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Antiphospholipid syndrome

Antiphospholipid antibodies are a heterogeneous group of antibodies primarily directed against various phospholipid-binding proteins.

Defining laboratory criteria: Repeated positive tests for antiphospholipid antibodies, lupus anticoagulant, anticardiolipin antibodies, anti-beta 2 glycoprotein I antibodies of immunoglobulin IgG, and/or IgM isotype at moderate to high titers.

Diagnosis requires one or more thrombotic, embolic or adverse obstetric events in combination with persistently elevated antiphospholipid antibodies and/or a lupus anticoagulant.

Cause syndrome of venous and arterial thrombosis, pregnancy complications, including miscarriage, fetal death, intrauterine growth retardation and pre-eclampsia.

The thrombotic manifestations include: venous, arterial, or micro vascular forms of thrombosis.

Approximately 50% of thrombotic events are deep vein thrombosis of the lower limbs or pulmonary embolism and 30% are stroke are transient ischemic attack.

Antiphospholipid antibodies  are directed at different pathways of the  coagulation process and inhibit natural anticoagulants  and the fibrolytic  system and activation of endothelial cells, platelets and the complement system.

Beta two glycoprotein I has high affinity for anionic membrane phospholipids and  in the presence ofantiphospholipid antibodies affect coagulation and/or fibrinolysis on those cellular services.

The dRVVT is one component of a workup of a suspected antiphospholipid antibody.

 

 

Other component being the serological testing for anticardiolipin antibodies and anti-β2 glycoprotein-I antibodies using ELISA technology. 

Antiphospholipid   anti-bodies can react with plasmin  and down regulate blood clot  lysis.

Antiphospholipid antibodies may inhibit activity of tissue factor pathway inhibitor, an inhibitor of coagulation activation.

Antiphospholipid antibodies maybe transitively elevated due to an infection.

A disease associated with arterial and venous thrombosis in virtually any organ, and is responsible for fetal losses and pregnancy disorders.

APS-associate a pregnancy mobility includes recurrent early unexplained miscarriage, fetal death after 10 weeks gestation, and premature delivery before 34 weeks gestation because of preeclampsia/eclampsia or placental insufficiency.

Associated with heterogeneous family of autoantibodies directed against proteins that anionic phospholipids.
The pathophysiology of thrombotic APS is binding of the Beta2 glycoprotein I to exposed negatively charged phospholipids.
A domain Arg39-Arg-43 -Beta 3GPI subsequently interacts with surface receptors, with activation of endothelial inflammatory cells causing prothrombotic and pro inflammatory hemostatic changes.

Such autoantibodies are the basis for the pro-thrombotic state of the APS.

Syndrome may be isolated or may be associated with autoimmune diseases such as SLE.

Approximately 15% of patients with SLE have APS, which is associated with a more complicated course.

The most common thrombotic events are DVT, pulmonary embolism, stroke, transit ischemic attack, and myocardial infarction.

In addition to thrombosis, vascular cellular infiltrates and fibrosis of the intima and media develop in affected patients.

Associated with intimal hyperplasia in the most severe forms of APS, and such lesions develop despite anticoagulation, suggesting the coagulation defect is not central to the lesions.

Such fibrotic lesions have been identified in the coronary, carotid, mesenteric, and renal arteries associated with life-threatening complications.

Renal involvement of intimal and media fibrosis may be associated with end-stage renal failure.

mTORC (mTOR Complex) plays a crucial and vascular stenosis that results from mechanical endothelial injury.

mTORC pathway is involved in the vascular lesions associated with antiphospholipid syndrome.

Fetal loss, early and late, and premature birth or frequent manifestation of the APS.

Prevalence of anti-phospholipid antibodies ranges from 1-10% in the general population and higher among the elderly.

Prevalence estimated at 40-50 per 100,000 people, with a female driving to male ratio approximately 5 to 1.

APS that is catastrophic accounts for approximately 1% of cases, slewith an overall mortality rate of 37%, and is the most severe form of APS, with multiple organ thromboses.

Prevalence of anti-phospholipid antibodies about 30-40% in patients with systemic lupus erythematosus (Petri M).

Risk of a thrombotic event in asymptomatic patients with antiphospholipid antibodies is about 3% per year (Erkan D et al).

In women with recurrent fetal loss 5-60% have antiphospholipid antibodies, and in unselected women such as the bodies were found in 3-5% (Heilmann L et al).

Antiphospholipid antibodies found in APS also found in malignancies, infections and with some medications.

Antigens for phospholipid antibodies include prothrombin, protein C complex, Beta 2 glycoprotein I, factors VII, XI, XII, fibrinolytic system proteins and annexin A5.

Secondary antiphospholipid syndrome associated with other conditions such as systemic lupus.

Primary antiphospholipid syndrome reflects an absence of underlying rheumatologic disorder or systemic lupus erythromatosus.

Defined as the occurrence of venous or arterial thrombosis or recurrent fetal loss in association with a positive lupus anticoagulant, or beta-2 glycoprotein 1 antibody levels in which the test remains positive for a minimum of of 12 weeks following the thrombotic process.

Primary AS associated with Libman-Sachs endocarditis 35-50% of patients with a potential for systemic embolization.

Seen with SLE, connective tissue disease, autoimmune disorders, malignancy, HIV infection and drug reactions.

Can be caused by infections due to bacteria, viruses, fungi or parasites.

Antiphospholipid antibody syndrome may be associated with medications such as chlorpromazine, hydralazine and procainamide.

May be seen in healthy individuals.

Catastrophic APS accounts for 1% of cases and is associated with a rapidly progressive multi-organ process with small blood vessel occlusions.

Catastrophic APS is associated with a mortality of about 50% (Cervera R et al).

46% of patients with catastrophic APS develop it de novo.

Catastrophic  APS presents primarily with pulmonary involvement  with acute respiratory distress syndrome and  pulmonary embolism, and abdominal  manifestations involving the kidney, liver, G.I. tract, spleen, adrenal gland, pancreas, cerebral manifestations with micro infarcts, seizures and headaches, cardiac disease with heart failure, valve lesions, myocardial infarction, and skin manifestations including  necrosis and livedo reticularis.

Diagnosis requires the presence of at least one clinical and one laboratory criterion as noted below.

Diagnostic  clinical criteria:1) the vascular thrombosis: one or more venous, arterial, or small vessel  thrombotic events, 2)  pregnancy morbidity: one or more unexplained deaths of a morphologically normal fetus at or beyond the 10th week of gestation, one or more premature births of a  morphologically normal neonate before the 34th week of gestation because of eclampsia,  severe preeclampsia, or placental insufficiency, or three or more consecutive spontaneous abortions before the 10th week of gestation in the absence of chromosomal causes and maternal anatomic or hormonal abnormalities.

Purely obstetric APS is characterized by pregnancy morbidity in women without a history of thrombosis, with repeated unexplained abortions before the 10th week, unexplained fetal loss at or after the 10th week, or premature birth before 34 weeks because of preeclampsia.

Nonbacterial thrombotic endocarditis secondary to antiphospholipid syndrome is to be considered in patients with stroke and cardiac vegetation, especially in the absence of sepsis.

Nonbacterial thrombotic endocarditis occasionally occurs in malignancy.

Patients who have drug induced antiphospholipid syndrome often have immunoglobulin IgM antibodies.

Overall incidence of thrombotic events 2.5% patients per year and higher if there has been a past history of a thrombotic episode.

Antiphospholipid antibodies can activate endothelial cells, increasing cellular adhesion molecules, tissue factor and enhance coagulation.

Antiphospholipid antibodies increase platelet GpIIb-IIIa expression and increase thromboxane A2 synthesis, stimulating platelet aggregation.

Fetal loss may involve beta2-GP1 binding to trophoblasts membranes and interfere with placentation (Di Simone N et al).

In a study of 1000 patients with a mean age of 34 years at onset of the APS the most frequent thrombotic events were DVT (31.7%), stroke (13.1%), superficial vein thrombosis (9.1%), pulmonary embolism (9%), TIA (9%), and myocardial infarction (2.8%) (Cervera R et al).

One of the characteristic renal manifestations is thrombotic microangiopathy with microalbuminuria.

About one third of patients with this syndrome present with venous thromboembolism (Farmer-Boatwright).

Approximately 20% of patients with DVT or pulmonary embolism have high levels of antiphospholipid antibodies before the thrombotic event.

Associated with an approximately twofold increase in the risk for recurrent venous thrombosis in the patient with unprovoked VTE.

Frequent manifestations at onset include thrombocytopenia, 21.9%, livedo reticularis, 20.4%, and less frequent manifestations are skin ulcers, hemolytic anemia, gangrenous digits, amaurosis fugax, epilepsy, and vascularlitic-like lesions

Coexistence of SLE or lupus like syndrome or other rheumatologic disorders has been documented in 47% of patients (Cercera R et al).

Fetal loss is the initial presentation in 10% of women.

Great majority of patients are healthy and have no underlying medical conditions and have primary rather than secondary antiphospholipid syndrome.

Antibodies may be transient and asymptomatic.

Most patients experience thrombotic disorders and a small minority experience bleeding complications.

The incidence of thrombosis ranges from 29-55% with an average follow-up of less than 6 years.

Recommended INR greater than 3.

Thromboprophylaxis with heparin and low dose aspirin is recommended for mothers with antiphospholipid syndrome and with a history of fetal loss.

Exacerbations in the syndrome reported to occur during postpartum hypercoagulability.

Catastrophic antiphospholipid antibody syndrome carries a high risk of death: preliminary criteria-involvement of three or more organs, or tissues, development of simultaneous manifestations or over less than 1 week, histological evidence of small vessel occlusion in at least one tissue, presence of lupus anticoagulant, anticardiolipin antibodies or both, definite diagnosis includes all four of the above criteria.

Catastrophic antiphospholipid syndrome associated with a death rate as high as 46% during the initial presentation (Erkan).

Catastrophic antiphospholipid syndrome diagnostic criteria: evidence of involvement of three or more organ systems, development of manifestations simultaneously or in less than 1 week, histopathological evidence of small vessel occlusion in at least one organ or tissue and lab confirmation of anti-phospholipid antibodies.

A negative test for lupus anticoagulant does not rule out the presence of the antiphospholipid syndrome, as antiphospholipid antibodies including IgG and IgM anticardiolipin antibodies, and IgG and IgM anti-beta 2 glycoprotein 1 antibodies need to be considered.

The more antiphospholipid antibodies that are present and the higher the levels, the greater the thrombotic risk.

The presence of factor V Leiden, prothrombin variant 20210, protein C, S and antithrombin III deficiencies with antiphospholipid antibodies increase the thrombotic risk to higher levels.

Risk of thrombosis during pregnancy with antiphospholipid antibodies is 5% (Branch), and it is recommended that aspirin and subcutaneous heparin or low-molecular heparin be utilized throughout pregnancy and for 6 weeks after delivery.

Presently, low molecular weight heparin is the preferred treatment for up symmetric APS because of its practicality and safety.

Following unprovoked venous thrombotic event with APLS patients should receive anticoagulation agents indefinitely.

Laboratory diagnostic criteria:

Lupus anticoagulant present in plasma on two or more occasions at least 12 weeks apart.

Anticardiolipin antibodies, IgG or IgM, present in serum or plasma on two or more occasions at lease 12 weeks apart.

Anti-beta2 glycoprotein1 antibodies IgG or IgM, present considerable plasma from two or more occasions at least 12 weeks apart.

Unexplained prolongation of the activated partial thromboplastin time (aPTT)is found in approximately 2/3 of patients at the time of initial diagnosis.

Heparin and warfarin may cause false positive test for lupus anticoagulants, while testing for cardiolipin or beta-2 glycoprotein I antibodies is not influenced by anticoagulant therapy.

Often treated by giving aspirin to inhibit platelet activation, and/or warfarin as an anticoagulant.

The goal of the prophylactic treatment with warfarin is to maintain the patient’s INR between 2.0 and 3.0.

Treatment usually not given to patients who have had no thrombotic symptoms.

Anticoagulation appears to prevent miscarriage in pregnant women.

In pregnancy, low molecular weight heparin and low-dose aspirin are used instead of warfarin because of warfarin’s teratogenicity.

Warfarin appears to be preferable to DOACs as the latter have recently been found less effective than expected.

Long term anticoagulation has been the only treatment shown to reduce vascular complications.

The Antiphospholipid antibody syndrome is an important marker for recurrent thrombosis.

 

Anticoagulation however does not prevent organ deterioration or death in high-risk patients, particularly in those who have catastrophic antiphospholipid syndrome.

Anti-phospholipid autoantibodies have been detected in 30-52% of samples of patients with severe Covid-19 accounting for the predisposition to thromboembolism.

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