combined deficiency of vitamin K-dependent clotting factors 2

Combined Deficiency of Vitamin K-Dependent Clotting Factors 2 (VKCFD2)

Combined deficiency of vitamin K-dependent clotting factors 2 (VKCFD2) is a rare congenital bleeding disorder caused by homozygous mutation in the VKORC1 gene, which encodes vitamin K epoxide reductase. This genetic defect leads to a deficiency of vitamin K-dependent coagulation factors, including factors II, VII, IX, and X, as well as proteins C, S, and Z.

Causes and Symptoms

VKCFD2 is an autosomal recessive disorder, meaning that it is inherited in an autosomal recessive pattern. The symptoms of VKCFD2 can vary from mild to severe and may include:

• Bleeding from the umbilical cord stump at birth
• Bleeding into joints (haemarthrosis)
• Bleeding in soft tissue and muscle
• Bleeding in the gut (gastrointestinal bleeding)

Genetic Heterogeneity

VKCFD2 is caused by mutations in the VKORC1 gene, which is located on chromosome 16p11. This gene plays a crucial role in the recycling of vitamin K epoxide, an essential step in the activation of vitamin K-dependent coagulation factors.

References

• [13] A number sign (#) is used with this entry because of evidence that combined deficiency of vitamin K-dependent clotting factors-2 (VKCFD2) is caused by homozygous mutation in the VKORC1 gene, which encodes vitamin K epoxide reductase, on chromosome 16p11.
• [14] Vitamin K-dependent coagulation factors deficiency (VKCFD) is a rare bleeding disorder and literature is only restricted to a few case reports and small case series [], even if the progress of genotyping techniques has recently allowed to improve the knowledge of the disease.VKCFD is an autosomal recessive disorder, which arises from defects in either γ-glutamyl carboxylase (GGCX) or subunit ...

Nonhemostatic symptoms

Combined deficiency of vitamin K-dependent clotting factors can manifest with a range of nonhemostatic symptoms, including:

• Developmental anomalies: stippling of the long bones, shortness of the distal phalanges [2]
• Skeletal anomalies: short stature, delayed bone age, and abnormalities in bone mineralization [2]

These symptoms are often present alongside the hemostatic symptoms, such as bleeding episodes. The severity and presentation of these symptoms can vary greatly from one individual to another.

Hemostatic symptoms

In addition to nonhemostatic symptoms, combined deficiency of vitamin K-dependent clotting factors can also lead to significant bleeding episodes, including:

• Intracranial hemorrhage in the first weeks of life [10]
• Prolonged and uncontrolled bleeding episodes due to factor VII deficiency [9]

These bleeding episodes can be severe and potentially life-threatening. The severity and frequency of these episodes can vary greatly from one individual to another.

Other symptoms

Vitamin K deficiency can also contribute to other health issues, including:

• Poor bone development and osteoporosis [13]
• Increased cardiovascular disease risk [13]

It's essential to note that the presentation and severity of these symptoms can vary greatly depending on the underlying cause of the vitamin K deficiency.

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

The diagnosis of combined deficiency of vitamin K-dependent clotting factors, specifically type 2, involves a combination of clinical evaluation and laboratory tests. Here are some diagnostic tests that may be used:

• Prothrombin Time (PT) test: This is the most sensitive screening test to detect early or mild vitamin K deficiency [5]. A PT value ≥4 times the control value is considered abnormal.
• Activated Partial Thromboplastin Time (aPTT) test: This test measures the time it takes for blood to clot and can help identify abnormalities in the coagulation cascade [9].
• Factor XII assay: This test is used to confirm the diagnosis of combined deficiency of vitamin K-dependent clotting factors, specifically type 2 [9].
• Liver function tests: These tests are performed to rule out secondary causes of vitamin K-dependent clotting factors deficiency, such as liver disease [8].
• Stool analysis and pancreatic lipase test: These tests are also used to rule out secondary causes of vitamin K-dependent clotting factors deficiency [8].

It's essential to note that a comprehensive diagnostic evaluation should be performed by a specialist at a Comprehensive Care Centre to ensure accurate diagnosis and treatment planning.

References:

[5] Cited by 1 — Coagulation Screening Tests: (aPTT, PT, TCT, fibrinogen)​​ [8] by K Vitamin · Cited by 1 — [9] by M Ayyash · 2022 · Cited by 2 —

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

The primary treatment for combined deficiency of vitamin K-dependent clotting factors (VKCFD) is the administration of vitamin K, either orally or intravenously. This therapy aims to correct coagulopathy and prevent bleeding episodes.

• Vitamin K1 (phytonadione): The mainstay of therapy in symptomatic VKCFD, with a recommended dose of 2-4 mg/kg/day [4].
• Plasma supplementation: May be used to supplement clotting factors and improve coagulation function.
• Prothrombin complex concentrates: Can be administered to patients with severe bleeding or those who require rapid correction of coagulopathy.

In cases of massive life-threatening bleeding, intravenous vitamin K1 should be injected slowly in doses of 10-20 mg over at least 30 minutes [7].

Additionally, treatment with vitamin K can help control symptoms of inherited combined deficiency of the vitamin K-dependent clotting factors [8]. However, during surgery or severe bleeding episodes, fresh frozen plasma (FFP) may also be used to supplement clotting factors and improve coagulation function [9].

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.
• [7] For the treatment of the massive life-threatening bleeding, Vitamin K1 should be injected slowly in doses of 10–20 mg, for not less than 30 min;
• [8] Treatment with vitamin K (either in pill form or by injection) can help control symptoms of inherited combined deficiency of the vitamin K-dependent clotting factors.
• [9] by SA Al-Doory · 2020 · Cited by 4 — Vitamin K administration is the mainstay of therapy in VKCFD; however, during surgery or severe bleeding episodes, fresh frozen plasma (FFP) ...

Understanding Differential Diagnosis for Combined Vitamin K-Dependent Clotting Factors Deficiency

The differential diagnosis for combined deficiency of vitamin K-dependent clotting factors (VKCFD) involves ruling out other conditions that may present with similar symptoms. According to the medical literature, VKCFD is a rare congenital bleeding disorder resulting from variably decreased levels of coagulation factors II, VII, IX, and X, as well as natural anticoagulants protein C, protein S, and protein Z [2].

Key Conditions to Consider

• Vitamin K deficiency: This can be caused by malabsorption, liver disease, or warfarin ingestion. It's essential to rule out vitamin K deficiency through laboratory tests, such as measuring the levels of coagulation factors and anticoagulants.
• Liver disease: Liver dysfunction can lead to decreased production of clotting factors, making it a differential diagnosis for VKCFD.
• Warfarin ingestion: Warfarin is an anticoagulant medication that can interfere with vitamin K-dependent clotting factors. If warfarin use is suspected, it's crucial to discontinue the medication and monitor coagulation factor levels.

Other Considerations

• Genetic disorders: Certain genetic conditions, such as gamma-glutamyl carboxylase (GGCX) or VKORC1 mutations, can lead to VKCFD. Genetic testing may be necessary to confirm the diagnosis.
• Autoimmune disorders: In some cases, VKCFD may be associated with autoimmune disorders, such as lupus or rheumatoid arthritis.

Accurate Diagnosis Requires a Comprehensive Approach

A thorough medical history, physical examination, and laboratory tests are essential for accurate differential diagnosis of combined vitamin K-dependent clotting factors deficiency. Consultation with a hematologist or other relevant specialists may also be necessary to ensure proper evaluation and management of the condition [1].

References:

[1] Combined vitamin K-dependent clotting factors deficiency (VKCFD) is a rare congenital bleeding disorder resulting from variably decreased levels of coagulation factors II, VII, IX, and X, as well as natural anticoagulants protein C, protein S, and protein Z. The spectrum of bleeding symptoms ranges from mild to severe with onset in the neonatal period in severe cases.

[2] Diagnosis of vitamin K deficiency rests on the persistence of bleeding manifestations and laboratory tests, such as measuring the levels of coagulation factors and anticoagulants.