Kembara Xtra - Medicine - Antiphospholipid Antibody Syndrome

Kembara Xtra - Medicine - Antiphospholipid Antibody Syndrome 
​ESSENTIAL DESCRIPTION
Antiphospholipid antibody syndrome (APS) is a systemic autoantibody-mediated thrombophilic disorder characterized by recurrent venous or arterial thrombosis and/or fetal loss in the presence of persistent antiphospholipid antibodies (APAs), as demonstrated by lupus anticoagulant (LAC), anticardiolipin antibodies (aCL), and/or anti-2 glycoprotein-I (GPI) antibody. By interacting with plasma proteins that bind to phospholipids, the APAs promote the formation of clots. Both pregnant and non-pregnant people may experience morbidity and mortality as a result of the APS:
APS subtypes according to clinical presentation
- Primary: no obvious underlying disease
- Secondary: transitory APAs have been connected to a number of infections, medications, and cancers; they are most frequently associated with autoimmune diseases such systemic lupus erythematosus (SLE).
- Asherson syndrome, also known as catastrophic APS (CAPS) (1%),
The most severe type of the illness is thrombotic microangiopathy, which is linked to multiorgan failure.
High mortality rate if therapy is postponed

pregnant women's issues
Maternal venous thromboembolism, stroke, fetal death, preeclampsia, placental insufficiency, fetal growth retardation, miscarriage, and preterm birth are among the complications.

The most significant risk factor is thought to be the presence of three antibodies.
The recommended medications during pregnancy include low-dose aspirin and low-molecular-weight heparin (LMWH) or unfractionated heparin.
Due to the significant risk of thrombosis during this time, prophylactic-dose heparin is advised in the postpartum period (unless the patient is taking therapeutic anticoagulation). More than 70% of APS patients who receive competent care give birth to live infants.

EPIDEMIOLOGY The prevalence of APAs rises with aging, however this is not always linked to an increased risk of thrombosis.
Female > male incidence for APS
Approximately 5 new cases of APS are reported annually for every 100,000 people.
The annual incidence risk of thrombosis is 0-3.8% in patients with positive APAs but no history of thrombosis. In individuals who test triple positive, this risk rises to 5.3%. The cause of 15–20% of repeat abortions is APS.
Prevalence
40 to 50 cases per 100,000 people each year on average. 1-5% of the general population and 40% of people with SLE have APAs. Patients who have experienced stroke, fetal loss, or venous thromboembolism have a greater prevalence of 10– 15%. According to estimates, APS are thought to be responsible for 50,000 miscarriages in the US.

Anti-2-GP1 antibodies are crucial in the etiology of APS. ETIOLOGY AND PATHOPHYSIOLOGY. There are several potential pathways that could mediate the procoagulant effect:
- Endothelial effects: reduction in prostacyclin synthesis and disappearance of the annexin V cellular barrier
- Platelet stimulation that causes aggregation and adhesion
- Complement activation - Interference with innate anticoagulant mechanisms (such as protein C inhibition) - Pregnancy-related problems are also brought on by autoantibody-mediated effects:
Proposed mechanisms include excessive production of natural antibodies, molecular mimicry brought on by infections, exposure to phospholipid antigens during platelet activation, cardiolipin peroxidation, and genetic predisposition. - Interference with the expression of trophoblastic adhesion molecules resulting in abnormal placentation and placental thrombosis
APS frequently requires a "second hit" from environmental circumstances.
Genetics The majority of APS cases are acquired. There have been a few research on the occurrence of aCL and LAC in families. APS and anti-2-GP1 antibodies may both be hereditary risks due to the valine 247/leucine polymorphism in 2-GP1.

RISK FACTORS Age >65 years for women and >55 years for men Cardiovascular risk factors (smoking, combined oral contraceptive usage, hypertension [HTN], hyperlipidemia, diabetes, obesity)
Autoimmune condition that is underlying (SLE, rheumatoid arthritis, collagen vascular disease, Sjögren syndrome, idiopathic thrombocytopenic purpura, Behçet syndrome)
Positive APAs: pregnancy, immobility, and surgery

DURATIONAL PREVENTION
Controlling high blood pressure and diabetes; quitting smoking; avoiding oral contraceptives in high-risk patients; beginning thromboprophylaxis in known cases; preconception evaluation are all examples of risk factor reduction.


CONDITIONS OFTEN Associated with
SLE is the most prevalent autoimmune disease connected to APS, followed by scleroderma, Sjögren syndrome, dermatomyositis, and rheumatoid arthritis.

Malignancy Viral, bacterial, parasitic, and rickettsial infections

Phenothiazines, hydralazine, procainamide, and phenytoin are among medications linked to the creation of APA without an increased risk of thrombosis. Hemolysis, high liver enzymes, and low platelet count in connection with pregnancy (HELLP) syndrome is another.
Sneddon syndrome, also known as APS variant syndrome, livedo reticularis syndrome, hypertension, and stroke
DIAGNOSIS
Sapporo criteria, updated in 2006 (also known as Sydney criteria):
 A minimum of one of the following clinical standards:
arterial thrombosis
1 clinical episode of arterial, venous, or small artery thrombosis in any tissue or organ, verified by unambiguous imaging tests or histopathology, without concomitant vessel wall inflammation
The criteria for APS are not met by superficial venous thrombosis.
- Pregnancy complications, include any of the following:
three successive spontaneous abortions occurring before the tenth week of pregnancy that are not related to maternal or paternal chromosomal abnormalities or maternal anatomical or hormonal reasons.
 1 unexplained deaths of morphologically normal fetuses at or before the 10th week of pregnancy (documented by ultrasound or by direct examination); 1 premature births of morphologically normal newborns at or before the 34th week of pregnancy due to severe preeclampsia, eclampsia, or placental insufficiency; AND the presence of at least one of the following laboratory findings (confirmed on
- Anticardiolipin IgG and/or IgM antibodies found in the blood using a standardized ELISA at moderate or high levels (>40 GPL or MPL or >99th percentile) indicate the presence of LAC.
- Blood anti-2-GP1 IgG and/or IgM antibody titer >99th percentile as determined by standardized ELISA


HISTORY Bleeding due to severe thrombocytopenia or acquired factor II deficiency; a personal or familial history of autoimmune disease; a history of venous thromboembolism or arterial thrombosis (stroke, MI); a history of recurrent fetal loss or other obstetric difficulties

Physical examination: venous thrombosis symptoms in the extremities; skin symptoms, such as a palpable purpura or livedo reticularis rash, superficial thrombophlebitis, or ulcers on the lower extremities;
Cardiac murmurs, focal neurologic or cognitive impairments, and Livedo reticularis

DIFFERENTIAL DIAGNOSIS Thrombophilic diseases - Acquired: Neoplastic and myeloproliferative disorders, hyperviscosity syndromes, and nephrotic syndrome - Inherited: deficiency of protein C, protein S, and antithrombin III; mutation of factor V Leiden, prothrombin gene mutation
Disseminated intravascular coagulation; paroxysmal nocturnal hemoglobinuria; heparin-induced thrombocytopenia; Behçet syndrome; CAPS: hemolytic-uremic syndrome, TTP, or malignant HTN; Embolic illness owing to atrial fibrillation, LV dysfunction, endocarditis, cholesterol emboli;

DETECTION & INTERPRETATION OF DIAGNOSIS
The preferred diagnostic tests include the LAC assay, IgG and IgM aCL by ELISA, and anti-2-GP1 IgG and IgM antibodies.
The LAC assay combines two confirming tests with at least two of the three screening tests (prolongation of aPTT, dilute Russell viper venom time [dRVVT], and kaolin clotting).
A weakly positive LAC result should be taken into consideration clinically.
Anti-2-GP1 antibodies have a critical role in the development of thrombosis. Testing for antibodies to phosphatidylserine and prothrombin can assist determine the risk of thrombosis, however frequent assessment for prothrombin antibodies is not advised.

Other autoantibodies (annexin V, phosphatidic acid, and phosphatidylinositol) are unknown clinically.

 The diagnostic and risk stratification usefulness of 2-GP1 anti-domain I antibodies is being thoroughly assessed.

Initial Examinations (Laboratory and Imaging): CBC, PT/INR, aPTT, LAC, aCL, and anti-2-GP1 antibodies

Imaging is based on clinical picture, suspected sites of thrombosis, and organ involvement. The prevalence of APAs in SLE ranges from 11% to 87%; therefore, it is crucial to screen for SLE.

Tests in the Future & Special Considerations
The LAC results in patients taking warfarin can be challenging to interpret. Fondaparinux and unfractionated heparin have no impact on the LAC assay.
 Repeat testing at 12 weeks to check for APA persistence.
Other/Diagnostic Procedures
It could be necessary to do a biopsy on the affected organ system to rule out vasculitis.
Interpretation of Tests
Thrombosis and minor perivascular or vascular irritation are typical findings:
Capillary congestion and non-inflammatory fibrin thrombi are acute alterations.
Chronic alterations include atrophy, fibrosis, and ischemic hypoperfusion

MEDICATION FOR TREATMENT First Line

Primary thromboprophylaxis is debatable in people with APS who don't have any obvious symptoms (3)[B]. A Cochrane review published in 2018 that included nine studies and 1,044 randomly assigned individuals was unable to demonstrate a clear advantage for aspirin use in patients without thrombotic events. Because the total risk of thrombosis is less than 4%, low-dose aspirin or heparin is only recommended for patients who have a high risk of thrombosis.
Secondary thromboprophylaxis: Permanent anticoagulation is required for all symptomatic, non-pregnant patients with APS. The severity and kind of the thrombus determine the goal INR:
- Arterial thrombosis or recurrent venous thrombosis despite anticoagulation: warfarin with goal INR of 3.0 to 4.0 - LMWH and fondaparinux are options. - Venous thrombosis (first episode): warfarin with target INR of 2.0 to 3.0.
Studies on APS are lacking, but direct oral anticoagulants (DOACs) like rivaroxaban, apixaban, and dabigatran have all been approved for the treatment of DVT/PE. A prospective randomized trial in 2016 comparing warfarin and rivaroxaban in patients with thrombotic APS revealed an increase in endogenous thrombin potential in patients who switched to rivaroxaban. There is insufficient data to prescribe DOACs in APS, according to the Task Force report from the 15th International Congress on Antiphospholipid Antibodies, which was published in 2017. In patients who cannot tolerate warfarin, DOACs may be used as a substitute.
In addition to failing to demonstrate noninferiority of rivaroxaban to dose-adjusted VKAs for thrombotic APS, a three-year open-label, randomized noninferiority trial in 2019 also revealed a non-statistically significant near-doubling of the risk for recurrent thrombosis.
– In extreme situations, possibly in individuals with thrombotic microangiopathy, rituximab may be an option.
When treating heparin-induced thrombocytopenia, danaparoid, fondaparinux, and argatroban should be taken into account.
Hydroxychloroquine can be given to resistant APS, statins can reduce proinflammatory and prothrombotic condition, although they are not advised in the absence of hyperlipidemia. Eculizumab may be helpful in refractory instances.
All APA-positive patients should have their vitamin D shortage or insufficiency treated, although further research is needed to determine how vitamin D affects APS.
Low-dose aspirin has an advantage over low-dose aspirin and low-dose warfarin because it reduces the risk of bleeding without affecting the number of thromboses.
In less severe situations, anticoagulants and high-dose steroids may be sufficient. In extreme cases, aggressive therapy, such as IVIG or plasma exchange, is frequently needed.
These actions have increased survival rates by up to 66%.

Treatment during pregnancy: Patients with APS who have not previously experienced thrombotic events may be prescribed low-dose aspirin; nonetheless, individual treatment choices should be made.
– Treatment options include 81 mg of aspirin alone or in combination with unfractionated heparin (5,000 to 10,000 U SC q12h) or LMWH (prophylactic dosage) for women who have had at least two early miscarriages without a history of thrombosis. A combination of aspirin and heparin is advised for people who have previously experienced a late pregnancy loss (>10 weeks' gestation) or premature delivery (34 weeks) as a result of severe preeclampsia.
– In some cases, preconception testing and treatment with low-dose aspirin, vitamin D, and folate should be made available.
– Low-dose aspirin combined with either therapeutic low-dose heparin (dosed every 8–12 hours to maintain mid-interval aPTT or factor Xa levels) or LMWH (therapeutic dose) is recommended for people with a history of thrombosis.
- Refractory situations: In spite of taking aspirin and heparin, up to 30% of patients experience repeated miscarriages.
Warfarin has no use because of the possibility of teratogenicity.
The best way to handle these situations is in consultation with a maternal-fetal medicine expert.
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OTHER PROCEDURES / URGENCY

When anticoagulation is contraindicated, patients with thrombosis may need a thrombectomy or an IVC filter.

CONTINUING CARE AFTERCARE RECOMMENDATIONS

Close monitoring is necessary throughout pregnancy. Patient monitoring. Standard guidelines for monitoring to maintain INR at therapeutic aim on warfarin medication.
Diet that is heart-friendly. Warfarin patients should stay away from foods high in vitamin K, such as kale, spinach, sprouts, and greens.

INFORMATION FOR PATIENTS Adherence to warfarin medication to maintain target INR Knowledge of food and drug interactions with warfarin Avoid oral hormonal contraceptives.


PROGNOSIS The prognosis is worsened by pulmonary HTN, neurologic involvement, cardiac ischemia, nephropathy, gangrene of the extremities, and CAPS.
In the absence of sufficient anticoagulation, there is a 30% risk of recurrent thrombosis.
COMPLICATIONS
Thrombotic problems are the most common cause of death, while pregnancy complications and pulmonary HTN are linked to greater morbidity and mortality.