​Kembara Xtra - Medicine - Factor V Leiden

​Kembara Xtra - Medicine - Factor V Leiden 
Factor V Leiden, also known as the activated protein C (APC) cleavage site mutation, is a genetic point mutation in the F5 gene that causes an increase in thrombin and, in turn, clot formation. This type of thrombophilia runs in families more frequently than any other.
The circulatory, digestive, hemo/lymphatic/immunologic, neurological, pulmonary, and reproductive systems are all impacted.
Factor V Leiden thrombophilia is also known as factor V Leiden mutation or inherited APC resistance. 

Concerns for Children
The annual rate of venous thrombosis in otherwise healthy youngsters is 0.07% per 100,000.
Patients with factor V Leiden may be at higher risk for thrombosis, and other hazards may be present as well.
Procoagulant conditions (including factor V Leiden) are weakly associated with coronary events in younger patients.

Women with a history of adverse pregnancy outcomes should be tested for thrombophilia before attempting another pregnancy. This is because recurrent pregnancy loss is a possible complication, as is an increased thrombotic risk in pregnancy and postpartum (additive in homozygous state).


Epidemiology Studies estimate that between 5% to 10% of the population is heterozygous for factor V Leiden; this number is lower in Hispanic Americans (2%), African Americans (1%), and Asian Americans (0.45%).
4-5% of the general population devoid of previous VTE history. Some regions of Greece, Sweden, and Lebanon have a higher prevalence (12-14%). There were no reports in either Chinese or Japanese.


The Cause and Effect Pathophysiology 

Factor V is a plasma protein that plays a role in the clotting cascade. Factor V's exposure to tissue factor amplifies the production of thrombin, which promotes clotting by activating factor V into procoagulant factor Va. To counteract this positive feedback loop, thrombin also promotes the production of activated protein C, which cleaves and inactivates factors V, Va, and VIII.
● APC's ability to cleave factor V or Va is diminished by a point mutation (Arg506Glu) in factor V Leiden. Due to the 20-fold slower degradation of factor Va, its anticoagulant activity as a cofactor to APC is diminished, while the procoagulant role of activated factor V is enhanced.

Causal Variables 
The risk of venous thromboembolism (VTE) is increased by a factor of around 7 in those who are heterozygous for factor V Leiden and by about 80 in those who are homozygous for the mutation. The following factors further heighten this danger: 2–4 times more likely if you have a blood type other than O (A, B, or AB).
Maximum efficacy for homozygotes is 100-fold for oral contraceptives; for heterozygotes, it's 35-fold. Desogestrel-containing oral contraceptives can cut the patient's risk in half.
– Patients with factor V Leiden are at an even greater risk of thrombosis when using hormone replacement therapy (HRT) or selective estrogen receptor modulators (SERMs).
– Testosterone replacement therapy can increase the risk of VTE in men predisposed to thrombosis.
– The risk of thrombosis during pregnancy and the puerperium is increased seven- to sixteen-fold in women who are homozygous for factor V Leiden.
Those with end-stage renal illness and a coagulation disorder are at increased risk for calciphylaxis.
– Factor V Leiden and prothrombin G2021A mutation account for 30% of individuals with venous thromboembolism (VTE), but their risk is lower than that of the general population (approximately 1%), which has deficiencies in antithrombin III, protein C, and protein S.
Patients with factor V Leiden have an increased risk for recurrent VTE, but the data are inconsistent.
It has been demonstrated that the probability of VTE recurrence is somewhat higher in people with factor V Leiden than in the general population.


Safety Precautions 

Prophylactic anticoagulation is not necessary for patients with factor V Leiden who have never had a thrombus.

Related Disorders 
Thrombosis of the veins

Differentiating between provoked and unprovoked VTE, as well as identifying risk factors, family history, and specific symptoms, is essential for an accurate diagnosis.

Up to 70% of patients with VTE had a precipitating cause.
However, compared to the general population, the incidence of isolated PE in the absence of DVT is lower; this is known as the "factor V Leiden paradox."

No unique clinical manifestation of factor V Leiden has been identified.
Until thrombosis has developed, most patients have no warning signs.
Repeated miscarriages
Thrombosis in the family History of the factor V Leiden mutation in the family 

Analyses in the Clinic 

No evidence of factor V Leiden on a physical exam
VTE (deep vein thrombosis, pulmonary embolism, brain thrombosis): Carriers of the factor V Leiden mutation range in frequency from 10-26% among VTE patients.

Patients with factor V Leiden are less likely to experience thrombosis in the sagittal sinus, mesentery, or portal systems than those with protein C or S insufficiency.

Differential Diagnosis Dysfibrinogenemia Dysplasminogenemia Homocystinemia Prothrombin 20210 mutation Elevated factor VIII levels Protein C deficiency Antithrombin deficiency Other causes of APC resistance (e.g., antiphospholipid antibodies)

Conclusions from Initial Testing and Laboratory Procedures
VTE testing and imaging can be found in the DVT/PE sections.
According to the National Institute for Health and Care Excellence (NICE) guidelines, thrombophilia testing, including factor V Leiden, should only be considered when the decision is being made to stop anticoagulant medication following an unprovoked VTE incident.
Suspecting factor V Leiden thrombophilia in those who exhibit the following characteristics: First and subsequent episodes of venous thromboembolism (DVT) or pulmonary embolism (PE), most frequently among women with a history of VTE during pregnancy or in conjunction with the use of estrogen-containing contraceptives, especially 3rd generation estrogen-containing contraceptives. Recurrent thrombosis in the family
Test for the Leiden mutation in the factor V gene: DNA-based factor V mutation testing is recommended for patients taking direct thrombin inhibitors or direct factor Xa inhibitors, as well as those with strong lupus inhibitors and significantly prolonged baseline aPTT. Functional assay for aPC resistance is a plasma-based coagulation assay in which patient plasma is added to factor V-deficient plasma along with purified APC.
The relative aPTT prolongation is utilized as a diagnostic tool. Drugs like heparin and direct thrombin inhibitors or factor Xa inhibitors can lead to erroneously negative results. Functional testing is favored over genetic testing in the absence of anticoagulant exposure because to expense and time to diagnosis.


Additional Evaluations & Cautious Thoughts
People who acquire VTE in an uncommon place, such as the portal vein, the cerebral vein, or who experience recurring VTE, especially those who are younger than 50, should be tested.

To identify the source of potential test interference for direct thrombin inhibitor or direct factor Xa inhibitor, genetic testing is recommended for people with a family history of factor V Leiden, especially if they have concomitant antiphospholipid syndrome or are taking anticoagulant.
Factor V Leiden, the 20210A prothrombin mutation, antithrombin, protein C, or protein S deficiencies, a non-O blood group, and variants in CYP2C9*2 and rs4379368 have all been identified as heritable risk factors for venous thromboembolism in females.
Therefore, it's important to keep an eye out for thrombogenicity generated by COC medication and consider testing for mutations before applying combined oral contraception.

Tests and Other Methods of Diagnosis

Thrombophilia testing is recommended for the pediatric population, particularly for those who have experienced VTE related to a central venous catheter (CVC) multiple times.
Testing for factor V Leiden, prothrombin 20210, antithrombin, protein C, protein S, and antiphospholipid should be performed on children with VTE if thrombophilia is suspected.
Testing for antiphospholipid antibodies and homocysteine level, as well as PCR for factor V Leiden mutation and prothrombin G2021A mutation, constitute the thrombophilia screen.

Management 

Thrombotic event is required for indication. Patients who have no signs of a thrombotic event should not take prophylaxis.

Methods in General 

Patients with factor V Leiden or other genetic thrombophilia should start anticoagulant medication for acute venous thrombosis at the same time as patients without factor V Leiden.
First-time venous thromboembolic events (VTEs) in individuals with factor V Leiden or other thrombophilias are treated in the same way as in patients without these conditions.

VTE treatment for the first episode should last at least 3 months, and in patients who experience recurrence, the risks and benefits of indefinite anticoagulation should be carefully evaluated.

Treatment with Medication First
Please refer to dedicated PE and DVT sections for further information.
Patients with and without factor V Leiden receive the same first treatment for their first VTE.

Anticoagulation therapy is preferred above no therapy (grade 1B) in patients with proximal DVT or PE.

Anticoagulation with dabigatran, rivaroxaban, apixaban, or edoxaban (all Grade 2B) is preferred over vitamin K antagonist in patients with DVT or PE who do not have malignancy.
Patients with thrombosis caused by malignancy should take low-molecular-weight heparin (LMWH).
SC: 1 mg/kg every 12 hours (preferred) or 1.5 mg/kg once every 24 hours of enoxaparin (Lovenox) (LMWH). A 1 mg/kg dose every 12 hours following the initial dose given in a hospital or urgent care center may be considered for outpatient treatment in certain low-risk patients. Daily subcutaneous (SC) doses of 5 mg (body weight 50 kg), 7.5 mg (50–100 kg), or 10 mg (>100 kg) of fondaparinux (Arixtra) Anticoagulation with warfarin (INR >= 2 for 2 days in a row) and tinzaparin (Innohep) (175 anti-Xa IU/kg SC daily for a minimum of 5 days) are both necessary. Dalteparin (Fragmin): 200 IU/kg subcutaneously once a day
Dosage for the oral anticoagulant Apixaban (Eliquis): 10 mg BID for 7 days, followed by 5 mg BID for 3 to 6 months Dosage for Rivaroxaban (Xarelto): 15 mg BID for 7 days, followed by 20 mg daily for 3 to 6 months Pradaxa (Dabigatran):
Dabigatran 150 mg BID for patients who have been on a parenteral anticoagulant for at least 5 days and are hemodynamically stable.
Warnings and Cautions
Both active bleeding and the risk of bleeding are absolute contraindications to long-term anticoagulation.
Safety Measures
Keep an eye on the patient in case there is an embolism, further thrombosis, or bleeding.
– Intramuscular injections should be avoided. Blood in the stool or urine should prompt a periodic CBC and platelet count testing.
Dosage adjustments for LMWH may be necessary during pregnancy and in cases of renal insufficiency. Potentially serious interactions Alcohol, allopurinol, amiodarone, anabolic steroids, androgens, many antimicrobials, cimetidine, chloral hydrate, disulfiram, all nonsteroidal anti-inflammatory drugs (NSAIDs), sulfinpyrazone, tamoxifen, thyroid hormone, vitamin E, ranitidine, salicylates, acetaminophen, and acetylsalicylic acid Some medications, such as antacids, barbiturates, carbamazepine, cholestyramine, diuretics, griseofulvin, rifampin, and oral contraceptives, can reduce the effectiveness of anticoagulants. Sequence Two
Continuous infusion of heparin at a rate of 18 g/kg per hour after an initial bolus of 80 mg/kg
Warfarin (Coumadin) oral anticoagulant, adjusted at an INR of 2-3, PO - Contraindications
An anticoagulant cannot be used if there is active bleeding.
A relative contraindication to long-term anticoagulation is the possibility of bleeding.
Patients with a prior history of warfarin skin necrosis should not take the blood thinner.
Pregnancy is a contraindication for using warfarin.
Safety Measures
Heparin-induced thrombocytopenia and paradoxical thrombosis Necrotic skin lesions (usually in the breasts, thighs, or buttocks) caused by Warfarin. 

Homozygous condition in pregnancy; referral; recurrent thrombosis despite anticoagulation; trouble with anticoagulation; genetic counseling;

Medical Interventions 
The use of an inferior vena cava filter in addition to anticoagulation is not recommended for most individuals with DVT unless there is a contraindication for anticoagulation.

Admission 
Criteria for admission/early stabilization: thromboembolic complications, including PE
Prescribe LMWH and warfarin education for nurses.
Criteria for release: anticoagulation stability


Constant Patient Check-Ins and Reporting
If you're on warfarin, your INR should be checked regularly (at least once every month after you've stabilized on the drug).
DIET Warfarin anticoagulation may be compromised by eating excessive amounts of foods high in vitamin K.
The following are things that patients need to know: Avoiding nonsteroidal anti-inflammatory drugs (NSAIDs) while using anticoagulants
Most people with this mutation do not experience thrombosis, hence the value of screening relatives is debatable. It is recommended to examine patients with a family history of factor V Leiden who are pregnant or who are considering using oral contraceptives.


Patients who are heterozygous for factor V Leiden typically do not develop thrombosis, hence their prognosis is good.
Thrombosis occurs in around 50% of homozygotes throughout the course of a lifetime.

It is unclear what the rate of recurrence is after a first thrombosis; some put it as high as 5%.
Overall mortality is unaffected by Factor V Leiden.

Complications Thromboembolic recurrence Bleeding while taking anticoagulants