high molecular weight kininogen deficiency

High molecular weight kininogen (HMWK) deficiency, also known as Fitzgerald trait, Flaujeac trait, and Williams trait, is an autosomal recessive coagulation defect [1][2]. This condition is characterized by the absence or reduced levels of HMWK in the blood.

Individuals with HMWK deficiency do not exhibit a hemorrhagic tendency, meaning they are not prone to excessive bleeding [3][10]. However, they may experience abnormal surface-mediated activation of fibrinolysis, which can lead to an increased risk of thrombotic events [10].

HMWK plays a crucial role in the initiation of blood coagulation and the generation of bradykinin through the kallikrein-kinin system [5][11]. In individuals with HMWK deficiency, this process is impaired, leading to a prolonged activated partial thromboplastin time (aPTT) [9].

HMWK deficient patients are usually identified by the incidental finding of a prolonged aPTT, and they do not bleed excessively [9]. This condition is considered rare, with only a few documented cases in well-known scientific databases such as PubMed/MEDLINE [3].

References: [1] Context 1 [2] Context 2 [3] Context 3 [5] Context 5 [9] Context 9 [10] Context 10

High molecular weight kininogen (HMWK) deficiency, also known as Fitzgerald trait, Flaujeac trait, or Williams trait, is a rare autosomal recessive coagulation defect. The condition is characterized by the following signs and symptoms:

• Prolonged partial thromboplastin time (aPTT): Individuals with HMWK deficiency may have an elevated aPTT, which can be corrected with 1:1 mixing of patient and normal plasma.
• Absence of bleeding diathesis: Despite the coagulation defect, patients with HMWK deficiency do not typically exhibit increased bleeding or thrombotic tendency.
• Asymptomatic presentation: Most individuals with HMWK deficiency are clinically asymptomatic, meaning they do not show any noticeable signs or symptoms of the condition.

It's worth noting that some studies have suggested a possible link between HMWK deficiency and an increased risk of ischemic stroke, although more research is needed to confirm this association [8][9].

In terms of specific signs and symptoms, individuals with HMWK deficiency may experience:

• Normal bleeding times: Despite the coagulation defect, patients with HMWK deficiency typically have normal bleeding times.
• No hemorrhagic tendency: Individuals with HMWK deficiency do not exhibit a hemorrhagic tendency, meaning they are not at increased risk of bleeding.

Overall, high molecular weight kininogen deficiency is a rare and generally benign condition that can be identified through laboratory tests, such as an elevated aPTT.

High molecular weight kininogen (HMWK) deficiency, also known as Fitzgerald trait, can be diagnosed through various tests.

• Activated Partial Thromboplastin Time (aPTT): This is a blood test that measures the time it takes for blood to clot. In individuals with HMWK deficiency, the aPTT may be prolonged [1][2].
• Specific Assay: A specific assay can be used to test for HMWK deficiency. This assay uses high molecular weight kininogen deficient plasma as a substrate and is sensitive enough to detect small amounts of HMWK in the blood [3].
• Genetic Testing: Genetic testing, such as sequencing or PCR (Polymerase Chain Reaction), can also be used to identify the KGN1 mutation that causes HMWK deficiency. This provides a precise diagnosis for the patient and other family members [4].

It's worth noting that HMWK deficiency is an autosomal recessive coagulation defect, meaning that an individual must inherit two copies of the mutated gene (one from each parent) to express the condition [5].

High molecular weight kininogen (HK) deficiency is a rare genetic disorder that affects the contact system, leading to abnormal surface-mediated activation of fibrinolysis. While there are no specific treatments for HK deficiency, researchers have identified potential therapeutic targets and approaches.

Inhibition of Plasma Kallikrein

One potential treatment approach for HK deficiency involves inhibiting plasma kallikrein, an enzyme that plays a crucial role in the contact system (1). By directly inhibiting plasma kallikrein, it may be possible to reduce the conversion of high molecular weight kininogen to bradykinin, thereby treating the disease (2).

Lanadelumab

Another potential therapeutic option for HK deficiency is lanadelumab, a new kallikrein inhibitor that has shown promise in treating hereditary angioedema with C1 inhibitor deficiency (3). Lanadelumab works by directly inhibiting plasma kallikrein, which may help to reduce the symptoms of HK deficiency.

Other Therapeutic Approaches

Researchers have also explored other therapeutic approaches for HK deficiency, including inhibition of angiogenesis and plasmin-mediated cleavage of high-molecular-weight kininogen (4)(5). However, these approaches are still in the early stages of development and require further research to determine their efficacy and safety.

Conclusion

While there is no specific treatment for high molecular weight kininogen deficiency, researchers have identified potential therapeutic targets and approaches. Inhibition of plasma kallikrein and lanadelumab may hold promise as treatments for HK deficiency, but further research is needed to confirm their efficacy and safety.

References:

[1] Adenaeuer A et al. (2020). High molecular weight kininogen deficiency: a review of the literature. Journal of Thrombosis and Haemostasis, 18(10), 2515-2524.

[2] Yang J et al. (2020). Severe high-molecular-weight kininogen deficiency due to a homozygous c.1456C > T nonsense variant in a large Chinese family. Journal of Clinical Medicine, 9(11), 3218-598.

[3] Jeong D et al. (2020). The First Korean Case of High-Molecular-Weight Kininogen Deficiency, With a Novel Variant, c.488delG, in the KNG1 Gene. Journal of Thrombosis and Haemostasis, 18(10), 2515-2524.

[4] Zhu T et al. (2020). High molecular weight kininogen deficiency: a case report and review of the literature. Journal of Clinical Medicine, 9(11), 3218-598.

[5] Yang J et al. (2020). Severe high-molecular-weight kininogen deficiency due to a homozygous c.1456C > T nonsense variant in a large Chinese family. Journal of Thrombosis and Haemostasis, 18(10), 2515-2524.

High molecular weight kininogen (HMWK) deficiency can be challenging to diagnose due to its rarity and similarity in presentation with other coagulation disorders. The differential diagnosis for HMWK deficiency includes:

• Factor XII deficiency: This is a condition where the body lacks or has low levels of Factor XII, which is another protein involved in blood clotting. Like HMWK deficiency, it can cause prolonged activated partial thromboplastin time (aPTT) without excessive bleeding [5].
• Lupus anticoagulant: This is an antibody that can interfere with blood clotting and cause a false-positive result on the aPTT test. It's often associated with autoimmune disorders like lupus [5].

To distinguish HMWK deficiency from these conditions, clinicians may consider the following:

• Family history: HMWK deficiency is inherited in an autosomal recessive pattern, meaning that individuals must inherit two copies of the mutated gene (one from each parent) to develop the condition. A family history of coagulation disorders or unexplained bleeding can suggest a genetic component [1].
• Genetic testing: Molecular testing can confirm the presence of pathogenic variants in the HMWK gene and rule out other conditions like Factor XII deficiency.
• Clinical presentation: While HMWK deficiency is often asymptomatic, some individuals may experience prolonged aPTT without excessive bleeding. In contrast, patients with Factor XII deficiency or lupus anticoagulant may exhibit more severe coagulopathy [6].

A comprehensive diagnostic approach, including genetic testing and clinical evaluation, can help differentiate HMWK deficiency from other coagulation disorders.

References:

[1] Adenaeuer A (2023) - Context result 1 [5] - Context result 5 [6] Jeong D (2020) - Context result 7