eMedicine Specialties > Pediatrics: General Medicine > Rheumatology

Antiphospholipid Antibody Syndrome: Differential Diagnoses & Workup

Author: Barry L Myones, MD, Associate Professor, Departments of Pediatrics and Immunology, Pediatric Rheumatology Section, Baylor College of Medicine; Director of Research, Pediatric Rheumatology Center, Texas Children's Hospital
Contributor Information and Disclosures

Updated: Aug 4, 2009

Differential Diagnoses

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

Other Problems to Be Considered

Carcinoma
Catastrophic antiphospholipid antibody 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
Hereditary Blood Coagulation Disorders
Hereditary Thrombophilia
Homocystinemia
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

Laboratory Studies

  • Antiphospholipid antibody (aPL) assays: If the clinical features are suggestive of an antiphospholipid antibody syndrome (APS), a thorough search for the presence of at least one of these antibodies is imperative.58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73 See the laboratory evaluation algorithm in Media file 5.

    One set of suggested algorithms for the workup an...

    One set of suggested algorithms for the workup and treatment of patients with antiphospholipid antibody 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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    One set of suggested algorithms for the workup an...

    One set of suggested algorithms for the workup and treatment of patients with antiphospholipid antibody 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.

    • Evaluate for anticardiolipin, antiphosphatidylethanolamine, antiphosphatidylinositol, antiphosphatidylserine, antiphosphatidylglycerol, and antiphosphatidic acid. These antibodies are primarily of the immunoglobulin G (IgG) and immunoglobulin M (IgM) isotypes, although evidence is mounting for the clinical significance of immunoglobulin A (IgA) antibodies as well.
    • Evaluate for lupus anticoagulant (LAC). 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 or 3:1 (patient-to-normal) plasma mix test should be performed to correct for any coagulation factor deficiencies but not dilute out a low-titer antiphospholipid 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 prothrombin time (dPT)
      • Textarin time (TT)
      • Taipan snake venom time (TSVT)
    • Evaluate for anti–β2-GPI antibodies. These antibodies are primarily of the IgG and IgM isotypes, although evidence is mounting for the clinical significance of IgA antibodies as well.
  • 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 or plasma. VRDL and RPR tests are usually less sensitive than direct antibody tests 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 RBCs
    • A 24-hour urine collection for protein and creatinine clearance
    • Serum albumin, BUN, and creatinine levels
  • Identification of persistent thrombocytopenia or evidence of hemolytic anemia
    • CBC count 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

  • In patients with venous thrombotic events (eg, deep vein thrombosis [DVT])
    • Doppler ultrasonography
    • Venography
    • Ventilation/perfusion scan (to document pulmonary emboli)
  • In patients with arterial thrombotic events (eg, cerebral vascular, cardiovascular, peripheral vascular ischemia/occlusion, bone infarction)
    • CT scanning (see Media file 19)

      A patient (the same as in Media files 16-18) with...

      A patient (the same as in Media files 16-18) with multisystem small vessel coagulopathy (microangiopathy) but no known underlying disease process. The technetium 99m bone scan reveals irregular multifocal areas of tracer accumulation within the left ventricle of the heart suggestive of myocardial infarction and altered calcium deposition. Irregular cutaneous and subcutaneous uptake is noted in multiple areas of the torso and upper arms (as well as in the upper thighs). High-resolution CT scanning of the chest reveals extensive calcification involving the myocardium, the mitral and tricuspid valve annuli, the aortic valve annulus, the proximal right coronary artery, and the left main coronary artery.

      [ CLOSE WINDOW ]
      A patient (the same as in Media files 16-18) with...

      A patient (the same as in Media files 16-18) with multisystem small vessel coagulopathy (microangiopathy) but no known underlying disease process. The technetium 99m bone scan reveals irregular multifocal areas of tracer accumulation within the left ventricle of the heart suggestive of myocardial infarction and altered calcium deposition. Irregular cutaneous and subcutaneous uptake is noted in multiple areas of the torso and upper arms (as well as in the upper thighs). High-resolution CT scanning of the chest reveals extensive calcification involving the myocardium, the mitral and tricuspid valve annuli, the aortic valve annulus, the proximal right coronary artery, and the left main coronary artery.

    • Nuclear imaging (see Media file 18-19)

      CAPS, Bone Infarction - MRI (High Resolution Prot...

      CAPS, Bone Infarction - MRI (High Resolution Proton Density and STIR images) and Nuclear Bone Scan - Patient (same as in images 16, 17, 19) with multisystem small vessel coagulopathy (microangiopathy) but no known underlying disease process. MRI shows multiple infarctions in the distal tibia, tarsal bones and metatarsal bones (extensive bone marrow edema and increased T1 with fat saturation signal in the calcaneus bones). Flow and early blood pool images of technetium 99m bone scan show increase in activity in both heel regions with focal areas of decreased activity in the center of each calcaneus.

      [ CLOSE WINDOW ]
      CAPS, Bone Infarction - MRI (High Resolution Prot...

      CAPS, Bone Infarction - MRI (High Resolution Proton Density and STIR images) and Nuclear Bone Scan - Patient (same as in images 16, 17, 19) with multisystem small vessel coagulopathy (microangiopathy) but no known underlying disease process. MRI shows multiple infarctions in the distal tibia, tarsal bones and metatarsal bones (extensive bone marrow edema and increased T1 with fat saturation signal in the calcaneus bones). Flow and early blood pool images of technetium 99m bone scan show increase in activity in both heel regions with focal areas of decreased activity in the center of each calcaneus.



      A patient (the same as in Media files 16-18) with...

      A patient (the same as in Media files 16-18) with multisystem small vessel coagulopathy (microangiopathy) but no known underlying disease process. The technetium 99m bone scan reveals irregular multifocal areas of tracer accumulation within the left ventricle of the heart suggestive of myocardial infarction and altered calcium deposition. Irregular cutaneous and subcutaneous uptake is noted in multiple areas of the torso and upper arms (as well as in the upper thighs). High-resolution CT scanning of the chest reveals extensive calcification involving the myocardium, the mitral and tricuspid valve annuli, the aortic valve annulus, the proximal right coronary artery, and the left main coronary artery.

      [ CLOSE WINDOW ]
      A patient (the same as in Media files 16-18) with...

      A patient (the same as in Media files 16-18) with multisystem small vessel coagulopathy (microangiopathy) but no known underlying disease process. The technetium 99m bone scan reveals irregular multifocal areas of tracer accumulation within the left ventricle of the heart suggestive of myocardial infarction and altered calcium deposition. Irregular cutaneous and subcutaneous uptake is noted in multiple areas of the torso and upper arms (as well as in the upper thighs). High-resolution CT scanning of the chest reveals extensive calcification involving the myocardium, the mitral and tricuspid valve annuli, the aortic valve annulus, the proximal right coronary artery, and the left main coronary artery.

    • MRI (see Media file 18)

      CAPS, Bone Infarction - MRI (High Resolution Prot...

      CAPS, Bone Infarction - MRI (High Resolution Proton Density and STIR images) and Nuclear Bone Scan - Patient (same as in images 16, 17, 19) with multisystem small vessel coagulopathy (microangiopathy) but no known underlying disease process. MRI shows multiple infarctions in the distal tibia, tarsal bones and metatarsal bones (extensive bone marrow edema and increased T1 with fat saturation signal in the calcaneus bones). Flow and early blood pool images of technetium 99m bone scan show increase in activity in both heel regions with focal areas of decreased activity in the center of each calcaneus.

      [ CLOSE WINDOW ]
      CAPS, Bone Infarction - MRI (High Resolution Prot...

      CAPS, Bone Infarction - MRI (High Resolution Proton Density and STIR images) and Nuclear Bone Scan - Patient (same as in images 16, 17, 19) with multisystem small vessel coagulopathy (microangiopathy) but no known underlying disease process. MRI shows multiple infarctions in the distal tibia, tarsal bones and metatarsal bones (extensive bone marrow edema and increased T1 with fat saturation signal in the calcaneus bones). Flow and early blood pool images of technetium 99m bone scan show increase in activity in both heel regions with focal areas of decreased activity in the center of each calcaneus.

    • Arteriography (see Media file 6)

      Occlusion of the right middle cerebral artery in ...

      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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      Occlusion of the right middle cerebral artery in ...

      Occlusion of the right middle cerebral artery in a 3-year-old child with severe headache and hemiparesis associated with anticardiolipin antibodies.

    • Doppler ultrasonography
    • Magnetic resonance arteriography (MRA)
  • In patients with cardiac events (including vegetative valvular lesions [eg, Libman-Sacks endocarditis])49
    • Two-dimensional echocardiography
    • Transesophageal echocardiography47,48
    • MRA
    • Cardiac angiography by catheterization
  • In patients with pulmonary hypertension
    • Two-dimensional echocardiography
    • Cardiac catheterization (to determine pulmonary artery pressure and calculate pulmonary vascular resistance)

Procedures

  • Performing a biopsy of the affected organ system (eg, skin, kidney) may be necessary to establish the vasculopathy and microangiopathic picture of antiphospholipid antibody syndrome versus vasculitis.

Histologic Findings

  • Antiphospholipid antibody syndrome is a thrombotic microangiopathic (TMA) 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-occlusive lesions of the intrarenal vessels. Interstitial fibrosis and tubular atrophy are also present. (See Media files 7-12.)

    Organizing thrombus in an aortic valve in a patie...

    Organizing thrombus in an aortic valve in 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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    Organizing thrombus in an aortic valve in a patie...

    Organizing thrombus in an aortic valve in 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.



    High-power degenerating aortic valve in a patient...

    High-power degenerating aortic valve in a patient who has positive test results for antiphospholipid antibody and lupus anticoagulant and who has systemic lupus erythematosus (SLE) and recurrent thrombotic events. The authors acknowledge the help of Hannes Vogel, MD, in preparing this image.

    [ CLOSE WINDOW ]
    High-power degenerating aortic valve in a patient...

    High-power degenerating aortic valve in a patient who has positive test results for antiphospholipid antibody and lupus anticoagulant and who has systemic lupus erythematosus (SLE) and recurrent thrombotic events. The authors acknowledge the help of Hannes Vogel, MD, in preparing this image.



    Trichrome stain of a thrombus in the intestinal s...

    Trichrome stain of a thrombus in the intestinal serosa in a patient who has positive test results for antiphospholipid antibody and lupus anticoagulant and who has systemic lupus erythematosus (SLE) and catastrophic antiphospholipid antibody syndrome (CAPS). The authors acknowledge the help of Hannes Vogel, MD, in preparing this image.

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    Trichrome stain of a thrombus in the intestinal s...

    Trichrome stain of a thrombus in the intestinal serosa in a patient who has positive test results for antiphospholipid antibody and lupus anticoagulant and who has systemic lupus erythematosus (SLE) and catastrophic antiphospholipid antibody syndrome (CAPS). The authors acknowledge the help of Hannes Vogel, MD, in preparing this image.



    Antiphospholipid antibody syndrome in a patient w...

    Antiphospholipid antibody syndrome in a patient with positive test results for antiphospholipid antibody and lupus anticoagulant who has systemic lupus erythematosus (SLE), World Health Organization (WHO) class IV lupus nephritis, and acute renal failure. Top: Thrombosed kidney vessels (periodic acid-Schiff [PAS], original magnification X40). Bottom: Thrombosed kidney vessels (PAS, original magnification X20). Lumen is filled with eosinophilic fibrin with overlying injured endothelial cells. The authors acknowledge the help of Karen W. Eldin, MD, in preparing this image.

    [ CLOSE WINDOW ]
    Antiphospholipid antibody syndrome in a patient w...

    Antiphospholipid antibody syndrome in a patient with positive test results for antiphospholipid antibody and lupus anticoagulant who has systemic lupus erythematosus (SLE), World Health Organization (WHO) class IV lupus nephritis, and acute renal failure. Top: Thrombosed kidney vessels (periodic acid-Schiff [PAS], original magnification X40). Bottom: Thrombosed kidney vessels (PAS, original magnification X20). Lumen is filled with eosinophilic fibrin with overlying injured endothelial cells. The authors acknowledge the help of Karen W. Eldin, MD, in preparing this image.



    Antiphospholipid antibody syndrome in a patient w...

    Antiphospholipid antibody syndrome in a patient with positive test results for antiphospholipid antibody and lupus anticoagulant who has systemic lupus erythematosus (SLE), World Health Organization (WHO) class IV lupus nephritis, and acute renal failure. Top: Thrombosed kidney vessel (hematoxylin and eosin [H&E] stain, original magnification X20). Lumen is occluded with fibrin. A perivascular stromal reaction with degenerating inflammatory cells is observed. Bottom: Thrombosed kidney vessel (H&E stain, original magnification X20). Lumen is occluded with fibrin. The authors acknowledge the help of Karen W. Eldin, MD, in preparing this image.

    [ CLOSE WINDOW ]
    Antiphospholipid antibody syndrome in a patient w...

    Antiphospholipid antibody syndrome in a patient with positive test results for antiphospholipid antibody and lupus anticoagulant who has systemic lupus erythematosus (SLE), World Health Organization (WHO) class IV lupus nephritis, and acute renal failure. Top: Thrombosed kidney vessel (hematoxylin and eosin [H&E] stain, original magnification X20). Lumen is occluded with fibrin. A perivascular stromal reaction with degenerating inflammatory cells is observed. Bottom: Thrombosed kidney vessel (H&E stain, original magnification X20). Lumen is occluded with fibrin. The authors acknowledge the help of Karen W. Eldin, MD, in preparing this image.



    Antiphospholipid antibody syndrome in a patient w...

    Antiphospholipid antibody syndrome in a patient with positive test results for antiphospholipid antibody and lupus anticoagulant who has systemic lupus erythematosus (SLE), World Health Organization (WHO) class IV lupus nephritis, and acute renal failure. Thrombosed kidney vessel with recanalization (arrows) (Jones stain, original magnification X20). Architectural distortion in the surrounding stroma is observed. The authors acknowledge the help of Karen W. Eldin, MD, in preparing this image.

    [ CLOSE WINDOW ]
    Antiphospholipid antibody syndrome in a patient w...

    Antiphospholipid antibody syndrome in a patient with positive test results for antiphospholipid antibody and lupus anticoagulant who has systemic lupus erythematosus (SLE), World Health Organization (WHO) class IV lupus nephritis, and acute renal failure. Thrombosed kidney vessel with recanalization (arrows) (Jones stain, original magnification X20). Architectural distortion in the surrounding stroma is observed. The authors acknowledge the help of Karen W. Eldin, MD, in preparing this image.

More on Antiphospholipid Antibody Syndrome

Overview: Antiphospholipid Antibody Syndrome
Differential Diagnoses & Workup: Antiphospholipid Antibody Syndrome
Treatment & Medication: Antiphospholipid Antibody Syndrome
Follow-up: Antiphospholipid Antibody Syndrome
Multimedia: Antiphospholipid Antibody Syndrome
References
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Further Reading

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Keywords

anti-phospholipid antibody syndrome, Hughes syndrome, Hughes' syndrome, antiphospholipid syndrome, anti-phospholipid syndrome, APS, APLS, Sneddon syndrome, Sneddon's syndrome, thrombosis, primary antiphospholipid syndrome, PAPS, secondary antiphospholipid syndrome, antiphospholipid, aPl, deep venous thrombosis, arterial occlusive events, migraine headache, Raynaud phenomenon, transient ischemic attack, TIA, systemic lupus erythematosus, SLE, lupus anticoagulant, LAC, migraine headache, peripheral vasospasm, thrombocytopenia, anticardiolipin antibody, aCL antibody, cerebrovascular accident, myocardial infarction, endocarditis, pulmonary emboli, treatment, diagnosis

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Contributor Information and Disclosures

Author

Barry L Myones, MD, Associate Professor, Departments of Pediatrics and Immunology, Pediatric Rheumatology Section, Baylor College of Medicine; Director of Research, Pediatric Rheumatology Center, Texas Children's Hospital
Barry L Myones, MD is a member of the following medical societies: American Academy of Pediatrics, American Association of Immunologists, American College of Rheumatology, American Heart Association, American Society for Microbiology, Clinical Immunology Society, and Texas Medical Association
Disclosure: Nothing to disclose.

Medical Editor

James M Oleske, MD, MPH, François-Xavier Bagnoud Professor of Pediatrics, Director, Division of Pulmonary, Allergy, Immunology and Infectious Diseases, Department of Pediatrics, New Jersey Medical School
James M Oleske, MD, MPH is a member of the following medical societies: Academy of Medicine of New Jersey, American Academy of Pediatrics, American Public Health Association, American Society for Microbiology, Infectious Diseases Society of America, and Pediatric Infectious Diseases Society
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

Managing Editor

David D Sherry, MD, Director, Clinical Rheumatology, Attending Physician, Pain Management, The Children's Hospital of Philadelphia; Professor of Pediatrics, University of Pennsylvania
David D Sherry, MD is a member of the following medical societies: American College of Rheumatology and American Pain Society
Disclosure: Nothing to disclose.

CME Editor

Daniel Rauch, MD, FAAP, Director, Pediatric Hospitalist Program, Associate Professor, Department of Pediatrics, New York University School of Medicine
Daniel Rauch, MD, FAAP is a member of the following medical societies: Ambulatory Pediatric Association, American Academy of Pediatrics, and Society of Hospital Medicine
Disclosure: Baxter Honoraria Consulting

Chief Editor

Lawrence K Jung, MD, Chief, Division of Pediatric Rheumatology, Children's National Medical Center
Lawrence K Jung, MD is a member of the following medical societies: American Association for the Advancement of Science, American Association of Immunologists, American College of Rheumatology, Clinical Immunology Society, and New York Academy of Sciences
Disclosure: Nothing to disclose.

 
 
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