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. [70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85] See the laboratory evaluation algorithm in the image below.
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.
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Dilute Russell Viper venom test (dRVVT)
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Hexagonal-phase LAC test
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Activated partial thromboplastin time (aPTT)
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Platelet neutralization procedure (PNP)
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Kaolin clotting time (KCT) or the Kaolin clot inhibition test
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Dilute prothrombin time (dPT)
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Textarin time (TT)
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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
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Urine dipstick analysis for hemoglobin or protein
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Urine microscopic examination for the presence of RBCs
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A 24-hour urine collection for protein and creatinine clearance
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Serum albumin, BUN, and creatinine levels
Identification of persistent thrombocytopenia or evidence of hemolytic anemia
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CBC count with platelet count and a blood smear examination
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Lactic acid dehydrogenase (LDH), bilirubin, haptoglobin
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Direct/indirect Coombs test
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Urine dipstick analysis for hemoglobin
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Antiplatelet antibody (to evaluate for associated autoimmune thrombocytopenic purpura)
Coexisting deficiencies of the coagulation system
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Protein C
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Protein S
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Antithrombin III
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Antibodies to coagulation proteins, such as anti–factor II (prothrombin) antibodies
Coexisting genetic polymorphisms
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Factor V Leiden mutation
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Prothrombin gene mutation 20210A
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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])
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Doppler ultrasonography
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Venography
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Ventilation/perfusion scan (to document pulmonary emboli)
In patients with arterial thrombotic events (eg, cerebral vascular, cardiovascular, peripheral vascular ischemia/occlusion, bone infarction)
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CT scanning (see the image below)
A patient 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.
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Nuclear imaging (see the images below)
CAPS, Bone Infarction - MRI (High Resolution Proton Density and STIR images) and Nuclear Bone Scan - Patient 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 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.
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MRI (see the image below)
CAPS, Bone Infarction - MRI (High Resolution Proton Density and STIR images) and Nuclear Bone Scan - Patient 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.
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Arteriography (see example below)
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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Doppler ultrasonography
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Magnetic resonance arteriography (MRA)
In patients with cardiac events (including vegetative valvular lesions [eg, Libman-Sacks endocarditis]) [60]
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Two-dimensional echocardiography
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MRA
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Cardiac angiography by catheterization
In patients with pulmonary hypertension
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Two-dimensional echocardiography
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Cardiac catheterization (to determine pulmonary artery pressure and calculate pulmonary vascular resistance)
Histologic Findings
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.
Antiphospholipid antibody syndrome is a thrombotic microangiopathic (TMA) process characterized by a noninflammatory vasculopathy without vasculitis. [86]
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 the images below.)
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 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 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 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 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 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.
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Palmar livedo reticularis associated with antiphospholipid antibody syndrome may range from a lacy, flat, reticulated pattern to a more confluent, nonblanching, slightly raised rash (secondary to extravasation of RBCs and plasma).
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Livedo reticularis of the upper and lower extremities in a 15-year-old adolescent with primary antiphospholipid antibody syndrome. The pattern is lacy, flat, and nonblanching. The purplish hue is from stasis in the small vessel beds.
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Muddy discoloration and mild diffuse swelling of the fingers observed as part of the Raynaud phenomenon, which is associated with antiphospholipid antibody syndrome. At room temperature, this patient still has decreased capillary refill and cold fingers despite treatment with pentoxifylline. The discoloration extends proximally onto the palms and turns blue-purple when exposed to cold.
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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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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.
-
Occlusion of the right middle cerebral artery in a 3-year-old child with severe headache and hemiparesis associated with anticardiolipin antibodies.
-
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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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.
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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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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.
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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.
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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.
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Antiphospholipid antibody syndrome in a patient with positive test results for antiphospholipid antibody and lupus anticoagulant who has systemic lupus erythematosus (SLE) and thrombocytopenia. Livedo reticularis of the upper extremities, which developed as petechiae in the classic lacy, reticular pattern, is observed.
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Livedo reticularis of the upper extremities, which developed as petechiae in the classic lacy, reticular pattern and evolved as a confluent, nonblanching, slightly raised purpuric rash in the same reticular pattern.
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Digital infarctions in a patient with systemic lupus erythematosus with antiphospholipid syndrome (APS) and long-standing Raynaud symptoms. Multiple and repeated digital infarctions are depicted, resulting in ulcerations and scarring. Scars and hyperpigmentation are also seen on the palmer aspect of hands and fingers.
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A patient with multisystem small vessel coagulopathy (microangiopathy) but no known underlying disease process. Extensive involvement of all digits is noted, some with distal infarction and dry gangrene, others healing with residual eschar (and undermining epithelialization), and some with re-epithelialization and scarring. Healed superficial epidermal damage and desquamation is also present.
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A patient with multisystem small vessel coagulopathy (microangiopathy) but no known underlying disease process. Eschar is still present on first digit bilaterally. More superficial lesions are shown here, with evolution and healing of lesions on all other toes.
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CAPS, Bone Infarction - MRI (High Resolution Proton Density and STIR images) and Nuclear Bone Scan - Patient 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.
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A patient 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.
