combined deficiency of vitamin K-dependent clotting factors 1

Combined Deficiency of Vitamin K-Dependent Clotting Factors 1 (VKCFD1)

Combined deficiency of vitamin K-dependent clotting factors 1 (VKCFD1) is a rare congenital bleeding disorder caused by homozygous or compound heterozygous mutation in the gene encoding gamma-glutamyl carboxylase (GGCX; 137167) on chromosome 2p11 [5]. This genetic defect leads to a deficiency of clotting factors II, VII, IX, and X, as well as natural anticoagulants protein C, protein S, and protein Z.

Causes and Symptoms

VKCFD1 is an autosomal recessive disorder, meaning that it is inherited in an autosomal recessive pattern [10]. The symptoms of VKCFD1 can range from mild to severe and include episodes of intracranial hemorrhage in the first weeks of life, sometimes leading to a fatal outcome [3][10].

Genetic Heterogeneity

VKCFD1 is caused by mutations in the GGCX gene, which encodes gamma-glutamyl carboxylase. This enzyme plays a crucial role in the post-translational modification of vitamin K-dependent clotting factors [12]. The genetic heterogeneity of VKCFD1 means that different mutations in the GGCX gene can lead to this condition.

References

[5] Ayyash, M. (2022). Hereditary combined vitamin K-dependent clotting factor deficiency (VKCFD): a rare autosomal recessive congenital bleeding disorder. [cited by 2]

[10] Napolitano, M., Mariani, G., & Lapecorella, M. (2010). Hereditary combined deficiency of the vitamin K-dependent clotting factors. Orphanet Journal of Rare Diseases, 5(1), 21.

[12] Fregin, V. H., et al. (2002). A novel missense mutation in the GGCX gene causing combined deficiency of vitamin K-dependent clotting factors. Blood Coagulation & Fibrinolysis, 13(6), 531-535.

Common Signs and Symptoms

Individuals with combined deficiency of vitamin K-dependent clotting factors may experience a range of nonhemostatic symptoms, including:

• Developmental and skeletal anomalies (e.g., stippling of the long bones, shortness of the distal phalanges) [1]
• Increased risk of bleeding due to failure of normal fibrin clot formation [3]
• Easy bruising or difficulty stopping bleeding [4]

Clinical Presentation

The clinical presentation of combined vitamin K-dependent clotting factor deficiency (VKCFD) can vary greatly from one individual to another. Some common symptoms include:

• Prolonged, uncontrolled bleeding episodes [9]
• Increased risk of bleeding due to inadequate intake or fat malabsorption [7]

Key Points

• Combined VKCFD is a rare autosomal recessive congenital bleeding disorder [5][6]
• Vitamin K deficiency results from extremely inadequate intake or fat malabsorption [7]
• Risk of bleeding is increased by use of coumarin anticoagulants [7]

Diagnostic Tests for Combined Deficiency of Vitamin K-dependent Clotting Factors

The diagnosis of combined deficiency of vitamin K-dependent clotting factors is made through a series of blood tests that assess the coagulation function of the blood. The following diagnostic tests are commonly used:

• Prothrombin Time (PT) test: This is the most sensitive screening test to detect early or mild vitamin K deficiency [3]. A prolonged PT indicates a problem with the production of clotting factors.
• Activated Partial Thromboplastin Time (aPTT) test: This test measures the time it takes for blood to clot and can help identify problems with the intrinsic coagulation pathway, which is affected in vitamin K-dependent clotting factor deficiency [5].
• Factor XII assay: This test helps confirm the diagnosis of combined deficiency of vitamin K-dependent clotting factors by measuring the level of Factor XII, a protein that plays a crucial role in blood coagulation [9].

In some cases, additional tests may be performed to rule out secondary causes of vitamin K-dependent clotting factor deficiency, such as liver function tests, stool analysis, and pancreatic lipase levels [8]. If possible, direct measurement of vitamin K levels can also be done.

These diagnostic tests are typically performed by a specialist at a Comprehensive Care Centre, and the results should be interpreted in conjunction with clinical features and other laboratory findings to confirm the diagnosis.

Treatment Options for Combined Deficiency of Vitamin K-Dependent Clotting Factors

The treatment for combined deficiency of vitamin K-dependent clotting factors involves correcting the coagulopathy and managing bleeding symptoms. The mainstay of therapy is Vitamin K administration, which can be given orally or intravenously.

• Vitamin K1 (phytonadione): This is the most commonly used form of Vitamin K for treating VKCFD. It is administered at a dose of 2 to 4 mg/kg/day, and it corrects coagulopathy over the course of 12 to 24 hours from initiation of therapy [4].
• Prothrombin Complex Concentrates (PCC): PCCs are also used to treat VKCFD. They contain a mixture of clotting factors II, VII, IX, and X, which can help restore normal coagulation function.
• Plasma Supplementation: In some cases, plasma supplementation may be necessary to provide additional clotting factors and help manage bleeding symptoms.

It's worth noting that the treatment approach may vary depending on the severity of the condition, age of the patient, and other individual factors. A healthcare professional should be consulted for personalized guidance on managing VKCFD.

References:

• [4] Replacement therapy with Vitamin K1 (phytonadione at 2 to 4 mg/kg/day) will correct coagulopathy over the course of 12 to 24 hours from initiation of therapy.
• [9] There are three treatments available for VKCFD. Vitamin K; Prothrombin Complex Concentrates; Plasma supplementation

Differential Diagnosis of Combined Deficiency of Vitamin K-Dependent Clotting Factors

The differential diagnosis of combined deficiency of vitamin K-dependent clotting factors (VKCFD) involves ruling out other conditions that may present with similar symptoms. Some of the key considerations include:

• Vitamin K deficiency: This is a common cause of bleeding disorders, and it's essential to rule out vitamin K deficiency as a cause of VKCFD.
• Warfarin ingestion: Warfarin is an anticoagulant medication that can interfere with vitamin K-dependent clotting factors. If warfarin use is suspected, it should be discontinued before making a diagnosis of VKCFD.
• Malabsorption: Malabsorption of fat-soluble vitamins, including vitamin K, can lead to bleeding disorders.
• Liver disease: Liver disease can impair the production of clotting factors and lead to bleeding disorders.

To differentiate VKCFD from these conditions, the following tests may be performed:

• Prothrombin time (PT) and activated partial thromboplastin time (aPTT): These tests measure the time it takes for blood to clot. In VKCFD, both PT and aPTT are typically prolonged.
• Factor V levels: Measuring factor V levels can help differentiate VKCFD from liver disease, as factor V is not affected by vitamin K deficiency.

References

• [3] Warfarin ingestion must be ruled out before making a diagnosis of VKCFD.
• [6] Factor V levels can help differentiate VKCFD from liver disease.
• [11] Prolonged PT and aPTT are characteristic of VKCFD.