AUTHOR INFORMATION

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Authored by Barry L Myones, MD, Director of Research, Pediatric Rheumatology Center, Texas Children's Hospital at Houston; Associate Professor, Departments of Pediatrics & Immunology, Pediatric Rheumatology Section, Baylor College of Medicine

Coauthored by Deborah McCurdy, MD, Director of Rheumatology, Department of Pediatric Rheumatology, Children's Hospital of Orange County

Barry L Myones, MD, is a member of the following medical societies: American Academy of Pediatrics, American Association for the Advancement of Science, American Association of Immunologists, American College of Rheumatology, American Heart Association, American Society for Microbiology, Clinical Immunology Society, and Texas Medical Association

Edited by Terry Chin, MD, Codirector of Cystic Fibrosis Center, Associate Professor, Department of Pediatrics, Loma Linda University and Children's Hospital; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; David Sherry, MD, Director of Clinical Pediatric Rheumatology, Department of Rheumatology, University of Washington Children's Hospital; Daniel Rauch, MD, Program Director, Associate Professor, Department of Pediatrics, Albert Einstein College of Medicine and Jacobi Medical Center; and Norman T Ilowite, MD, Chief, Rheumatology Division, Schneider Children's Hospital, Professor, Department of Pediatrics, Albert Einstein College of Medicine

  September 4 2002

INTRODUCTION

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Background: Antiphospholipid (aPL) antibodies have been found in association with clinical symptoms such as deep venous thrombosis, arterial occlusive events (eg, stroke, myocardial infarction), and recurrent fetal loss and with vasospastic phenomena such as migraine headache, Raynaud phenomenon, and transient ischemic attack (TIA).

The terminology associated with aPL antibodies has been fraught with misnomers. Conley and Hartmann’s observation of prolongation of the prothrombin time (PT) in a series of patients with systemic lupus erythematosus (SLE) later was termed the "lupus anticoagulant" (LAC). This term is misleading for the following reasons:  

• The LAC phenomenon can be caused by any number of antibodies to the phospholipid template of the coagulation cascade.  
• These antibodies are frequently found outside the clinical spectrum of SLE.
• Although these antibodies are responsible for a prolongation of the activated partial thromboplastin time in vitro, they are associated with a hypercoagulable state in vivo.

In the early 1980s, Harris identified anticardiolipin antibodies in a subset of these patients. Since that time, it has been determined by doctor Graham Hughes that antibodies to phospholipids alone are more often associated with infectious causes. In contrast, antibodies to combinations of phospholipids and serum proteins (eg, b2-glycoprotein I [b2-GPI] or prothrombin) are more likely associated with vasculopathic events of the antiphospholipid syndrome (APS).

The occurrence of aPL antibodies associated with vaso-occlusive events without any underlying disease process is termed the primary antiphospholipid syndrome (PAPS). The presence of aPL antibodies and a vaso-occlusive event superimposed on an underlying disease, such as SLE or malignancy, is a secondary antiphospholipid syndrome.

Preliminary classification criteria for "definite" APS were proposed in a report from the Eighth International Symposium on Antiphospholipid Antibodies and published in Arthritis and Rheumatism (Wilson, 1999).

The purpose of the report was to define the essential features of APS in order to facilitate studies of treatment and causation. These essential features of APS would encompass the clinical and laboratory features that are most closely associated with aPL in prospective studies and based on the strongest experimental evidence. The hope was to use the "cleanest" patient populations for basic research and clinical treatment studies. These criteria were not meant to supplant the physician's clinical judgment in making the diagnosis in any particular patient. Features such as migraine headache, peripheral vasospasm, and thrombocytopenia, while excluded from these published criteria, were argued at the Ninth International Symposium on Antiphospholipid Antibodies to be valid and useful clinical parameters in arriving at the diagnosis of APS in the clinical setting.

Clinical criteria  

• Vascular thrombosis - One or more clinical episodes of arterial, venous, or small vessel thrombosis in any tissue/organ confirmed by imaging/Doppler studies or histopathology (without vessel inflammation)  
• Pregnancy morbidity (normal morphology)  
  • One or more unexplained fetal deaths at more than 10 weeks of gestation  
  • One or more premature births at less than 34 weeks of gestation because of severe preeclampsia or eclampsia or placental insufficiency  
  • Three or more unexplained consecutive spontaneous abortions at less than 10 weeks of gestation, excluding maternal anatomic and/or hormonal abnormalities and paternal and/or maternal chromosomal causes

Laboratory criteria  

• Anticardiolipin (aCL) antibody of the immunoglobulin G (IgG)/immunoglobulin M (IgM) isotype in medium/high titer on 2 or more occasions at least 6 weeks apart (measured by a b2-GPI–dependent enzyme-linked immunosorbent assay [ELISA]).
• Lupus anticoagulant on 2 or more occasions at least 6 weeks apart according to the guidelines set forth by the International Society of Thrombosis and Hemostasis (for LAC/phospholipid-dependent antibodies).  
  • Prolonged phospholipid-dependent coagulation (eg, activated partial thromboplastin time [aPTT], Kaolin clotting time [KCT], dilute Russell viper venom test [DRVVT], dilute PT) 
  • Failure to correct the prolonged coagulation time by a mix with platelet poor plasma (PPP) 
  • Shortening or correction of the prolonged coagulation time with excess phospholipid
  • Exclusion of other coagulopathies (eg, factor VIII inhibitor, heparin)

A patient must meet at least one clinical and one laboratory criterion for a diagnosis of APS.

A postconference workshop was held after the Ninth International Symposium on Phospholipid Antibodies during which data were presented for modifying and expanding the above criteria, and a decision was reached not to change the criteria for research studies pending further validation studies. Future efforts, however, were to focus on guidelines for the clinical diagnosis as distinct from classification of APS.  

Pathophysiology: The mechanism or mechanisms by which the antiphospholipid antibodies interact with the coagulation cascade to produce clinical events are largely speculative and have not been elucidated clearly. The presence of preexisting or coincident vascular (endothelial) damage along with the identification of an aPL antibody as requisites for the emergence of a thrombotic complication has been coined the “two-hit” hypothesis. 

• Possible mechanisms by which aPL might induce thrombotic events include the following: 
  • aPL may combine with platelet membrane phospholipids, resulting in increased platelet adhesion and aggregation.  
  • aPL may combine with the endothelial cell membrane phospholipids along with b2-GPI and induce endothelial cell damage, impaired prostacyclin production, increased platelet adhesion, and aggregation. 
  • Endothelial cell damage may also result in decreased production of endothelium-derived relaxing factor and, thus, increased vasospasm and ischemia. 
  • In the secondary APS, vascular endothelial cell damage has already occurred, enhancing the vascular spasm/occlusion, ischemia/infarction, and reperfusion injury. 
  • b2-GPI may be bound up by aPL and (1) prevented from covering up exposed procoagulant inner membrane leaflet phospholipids or (2) blocked from inhibiting platelet prothrombinase activity.  
  • aPL may interfere with the interaction of coagulation protein C and coagulation protein S and, thus, affect the formation of the APC coagulation control complex (activated protein C, protein S, and factor V).
• Possible mechanisms by which aPL might be generated include the following:
  • Autoimmunity may be a factor; a break in tolerance may lead to an "escaped clone." 
  • Closely related to the above is the concept that aPL antibodies are a response to inner membrane leaflet antigens (ie, phosphoserine) that are exposed in apoptotic blebs on cells not eliminated from the circulation because of an overloaded or defective clearance system. 
  • aPLs may also be cross-reactive antibodies induced by exogenous antigens from infectious organisms (eg, viral or bacterial). 

Frequency:

• In the US: aPL antibodies are reportedly present in 1-15% of the general population (higher in elderly persons). The presence of these antibodies in patients with SLE is reported to be as high as 70%; however, the frequency of APS (ie, aPL antibodies plus a clinical event) is far less. In patients with SLE, a history of thrombosis was present in 61% of those with positive test results for LAC, 52% who had positive anticardiolipin antibodies, and 24% who had no aPL antibodies.

• Internationally: No major differences have been noted. A large multicenter European SLE registry suggests that 3-7% of patients with SLE and aPL are at risk for new-onset thrombosis.

Mortality/Morbidity: Mortality and morbidity are related to the clinical manifestations; an increased incidence of the following is seen in young individuals: 

• Cerebrovascular accident (CVA, stroke) 
• Myocardial infarction (MI)  
• Endocarditis (may lead to valvular replacement)  
• Pulmonary emboli (may lead to pulmonary hypertension)  
• Deep vein thrombosis (DVT) 
• Fetal loss from second trimester to the perinatal period, including intrauterine growth retardation (IUGR), prematurity, and symptoms of toxemia 
• Catastrophic APS (Multisystem failure secondary to thrombosis/infarction may lead to death in 50% of cases.)

Race: Overall, no specific race predilection exists.

• Frequency in PAPS is skewed by race predilection of risk factors for thrombosis and atherosclerotic disease.
• Frequency in secondary APS is skewed by race predilection for autoimmune diseases.

Sex:

• In secondary APS, the frequency is skewed by the female predominance in autoimmune diseases (eg, SLE) in general.
• In PAPS, the frequency is skewed by the inclusion of pregnancy-related events in the classification schema.
• In both APS and PAPS, the frequency related to sex is equalized in young patients, especially prior to the onset of puberty.

Age:

• APS has been described in patients of all ages. The prenatal, perinatal, and neonatal periods can be affected.

CLINICAL

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History: Vasospastic or vaso-occlusive events can occur in any organ system; thus, a thorough history should be taken, and an organ-specific review of systems should be performed. A broad spectrum of involvement ranging from rapidly progressive to clinically silent and indolent may be present.

• Head, ears, eyes, nose, and throat
  • Blurred or double vision 
  • Visual disturbance ("wavy lines," "flashing lights")  
  • Visual loss (field cuts, total vision loss)

• Cardiorespiratory
  • Chest pain 
  • Radiating arm pain 
  • Shortness of breath

• Gastrointestinal
  • Abdominal pain
  • Abdominal distension (bloating) 
  • "Abdominal migraine"  
  • Emesis

• Peripheral vascular
  • Leg pain  
  • Leg swelling 
  • Claudication 
  • Digital ulcerations 
  • Leg ulcerations 
  • Cold-induced finger and/or toe pain

• Musculoskeletal
  • Bone pain 
  • Joint pain
  • Muscular pain

• Cutaneous
  • Purpuric and/or petechial rashes 
  • Persistent or transient lacy rashes of livedo reticularis 
  • Dusky fingers and/or toes 
  • Blanching of fingers and/or toes

• Neurologic and psychiatric
  • Syncope 
  • Seizures  
  • Headache (migraine) 
  • Paresthesias 
  • Paralysis 
  • Ascending weakness 
  • Tremors 
  • Abnormal movements 
  • Memory loss 
  • Problems with concentrating, reading comprehension, calculations (change in school performance)

• Endocrine - Weakness, chronic fatigue, arthralgia, abdominal pain (Addisonian features)

• Genitourinary
  • Hematuria 
  • Peripheral edema

• Pregnancy-related history - Not expected to be of frequent concern in the field of pediatrics but may be significant in teenagers

• Family history - A strong family history is more pertinent to most pediatric patients; it may be a clue to identifying patients at risk. 
  • Family history of frequent miscarriage, premature birth, IUGR, oligohydramnios, chorea gravidarum, placental infarction, preeclampsia, toxemia of pregnancy, or neonatal thromboembolism 
  • Family history of MI or stroke in persons younger than 50 years  
  • Family history of DVT, phlebitis, or pulmonary embolus 
  • Strong family history of migraine, Raynaud phenomenon, or TIAs

• Medication history - Use of oral contraceptives at the time of a clinical event

Physical: Physical findings are specific to the affected organ and can involve any organ system. Catastrophic antiphospholipid syndrome is a multisystem failure secondary to thrombosis/infarction and has a picture of microangiopathy on histology.

• Peripheral vascular 
  • Point tenderness to palpation of bone or joints (bone infarction)  
  • Pain on range of motion of joints without arthritis (avascular necrosis)
  • Limb swelling (DVT)
  • Muscular pain (circulatory problems or DVT)
  • Peripheral edema (DVT, renal vein thrombosis)  
  • Decreased capillary refill (arterial thrombosis/vasospasm)  
  • Decreased pulses (arterial thrombosis/vasospasm)
  • Decreased perfusion (arterial thrombosis/vasospasm)  
  • Gangrene (arterial thrombosis/infarction)

• Pulmonary - Respiratory distress, tachypnea (pulmonary embolism [PE], pulmonary hypertension)

• Renal  
  • Hypertension (renal artery thrombosis, intrarenal vascular lesions) 
  • Hematuria (renal vein thrombosis)

• Cardiac 
  • Insufficiency murmur of aortic, mitral valve (endocarditis) 
  • Chest pain, diaphoresis (MI)

• Gastrointestinal
  • Right upper quadrant tenderness, hepatomegaly (Budd-Chiari syndrome, hepatic small vessel thrombosis, hepatic infarction)  
  • Abdominal tenderness (mesenteric artery thrombosis)

• Endocrine - Muscle weakness (including pain), progressive stiffening of pelvic and thigh muscles with flexion contractures associated with adrenal insufficiency (adrenal infarction/hemorrhage)

• Ocular
  • Retinal artery occlusion
  • Retinal vein thrombosis

• Skin manifestations
  • Livedo reticularis (see Images 1-2)
  • Purpuric lesions 
  • Superficial thrombophlebitis
  • Vasospasm (ie, Raynaud phenomenon) (see Image 3)
  • Splinter hemorrhages (periungual, subungual) (see Image 4)
  • Peripheral infarctions (digital pitting) 
  • Skin ulcerations (eg, leg ulcers) 
  • Bruising (associated with thrombocytopenia)

• Central or peripheral nervous system abnormalities
  • Stroke/CVA
  • TIA
  • Paresthesia, polyneuritis or mononeuritis multiplex (vasovasorum ischemia/infarction 
  • Paralysis, hyperreflexia, weakness (transverse myelitis, Guillain-Barré syndrome) 
  • Movement disorders - Choreiform tremors (cerebral, cerebellar, basal ganglia infarction)
  • Multiple sclerosis–like disorder 
  • Learning disability  
  • Short-term memory loss

Causes: The causes of antiphospholipid antibody syndrome are unknown (see Pathophysiology).

The association of thrombotic events with preexisting or coincident vascular perturbation is emphasized by the high incidence of APS in the following:

• Vascular inflammation, vasculitis
  • Autoimmune disease (eg, SLE, cryoglobulinemia)
  • Infectious processes (eg, hepatitis, parvovirus, syphilis)

• Malignancy (eg, carcinoma, leukemia)

• Vascular trauma
  • Postsurgery (eg, cardiac)
  • Trauma (eg, accidental)

• Drug-induced state (eg, procainamide, phenytoin, hydralazine, chlorpromazine)

• Hemodialysis-associated condition (increased aPL antibodies with time on dialysis)
  • Cuprophane membrane exposure
  • Oxidative stress

DIFFERENTIALS

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Adrenal Insufficiency
Antithrombin III Deficiency
Consumption Coagulopathy
Endocarditis, Bacterial
Hepatitis A
Hepatitis B
Hepatitis C
Mixed Connective Tissue Disease
Mononucleosis and Epstein-Barr Virus Infection
Myocardial Infarction in Childhood
Parvovirus B19 Infection
Pulmonary Infarction
Rheumatic Fever
Rheumatic Heart Disease
Syphilis
Systemic Lupus Erythematosus
Thrombasthenia
Thromboembolism
Tuberculosis
Vasculitis and Thrombophlebitis

Other Problems to be Considered:

Carcinoma
Catastrophic antiphospholipid syndrome
Cerebrovascular disease
Coagulation factor deficiencies
Coagulation factor inhibitors
Disseminated intravascular coagulation (DIC)
Essential mixed cryoglobulinemia
Factor V Leiden mutation
Fetal loss, recurrent
Guillain-Barré syndrome
Hemodialysis
Homocysteinemia
Immune thrombocytopenic purpura (ITP)
Infectious processes
Leukemia
Libman-Sacks endocarditis
Lymphoma
Malignancy
Methylene tetrahydrofolate reductase mutation (MTHFR)
Multiple sclerosis
Prothrombin 20210A mutation
Pulmonary embolus
Reactive airway disease
Sneddon syndrome
Stroke
Thrombocytopenia

 

WORKUP

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Lab Studies:

• Antiphospholipid antibody assays - If the clinical features are suggestive of an aPL antibody syndrome, a thorough search for the presence of at least one of these antibodies is imperative. See the laboratory evaluation algorithm in Image 5.
  • Evaluate for anticardiolipin, antiphosphatidylethanolamine, antiphosphatidylinositol, antiphosphatidylserine, antiphosphatidylglycerol, and antiphosphatidic acid. These antibodies are primarily of the IgG and IgM isotypes, although evidence is mounting for the clinical significance of immunoglobulin A (IgA) antibodies as well.
  • Lupus anticoagulant test: At least 2 assays need to be performed, and at least one should contain a phospholipid-dependent step. If results are positive for LAC, a 4:1 (patient-to-normal) plasma mix test should be performed to correct for any coagulation factor deficiencies but not dilute out a low-titer aPL antibody.  
    • Dilute Russell viper venom test (DRVVT)  
    • Hexagonal-phase LAC test
    • Activated partial thromboplastin time (aPTT) 
    • Platelet neutralization procedure (PNP) 
    • Kaolin clotting time (KCT) or the Kaolin clot inhibition test 
    • Dilute PT (dPT)
    • Textarin time (TT)  
    • Taipan snake venom time (TSVT)
  • Anti–b2-GPI antibodies
  • Venereal Disease Research Laboratories (VDRL) test or rapid plasma reagin (RPR) test: Extracts of bovine heart, which contain cardiolipin, are used in these tests. These assays for syphilis may produce "false"-positive results if anticardiolipin antibodies are present in the serum/plasma. VRDL and RPR tests are usually less sensitive than direct antibody testing but have a rapid turn-around time.

• Identification of intrarenal, renal artery, or renal vein thrombosis
  • Urine dipstick analysis for hemoglobin or protein
  • Urine microscopic examination for the presence of red blood cells
  • A 24-hour urine collection for protein and creatinine clearance

• Identification of persistent thrombocytopenia or evidence of hemolytic anemia 
  • Complete blood count (CBC) with platelet count and a blood smear examination 
  • Lactic acid dehydrogenase (LDH), bilirubin, haptoglobin
  • Direct/indirect Coombs test
  • Urine dipstick analysis for hemoglobin  
  • Antiplatelet antibody (to evaluate for associated autoimmune thrombocytopenic purpura)

• Coexisting deficiencies of the coagulation system
  • Protein C
  • Protein S
  • Antithrombin III
  • Antibodies to coagulation proteins, such as anti–factor II (prothrombin) antibodies

• Coexisting genetic polymorphisms
  • Factor V Leiden mutation
  • Prothrombin gene mutation 20210A
  • Methylene tetrahydrofolate reductase (MTHFR) mutations (leading to hyperhomocysteinemia) 
    • The A677V (alanine to valine) polymorphism is present in 50% of Caucasians (40% heterozygotes, 10% homozygotes).  
    • Plasma homocysteine levels should also be measured.

Imaging Studies:

• For venous thrombotic events (eg, DVT)
  • Doppler ultrasonography
  • Venography 
  • Ventilation/perfusion scan (to document pulmonary emboli)

• For arterial thrombotic events (eg, cerebral vascular, cardiovascular, peripheral vascular ischemia/occlusion)
  • Computerized tomography (CT)
  • Magnetic resonance imaging (MRI)
  • Arteriography (see Image 6)
  • Doppler ultrasonography
  • Magnetic resonance arteriography (MRA)

• For cardiac events (including vegetative valvular lesions, eg, Libman-Sacks endocarditis)
  • Two-dimensional echocardiography
  • Transesophageal echocardiography
  • MRA
  • Cardiac angiography by catheterization

Procedures:

• Biopsy of a sample of the affected organ system (eg, skin, kidney) may be necessary to establish the vasculopathy/microangiopathic picture of APS versus vasculitis.

 

TREATMENT

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Medical Care: The following are potential therapeutic interventions for various patient care scenarios. Classes of medications are suggested below, and specific drugs are covered in Medication. See the therapeutic algorithm in Image 5.

• The healthy asymptomatic patient with no risk factors and a negative family history for arterial/venous thrombosis or fetal loss: No treatment or specific follow-up care is recommended.

   

• The asymptomatic patient with a family history positive for arterial/venous thrombosis or fetal loss: Many physicians use antiplatelet prophylaxis, such as aspirin; however, others do not treat in the absence of other risk factors.

• PAPS with venous thrombosis: The initial treatment consists of heparin followed by coumadin or low molecular weight (LMW) heparin. The highest risk for recurrence is in the first 6-12 weeks postthrombosis, but many physicians treat for at least 6 months in the absence of other risk factors. Some physicians advocate treatment for life.

• PAPS with arterial thrombosis/infarction: In the absence of other risk factors, many would treat with antiplatelet therapy, but the use of anticoagulants is controversial. Some have advocated anticoagulation for life, but the recent Antiphospholipid Antibodies in Stroke Study (APASS) did not show a statistical difference between the group treated only with aspirin versus the group treated with aspirin and coumadin with regard to recurrence of stroke.

• Secondary APS with arterial or venous thrombosis: The ongoing endothelial perturbation secondary to the underlying vasculitis places these patients at continuous risk for recurrence. Antiplatelet therapy (often with combinations of aspirin, hydroxychloroquine, and pentoxifylline) plus anticoagulation (with coumadin or LMW heparin) is indicated. If the patient has positive test results for LAC and any other risk factors (eg, factor V Leiden mutation, prothrombin gene mutation, MTHFR mutation [see Coexisting genetic polymorphisms]), anticoagulation may be necessary for life.

• Catastrophic antiphospholipid syndrome
  • Antiplatelet therapy, anticoagulation, corticosteroids, and immunosuppression all have been used with varied success; however, all should be considered in this potentially lethal condition.

     

  • Consider plasmapheresis in cases of coagulopathy with an underlying vasculitis or in the catastrophic APS.

     

    • Precautions include worsening of the hypercoagulable state through the removal of coagulation control proteins such as antithrombin III. This can be ameliorated by replacement with fresh frozen plasma or concentrates instead of albumin.

       

    • Some suggest the use of intravenous immunoglobulin (IVIG) as final replacement after pheresis to decrease B-cell immunoglobulin production.

Surgical Care:

• Insertion of venous umbrella

• Thrombectomy

• Organ-specific biopsy for diagnostic purposes

• Central-line insertion for vascular access (for medications or plasmapheresis)

• Cardiac valve replacement or papillary muscle repair

Consultations: Multiple consultations may be appropriate and are dependent on the organ system involvement.

• Medical - Rheumatologist, hematologist, cardiologist, neurologist, dermatologist, ophthalmologist

• Surgical - Plastic surgeon (for peripheral vascular insults/ulcerations), cardiovascular surgeon (for valvular infarctions, papillary muscle rupture), vascular surgeon (for arterial graft/bypass, thrombus removal)

Diet:

• Identification and correction of folate deficiencies and/or elevated homocysteine levels
  • Dietary supplementation with folic acid, vitamin B-12, or both is indicated for patients with hyperhomocysteinemia.

     

  • Dietary manipulation is indicated to decrease consumption of methionine-containing foods, which may increase homocysteine levels in patients carrying mutations of the gene for MTHFR.

• Dietary counseling for patients on oral anticoagulant therapy
  • Patients should maintain a consistent diet of foods containing vitamin K. Foods rich in vitamin K include asparagus, broccoli, brussel sprouts, cabbage, cauliflower, egg yolk, kale, lettuce, liver and pâtés, potatoes, spinach, turnip greens, vegetable oils, and watercress.
  • Patients should avoid foods that have anticoagulant properties. Herbs with anticoagulant properties include dong quai (Angelica sinensis), fenugreek (Trigonella foenum-graecum), feverfew (Tanacetum parthenium), garlic (Allium sativum), ginger (Zingiber officinale), ginkgo (Ginkgo biloba), and ginseng (Panax ginseng).

• Dietary manipulation to prevent obesity, hyperlipidemia, and hypertension, starting at a young age, especially in patients with a family history of these problems

Activity:

• Physical activity: No specific limitations on activity are needed for individuals with aPL antibodies or APS other than those imposed by residua from a thromboembolic event (eg, stroke, MI). However, certain restrictions are prudent for individuals who are anticoagulated.
  • Avoid contact sports and high impact activities.
  • Use protective headgear (helmet) for sports (eg, bicycle riding, skating).

• Travel: Recent studies have demonstrated Doppler evidence of DVT after prolonged air travel. These data have stimulated discussion of possible prophylaxis for travelers with aPL antibodies.
  • Antiplatelet therapy for asymptomatic individuals with aPL and additional risk factors for the duration of any prolonged travel
  • Anticoagulation with LMW-heparin injections for the duration of air travel (or any travel in which the individual is cramped and stationary) longer than 6 hours if the patient has positive test results for LAC and additional risk factors

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Very few studies have addressed the efficacy of any treatment protocol. Most are small retrospective analyses or anecdotal reports. Many prospective studies have included too few patients and have been hampered by a lack of homogeneity of test groups. The Sapporo criteria were established, in part, to ensure a uniform homogeneous test population in order to promote accurate prospective studies of treatment protocols for patients with APS.

Drug Category: Antiplatelet agents -- Aspirin inhibits prostaglandin synthesis, preventing formation of platelet-aggregating thromboxane A₂. It is used in low doses to inhibit platelet aggregation and improve complications of venous stases and thrombosis. However, doses as low as 5 mg/kg appear to additionally inhibit prostacyclin, thus promoting a procoagulant state. Ticlopidine does not inhibit cyclooxygenase and, in this way, differs from aspirin. It inhibits the primary and secondary phase of aggregation induced by adenosine 5’-diphosphate (ADP) and reduces platelet-derived growth factor. Ticlopidine may also impair platelet adhesion, resulting in prolonged bleeding time. Dipyridamole potentiates the inhibitory effects of aspirin on platelet aggregation.

FOLLOW-UP

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Further Inpatient Care:

• Further inpatient care is only on an as-needed basis for management of thrombotic events but may include the following:
  • Imaging
  • Medical therapy
  • Invasive procedures for thrombolytic therapy
• Further inpatient care is indicated if a catastrophic APS occurs.

Further Outpatient Care:

• Interval care includes the following:
  • History and physical examination for signs and symptoms of thrombotic or vasospastic events
  • Laboratory testing for monitoring anticoagulant therapy, aPL antibody testing, and, in the case of secondary APS, underlying disease activity
  • Imaging/Doppler studies for follow-up of previous thrombotic process
  • Dietary and lifestyle counseling

In/Out Patient Meds:

• Antiplatelet therapy, such as aspirin, dipyridamole, hydroxychloroquine, ticlopidine, clopidogrel, or combinations of these agents
• Vasodilator and/or antiplatelet therapy, such as pentoxifylline or cilostazol
• Vasodilators, such as niac