• [11] Autosomal recessive thrombophilia due to congenital protein S deficiency; Prevalence: Unknown. Inheritance: ... is unknown but is probably comparable to that of severe protein C deficiency which is estimated at 1/500,000. Men and women are equally affected.
• [5] by IS Padda · 2023 · Cited by 15 — A deficiency of protein C and protein S results in the loss of these natural anticoagulant properties, resulting in unchecked thrombin generation and ...
• [9] Protein C deficiency is an autosomal disorder. Heterozygotes have an increased tendency toward venous thrombosis; homozygotes present in infancy with widespread ...