Kembara Xtra - Medicine - Protein S Deficiency

Kembara Xtra - Medicine - Protein S Deficiency 
I Protein S is a glycoprotein that is mostly made in the liver and is vitamin K dependent. It functions as a cofactor for protein C. Megakaryocytes and endothelial cells both produce it.
When thrombin interacts to the endothelium receptor thrombomodulin, protein C is activated. Together with protein S (a cofactor), active protein C inactivates the clotting factors Va and VIIIa, promoting fibrinolysis.
In addition, protein S has the power to block factors Va, VIIa, and Xa without the assistance of activated protein C.
Congenital thrombophilia Protein S deficiency, which mainly affects the venous system, raises the risk of thromboembolism.
cardiovascular, hematologic/immunologic, and pulmonary system(s) affected 

Epidemiology
​Incidence: Predominant sex: male = female; Mean age of first thrombosis: second decade; 0.2% of the general population are predisposed, whereas only 1% of people with venous thromboembolism (VTE) have it. 

Pathophysiology and Etiology 
Only the free form of protein S (30–40%) functions as a cofactor for activated protein C. It is an autosomal dominant illness. Reversible protein S binding to the C4b protein results in situations where free protein S levels are low but total protein S levels are normal. These people are at risk for thrombosis.
Pregnancy, DIC, liver illness, nephrotic syndrome, HIV, acute thrombosis, and acute varicella-zoster virus infection are conditions with decreased protein S. Drugs: warfarin, oral contraceptives, and chemotherapy with L-asparaginase Genetics
is brought on by changes in the PROS1 gene on chromosome 3.
The majority of people are heterozygous.
The odds ratio (OR) of VTE for heterozygotes ranges from 1.6 to 11.5.
If left untreated, homozygosity or compound heterozygosity is typically incompatible with adulthood.
Neonatal purpura fulminans, a fulminant thrombotic event in homozygotes, can occur in infancy.


Risk Elements 
In patients with protein S deficiency, oral contraceptives, pregnancy, and the use of hormone replacement therapy (HRT) all raise the risk of VTE.
The rate of thrombosis is considerably raised in patients with protein S deficiency and other prothrombotic conditions.
Patients with protein S deficiency who smoke had a higher incidence of arterial thrombosis.
The half-life of other vitamin K-dependent clotting factors, such as prothrombin, factor IX, and factor X, is much longer than the anticoagulant protein S (4 to 8 hours), leading to a temporary hypercoagulable state when protein S is depleted in patients heterozygous for protein S deficiency who are started on warfarin without concurrent heparin. These individuals experience abnormally low protein S levels and skin necrosis over central body parts such the breast, abdomen, buttocks, and genitalia.

pregnant women's issues
increased risk of thrombosis and miscarriages


Basic Prevention 

There are no safeguards in place.

Accompanying Conditions 

 Deep and superficial VTE, frequently without warning One-half or more of homozygotes will develop thrombosis.
Neonatal purpura fulminans, a severe thrombotic birth condition, is linked to homozygosity.
Arterial thrombosis is uncommon but has been recorded in multiple case reports. Unusual sites of thrombosis include the mesentery, cerebral veins, and axillary veins.
Skin necrosis in warfarin-treated patients with recurrent miscarriages

Diagnosis 

Unprovoked VTE before the age of 50; VTE with a significant family history of VTE or known familial protein S deficiency; VTE in unexpected places, such as the mesenteric or cerebral vein; and Recurrent VTE are all indications that inherited thrombophilias may be present.

Clinical Evaluation Standard

Multiple Diagnoses 
Other inherited thrombophilias include Protein C deficiency (in Caucasians) and Factor V Leiden (the most prevalent; typically found in Caucasians).  Dysfibrinogenemia Deficiency in antithrombin
A dysplasminogenemia
• Homocystinemia
Acquired VTE risk factors include surgery, immobilization, malignancy, myeloproliferative neoplasms, trauma, antiphospholipid syndrome, paroxysmal nocturnal hemoglobinuria, pregnancy, HRT, postpartum, DIC, and prothrombin G20210A mutation.

Initial test results from the laboratory and imaging
The following tests should be performed on a patient who is at risk for clotting to determine whether a new clot has formed: CBC with peripheral smear, PT/INR, aPTT, thrombin time, lupus anticoagulant, antiphospholipid antibodies, anticardiolipin antibodies, anti-2-glycoprotein I antibodies, activated protein C resistance, protein S antigen and resistance, antithrombin III assay, fibrinogen,  Immunoassay for the measurement of total and free protein S levels in a quantitative manner Activated protein C resistance was obtained before doing the protein S activity assay. Acute thrombosis, vitamin K antagonists (VKA), any acute sickness reaction, liver disease, and pregnancy-reduced protein S levels are among the conditions that can affect lab results. Protein S activity test is affected by direct oral anticoagulants.
Total protein S levels are considerably lowered in newborns and young babies; apply age-adjusted norms. Heparin and low-weight heparin do not affect test results.

Management 

It is not advised to administer routine anticoagulation to asymptomatic protein S deficient individuals.
Antithrombotic therapy for VTE illness guidelines can be used to make recommendations for patients with protein S deficiency.
Patients with spontaneous VTE who have a low or moderate risk of bleeding are advised to take anticoagulants for an extended period of time—over three months—while those with a high risk of bleeding should take them for just three months.
Patients with VTE and no history of cancer are advised to receive dabigatran, rivaroxaban, apixaban, or edoxaban over VKA therapy as long-term (first 3 months) anticoagulant therapy; VKA therapy over low-molecularweight agents. Patients with a second unprovoked VTE are advised to receive extended anticoagulant therapy over 3 months; those with a high bleeding risk are advised to do so.  For long-term anticoagulation, patients with VTE with active cancer are advised to use LMWH, rivaroxaban, or edoxaban. These individuals should get prolonged anticoagulant medication, it is advised. 
LMWH is preferred to unfractionated heparin for the treatment of thrombosis, unless the patient has significant renal failure.
If at all possible, treat as an outpatient.
In risky scenarios like surgery, immobilization, or postpartum, especially in patients with family history, prophylaxis should be taken into consideration.
Because the majority of patients with this mutation do not have thrombosis, it is unclear what use familial screening for protein S deficiency serves. Women who are considering using oral contraceptives or getting pregnant who have a family history of protein S deficiency should think about getting screened.

Medication 
Enoxaparin (Lovenox), 1 mg/kg SC BID, LMWH
A different option is 1.5 mg/kg/day SC.
- Tinzaparin 175 anti-Xa U/kg/day SC (Innohep).
- 200 U/kg/day SC divided QD-BID of dalteparin (Fragmin).
Fondaparinux (Arixtra), a factor Xa inhibitor Dual oral anticoagulants (DOACs) are contraindicated if CrCl is below 30 mL/min in patients weighing less than 50 kg and between 50 and 100 kg. - Dabigatran 150 mg PO BID (5–10 days following parenteral anticoagulation). - Apixaban 10 mg PO BID for 7 days, then 5 mg PO BID - Rivaroxaban 15 mg PO BID for 21 days, followed by 20 mg PO QD
If a person weighs more than 60 kg, they should take 60 mg of edoxaban every day (after 5 to 10 days of parenteral anticoagulation).  Oral anticoagulant: warfarin (Coumadin): 2 to 5 mg PO QD then adjusted to an INR of 2 to 3 LMWH first for at least 5 days and two consecutive INRs between 2 and 3; contraindications Active bleeding makes anticoagulation impossible, and the danger of bleeding makes long-term anticoagulation generally inappropriate. Warfarin is not recommended for patients who have previously experienced warfarin-induced skin necrosis.
 Safety measures
Avoid giving IM injections; monitor the patient for evidence of embolization, additional thrombosis, or bleeding.
- Regularly examine your stool and urine for hidden blood; keep an eye on your CBC, including your platelets.
- Heparin: paradoxical thrombosis with thrombocytopenia and/or thrombocytopenia - Warfarin: necrotic skin lesions, usually on the thighs, buttocks, and breasts. - LMWH: If renal insufficiency, adjust the dosage.
Significant interactions that could occur Alcohol, allopurinol, amiodarone, anabolic steroids, androgens, many antibiotics, cimetidine, chloral hydrate, disulfiram, NSAIDs, sulfinpyrazone, tamoxifen, levothyroxine, vitamin E, ranitidine, salicylates, and acetaminophen are substances that amplify the response to oral anticoagulants. - Substances like aminoglutethimide, antacids, barbiturates, carbamazepine, cholestyramine, diuretics, griseofulvin, rifampin, and oral contraceptives reduce the reaction to oral anticoagulants. 

Referral Screening and preventative treatment of asymptomatic family members are not justified in patients with suspected protein S deficiency.


Surgery Anticoagulation must be withheld for surgical operations, and routine vena cava filter use is not advised for the majority of DVT patients in addition to anticoagulation. Only in situations when anticoagulation is contraindicated is an IVC filter advised.

Alternative Medicine If Taking VKA, Change Your Diet

Look for symptoms of bleeding while receiving anticoagulant therapy; admission; life-threatening VTE; significant bleeding; and admission.

Patient Follow-Up Monitoring
The INR must be periodically monitored (monthly after initial stability).
 Regular INR measurements to keep the range between 2 and 3
LMWH is the preferred therapy during pregnancy. Anti-Xa levels should be periodically monitored in specific circumstances, such as borderline renal failure and obesity.

Unrestricted diet, except using VKA
Patients should be informed about the usage of oral anticoagulant treatment if they are taking it.
Patients on warfarin should refrain from daily alcohol consumption.
Avoid NSAIDs if you are taking warfarin.


A person with protein S deficiency has a normal lifetime; by the age of 45, 50% of heterozygous individuals with protein S deficiency will have VT, half of which will be spontaneous.

Complications 
Repeated thromboses (needs lifelong anticoagulation)