Pediatric Antiphospholipid Antibody Syndrome 

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. They are also associated with vasospastic phenomena such as migraine headache, Raynaud phenomenon, and transient ischemic attack (TIA).[1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11]

The terminology associated with antiphospholipid antibodies has been fraught with misnomers. Conley and Hartmann observed a prolongation in the prothrombin time (PT) in a series of patients with systemic lupus erythematosus (SLE), which was later 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 (aPTT) 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, antibodies to phospholipids alone have been determined to be associated with infectious causes more often. In contrast, antibodies to combinations of phospholipids and serum proteins (eg, β 2-glycoprotein I [β 2-GPI] or prothrombin) are more likely associated with the vasculopathic events of antiphospholipid antibody syndrome (APS).

Antiphospholipid antibodies associated with vaso-occlusive events without any underlying disease process is termed the primary antiphospholipid antibody syndrome (PAPS). The presence of antiphospholipid antibodies and a vaso-occlusive event superimposed on an underlying disease, such as SLE or malignancy, is a secondary antiphospholipid antibody syndrome.[12]

Preliminary classification criteria for "definite" antiphospholipid antibody syndrome were proposed in a report from the Eighth International Symposium on Antiphospholipid Antibodies and were published in Arthritis and Rheumatism.[13]

The purpose of the report was to define the essential features of antiphospholipid antibody syndrome in order to facilitate studies of treatment and causation. This definition was intended to encompass the clinical and laboratory features most closely associated with antiphospholipid antibodies in prospective studies 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. Although features such as migraine headache, peripheral vasospasm, and thrombocytopenia were excluded from the published criteria, they were argued to be valid and useful clinical parameters in arriving at the diagnosis of antiphospholipid antibody syndrome in the clinical setting at the Ninth International Symposium on Antiphospholipid Antibodies.[14, 15, 16]

In a consensus conference held at the 11th International Symposium on Antiphospholipid Antibodies, existing evidence on clinical and laboratory features of antiphospholipid antibody syndrome was appraised and amendments to the Sapporo criteria were proposed. The criteria were reiterated to be used for clinical research to define homogenous populations for studies. Therefore, in order to address the needs of clinicians and to expand the data for future research, the discussion included definitions on features of antiphospholipid antibody syndrome that were not included in the updated criteria for use clinically and in research. These were published as the "International Consensus Statement on an Update of the Classification Criteria for Definite Antiphospholipid Antibody Syndrome (APS)" in J Thrombosis Haemost.[17]

Updated clinical criteria

Clinical criteria include the following:

• Vascular thrombosis - One or more clinical episodes of arterial, venous, or small vessel thrombosis in any tissue or organ confirmed by imaging studies, Doppler studies, or histopathology (without significant vessel wall inflammation)

• Pregnancy morbidity (normal morphology on ultrasonography or direct examination findings)

  • One or more unexplained fetal deaths at more than 10 weeks’ gestation

  • One or more premature births at less than 34 weeks’ gestation due to severe preeclampsia, eclampsia, or placental insufficiency

  • Three or more unexplained consecutive spontaneous abortions at less than 10 weeks’ gestation, excluding maternal anatomic or hormonal abnormalities and paternal and maternal chromosomal causes

In research studies of patient populations that contain more than one type of pregnancy morbidity, investigators are strongly encouraged to stratify subjects according to the 3 groups above.

Updated laboratory criteria

Laboratory criteria include the following:

• Anticardiolipin (aCL) antibody of the immunoglobulin G (IgG)/immunoglobulin M (IgM) isotype in medium/high titer (>40 IgG phospholipid units [GPL], >40 IgM phospholipid units [MPL], or >99th percentile) on 2 or more occasions at least 12 weeks apart (measured by a b2-GPI–dependent enzyme-linked immunosorbent assay [ELISA]).

• Lupus anticoagulant on 2 or more occasions at least 12 weeks apart, according to the guidelines set forth by the International Society of Thrombosis and Hemostasis Scientific Subcommittee on Lupus Anticoagulants/Phospholipid-dependent Antibodies.[18]

  • Prolonged phospholipid-dependent coagulation (eg, aPTT, Kaolin clotting time [KCT], dilute Russell viper venom test, 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)

Investigators are strongly advised to classify patients (in research studies) with antiphospholipid antibody syndrome into one of the following categories:

• I - Patients with more than 1 laboratory criteria (any combination)

• IIa - Patients with LAC present alone

• IIb - Patients with aCL antibody present alone

• IIc - Patients with anti-β 2-glycoprotein-I antibody present alone

A patient must meet at least one clinical and one laboratory criterion for a diagnosis of antiphospholipid antibody syndrome. Classification of antiphospholipid antibody syndrome should be avoided if less than 12 weeks or more than 5 years separate a positive antiphospholipid antibody test and the clinical manifestation.[19]

Patients with antiphospholipid antibody syndrome participating in research studies should be further subgrouped according to the presence or absence of additional risk factors for thrombosis. Patients should not be excluded from APS trials because of coexistent inherited or acquired factors for thrombosis.

Patients with antiphospholipid antibody syndrome participating in research studies who fulfill the revised classification criteria should be classified separately from patients with “features associated with antiphospholipid antibody syndrome” or with “noncriteria features of antiphospholipid antibody syndrome.” These features, which were discussed by the consensus panel but not included in the revised criteria, include the following:

• Heart valve disease

• Livedo reticularis

• Thrombocytopenia

• Nephropathy

• Neurological manifestations[20]

• Immunoglobulin A (IgA) aCL

• IgA anti-b2GPI

• Antiphosphatidylserine antibodies

• Antiphosphatidylethanolamine antibodies

• Antibodies against prothrombin alone

• Antibodies to the phosphatidylserine-prothrombin complex

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 clearly elucidated. The presence of preexisting or coincident vascular (endothelial) damage along with the identification of an antiphospholipid antibody as requisites for the emergence of a thrombotic complication has been coined the "2-hit" hypothesis.[21, 22, 23, 24, 25, 26, 1, 27, 28, 29, 30, 31, 32, 33, 34, 35]

• Possible mechanisms by which antiphospholipid antibodies may induce thrombotic events include the following:

  • Antiphospholipid antibodies may combine with platelet membrane phospholipids, resulting in increased platelet adhesion and aggregation.

  • Antiphospholipid antibodies 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.

  • Antiphospholipid antibodies can stimulate tissue factor expression by endothelial cells, monocytes, and neutrophils with induction of cellular activation and respiratory burst leading to membrane damage.

  • In secondary antiphospholipid antibody syndrome, vascular endothelial cell damage has already occurred, enhancing the vascular spasm/occlusion, ischemia/infarction, and reperfusion injury.

  • b2-GPI may be bound up by antiphospholipid antibodies and (1) prevented from covering up exposed procoagulant inner membrane leaflet phospholipids or (2) blocked from inhibiting platelet prothrombinase activity.

  • b2-GPI and oxidized low-density lipoprotein (oxLDL) complexes may be bound up by antiphospholipid antibodies, cleared by macrophages, and, thus, promote accelerated development of atherosclerosis in autoimmune patients.

  • Antiphospholipid antibodies 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 antiphospholipid antibody 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 previously mentioned mechanism is the concept that antiphospholipid 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.

  • Antiphospholipid antibodies may also be cross-reactive antibodies induced by exogenous antigens from infectious organisms (eg, viral or bacterial).

Canaud et al studied the molecular pathways involved in the vasculopathy of the antiphospholipid syndrome. The researchers used double immunostaining to evaluate pathway activation in the mammalian target of rapamycin complex (mTORC) and the nature of cell proliferation in the vessels of patients with primary or secondary antiphospholipid syndrome nephropathy. The mTORC pathway is involved in the vascular lesions that occur in patients with antiphospholipid syndrome. According to this study the mTOR inhibitor sirolimus may help prevent vasculopathy in patients with the disease.[36, 37]

Frequency

United States

• Antiphospholipid antibodies are reportedly present in 1-15% of the general population (higher in elderly persons). These antibodies are reportedly present in as many as 70% of patients with SLE; however, the frequency rate of antiphospholipid antibody syndrome (ie, antiphospholipid antibodies plus a clinical event) is far lower.

• In patients with SLE, a history of thrombosis was reported in 61% of those with positive test results for LAC, in 52% of those who had positive anticardiolipin antibodies, and 24% of those who had no antiphospholipid antibodies.

International

• No major differences have been noted between frequency rates in the United States and frequency rates worldwide.

• A large multicenter European SLE registry suggests that 3-7% of patients with SLE and antiphospholipid antibodies are at risk for new-onset thrombosis.

Mortality/Morbidity

Mortality and morbidity are related to clinical manifestations. An increased incidence of the following is seen in young individuals:

• Cerebrovascular accident (CVA), stroke

• Myocardial infarction

• 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 antiphospholipid antibody syndrome (Multisystem failure secondary to thrombosis, infarction, or both may lead to death in 50% of cases.)

Race

Overall, no specific race predilection has been observed.

• The frequency rate of primary antiphospholipid antibody syndrome is skewed by race predilection of risk factors for thrombosis and atherosclerotic disease.

• The frequency of secondary antiphospholipid antibody syndrome is skewed by race predilection for autoimmune diseases.

Sex

See the list below:

• In secondary antiphospholipid antibody syndrome, the frequency rate is skewed by the female predominance in autoimmune diseases (eg, SLE) in general.

• In primary antiphospholipid antibody syndrome, the frequency rate is skewed by the inclusion of pregnancy-related events in the classification schema.

• In both antiphospholipid antibody syndrome and primary antiphospholipid antibody syndrome, the frequency rate related to sex is equalized in young patients, especially prior to the onset of puberty.

Age

See the list below:

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

Vasospastic or vaso-occlusive events can occur in any organ system in patients with antiphospholipid antibody (aPL) syndrome (APS); 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.[2, 3, 4, 5, 6, 11]

• 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 pain, toe pain, or both

• Musculoskeletal

  • Bone pain

  • Joint pain

• Cutaneous

  • Purpuric rashes, petechial rashes, or both

  • Persistent or transient lacy rashes of livedo reticularis

  • Dusky fingers, dusky toes, or both

  • Blanching of fingers, blanching of toes, or both

• Neurologic and psychiatric

  • Syncope

  • Seizures[38]

  • Headache (migraine)

  • Paresthesias

  • Paralysis

  • Ascending weakness

  • Tremors

  • Abnormal movements

  • Memory loss

  • Problems with concentrating, reading comprehension, calculations (change in school performance)

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

• Genitourinary/renal

  • 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 and may assist in identifying patients at risk.

  • Family history may include the following:

    • Frequent miscarriage, premature birth, intrauterine growth retardation (IUGR), oligohydramnios, chorea gravidarum, placental infarction, preeclampsia, toxemia of pregnancy, or neonatal thromboembolism

    • Myocardial infarction or stroke in persons younger than 50 years

    • Deep vein thrombosis (DVT), phlebitis, or pulmonary embolus

    • Strong family history of migraine, Raynaud phenomenon, or transient ischemic attacks (TIAs)

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

Physical findings are specific to the affected organ and can involve any organ system.[39] Catastrophic antiphospholipid antibody syndrome (CAPS) is a multisystem failure secondary to thrombosis, infarction, or both and has a picture of microangiopathy on histology.[40, 41, 42, 43, 18, 44]

• Peripheral vascular

  • Point tenderness to palpation of bone or joints (bone infarction), as shown 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.

  • Pain on range of motion of joints without arthritis (avascular necrosis)

  • Limb swelling (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), as shown below

    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.
    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.

• Pulmonary - Respiratory distress, tachypnea (pulmonary embolism [PE], pulmonary hypertension)[45]

• Renal[46, 47, 48, 49, 50, 51]

  • Hypertension (renal artery thrombosis, intrarenal vascular lesions)

  • Hematuria (renal vein thrombosis)

  • Acute renal insufficiency (intrarenal vascular lesions), as shown below

    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.

• Cardiac[52, 53, 54, 55, 56, 57]

  • Insufficiency murmur of aortic, mitral valve (endocarditis)

  • Chest pain, diaphoresis (myocardial infarction)

• GI

  • Right upper quadrant tenderness, hepatomegaly (Budd-Chiari syndrome,[58] hepatic small vessel thrombosis, hepatic infarction)

  • Abdominal tenderness (mesenteric artery thrombosis)

• Endocrine - Muscle weakness, progressive stiffening of pelvic and thigh muscles with flexion contractures associated with adrenal insufficiency (adrenal infarction/hemorrhage)[59]

• Ocular

  • Retinal artery occlusion

  • Retinal vein thrombosis

• Skin manifestations

  • Livedo reticularis, shown below

    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).
    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.

  • Purpuric lesions, as shown below

    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.

  • Superficial thrombophlebitis

  • Vasospasm (ie, Raynaud phenomenon), as shown below

    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.

  • Splinter hemorrhages (periungual, subungual), as shown below

    Linear splinter hemorrhages are found under the nails of fingers and toes. These may be solitary or multiple and appear intermittently.

  • Peripheral infarctions (digital pitting), as below

    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.

  • Skin ulcerations (eg, leg ulcers)

  • Petechiae (associated with thrombocytopenia), as shown below

    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.
    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.

  • Bruising (associated with thrombocytopenia)

• Central or peripheral nervous system abnormalities[60, 61, 62, 63]

  • Stroke, cerebrovascular accident (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

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 antibody syndrome in patients with the following conditions:

• Vascular inflammation, vasculitis

  • Autoimmune disease (eg, systemic lupus erythematosus [SLE][64] , 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 antiphospholipid antibody antibodies over time on dialysis)

  • Cuprophane membrane exposure

  • Oxidative stress

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.[65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80] 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.

• 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.

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 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.

• 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.

• 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.

• 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.

• Doppler ultrasonography

• Magnetic resonance arteriography (MRA)

In patients with cardiac events (including vegetative valvular lesions [eg, Libman-Sacks endocarditis])[54]

• Two-dimensional echocardiography

• Transesophageal echocardiography[52, 53]

• 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)

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.[81]

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.

The following are potential therapeutic interventions for various care scenarios in patients with antiphospholipid antibody (aPL) syndrome (APS). Classes of medications are suggested below, and specific drugs are covered in Medication. See the therapeutic algorithm in the image below.[82, 83, 84, 85, 1, 27, 40, 44, 86, 87, 88, 89, 90, 91, 92]

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.

See the list below:

• In healthy patients who are asymptomatic and have no risk factors and a negative family history for arterial or venous thrombosis or fetal loss, no treatment or specific follow-up care is recommended.

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

• In patients with primary antiphospholipid antibody syndrome (PAPS) with venous thrombosis, the initial treatment consists of heparin followed by warfarin (Coumadin) or low molecular weight (LMW) heparin. The highest risk for recurrence is in the first 6-12 weeks after thrombosis, but many physicians treat for at least 6 months in the absence of other risk factors. Some physicians advocate treatment for life.

• In patients with primary antiphospholipid antibody syndrome with arterial thrombosis or infarction, many physicians administer antiplatelet therapy in the absence of other risk factors, but the use of anticoagulants is controversial.[93] 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 warfarin (Coumadin) with regard to recurrence of stroke.[94]

• In patients with secondary antiphospholipid antibody syndrome 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 lupus anticoagulant (LAC) and any other risk factors (eg, factor V Leiden mutation, prothrombin gene mutation, methylene tetrahydrofolate reductase mutation (MTHFR) mutation), anticoagulation therapy may be necessary for life.

• Patients with catastrophic antiphospholipid antibody 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 catastrophic antiphospholipid antibody syndrome.

    • 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) or targeted B cell therapy (rituximab) as final replacement after pheresis to decrease B-cell immunoglobulin production.

See the list below:

• 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

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)

Identification and correction of folate deficiencies, elevated homocysteine levels, or both[90]

• 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 with mutations in the gene that encodes for MTHFR.

Dietary counseling for patients on oral anticoagulant therapy

• Patients should maintain a consistent diet of foods that contain 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

Physical activity: No specific limitations on activity are needed for individuals with aPL antibodies or antiphospholipid antibody syndrome other than those imposed by residua from a thromboembolic event (eg, stroke, myocardial infarction). However, certain restrictions are prudent for individuals with anticoagulation.

• 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 antiphospholipid antibodies 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

Very few studies have addressed the efficacy of any treatment protocol in antiphospholipid antibody syndrome (APS). 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 antibody syndrome.

Class Summary

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. No prevalence data on aspirin resistance in children has been reported. The effect of aspirin on platelet function can be assessed by optical platelet aggregometry or Platelet Function Analyzer (PFA-100). 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.

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.

Ticlopidine (Ticlid)

Used for livedoid vasculitis and thromboembolic disorders. Second-line antiplatelet therapy for patients who cannot tolerate or in whom aspirin therapy has failed.

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 PO anticoagulant therapy (with or without aspirin) in children with mechanical prosthetic heart valves.

Class Summary

Unfractionated intravenous heparin and fractionated LMW subcutaneous heparin are the choices for initial anticoagulation therapy. If warfarin is chosen as maintenance therapy, it is initiated and concurrently administered with heparin for several days until the international normalized ratio (INR) reaches the target range.

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 PO warfarin therapy.

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)

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.

Class Summary

Immune globulin is a purified preparation of gamma globulin derived from large pools of human plasma. It is composed of 4 subclasses of IgG antibodies, approximating the distribution of human serum. IgA-depleted products are also low in the IgG4 component.

Immune globulin intravenous (Sandoglobulin, Gammagard, Gamimune, Gammar-P, Gamunex)

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%).

Class Summary

These agents are used to lower elevated blood pressure, decrease vasospasm, or prevent ischemia. Niacin is also used to decrease hyperlipidemia.

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 20-60 min. Duration of effect is 2-12 h.

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.

Class Summary

These drugs appear to have multiple mechanisms in the prevention of thrombosis and vascular spasm. The exact mechanisms are largely unexplained, but the properties of these drugs include changes in RBC rheology, inhibition of platelet adhesiveness/activation, inhibition of TNF-alpha production, and decreases in neutrophil and endothelial cell activation.

Pentoxifylline (Trental)

Used in vascular disease. May alter rheology of RBCs, 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.

Hydroxychloroquine (Plaquenil)

Inhibits platelets, chemotaxis of eosinophils, and 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.

Cilostazol (Pletal)

Affects vascular beds and cardiovascular function. May improve blood flow by altering rheology of RBCs. 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.

Class Summary

These agents are used to augment platelet recovery.

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.

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.

Class Summary

Medications with vasodilatory and antiplatelet activity with specific usage in the treatment of pulmonary hypertension and/or healing of refractory skin ulcerations have been administered in patients with APS.[86, 87, 88]

Bosentan (Tracleer)

Endothelin-receptor antagonist indicated for the treatment of pulmonary arterial hypertension in patients with WHO class III or class IV symptoms to improve exercise ability and decrease rate of clinical worsening. Inhibits vessel constriction and elevation of blood pressure by competitively binding to the endothelin-1 (ET-1) receptors ETA and ETB in endothelium and vascular smooth muscle. This leads to a significant increase in the cardiac index (CI) associated with significant reduction in pulmonary artery pressure (PAP), pulmonary vascular resistance (PVR), and mean right atrial pressure (RAP). Due to teratogenic potential, can only be prescribed through the Tracleer Access Program (1-866-228-3546).

Epoprostenol (Flolan)

Prostacyclin, PGI2 analogue that has potent vasodilatory properties. Elicits immediate onset of action. Half-life is approximately 5 min. In addition to vasodilator properties (all vascular beds), also contributes to inhibition of platelet aggregation (activates intracellular adenylate cyclase and results in increased CAMP in platelets) and plays role in inhibition of smooth muscle proliferation.

Sildenafil (Viagra, Revatio)

FDA-approved for pulmonary hypertension. Promotes selective smooth muscle relaxation in lung vasculature possibly by inhibiting phosphodiesterase type 5 (PDE5). This results in subsequent reduction of blood pressure in pulmonary arteries and increase in cardiac output. Elicits vasodilation and inhibits platelet aggregation. Also aids in healing refractory skin ulcerations.

Class Summary

Therapy for dyslipoproteinemia or hyperlipidemia may reduce vascular risk factors for thrombosis. In vitro and animal model evidence suggests decreased endothelial cell and granulocyte activation.[95, 91]

Atorvastatin (Lipitor)

The most efficacious of the statins at high doses. Inhibits 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA reductase), which in turn inhibits cholesterol synthesis and increases cholesterol metabolism. Reports have shown as much as a 60% reduction in LDL-C. The Atorvastatin versus Revascularization Treatment study (AVERT) compared 80 mg atorvastatin daily to standard therapy and angioplasty in patients with CHD. While events at 18 mo were the same between both groups, the length of time until the first CHD event occurred was longer with aggressive LDL-C lowering. The half-life of atorvastatin and its active metabolites is longer than that of all the other statins (ie, approximately 48 h compared to 3-4 h).

May modestly elevate HDL-C levels. Clinically, reduced levels of circulating total cholesterol, LDL-C, and serum TGs are observed.

Before initiating therapy, patients should be placed on a cholesterol-lowering diet for 3-6 mo; the diet should be continued indefinitely.

Pravastatin (Pravachol)

Effective in reducing circulating lipid levels and improving the clinical and anatomic course of atherosclerosis.

Simvastatin (Zocor)

Inhibits cholesterol synthesis and increases cholesterol metabolism.

Class Summary

Targeted anti-B cell therapy has been used in the treatment of refractory idiopathic thrombocytopenic purpura (ITP) postsplenectomy. The use of this modality has been extrapolated to treatment protocols for antiphospholipid syndrome.[96, 97, 98]

Rituximab (Rituxan)

Indicated to reduce signs and symptoms for moderately-to-severely active rheumatoid arthritis in combination with methotrexate. For use in adults who have experienced an inadequate response to one or more TNF antagonist therapies. Antibody genetically engineered. Chimeric murine/human monoclonal antibody directed against the CD20 antigen found on surface of B-lymphocytes.

Interval care includes the following:

• History and physical examination for signs and symptoms of thrombotic or vasospastic events

• Laboratory testing for monitoring anticoagulant therapy, antiphospholipid antibody testing, and, in the case of secondary antiphospholipid syndrome, underlying disease activity

• Imaging and Doppler studies for follow-up of previous thrombotic process

• Dietary and lifestyle counseling

Further inpatient care in patients with antiphospholipid (aPL) antibody syndrome (APS) is only on an as-needed basis for management of thrombotic events but may include the following:

• Imaging studies

• Medical therapy

• Invasive procedures for thrombolytic therapy

Further inpatient care is indicated if a catastrophic antiphospholipid antibody syndrome (CAPS) occurs.

See the list below:

• Antiplatelet therapy, such as administration of 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 low molecular weight (LMW) heparin[99, 100, 101]

  • 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 antiphospholipid 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 prothrombin time (PT), standard partial thromboplastin time, or both may be prolonged in the presence of an antiphospholipid antibody, thus diminishing the accuracy of these assays in monitoring of the effectiveness of anticoagulant therapy.

  • The PT/international normalized ratio (INR) assays are also inaccurate in the presence of the lupus anticoagulant (LAC) and may provide results that vary according to the 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 post-injection, kept at 4°C, and processed as soon as possible.

  • Antiphospholipid antibody can bind to platelet factor 4 (PF4), and/or β2-glycoprotein I [GPI]) in the enzyme-linked immunosorbent assay (ELISA) test for heparin antibodies. A false-positive test in the presence of antiphospholipid antibody–associated thrombocytopenia may be falsely interpreted as heparin-induced thrombocytopenia (HIT), and anticoagulation may be inappropriately halted. Confusion may be avoided by obtaining this test prior to exposure to heparin.[102]

• Immunomodulators, such as intravenous immunoglobulin or rituximab

• Therapy for thrombocytopenia, such as steroids, danazol, dapsone, intravenous immunoglobulin (IVIG), or vincristine

• Therapy for pulmonary hypertension: This may include epoprostenol (prostacyclin PGI2), bosentan (non-selective oral endothelin receptor antagonist), sildenafil (phosphodiesterase-5 inhibitor)[86, 87, 88, 103]

• Therapy for dyslipoproteinemia or hyperlipidemia: This may include statin drugs or niacin.[95]

• Dietary supplementation with folic acid, vitamin B-12, or both for patients with hyperhomocysteinemia: See Medication and the therapeutic 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.

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 antiphospholipid antibody syndrome require admission to an ICU, high-level supportive care, and multiple consultative services.

See the list below:

• Adequate medical therapy

• Patient education

• Monitoring for new events

• Monitoring for drug adverse effects and toxicity

Hemorrhage may occur as a result of overaggressive therapy.

Rethrombosis may occur as a result of inadequate therapy.

Catastrophic antiphospholipid antibody syndrome can lead to death (50% mortality rate).

The long-term prognosis varies and depends on the tissue damage incurred and the organ system or systems affected. Clinical manifestations that are associated with a worse prognosis include the following:[104, 105, 106]

• Pulmonary hypertension

• Neurologic involvement (eg, CNS involvement, transverse myelopathy)

• Myocardial ischemia

• Nephropathy

• Gangrene of the extremities

• Catastrophic antiphospholipid antibody syndrome

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 antibody syndrome.

• 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 that encodes for methylene tetrahydrofolate reductase mutation (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 antiphospholipid antibody syndrome, encourage compliance with medications for control of underlying disease processes, such as vasculitis and systemic lupus erythematosus (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.

Current information for patients and their families can be obtained from the excellent Web sites from the St. Thomas Hospital in London (Hughes Syndrome, Hughes Syndrome Foundation).

For excellent patient education resources, visit eMedicineHealth's Brain and Nervous System Center. Also, see eMedicineHealth's patient education articles Blood Clot in the Legs and Stroke.