​Kembara Xtra - Medicine - Prothrombin 20210 Mutation

​Kembara Xtra - Medicine - Prothrombin 20210 Mutation 
The prothrombin (also known as factor II) gene has a gain-of-function mutation called G20210A where adenine is swapped for guanine at the 20210 noncoding site.
The mechanism of increasing the risk of thrombosis is not fully understood, but has been attributed to increased prothrombin or factor II levels in circulation by increased prothrombin protein translation without changing the levels of prothrombin mRNA transcription. The prothrombin 20210 mutation is the second most common venous thrombophilia after the factor V Leiden mutation.
 In an autosomal dominant disease, heterozygotes had a 3- to 4-fold higher risk of venous thromboembolism (VTE) and a 30% higher prothrombin level.
cardiovascular, hematologic/lymphatic/immunologic, neurological, pulmonary, reproductive, and hepatic system(s) affected
Prothrombin G20210A mutation, prothrombin G20210A gene polymorphism, prothrombin gene mutation, and FII A20210 mutation are some of the synonyms for this condition.


Epidemiology 
Prevalent in the Caucasian population with a prevalence between 1% and 6%, but it is generally around 2%
Prothrombin 20210 mutation occurrence in individuals with VTE ranges from 4.6% to 18%; greater prevalence is associated with highly thrombophilic families; first thrombosis often occurs in the second decade of life; and inheritance is identical in both sexes (autosomal).

Pathophysiology and Etiology 

Prothrombin (factor II) levels are enhanced by increased translation of prothrombin mRNA but not transcription due to a noncoding substitution of adenine for guanine at the 20210 position at the terminal nucleotide of the 3′.
The 3′ terminal nucleotide of the untranslated region linked to the mRNA sequence for polyadenylation is where the base change is located. The gain of function may result from an accelerated rate of processing, a changed cleavage site, or improved mRNA stability.
● Prothrombin (factor II) is the precursor of thrombin, which cleaves fibrinogen to form fibrin, in the coagulation cascade.
Elevated thrombin levels and subsequent clot formation are caused by elevated prothrombin activity.
The majority of thrombus development, including cerebral, mesenteric, and deep venous thrombosis (DVT)/PE, takes place in the venous circulation. Recent research has demonstrated that neither a portal vein thrombosis nor a Budd-Circhi syndrome are associated with the prothrombin 20210 mutation.
The G20210A mutation is more common in individuals with critical limb ischemia, despite the fact that it is not known to enhance the risk of any arterial thrombotic events (myocardial infarction or acute ischemic stroke).


Caused by the G20210A mutation of the F2 gene (prothrombin gene), which results in a gain of function and is situated in the short (p) arm of chromosome 11.
Heterozygotes have prothrombin levels that are 30% higher and experience 3- to 4-fold more VTE incidents. Homozygotes are significantly more vulnerable.
● Three more prothrombin variants that are unrelated to the G20210A region include:
- Yukuhashi: extended procoagulant activity caused by the missense mutation G1787T, which changes arginine to leucine at amino acid 596.
- C20209T: This mutation, which is located close to G20210A and is mostly seen in African people, has recently been linked to recurrent pregnancy loss, albeit the exact nature of this link is unclear.
- A19911G: Located in the prothrombin gene's intron, this mutation may have an impact on the G20210A mutation by raising the likelihood that a venous thromboembolic event would occur.
The mechanism is still a mystery.

Risk Factors Because this mutation is genetic, there is a chance that it will be passed on to the children.
 In relation to the possibility of getting VTE:
- Patients who have both the prothrombin 20210 mutation and the factor V Leiden mutation have a 20-fold increased risk of developing VTE.
- The three components of the Virchow triad of thrombogenesis are stasis, endothelial damage, and thrombophilia. Any factor, such as oral contraceptives, pregnancy, cancer, orthopedic surgery, congestive heart failure, recent cerebrovascular accident, air travel, obesity, and smoking, that encourages stasis and endothelial injury will therefore raise the risk of VTE.
pregnant women's issues
Relative stasis is thought to be the cause of increased thrombotic risk in pregnant and postpartum patients with prothrombin 20210 mutation.
Because the risk of VTE rises in the first trimester of pregnancy, anticoagulation should start then and should end before the scheduled induction or cesarean section. Anticoagulation can be resumed 4 to 6 hours after a vaginal delivery or 6 to 12 hours after surgery. Postpartum VTE risk is often higher. Warfarin's gradual onset of effect may cause it to start working right away.
Although it has not been thoroughly researched, the C20209T mutation may have some relationship to recurrent pregnancy loss.


Basic Prevention 

Individuals with the mutation who are asymptomatic are exempt from preventive anticoagulation. Pregnant women with very high-risk thrombophilic mutations (often factor V Leiden) and a significant family history typically receive an exception. If certain characteristics are present after the initial VTE, such as being unprovoked or occurring in an uncommon location like the liver, portal, mesenteric, or cerebral, lifelong prevention may be necessary.

Conditions Related to VTE and Factor V Leiden


diagnosis Previous VTE, VTE in the family, and prothrombin 20210 mutation in the family

clinical assessment 

A single painful, erythematous, and swollen calf indicates a potential DVT.
Positive Homans sign, specificity of 39-89% for DVT, sensitivity of 10-54%
Tachycardia is the most typical pulmonary embolism warning symptom, however depending on how severe it is, patients may also experience chest pain and hypotension. Although other causes of an acute abdomen should be investigated as needed, a sensitive abdomen may be a sign of mesenteric vein thrombosis.

Factor V Leiden mutation differential diagnosis
Antiphospholipid antibodies are one such cause of activated protein C resistance. Other reasons include protein C deficiency, protein S deficiency, antithrombin deficiency, dysfibrinogenemia, dysplasminogenemia, homocystinemia, and increased factor VIII levels.


Laboratory Results 

It is not advised to screen for the prothrombin G20210A mutation in asymptomatic people, unless they have a very strong family history. Patients with thrombosis at a young age, recurring unprovoked VTE, or thrombosis in odd places can all undergo testing.
Initial examinations (lab, imaging)
By combining PCR with electrophoresis or immunoassays, this mutation can be identified.
Testing for an inherited thrombophilic condition is reliable during an acute embolic event or with the use of anticoagulation (4)[A]. Imaging should be obtained as appropriate for the suspected site of thrombosis, including ultrasound with Doppler, computed tomography scan with contrast to evaluate venous phase, and V/Q scan.
Tests in the Future & Special Considerations
Despite high prothrombin levels, this is not a sensitive test to establish a diagnosis.
Diagnostic Techniques/Other Venography, MR angiography (MRA), or arteriography to identify thrombosis
Imaging is likely to reveal the presence of an arterial or venous thrombus.

With or without an acquired thrombophilic syndrome, management of patients with a first VTE is often fairly similar.

Medication 

aims to treat patients who have VTE (prophylactic doses may vary). We advise the reader to review the most recent dosage information, dose modifications, and contraindications for the drugs listed below. Most adults should take the doses suggested.
Initial Line
The following oral anticoagulants are preferable over warfarin and low-molecular-weight heparin (LMWH) in adult patients without cancer: dabigatran, rivaroxaban, apixaban, or edoxaban.
Apixaban (Eliquis): The recommended starting dose is 10 mg BID for 7 days, then 5 mg BID.
Dabigatran (Pradaxa): 150 mg BID after initial parenteral anticoagulation for 5 to 10 days.
Edoxaban (Savaysa) must be administered parenterally for the first 5 to 10 days, thereafter daily doses of 60 mg must be taken.
Rivaroxaban (Xarelto): The recommended starting dose is 15 mg BID with food for 21 days, then 20 mg daily with food.
Next Line
Warfarin is favored over LMWH for people without cancer who cannot be treated with DOAC.
Warfarin (Coumadin): The recommended starting dose is 2 to 10 mg PO once day, which is thereafter increased to an INR of 2 to 3.
 Subcutaneous injection of 1 mg/kg of enoxaparin (Lovenox) every 12 hours



Absolute contraindications include ongoing bleeding, severe bleeding diathesis, planned or previous high bleeding risk surgery or procedure, serious trauma, and cerebral hemorrhage that has occurred recently or in the past.
Recurrent gastrointestinal bleeding, spinal tumors, massive AAA with severe hypertension, thrombocytopenia with platelets 50,000, recent or urgent low bleeding risk surgery are relative contraindications. The dose of enoxaparin can be changed based on the severity of the thrombocytopenia.
- Warfarin: prior cases of warfarin-related skin necrosis
- In individuals with renal impairment, the doses of LMWH and new oral anticoagulants must be changed. When treating patients with severe renal failure, rivaroxaban should be avoided. Apixaban has a much reduced risk of major bleeding or clinically relevant nonmajor bleeding than rivaroxaban or dabigatran, making it potentially safer to use in CKD patients. Apixaban can be administered for DVT prevention at a lower dose of 2.5 mg PO BID.
Observe the patient for any evidence of embolization, further thrombosis, or bleeding. Regularly check the patient's CBCs.
- In general, oral contraceptives should not be used by women who already have the mutation; nevertheless, it is not advised to test asymptomatic women for the mutation before to commencing oral contraceptives.
Significant potential interactions include substances that increase the effect of some anticoagulants, including alcohol, allopurinol, amiodarone, anabolic steroids, androgens, many antimicrobials, cimetidine, chloral hydrate, disulfiram, all NSAIDs, sulfinpyrazone, tamoxifen, thyroid hormone, vitamin E, ranitidine, salicylates, and accutane. Complications of medications


Referral, difficulty anticoagulating, recurrent thrombosis while on medication, and genetic counseling

Surgical Interventions Anticoagulation must be held during surgical procedures.
The majority of DVT patients are advised against routinely using a vena cava filter in addition to anticoagulation, unless anticoagulation is contraindicated.
Thrombectomy may be required in specific circumstances.

Admission 
Patient can be safely discharged if patient is stable on anticoagulation. Admission criteria/initial stabilization: complex thrombosis, such as pulmonary embolus; required heparin drip.

Continuous Care – DVT prophylaxis as necessary if patient is admitted to hospital – Compression stockings for prevention


Patient Follow-Up Monitoring
Warfarin use necessitates periodic INR readings, with a target of 2 to 3 (weekly, then monthly after initial stability).
The risk of recurrent VTE is only marginally increased by heterozygosity for the prothrombin 20210 mutation, therefore its presence does not affect the time of anticoagulant treatment.

Foods high in vitamin K may interfere with warfarin's ability to prevent clotting, and grapefruit and St. John's wort can affect the levels and clearance of anticoagulant medication by interfering with the cytochrome P450 enzyme.


Modification of Lifestyle 

Patients should be informed about the following: Oral anticoagulant medication Acute blood loss signs and symptoms Avoiding NSAIDs while taking warfarin

Prothrombin 20210 patients have typical lifespans when compared to people in the general population.

Complications might result in mortality, possibly from a severe pulmonary embolism, and include recurrent thrombosis on anticoagulation and bleeding on anticoagulation as well as 
ulcers from venous stasis