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  APLS - Latest Information

Latest Information

Synonyms, Key Words, and Related Terms: anti-phospholipid antibody syndrome, Hughes syndrome, Hughes' syndrome, antiphospholipid syndrome, anti-phospholipid syndrome, APS, APLS, Sneddon syndrome, Sneddon’s syndrome, thrombosis

AUTHOR INFORMATION Section 1 of 12    Click here to go to the top of this page Click here to go to the next section in this topic

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 Section 2 of 12   Click here to go to the next section in this topic Click here to go to the top of this page Click here to go to the next section in this topic

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 or APLS).

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" Antiphospholipid Syndrome (APS or APLS) 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 Antiphospholipid Syndrome (APS or APLS) in order to facilitate studies of treatment and causation. These essential features of Antiphospholipid Syndrome (APS or APLS) 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 Antiphospholipid Syndrome (APS or APLS) 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 Antiphospholipid Syndrome (APS or APLS).

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 Antiphospholipid Syndrome (APS or APLS).  

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 Antiphospholipid Syndrome (SAPS or SAPLS), 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 Antiphospholipid Syndrome (APS or APLS) (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 Antiphospholipid Syndrome (SAPS or SAPLS) is skewed by race predilection for autoimmune diseases.

Sex:

  • In secondary Antiphospholipid Syndrome (SAPS or SAPLS), 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 Antiphospholipid Syndrome (APS or APLS) and PAPS, the frequency related to sex is equalized in young patients, especially prior to the onset of puberty.

Age:

  • Antiphospholipid Syndrome (APS or APLS) has been described in patients of all ages. The prenatal, perinatal, and neonatal periods can be affected.
CLINICAL Section 3 of 12   Click here to go to the next section in this topic Click here to go to the top of this page Click here to go to the next section in this topic

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
    • 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 Antiphospholipid Syndrome (APS or APLS) 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 Section 4 of 12   Click here to go to the next section in this topic Click here to go to the top of this page Click here to go to the next section in this topic

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 Section 5 of 12   Click here to go to the next section in this topic Click here to go to the top of this page Click here to go to the next section in this topic

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)
    • 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 Antiphospholipid Syndrome (APS or APLS) versus vasculitis.
Histologic Findings: This is a thrombotic microangiopathic process characterized by a noninflammatory vasculopathy without vasculitis. Fibrin thrombi are associated with fibrous intimal hyperplasia and obstruction by recanalized intimal connective tissue. Renal lesions, in particular, are characterized by fibrotic vascular occlusion with acute thrombosis and vaso-oclusive lesions of the intrarenal vessels. Interstitial fibrosis and tubular atrophy are also present. See histopathology Images 7-9.

 
TREATMENT Section 6 of 12   Click here to go to the next section in this topic Click here to go to the top of this page Click here to go to the next section in this topic

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.
  • Primary Antiphospholipid Syndrome (PAPS or PAPLS) 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 Antiphospholipid Syndrome (APS or APLS) 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
Section 7 of 12   Click here to go to the next section in this topic Click here to go to the top of this page Click here to go to the next section in this topic

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 Antiphospholipid Syndrome (APS or APLS).

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.

 

Drug Name

Aspirin (Anacin, Ascriptin, Bayer Aspirin, Bayer Buffered Aspirin) -- Used for antiplatelet effect. Inhibits prostaglandin synthesis, preventing formation of platelet-aggregating thromboxane A2. May be used in low dose to inhibit platelet aggregation and improve complications of venous stases and thrombosis.

Adult Dose

1-2 mg/kg/d PO for antiplatelet effect

Pediatric Dose

Limited comparative data exist for effective antiplatelet dose in pediatrics; 1-2 mg/kg/d PO is a typical dose

Contraindications

Documented hypersensitivity; liver damage, hypoprothrombinemia, vitamin K deficiency, bleeding disorders, asthma; because of association of aspirin with Reye syndrome, do not use in children (<16 y) with influenzalike illnesses

Interactions

Effects may decrease with antacids and urinary alkalinizers; corticosteroids decrease salicylate serum levels; additive hypoprothrombinemic effects and increased bleeding time may occur with coadministration of anticoagulants; may antagonize uricosuric effects of probenecid and increase toxicity of phenytoin and valproic acid; doses >2 g/d may potentiate glucose lowering effect of sulfonylurea drugs

Pregnancy

D - Unsafe in pregnancy

Precautions

May cause transient decrease in renal function and aggravate chronic kidney disease; avoid use in patients with severe anemia, with history of blood coagulation defects, or taking anticoagulants

 

Drug Name
Ticlopidine (Ticlid) -- Used for livedoid vasculitis/thromboembolic disorders. Second-line antiplatelet therapy for patients who cannot tolerate or in whom aspirin therapy has failed.
Adult Dose 250 mg PO bid
Pediatric Dose Not established
Contraindications Documented hypersensitivity; neutropenia or thrombocytopenia, liver damage, and active bleeding disorders
Interactions Effects may decrease with coadministration of corticosteroids and antacids; toxicity increases when taken concurrently with theophylline, cimetidine, aspirin, or NSAIDs
Pregnancy B - Usually safe but benefits must outweigh the risks.
Precautions Discontinue if absolute neutrophil count decreases to <1200/mm3 or if platelet count falls to <80,000/mm3

 

Drug Name
Dipyridamole (Persantine) -- Used for thromboembolic disorders to complement usual aspirin or warfarin therapy. Platelet adhesion inhibitor that possibly inhibits RBC uptake of adenosine, which is an inhibitor of platelet reactivity. In addition, may inhibit phosphodiesterase activity, leading to increased cyclic-3',5'-adenosine monophosphate within platelets and formation of the potent platelet activator thromboxane A2.
Used alone or in combination with low-dose aspirin therapy as indicated above. Also used in combination with low-dose oral anticoagulant therapy (with or without aspirin) in children with mechanical prosthetic heart valves.
Adult Dose 75-400 mg/d PO divided tid/qid
Pediatric Dose <12 years: 3-6 mg/kg/d PO divided tid
>12 years: Administer as in adults
Contraindications Documented hypersensitivity
Interactions Theophylline may decrease the hypotensive effects; antiplatelet activity of dipyridamole may increase heparin toxicity
Pregnancy B - Usually safe but benefits must outweigh the risks.
Precautions Caution in hypotension; medication has peripheral vasodilating effects

 

Drug Name
Heparin -- Used for thromboembolic disorders. Augments activity of antithrombin III and prevents conversion of fibrinogen to fibrin. Does not actively lyse, but is able to inhibit further thrombogenesis. Prevents reaccumulation of clot after spontaneous fibrinolysis. Used as a continuous infusion while initiating oral warfarin therapy.
Adult Dose Initial dose: 40-170 U/kg IV
Maintenance infusion: 18 U/kg/h IV
Alternatively, 50 U/kg/h IV initially, followed by continuous infusion of 15-25 U/kg/h, increase dose by 5 U/kg/h q4h prn using PTT results (PTT at 2 times baseline)
Pediatric Dose Initial dose: 50 U/kg IV
Maintenance infusion: 15-25 U/kg/h IV
Increase dose by 2-4 U/kg/h q6-8h prn using PTT results (PTT at 2 times baseline)
Contraindications Documented hypersensitivity; subacute bacterial endocarditis, active bleeding, history of heparin-induced thrombocytopenia
Interactions Digoxin, nicotine, tetracycline, and antihistamines may decrease effects; NSAIDs, aspirin, dextran, dipyridamole, and hydroxychloroquine may increase heparin toxicity
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions In neonates, preservative-free heparin recommended to avoid possible toxicity (gasping syndrome) by benzyl alcohol, which is used as preservative; caution in severe hypotension and shock; monitor for bleeding in peptic ulcer disease, menstruation, increased capillary permeability, and when giving IM injections

 

Drug Name
Enoxaparin (Lovenox) -- Used for thromboembolic disorders. Prevents DVT, which may lead to PE in patients undergoing surgery who are at risk for thromboembolic complications.
Enhances inhibition of factor Xa (preferentially) and thrombin (factor IIa) by increasing antithrombin III activity. The ratio of antifactor Xa to antifactor IIa activity is approximately 4:1 (1:1 for unfractionated heparin)
Adult Dose Prophylaxis (average dose): 30 mg SC q12h
Treatment (suggested dose): 1 mg/kg/dose SC q12h
Pediatric Dose Not established; suggested dose for prophylaxis:
<2 months: 0.75 mg/kg/dose SC q12h
>2 months: 0.5 mg/kg/dose SC q12h
Suggested dose for treatment:
<2 months: 1.5 mg/kg/dose SC q12h
>2 months: 1 mg/kg/dose SC q12h
Adjust dose by monitoring anti–factor Xa and aPTT
Contraindications Documented hypersensitivity; major bleeding, thrombocytopenia
Interactions Platelet inhibitors or oral anticoagulants such as dipyridamole, salicylates, aspirin, NSAIDs, sulfinpyrazone, and ticlopidine may increase risk of bleeding
Pregnancy B - Usually safe but benefits must outweigh the risks.
Precautions If thromboembolic event occurs despite LMW-heparin prophylaxis, discontinue drug and initiate alternate therapy; elevation of hepatic transaminases may occur but is reversible; heparin-associated thrombocytopenia may occur with fractionated LMW heparins; 1 mg of protamine sulfate reverses effect of approximately 1 mg of enoxaparin if significant bleeding complications develop

 

Drug Name
Warfarin (Coumadin) -- Used for thromboembolic disorders. Interferes with hepatic synthesis of vitamin K–dependent coagulation factors. Used for prophylaxis and treatment of venous thrombosis, pulmonary embolism, and thromboembolic disorders.
Adjust dose to maintain an INR in the range of 2.5-3.5.
Adult Dose 5-15 mg/d PO qd for 2-5 d; adjust dose according to desired INR (range 2.5-3.5)
Pediatric Dose Administer weight-based dose of 0.05-0.34 mg/kg/d PO; adjust dose according to desired INR (range 2.5-3.5)
Contraindications Documented hypersensitivity; severe liver or kidney disease; open wounds or GI ulcers
Interactions Drugs that may decrease anticoagulant effects include griseofulvin, carbamazepine, glutethimide, estrogens, nafcillin, phenytoin, rifampin, barbiturates, cholestyramine, colestipol, vitamin K, spironolactone, oral contraceptives, and sucralfate
Medications that may increase anticoagulant effects of warfarin include oral antibiotics, phenylbutazone, salicylates, sulfonamides, chloral hydrate, clofibrate, diazoxide, anabolic steroids, ketoconazole, ethacrynic acid, miconazole, nalidixic acid, sulfonylureas, allopurinol, chloramphenicol, cimetidine, disulfiram, metronidazole, phenylbutazone, phenytoin, propoxyphene, gemfibrozil, acetaminophen, and sulindac
Pregnancy X - Contraindicated in pregnancy
Precautions Do not switch brands after achieving therapeutic response; caution in active tuberculosis or diabetes mellitus; patients with protein C or S deficiency are at risk of developing skin necrosis; abrupt withdrawal of warfarin may result in a thrombotic event

 

Drug Category: Immunomodulators -- Immune globulin is a purified preparation of gamma globulin. It is derived from large pools of human plasma and is comprised of 4 subclasses of IgG antibodies, approximating the distribution of human serum. IgA-depleted products are also low in the IgG4 component.
Drug Name
Immune globulin intravenous (Sandoglobulin, Gammagard, Gamimune, Gammar-P) -- Used for autoimmune diseases. Neutralizes circulating myelin antibodies through antiidiotypic antibodies; down-regulates proinflammatory cytokines, including INF-gamma; blocks Fc receptors on macrophages; suppresses inducer T and B cells and augments suppressor T cells; blocks complement cascade; promotes remyelination; may increase CSF IgG (10%).
Adult Dose 2 g/kg IV over 2-5 d
Pediatric Dose Not established
Suggested dose: 1-2 g/kg IV over 2-5 d
Contraindications Documented hypersensitivity; IgA deficiency; IgE/IgG anti-IgA antibodies
Interactions Globulin preparation may interfere with immune response to live virus vaccine (MMR) and reduce efficacy (do not administer within 3 mo of vaccine)
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions Check serum IgA before IVIG (use IgA-depleted product, eg, Gammagard S/D); infusions may increase serum viscosity and thromboembolic events; infusions may increase risk of migraine attacks, aseptic meningitis (10%), urticaria, pruritus, or petechiae (2-5 d postinfusion to 30 d)
Increases risk of renal tubular necrosis in elderly patients and in diabetes mellitus, volume depletion, and preexisting kidney disease; lab result changes associated with infusions include elevated antiviral or antibacterial antibody titers for 1 mo, 6-fold increase in ESR for 2-3 wk, and apparent hyponatremia

 

Drug Category: Vasodilators -- These agents are used to lower elevated blood pressure, decrease vasospasm, or prevent ischemia. Niacin is also used to decrease hyperlipidemia.
Drug Name
Nitroglycerin ointment (Nitrol, Nitro-Bid) -- Causes relaxation of vascular smooth muscle by stimulating intracellular cyclic guanosine monophosphate production. The result is a decrease in blood pressure.
Onset of action for ointment is in 20-60 min. Duration of effect is 2-12 h.
Adult Dose 2% ointment (20 mg/g): Apply 1-2 inches topically to chest wall or extremity with occlusive dressing, such as Tegaderm q8h
Adjust dose for clinical effect
Pediatric Dose 2% ointment (20 mg/g): Apply 0.5-1 inch topically to chest wall or extremity with occlusive dressing, such as Tegaderm q8h
Adjust dose for clinical effect
Contraindications Documented hypersensitivity; severe anemia, shock, postural hypotension, head trauma, closed-angle glaucoma, or cerebral hemorrhage
Interactions Aspirin may increase serum nitrate concentrations; marked symptomatic orthostatic hypotension may occur with coadministration of calcium channel blockers (dose adjustment of either agent may be necessary)
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions Caution in coronary artery disease and low systolic blood pressure; care must be taken to avoid placing fingers in mouth or near eyes

 

Drug Name
Niacin (Niacor, Niaspan, Nicotinex, Slo-Niacin) -- Also called nicotinic acid or vitamin B-3. Component of 2 coenzymes necessary for tissue respiration, lipid metabolism, and glycogenolysis; inhibits synthesis of VLDL. Used as a dietary supplement and as adjunctive treatment of hyperlipidemias, peripheral vascular disease, circulatory disorders, and treatment of pellagra.
Onset of action within 20 min (extended release within 1 h). Duration of effect 20-60 min (extended release 8-10 h). Half-life 45 min.
Adult Dose 50-100 mg PO tid with an upward titration until desired effect is obtained or until adverse effects are not tolerable (used in hyperlipidemia at a dosage range of 1.5-6 g/d PO divided tid)
Once dosage established, sustained-release capsule or tablet can be used
Pediatric Dose Not established
Suggested dose: Administer as in adults with gradual upward titration
Contraindications Documented hypersensitivity; severe hypotension; arterial hemorrhage; active liver disease or unexplained, significant increases in AST and ALT; large doses of niacin, especially when administered in a sustained-release form (associated with severe hepatotoxicity); a definite and recent history of peptic ulcer disease (can reactivate ulcers); GERD
Interactions Cutaneous vasodilation may be a problem if high dose used with peripheral dilators, such as nitroglycerin, or with adrenergic blocking agents
Taking aspirin 30-60 min before first dose of the day may help alleviate prostaglandin-mediated adverse effects of niacin (ie, flushing, itching, headache); clonidine may inhibit niacin-induced flushing
May decrease effect of oral hypoglycemic agents, may inhibit uricosuric effects of sulfinpyrazone and probenecid, and may increase risk of myopathy with lovastatin
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions Caution in gallbladder disease or diabetes mellitus and in persons predisposed to gout; monitor blood glucose; may elevate uric acid levels; pregnancy category C when used at doses higher than RDA; some products may contain tartrazine

 

Drug Category: Drugs with effects on vascular endothelium, platelets, red blood cells -- These drugs appear to have multiple mechanisms in the prevention of thrombosis and vascular spasm. The exact mechanisms are largely unexplained, but changes in red blood cell rheology, inhibition of platelet adhesiveness/activation, inhibition of TNF-alpha production, and decreases in neutrophil and endothelial cell activation are some of the properties of these drugs.
Drug Name
Pentoxifylline (Trental) -- Used for vascular disease. May alter rheology of red blood cells, which, in turn, reduces blood viscosity. Improves peripheral perfusion and vascular spasm in Raynaud phenomenon and vasculopathy/vasculitis.
Other effects include inhibition of platelet adhesiveness/activation, inhibition of TNF-alpha production, and decrease in neutrophil and endothelial cell activation.
Adult Dose 400 mg PO tid pc; may reduce frequency to bid if GI or CNS adverse effects occur
Pediatric Dose Not established
Suggested doses:
<25 kg: Not established, doses of 20 mg/kg/d PO divided tid (and higher) have been used in Kawasaki disease; doses of 30 mg/kg/d have been infused IV over 6-h periods in preterm infants; doses of 40-60 mg/kg/d have been used in peripheral vascular disease
25-40 kg: 400 mg PO bid
>40 kg: 400 mg PO tid
Decrease dose frequency if GI or CNS adverse effects occur
Contraindications Documented hypersensitivity; cerebral and/or retinal hemorrhage
Interactions Coadministration with cimetidine or theophylline, increases effect/toxic potential; pentoxifylline increases effect of antihypertensives
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions Caution in renal impairment

 

Drug Name
Hydroxychloroquine (Plaquenil) -- Inhibits platelets, chemotaxis of eosinophils, locomotion of neutrophils, and impairs complement-dependent antigen-antibody reactions.
Hydroxychloroquine sulfate 200 mg is equivalent to 155 mg hydroxychloroquine base and 250 mg chloroquine phosphate.
Adult Dose 310 mg (base) PO qd or bid for several wk depending on response; 155-310 mg/d for prolonged maintenance therapy
Pediatric Dose 3-5 mg base/kg/d PO qd or divided bid; not to exceed 7 mg/kg/d
Contraindications Documented hypersensitivity; psoriasis; retinal and visual field changes attributable to 4-aminoquinolones
Interactions Serum levels increase with cimetidine; magnesium trisilicate may decrease absorption
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions Caution in hepatic disease, G-6-PD deficiency, psoriasis, and porphyria; not recommended for long-term use in children (but has been used for long courses in the treatment of JRA); perform periodic (6 mo) ophthalmologic examinations especially for color and peripheral vision; test periodically for muscle weakness

 

Drug Name
Cilostazol (Pletal) -- Affects vascular beds and cardiovascular function. May improve blood flow by altering rheology of red blood cells. Produces nonhomogenous dilation of vascular beds, with more dilation in femoral beds than in vertebral, carotid, or superior mesenteric arteries.
Cilostazol and its metabolites are inhibitors of phosphodiesterase III and, as a result, cyclic AMP is increased, which leads to inhibition of platelet aggregation and vasodilation.
Adult Dose 100 mg PO bid at least 30 min ac or 2 h pc
Decrease to 50 mg bid if coadministering drugs that inhibit clearance (see interactions)
Pediatric Dose <12 years: Not established
>12 years: Administer as in adults
Contraindications Documented hypersensitivity; CHF; coadministration with grapefruit juice
Interactions Inhibitors of CYP3A4 (eg, diltiazem, erythromycin, grapefruit juice, itraconazole, ketoconazole, macrolide antibiotics) or CYP2C19 (eg, ketoconazole, omeprazole) may increase levels
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions Caution in renal impairment; do not prescribe or administer without thoroughly reading complete prescribing information

 

Drug Category: Platelet count enhancers -- These agents are used to augment platelet recovery.
Drug Name
Vincristine (Oncovin, Vincasar PFS) -- Mechanism of action for treatment of thrombocytopenia is uncertain. May involve a decrease in reticuloendothelial cell function or an increase in platelet production. However, neither of these mechanisms fully explains the effect in TTP and HUS.
Adult Dose 0.4-1.4 mg/m2 IV; not to exceed 2 mg/dose IV push; repeat weekly prn for effect
Pediatric Dose 1-2 mg/m2 IV; not to exceed 2 mg/dose IV push; repeat weekly prn for effect
Contraindications Documented hypersensitivity; IT administration (may be fatal)
Interactions Acute pulmonary reaction may occur when taken concurrently with mitomycin-C; asparaginase, CYP3A4 inhibitors (eg, itraconazole, quinupristin/dalfopristin, sertraline, ritonavir), GM-CSF (eg, sargramostim, filgrastim), and nifedipine increase toxicity; CYP3A4 inducers (eg, carbamazepine, phenytoin, phenobarbital, rifampin) may decrease effects
Pregnancy D - Unsafe in pregnancy
Precautions Caution in severe cardiopulmonary disease, hepatic impairment (adjust dose), or preexisting neuromuscular dysfunction

 

Drug Name
Danazol (Danocrine) -- Synthetic steroid analog with strong antigonadotropic activity (inhibits LH and FSH) and weak androgenic action.
Increases levels of C4 component of complement and reduces attacks associated with angioedema. In hereditary angioedema, danazol increases level of deficient C1 esterase inhibitor.
Adult Dose 200-600 mg/d PO divided bid/tid
Angioedema: 200 mg PO bid/tid; after favorable response, decrease the dosage by 50% or less at intervals of 1-3 mo or longer if the frequency of attacks dictates; if an attack occurs, increase the dosage by up to 200 mg/d
Pediatric Dose Not established
Contraindications Documented hypersensitivity; seizure disorders; hepatic, renal, or hepatic insufficiency; lactation; conditions influenced by edema; undiagnosed genital bleeding; porphyria
Interactions Decreases insulin requirements and increases effects of anticoagulants; may increase carbamazepine levels
Pregnancy X - Contraindicated in pregnancy
Precautions Caution in seizure disorders and renal, hepatic, or cardiac insufficiency

 

FOLLOW-UP Section 8 of 12   Click here to go to the next section in this topic Click here to go to the top of this page Click here to go to the next section in this topic

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 Antiphospholipid Syndrome (CAPS or CAPLS) 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 niacin or topical nitroglycerin (nitropaste)
  • Anticoagulation therapy, such as warfarin, heparin, or LMW heparin
    • Warfarin sensitivity is conferred by the presence of a cytochrome oxidase P-450 mutation (CYP2C9) and can be associated with severe bleeding (*3 isoleucine to leucine in 10% of Caucasians; *4 asparagine to glutamine in 3% of African-Americans).
    • The presence of an aPL antibody accentuates the prothrombotic state that exists when warfarin is withdrawn (because of low protein C synthesis and the presence of plasminogen activator inhibitors).  
      • Abrupt withdrawal of warfarin by the physician or by the patient through noncompliance may result in a thrombotic event.  
      • Coverage with LMW heparin during the period of warfarin withdrawal (approximately 3-5 d until protein C levels return to normal) may reduce this risk. 
    • The PT, standard partial thromboplastin time (PTT), or both may be prolonged in the presence of an aPL antibody, thus diminishing the accuracy of these assays in monitoring of the effectiveness of anticoagulant therapy.  
    • The PT/INR assays are also inaccurate in presence of the LAC and may provide results that vary according to source of thromboplastin (manufacturer or lot to lot).
    • Chromogenic factor X levels and the prothrombin–proconvertin time more accurately reflect the level of anticoagulation in patients with a LAC who are on warfarin therapy.  
    • The adequacy of therapy with LMW heparin should be assessed with a plasma anti–factor Xa assay, which measures the inactivation of factor Xa. Ideally, the sample should be drawn 3 hours postinjection, kept at 4°C, and processed as soon as possible.
  • Immunomodulators, such as intravenous immunoglobulin
  • Therapy for thrombocytopenia, such as steroids, danazol, dapsone, IVIG, or vincristine
  • Dietary supplementation with folic acid, vitamin B-12, or both for patients with hyperhomocysteinemia
  • See Medication and the therapeutic algorithm in Image 5.

Transfer:

  • Patients with CNS, cardiovascular, or peripheral vaso-occlusive events may need to be transferred to facilities with appropriate support personnel, experience, and equipment.
  • Patients with catastrophic APS require intensive care units, high-level supportive care, and multiple consultative services.

Deterrence/Prevention:

  • Adequate medical therapy
  • Patient education
  • Monitoring for new events
  • Monitoring for drug adverse effects and toxicity

Complications:

  • Hemorrhage may occur as a result of overaggressive therapy.
  • Rethrombosis may occur as a result of inadequate therapy.
  • Catastrophic APS can lead to death (50% mortality rate).

Prognosis:

  • The long-term prognosis is varied and dependent on the tissue damage incurred and organ system(s) affected. Clinical manifestations that are associated with a worse prognosis include the following:
    • Pulmonary hypertension
    • Neurologic involvement (eg, CNS involvement, transverse myelopathy)
    • Myocardial ischemia
    • Nephropathy
    • Gangrene of the extremities
    • Catastrophic APS

Patient Education:

  • Lifestyle counseling is indicated to educate patients and their families about the risk factors that are known to complicate the prognosis of patients with Antiphospholipid Syndrome (APS or APLS).
    • Dietary manipulation is recommended to prevent obesity, hyperlipidemia, and hypertension, starting at a young age, especially in patients with a family history of these problems.
    • Dietary manipulation is recommended to decrease consumption of methionine-containing foods that might increase homocysteine levels in patients carrying mutations of the gene for methylyene tetrahydrofolate reductase (MTHFR). Folate deficiencies need to be identified and corrected in these patients to control homocysteine levels.
    • Counsel adolescents about the potential risks of smoking tobacco in this setting. Provide smoking cessation programs for patients who already have started smoking.
    • In patients with a secondary APS, encourage compliance with medications for control of underlying disease processes, such as vasculitis and SLE.
    • Dietary counseling is indicated for patients on oral anticoagulants.
      • Maintenance of a consistent diet of foods containing vitamin K 
      • Avoidance of foods and herbs with anticoagulant properties
    • Counsel patients regarding the risks of oral contraceptive use and the need for alternative methods of contraception.
MISCELLANEOUS Section 9 of 12   Click here to go to the next section in this topic Click here to go to the top of this page Click here to go to the next section in this topic

Medical/Legal Pitfalls:

  • Failure to recognize symptoms of venous or arterial thrombosis/ischemia
  • Failure to recognize symptoms of inadequate therapy (rethrombosis) or therapy that is too aggressive (bleeding)
  • Failure to interpret laboratory analyses correctly
    • Overtreatment for the presence of a positive antibody titer alone without clinical symptoms
    • Undertreatment when laboratory test results are misinterpreted as negative in the presence of a clinical event

Special Concerns:

  • One should exercise restraint in ordering aPL antibody testing in healthy, asymptomatic individuals with no known additional risk factors. In general, these patients are not treated because little direct evidence exists of increased risk of clinical events. However, insurance carriers (eg, life insurers, long-term care insurers) have scanned the literature and have subsequently assigned these individuals to a higher risk category.
  • Loss of transplanted organs due to thrombosis occurs at a high rate in patients with preexisting aPL.
  •  
TEST QUESTIONS Section 10 of 12   Click here to go to the next section in this topic Click here to go to the top of this page Click here to go to the next section in this topic

 CME Question 1: Which of the following is not a test for the lupus anticoagulant?


A: Activated partial thromboplastin time (aPTT)
B: Dilute Russell viper venom time (DRVVT)
C: Kaolin clotting time (KCT)
D: Hexagonal-phase phospholipid test
E: Rapid plasma reagin (RPR)

The correct answer is E: The RPR is an insensitive test for the antiphospholipid antibody and is not a test for the lupus anticoagulant, which is a functional assay. This test is a variation on the Venereal Disease Research Laboratories (VDRL) test, which contains reagin (a cardiolipin-containing extract of bovine heart).

CME Question 2: Which of the following is not a factor when choosing therapy in the face of an antiphospholipid antibody–associated event?


A: The titer of the detected antiphospholipid antibody
B: Arterial versus venous thrombotic event and organ system affected
C: Presence of a cytochrome oxidase P-450 mutation (CYP2C9)
D: Availability of monitoring tests for anticoagulant therapy
E: Compliance and reliability of the patient and family

The correct answer is A: No relationship exists between antibody titer and response to anticoagulation. Therapy for arterial events is weighted heavily toward antiplatelet drugs with or without anticoagulation. Venous events are primarily treated with anticoagulation. Myocardial infarction and stroke are primarily treated with antiplatelet therapy, although concomitant anticoagulation has been used. Antiplatelet therapy has been used to treat migraine headache and Raynaud phenomenon but not thrombocytopenia. The presence of a cytochrome oxidase P-450 mutation (resulting in warfarin sensitivity) complicates warfarin therapy and has been associated with severe bleeding. Therapy with low molecular weight (LMW) heparin is monitored by a factor Xa inhibition assay, which is not always available with rapid turn-around time.
Compliance with lab testing and drug dosing is vital to most therapy, but noncompliance is particularly dangerous with warfarin. The prothrombotic state that exists when warfarin is withdrawn (because of low protein C synthesis and the presence of plasminogen activator inhibitors) is accentuated in the presence of an antiphospholipid antibody.

Pearl Question 1 (T/F): To secure a diagnosis of the antiphospholipid syndrome, a patient must fulfill the strict ²Sapporo² criteria, which were published in 1999.

The correct answer is False: The ²Sapporo² criteria were meant as guidelines for the establishment of uniform populations for research studies. Only those features confirmed by prospective studies were included in these guidelines. A clinical diagnosis of antiphospholipid syndrome can be made using the original guidelines, which include the vasospastic symptoms (eg, Raynaud phenomenon, migraine headache) and thrombocytopenia, as well as tests for antiphospholipid antibodies other than anticardiolipin immunoglobulin G (IgG)/immunoglobulin M (IgM) and the lupus anticoagulant.

Pearl Question 2 (T/F): A prolonged activated partial thromboplastin time (aPTT) is sufficient to fulfill criteria for presence of lupus anticoagulant.

The correct answer is False: Coagulation factor deficiencies (genetic or consumptive) can prolong the aPTT. A mix with normal plasma is necessary to confirm that the prolongation is secondary to an antiphospholipid antibody. A 4:1 mix (patient-to-normal plasma) is sufficient to correct for factor deficiencies; however, a 1:1 mix may dilute out any low titer antiphospholipid antibodies. A phospholipid-dependent absorption assay, such as the platelet neutralization procedure (PNP) or the phosphoethanolamine-containing hexagonal-phase assay is necessary to differentiate antiphospholipid antibodies from antibodies to coagulation factors. The hexagonal-phase assay has a built-in 1:1 mix so that it corrects for factor deficiencies but, because of the dilution, may be less sensitive to low-level antiphospholipid antibodies.

Pearl Question 3 (T/F): A 14-year-old adolescent girl presents with a deep vein thrombosis in the left lower extremity and symptoms of a pulmonary embolus. Test results are negative for anticardiolipin antibody immunoglobulin G (IgG)/immunoglobulin M (IgM), and a standard partial thromboplastin time (PTT) is within reference range; therefore, a diagnosis of antiphospholipid syndrome can be eliminated, and another cause must be sought.

The correct answer is False: Up to two thirds of positive sera may be missed using anticardiolipin IgG/IgM antibody test alone. The PTT is not a sensitive test (50-60%), and even the most sensitive aPTT is at best 70% sensitive. At least 2 and perhaps 3 assays for lupus anticoagulant are necessary because of nonoverlapping specificities of many of the assays. Some patients with previously documented positive test results for antiphospholipid antibodies and lupus anticoagulants will have negative test results immediately before and during a thrombotic event (only to have positive results again later). Other causes for thrombosis should be investigated, regardless of antiphospholipid antibody status. Coexistent factor deficiencies (eg, protein S, protein C, antithrombin III) and gene mutations (eg, factor V Leiden, prothrombin 20210A, methylene tetrahydrofolate reductase [MTHFR]) are additional risk factors and should influence any decisions on the choice of anticoagulants, duration of therapy, and lifestyle counseling.

Pearl Question 4 (T/F): A child who had a single venous thrombotic event and was treated with warfarin should be given anticoagulation therapy for as long as the child has positive test results for lupus anticoagulant.

The correct answer is False: Anticoagulants do not decrease the levels of antiphospholipid antibodies (although with a decrease in antigenic stimulus, one may see lower titers of antibody). The assays for lupus anticoagulant are affected by the presence of warfarin (some more than others); thus, prolonged activated partial thromboplastin time (aPTT) and positive hexagonal-phase or dilute Russell viper venom time (DRVVT) assays do not reflect the patient`s antiphospholipid antibody status. The decision to discontinue therapy is based on many factors and depends on careful assessment of the etiology of the event. Risk factors, such as the presence of an underlying disease process (eg, systemic lupus erythematosus [SLE]), coagulation factor deficiencies, metabolic defects (eg, homocysteinemia), and gene mutations (eg, factor V Leiden, prothrombin 20210A, methylene tetrahydrofolate reductase) weigh heavily in the decision.

 

PICTURES Section 11 of 12   Click here to go to the next section in this topic Click here to go to the top of this page Click here to go to the next section in this topic

 

Caption: Picture 1. Antiphospholipid antibody syndrome. Shown is the palmar livedo reticularis that is associated with the antiphospholipid syndrome. This may range from a lacy, flat, reticulated pattern to a more confluent, nonblanching, slightly raised rash (secondary to extravasation of red blood cells and plasma).
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Picture Type: Photo

 

Caption: Picture 2. Antiphospholipid antibody syndrome. Shown is livedo reticularis of the upper and lower extremities in a 15-year-old adolescent with primary antiphospholipid syndrome. The pattern is lacy, flat, and nonblanching. The purplish hue is from stasis in the small vessel beds.
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Picture Type: Photo

 

Caption: Picture 3. Antiphospholipid antibody syndrome. Shown is the muddy discoloration and mild diffuse swelling of the fingers that is observed as part of the Raynaud phenomenon which is associated with the antiphospholipid syndrome. At room temperature, this patient still has decreased capillary refill and cold fingers, even while being treated with pentoxifylline. The discoloration extends proximally onto the palms and turns blue-purple when exposed to cold.
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Picture Type: Photo

 

Caption: Picture 4. Antiphospholipid antibody syndrome. Linear splinter hemorrhages are found under the nails of fingers and toes. These may be solitary or multiple and appear intermittently.
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Picture Type: Photo

 

Caption: Picture 5. One set of suggested algorithms for the workup and treatment of patients with antiphospholipid syndrome. This should not be considered dogmatic because laboratory evaluation is not standardized and treatment remains empiric and controversial. Laboratory testing is not recommended in healthy asymptomatic individuals with no risk factors and a negative family history.
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Picture Type: Graph

 

Caption: Picture 6. Antiphospholipid antibody syndrome. Shown is occlusion of the right middle cerebral artery in a 3-year-old child with severe headache and hemiparesis associated with anticardiolipin antibodies.
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Picture Type: X-RAY

 

Caption: Picture 7. Antiphospholipid antibody syndrome. Organizing thrombus in an aortic valve from a patient with positive test results for antiphospholipid antibody and lupus anticoagulant who has systemic lupus erythematosis and Antiphospholipid antibody syndrome. Organizing thrombus in an aortic valve from a patient with positive test results for antiphospholipid antibody and lupus anticoagulant who has systemic lupus erythematosus (SLE) and recurrent thrombotic events. The authors acknowledge the help of Hannes Vogel, MD, in preparing this image.
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Caption: Picture 8. Antiphospholipid antibody syndrome. High-power degenerating aortic valve from a patient who has positive test results for antiphospholipid antibody and lupus anticoagulant and has systemic lupus erythematosus (SLE) and recurrent thrombotic events. The authors acknowledge the help of Hannes Vogel, MD, in preparing this image.
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Capotin: Picture 9. Antiphospholipid antibody syndrome. Trichrome stain of a thrombus in the intestinal serosa from a patient who has positive test results for antiphospholipid antibody and lupus anticoagulant and has systemic lupus erythematosus (SLE) and catastrophic antiphospholipid antibody syndrome. The authors acknowledge the help of Hannes Vogel, MD, in preparing this image.
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BIBLIOGRAPHY Section 12 of 12   Click here to go to the next section in this topic Click here to go to the top of this page

 

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Medical Keywords: systemic antiphospholipid antibody syndrome, Antiphospholipid, Antiphospholipid Antibody Syndrome, Antiphospholipid Syndrome, APS, APLS, Hughes Syndrome, Sticky Blood, Clotting Disorder, Stroke, TIA, PE, death, Antiphospholipid Antibody Syndrome, Antiphospholipid Syndrome, APS, APLS, Hughes Syndrome, Sticky Blood, Clotting Disorder, Stroke, TIA, PE, death