​Kembara Xtra - Medicine - Protein C Deficiency

​Kembara Xtra - Medicine - Protein C Deficiency 
a rare hereditary condition or acquired risk factor that increases the risk of blood clots by lowering anticoagulation. Asymptomatic presentation to severe disseminated intravascular coagulation (DIC), neonatal purpura fulminans, or recurrent venous thromboembolism (VTE) are all examples of symptoms.
The liver produces protein C, an inactive anticoagulant protein that is dependent on vitamin K.
Activated protein C (APC), which uses protein S as a cofactor, prevents the production of thrombin by inactivating factors Va and VIIIa.
Therefore, a prothrombotic state is brought on by a lack of protein C activity.
cardiovascular, pulmonary, integumentary, hematologic, and immunologic system(s) affected

Prevention Incidence
The incidence is thought to range from 1 in 200 to 1 in 500.
The prevalence of clinically significant protein C deficiency (PCD) is 1 in 20,000. One in every four million infants are likely to have severe PCD.
The prevalence is 0.3% in the general population, 3-5% in people with VTE, 45 years old on average for first thrombosis, and no gender preponderance is known.

Pathophysiology and Etiology 
PCD can be acquired or inherited.
There are two forms of PCD that can result from genetic changes, although the differences between the two are not clinically significant.
- Protein C levels are decreased as a result of Type I (the most frequent).
- Despite having normal quantities of protein C, Type II results in diminished functionality. - Acquired PCD is more common and can arise in numerous illness situations, such as: - DIC - Liver disease
- Serious infections, including meningococcal disease
- Autoantibody-directed protein C inhibitors
- Cancer with chemotherapy (including cyclophosphamide, methotrexate, and 5-FU) - Warfarin, a vitamin K antagonist, when first used
- A vitamin K deficit (malabsorption of fat-soluble vitamins due to starvation) The degree of symptoms caused by heterozygous PCD and mild deficiency might range from asymptomatic to recurrent thromboses.
- There is a higher risk of DVT, PE, and complications such pregnancy-related thrombosis and ischemic artery stroke.
Genetics: Incomplete penetrance autosomal dominant inheritance pattern The protein C (PROC) gene has at least 270 genetic variations that have been identified; these variations can cause functional deficiencies.
Homozygous patients or those with another genetic thrombophilia frequently have more severe disease; heterozygous patients frequently have mild or asymptomatic disease. In addition, mutations in other genes (GCKR, EDEM2, BAZ1B, etc.) are linked to variation in the levels of protein C expression in the general population, although their clinical significance is currently unknown.
Warfarin-induced skin necrosis (WISN) is a condition that can occur in patients with PCD who start using warfarin without concurrent heparin therapy. This is believed to be because protein C has a shorter half-life (5 to 8 hours) than other vitamin K-dependent clotting factors. But not all patients with WISN also have PCD.
ALERT
By avoiding loading dosages of warfarin and using heparin bridging, warfarin necrosis has been prevented. Because many patients with confirmed deficit do not advance to WISN, screening all patients for hereditary or acquired variants of PCD prior to starting warfarin is neither cost-effective nor predictive.

Risk Elements 

acquired diseases such vitamin K antagonists, severe liver illness, DIC, and heart failure.

Prevention 

There are no preventative methods for PCD because it is typically a congenital illness.

Accompanying Conditions 

 VTE everywhere, frequently spontaneous Because arterial thrombosis is uncommon, a clear causative link has not been established.
 Homozygosity may lead to severe thrombotic birth problems, such as purpura fulminans.
• Repeated miscarriages 

Diagnosis 
can be suspected if the history is longer, as seen below.


History: Recurrent VTE; VTE before the age of 40; thrombosis in odd sites, such as the mesentery, sagittal sinus, or portal vein; thrombosis before the age of 50.  Thrombosis, spontaneous abortion, or WISN in the family


Normal Physical Examination

Factor V Leiden, Protein S Deficiency, Antithrombin Deficiency, Dysfibrinogenemia, Dysplasminogenemia, and Hyperhomocysteinemia are all included in the differential diagnosis.
Antiphospholipid antibody syndrome, elevated factor VIII, IX, or XI levels, the prothrombin 20210 mutation, and DIC
HIT, or thrombocytopenia brought on by heparin, 

Laboratory Results 
Clotting assays, ELISA, and chromogenic tests to measure protein C levels can all be used to identify PCD. The study of PROC gene mutations is also available.
Initial examinations (lab, imaging)
A CBC with peripheral smear, INR, aPTT, hepatic and renal function tests, as well as the relevant imaging, should all be performed as part of a patient's initial examination for a new clot.
It is not recommended to test unselected patients who are experiencing a first-time VTE (whether provoked or not) for heritable causes of thrombophilia.
If a woman experiences three early pregnancy losses before 10 weeks' gestation, she should be screened for antiphospholipid syndrome rather than another thrombophilia (PCD).


Tests in the Future & Special Considerations
It is advised to get tested for inherited or acquired thrombophilia in the following situations: - Patient age 40 years and first VTE episode
- Recurrent VTE independent of risk variables present
- Patients suffering VTE in unexpected locations
Patients with a history of WISN should consider undergoing PCD testing, and children and newborns suspected of having purpura fulminans should undergo immediate protein C and S deficiency testing.
Testing for hereditary thrombophilia should only be taken into account in female first-degree relatives who are of reproductive age, have never experienced pregnancy difficulties, and are asymptomatic. The following circumstances should be taken into account when ordering extra testing for inherited or acquired thrombophilia: Protein S deficiency, PCD, Antiphospholipid antibody syndrome, Antithrombin III deficiency, Factor V Leiden, Prothrombin G20210A


Other/Diagnostic Procedures

Two distinct lab tests are used to screen for PCD:  A functional activity assay using a snake venom protease to activate protein C An immunoassay for a quantitative evaluation of protein C levels


Drugs that could affect test interpretation: Oral contraceptives have been shown to increase protein C levels. Warfarin lowers protein C levels and should be stopped two to three weeks prior to accurate testing.
 Conditions that could change lab results: Liver disease lowers protein C levels.

Caution 
Protein C levels may be lowered by acute thrombosis. It is advised to repeat the confirmatory test for low protein C level at a different time. A deficit can be ruled out if protein C levels are found to be normal at the time of presentation.

Treatment of active thrombosis; monitoring

General Actions 

It is important to inform people with PCD about the symptoms and indicators of VTE.
 Estradiol-containing birth control and hormone replacement treatment should be avoided by women going through menopause if they have any of the following histories: PCD diagnoses, a first-degree relative who also has PCD, and a first-degree relative who has VTE at age 50 or younger
Women have access to hormonal contraceptives that simply include progestin.
It is not advised to administer routine anticoagulation to PCD patients who are asymptomatic.
Following a first VTE, anticoagulation is advised for at least 3 months in patients with hereditary thrombophilia.
- There are some arguments in favor of anticoagulation that lasts forever, but the evidence is scant.
- For decisions on therapy durations longer than three months, shared decision-making should be adopted.
When possible, treat VTE as an outpatient procedure if the patient is clinically stable. Severe congenital PCD may be treated with protein C concentrates. Patients with recurrent VTE should be placed on indefinite anticoagulation.
pregnant women's issues
When therapeutic or preventative VTE treatment is required during pregnancy, heparin-based medicines should be utilized.
 Antepartum and postpartum clinical surveillance is advised over preventative medication for pregnant women with known PCD but no personal history of VTE or additional thrombotic risk factors (such as familial history of VTE in a first-degree relative under 50 years of age, obesity, or extended immobility).
Antepartum surveillance is advised for expectant mothers with known PCD who have no personal history of VTE but who also have another thrombotic risk factor, along with postpartum prophylactic medication for six weeks of either prophylactic or intermediate dose.
It is advised to administer postpartum preventative medication with prophylactic or intermediate-dose LMWH to expectant mothers with known PCD and prior VTE. The clinician may decide to administer this antepartum rather than through observation.


First Line of Medicine
LMWH: Warfarin was originally administered for a minimum of 5 days, followed by two consecutive INRs of 2 to 3 to bridge. Additionally, dabigatran or edoxaban may be started 5 to 10 days after beginning LMWH.
- Enoxaparin (Lovenox), 1.5 mg/kg/day SC or 1 mg/kg/SC BID
- Tinzaparin, 175 anti-Xa IU/kg/day SC (Innohep).
Novel oral anticoagulants (NOACs): - Dalteparin (Fragmin), 200 U/kg/day; - Rivaroxaban (Xarelto), 15 mg PO BID with food for 21 days, then 20 mg PO QD with food - 10 mg PO BID for 7 days, followed by 5 mg PO BID of apixaban (Eliquis).
- 150 mg PO BID of dabigatran (Pradaxa) (after 5–10 days of parenteral anticoagulation). - 60 mg PO QD of edoxaban (Savaysa) (after 5–10 days of parenteral anticoagulation). Warfarin (Coumadin), titrated to an INR of 2 to 3, is an oral vitamin K antagonist. Factor Xa inhibitors include:
- Fondaparinux (Arixtra) <50 kg: 5 mg/day SC; 50 to 100 kg: 7.5 mg/day SC; >100 kg: 10 mg/day SC; contraindicated if CrCl <30 mL/min ● Contraindications - Active bleeding - Risk of bleeding is a relative contraindication to longterm anticoagulation ● Precautions - Observe patient for signs of embolization, further thrombosis, or bleeding.
- Keep an eye on your renal function, drug interactions, and your CBC, including your platelets (HIT is a worry).
Next Line
Heparin 80 U/kg IV bolus, 18 U/kg/hr; adjust dose according on PPT.
Measure an anti-Xa level in patients who need high doses of heparin every day to help with dosing.
As an alternative, unfractionated heparin can be administered to outpatients without supervision at 333 U/kg and then 250 U/kg SC.
Replacement protein C concentrate may be used to treat this condition.
Fresh frozen plasma (FFP) protein C supplementation helps control neonatal purpura fulminans.

Referral 
Referrals to hematologists should be made for patients with suspected PCD.

Surgery In patients with acute proximal DVT of the lower extremity and an absolute contraindication to anticoagulation, inferior vena cava (IVC) filters are advised; however, the use of an IVC filter in addition to anticoagulants is not advised in all other cases.


Life-threatening VTE at admission; significant bleeding while receiving anticoagulant treatment.


Patient Follow-Up Monitoring
INR monitoring is necessary for warfarin to maintain a range of 2 to 3 on a monthly basis following initial stabilization.
LMWH is the preferred therapy during pregnancy. In these patients, routine anti-Xa level monitoring is advised.

Unrestricted diet (unless if taking warfarin; avoid altering diet with items high in vitamin K) 

Patients should be informed about the warning signs and symptoms of VTE as well as the usage of oral anticoagulant treatment, if they are taking it.
Avoid NSAIDs if you are taking warfarin.
Avoid OCPs due to the higher thrombosis risk.

Prognosis People with PCD have normal life spans when compared to people in the general population.


Recurrent or primary VTE are the  complications