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Deficiencies in the natural anticoagulants antithrombin, protein C and S, due to mutations in the corresponding genes, increase the risk of venous thrombosis by at least two fold.
Deficiencies in the natural anticoagulants antithrombin, protein C and S, due to mutations in the corresponding genes, increase the risk of venous thrombosis by at least two fold.
True (A)
The mutation commonly referred to as the prothrombin gene mutation is F5G1691A.
The mutation commonly referred to as the prothrombin gene mutation is F5G1691A.
False (B)
The mutation F2G20210A is located in the FVL gene.
The mutation F2G20210A is located in the FVL gene.
False (B)
Heritable thrombophilias are genetic conditions that increase the risk of developing blood clots in the veins.
Heritable thrombophilias are genetic conditions that increase the risk of developing blood clots in the veins.
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All heritable thrombophilias cause a greater than twofold increase in the risk of venous thrombosis.
All heritable thrombophilias cause a greater than twofold increase in the risk of venous thrombosis.
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A pulmonary embolism (PE) is always caused by an infection in the lungs.
A pulmonary embolism (PE) is always caused by an infection in the lungs.
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A blood clot can travel through the bloodstream to the lungs and cause a pulmonary embolism.
A blood clot can travel through the bloodstream to the lungs and cause a pulmonary embolism.
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Permanent damage to the lungs can result from a pulmonary embolism.
Permanent damage to the lungs can result from a pulmonary embolism.
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Pulmonary embolism only affects older adults.
Pulmonary embolism only affects older adults.
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A pulmonary embolism involves a blockage in a lung artery.
A pulmonary embolism involves a blockage in a lung artery.
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Hereditary thrombophilia affects the management of patients during the peripartum period.
Hereditary thrombophilia affects the management of patients during the peripartum period.
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The article by Kobayashi et al. was published in 2020.
The article by Kobayashi et al. was published in 2020.
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The Journal of Obstetrics and Gynaecology Research published the findings on hereditary thrombophilia in 47.9 issues.
The Journal of Obstetrics and Gynaecology Research published the findings on hereditary thrombophilia in 47.9 issues.
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Clinical guidance for peripartum management is only relevant for healthy patients.
Clinical guidance for peripartum management is only relevant for healthy patients.
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Kobayashi et al. authored a study focusing solely on postpartum management of thrombophilia.
Kobayashi et al. authored a study focusing solely on postpartum management of thrombophilia.
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Study Notes
Blood Homeostasis and Coagulation
- The human hemostatic system represents a balance between procoagulant (thrombogenic) factors and anticoagulant (fibrinolytic) activity.
- Hypercoagulable states involve increased procoagulant or clotting activity or reduced anticoagulant activity.
- Thrombosis is the formation of a blood clot (thrombus) within a vessel.
- Heritable thrombophilia is an inherited tendency for venous thrombosis (e.g., deep vein thrombosis, DVT).
- Deficiency of natural anticoagulants (antithrombin, protein C, protein S) are inherited risk factors for venous thromboembolism (VTE).
- Factor V Leiden (F5G1691A) and prothrombin gene mutation (F2G20210A) mutations are also linked to increased thrombosis risk.
- There is a gene-environment interaction in heritable thrombophilia. The effect of the genotype on disease risk depends on exposure to environmental factors.
Inhibition of Coagulation
- The coagulation system is regulated by various regulatory systems.
- APC (activated protein C) regulatory system, TFPI (tissue factor pathway inhibitor) regulatory system and AT (antithrombin) regulatory system are crucial mechanisms for inhibiting coagulation.
- Activated protein C, antithrombin, protein S and protein C are important anticoagulant pathways.
- Heparin-like substances regulate coagulation through interaction with vascular endothelial cells.
Factors Affecting AT, PC, and PS Activity
- Decreased production or consumption of antithrombin, protein C, and protein S can occur due to various factors.
- Liver dysfunction (cirrhosis, fulminant hepatitis) and inflammatory conditions can lead to decreased synthesis capacity of these proteins.
- Inflammatory responses, disseminated intravascular coagulation, and sepsis are among various other factors that cause these changes.
- Some drugs, such as long-term heparin use or oral anticoagulants can also affect the production or consumption of these critical anticoagulants.
- Pregnancy can also lead to a decrease in these critical proteins, with a reduction especially pronounced in the early stages.
Heritable Thrombophilias Associated with Venous Thrombosis
- Deficiencies in antithrombin, protein C, and protein S due to genetic mutations increase the likelihood of venous thrombosis.
- Mutations in genes encoding procoagulant factors, such as factor V Leiden (FVL) and prothrombin gene mutation (FII G20210A), are also associated with heightened thrombosis risk.
Heritable Thrombophilias General Investigation
- Screening blood tests (e.g., AT, PC, and PS activity measurement) are utilized to identify potential inherited thrombophilias.
- Genetic tests help confirm diagnoses of potential mutations.
- Individuals with a hereditary tendency for thrombosis often experience earlier onset, more frequent episodes, unusual sites of thrombosis or associated with family history of thrombosis.
Physiologic Alterations Contributing to Thrombosis
- Endothelial cell damage, loss of subendothelial tissues, platelet activation and circulating agonists are significant factors in triggering thrombogenic processes.
- Coagulation proteins play an important role in vascular thrombogenesis.
- Fibrinolysis inhibition can also contribute to an increased risk of developing thrombosis.
- Venous stasis, characterized by slow blood flow in veins (especially in lower limbs), is crucial in venous thrombosis.
Thrombus Formation
- Thrombi consist of fibrin, platelets, and entrapped cells.
- White thrombi, which include platelet aggregates and relatively few leukocytes, are prevalent in arterial thrombosis.
- The predominant components of venous thrombi are enmeshed red blood cells within a fibrin mesh and fewer platelets.
- Arterial thrombi are more common at sites of endothelial damage, often associated with atherosclerosis.
- Venous thrombi frequently occur in the lower limbs, and superficial thrombi are often benign.
- Deep vein thrombosis is more severe.
DVT vs. PE
- Pulmonary embolism is a blockage in a lung artery that can result from a dislodged thrombus from deep veins.
- Embolization of a thrombus in deep veins (DVT) can cause a pulmonary embolism.
- VTE includes both DVT and PE.
- These events may involve different stages and presentations.
Thrombophilia
- Thrombophilia is a clinical term used to describe factors that increase an individual's susceptibility to venous thrombosis.
- It can be used to describe a condition with inherited tendency to have thrombosis.
- Often cases of thrombophilia are asymptomatic and can be diagnosed only in cases of recurrent or unexpected thrombosis.
Classification of Thrombophilic Abnormalities
- Heritable thrombophilia involves deficiencies of natural anticoagulants (AT, PC, and PS) and elevated procoagulant activity.
- Acquired antiphospholipid syndrome and hyperhomocysteinemia and other mixed etiologies are examples of mixed etiology thrombophilia.
- Elevated levels of specific coagulation factors like factor VIII can also lead to increased risk of thrombosis.
PCR Analysis for Factor V Leiden (FVL)
- The Factor V Leiden mutation involves a change (substitution) in a gene resulting in the amino acid sequence being affected.
- PCR analysis confirms the presence of the Factor V Leiden mutation by detecting the genetic change.
- FVL is linked to an increased risk of developing venous thrombosis.
- A decreased or non-functional APC (activated protein C) pathway can result in an increased incidence of VTEs.
Protein C
- Protein C is a vitamin K-dependent protein synthesized by the liver that plays a critical role in the anticoagulant pathway.
- Protein C is activated through binding to thrombomodulin on endothelial cells.
- Activated protein C (aPC) inactivates factors Va and VIIIa, inhibiting the coagulation cascade.
Protein S
- Protein S is a vitamin K-dependent protein that assists in the activation of protein C through forming a complex with protein C.
- Protein S contributes significantly to the regulation of blood coagulation via the protein C activation pathway.
- Deficiency in protein S is linked with elevated risk of thrombosis.
APC Resistance
- APC resistance is a condition where the anticoagulant activity of protein C is reduced/impaired.
- This condition is often associated with mutations in factor V genes (e.g., factor V Leiden).
- A significant risk factor for the development of venous thromboembolism is a factor V gene mutation.
Heritable APC Resistance Not Due to FVL
- This type of resistance is associated with mutations or defects other than FVL.
- Rare mutations in the factor V gene can lead to APC resistance.
- Individuals with these mutations may have a heightened risk of VTE.
Factor V Leiden
- Factor V Leiden is a genetic mutation associated with APC resistance.
- This leads to an increased risk of venous thromboembolism (VTE) and particularly deep vein thrombosis (DVT) .
- Presence of FVL necessitates assessment for other mutations.
Prothrombin G20210A Mutation
- Prothrombin G20210A is a genetic mutation found in the 3' untranslated region of the prothrombin gene.
- This mutation can increase the amount of prothrombin in plasma, which is a procoagulant factor and is a significant risk factor for venous thrombosis.
- The mutation might increase the risk if individuals are experiencing heightened risk factors like estrogen exposure, combined with other factors such as obesity.
Dysfibrinogenemia
- Dysfibrinogenemia is a condition involving defective thrombin binding to fibrin.
- It leads to elevated thrombin levels in the plasma.
- Clinical presentation can include a prolonged thrombin time.
- Potential diagnosis can be determined by discordance between functional and immunological assay results.
Mixed Etiology Thrombophilia: Elevated FVIII Levels
- Elevated levels of factor VIII increase thrombosis risk.
- This elevated factor VIII is an independent risk factor for venous thromboembolism (VTE).
- A high risk of venous and arterial thrombosis is observed in individuals with factor VIII levels above the 90th percentile, particularly in those with non-O blood types.
Thrombophilia Screen: Clinical Assessment
- Personal and family history are crucial to a thrombophilia screen.
- Screening for associated factors (e.g., advancing age, immobility, surgery, hormonal use) should be considered with a thorough clinical assessment.
Thrombophilia Screening: First and Second Line Tests
- A coagulation screen (e.g., APTT, PT, TT), antithrombin (AT) activity, protein C (PC), and protein S (PS) are frequently part of preliminary thrombophilia tests.
- Further tests may involve a modified APC/SR (activated protein C resistance) test, FV Leiden, FII G20210A, antiphospholipid antibodies (anticardiolipin antibodies or Lupus anticoagulant) levels, and if necessary, fibrinogen determination.
Diagnostic Algorithm for Thrombophilia Screening (VTE)
- The algorithm is used for a patient with suspected thrombophilia and includes factors like age, family history, recurrent thrombosis, and presence of additional risk factors such as surgery or prior pregnancy
- Patients should be assessed for acquired risks such as pregnancy, hormone use etc
- If results of the screening tests are positive, confirmatory genetic testing is recommended.
Assignment Questions
- The provided clinical questions about thrombophilia are for consideration for diagnosis of thrombophilia and for the management of patients with hereditary thrombophilia during pregnancy and delivery.
(Note: The provided information suggests various genetic mutations, but this is for informational purposes only and should not be interpreted as medical advice. Please consult with a healthcare professional for any concerns or diagnosis.)
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Test your knowledge on heritable thrombophilias, genetic mutations, and the implications of blood clots in the context of pulmonary embolism. This quiz covers the risk factors, causes, and effects of venous thrombosis. Perfect for students studying hematology or related fields.
