Antiphospholipid Syndrome

Antiphospholipid syndrome (APLS) is an acquired autoimmune disorder characterized by the persistent presence of antiphospholipid antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins, which create a hypercoagulable Hypercoagulable Hypercoagulable states (also referred to as thrombophilias) are a group of hematologic diseases defined by an increased risk of clot formation (i.e., thrombosis) due to either an increase in procoagulants, a decrease in anticoagulants, or a decrease in fibrinolysis. Hypercoagulable States state. These antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins are most commonly discovered during a workup for a thrombotic event or recurrent pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-HCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care loss, which are the 2 most common clinical manifestations of APLS. Patients with APLS are at risk for both arterial and venous thrombosis, and after a thrombotic event, patients are managed with long-term anticoagulation therapy.

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

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Overview

Definition

Antiphospholipid syndrome (APLS) is an autoimmune phenomenon that presents with thrombotic events and/or adverse pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-HCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care outcomes related to the presence of persistent antiphospholipid antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins (aPL), which produce a hypercoagulable Hypercoagulable Hypercoagulable states (also referred to as thrombophilias) are a group of hematologic diseases defined by an increased risk of clot formation (i.e., thrombosis) due to either an increase in procoagulants, a decrease in anticoagulants, or a decrease in fibrinolysis. Hypercoagulable States state. 

  • aPL: autoantibodies directed against phospholipid-binding proteins
  • Primary APLS: APLS occurring due to isolated aPLs
  • Secondary APLS: APLS occurring in the setting of underlying systemic autoimmune disease

Epidemiology

In the United States:

  • Incidence: approximately 5 cases per 100,000 persons per year
  • Prevalence: approximately 50 cases per 100,000 persons
  • Typical age affected: young to middle-aged adults
  • Gender bias Bias Epidemiological studies are designed to evaluate a hypothesized relationship between an exposure and an outcome; however, the existence and/or magnitude of these relationships may be erroneously affected by the design and execution of the study itself or by conscious or unconscious errors perpetrated by the investigators or the subjects. These systematic errors are called biases. Types of Biases: females > males
  • Associated with aPL are:
    • 6%–9% of pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-HCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care losses (50,000 annually)
    • 14% of strokes (110,000 annually)
    • 11% of myocardial infarctions (100,000 annually)
    • 10% of deep vein thrombosis Deep vein thrombosis Deep vein thrombosis (DVT) usually occurs in the deep veins of the lower extremities. The affected veins include the femoral, popliteal, iliofemoral, and pelvic veins. Proximal DVT is more likely to cause a pulmonary embolism (PE) and is generally considered more serious. Deep Vein Thrombosis (30,000 annually)

Classification

Patients with APLS are classified based on their clinical manifestations.

Table: Classification of APLS
Classification Patients present with:
Thrombotic APLS Arterial or venous thrombosis
Obstetric APLS Obstetric complications:
  • Recurrent pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-HCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care loss
  • Preterm birth Preterm birth Preterm labor refers to regular uterine contractions leading to cervical change prior to 37 weeks of gestation; preterm birth refers to birth prior to 37 weeks of gestation. Preterm birth may be spontaneous due to preterm labor, preterm prelabor rupture of membranes (PPROM), or cervical insufficiency. Preterm Labor and Birth associated with placental insufficiency
Catastrophic APLS Life-threatening thromboembolic events resulting in multiple end-organ damage (usually microvascular disease with acute onset)

Etiology and Pathophysiology

The prothrombotic state of APLS is related to the presence of aPL.

Etiology

  • Primary (50%):
    • Genetic predisposition to develop antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins
    • Due to mutations in HLA-D7, DR4, DQw7, and/or C4 
  • Secondary (50%):
    • Systemic lupus erythematosus Systemic lupus erythematosus Systemic lupus erythematosus (SLE) is a chronic autoimmune, inflammatory condition that causes immune-complex deposition in organs, resulting in systemic manifestations. Women, particularly those of African American descent, are more commonly affected. Systemic Lupus Erythematosus ( SLE SLE Systemic lupus erythematosus (SLE) is a chronic autoimmune, inflammatory condition that causes immune-complex deposition in organs, resulting in systemic manifestations. Women, particularly those of African American descent, are more commonly affected. Systemic Lupus Erythematosus) (most common, 35%)
    • Rheumatoid arthritis Rheumatoid arthritis Rheumatoid arthritis (RA) is a symmetric, inflammatory polyarthritis and chronic, progressive, autoimmune disorder. Presentation occurs most commonly in middle-aged women with joint swelling, pain, and morning stiffness (often in the hands). Rheumatoid Arthritis (RA)
    • Sjögren syndrome (SS)
    • Immune thrombocytopenic purpura Immune thrombocytopenic purpura Immune thrombocytopenic purpura (ITP), formerly known as idiopathic thrombocytopenic purpura, is a condition that develops secondary to immune-mediated destruction of platelets, resulting in thrombocytopenia (platelet count < 100,000/mm³). Immune thrombocytopenic purpura can be either primary or secondary due to drugs or underlying disease. Immune Thrombocytopenic Purpura ( ITP ITP Immune thrombocytopenic purpura (ITP), formerly known as idiopathic thrombocytopenic purpura, is a condition that develops secondary to immune-mediated destruction of platelets, resulting in thrombocytopenia (platelet count < 100,000/mm³). Immune thrombocytopenic purpura can be either primary or secondary due to drugs or underlying disease. Immune Thrombocytopenic Purpura)
    • HIV
    • Hepatitis C virus Hepatitis C Virus Hepatitis C is an infection of the liver caused by the hepatitis C virus (HCV). Hepatitis C virus is an RNA virus and a member of the genus Hepacivirus and the family Flaviviridae. The infection can be transmitted through infectious blood or body fluids and may be transmitted during childbirth or through IV drug use or sexual intercourse. Hepatitis C Virus ( HCV HCV Hepatitis C is an infection of the liver caused by the hepatitis C virus (HCV). Hepatitis C virus is an RNA virus and a member of the genus Hepacivirus and the family Flaviviridae. The infection can be transmitted through infectious blood or body fluids and may be transmitted during childbirth or through IV drug use or sexual intercourse. Hepatitis C Virus)

Pathophysiology

  • Antibodies against phospholipid-binding proteins: 
    • Anticardiolipin
    • Anti-β2-glycoprotein I 
    • Lupus anticoagulant
  • Antibodies result in:
    • Activation of inflammatory cells, endothelial cells, and platelets Platelets Platelets are small cell fragments involved in hemostasis. Thrombopoiesis takes place primarily in the bone marrow through a series of cell differentiation and is influenced by several cytokines. Platelets are formed after fragmentation of the megakaryocyte cytoplasm. Platelets, promoting thrombosis
    • Inactivation of anticoagulant factors (proteins C and S), promoting thrombosis
    • Increased complement activity toward the trophoblasts, resulting in recurrent pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-HCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care loss
  • Transient aPL are common, especially following an acute illness.
    • Diagnosis of APLS requires persistence of the antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins.

Clinical Presentation

Antiphospholipid syndrome tends to present in young to middle-aged women with either thromboembolic events and/or pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-HCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care complications. Other autoimmune conditions may be present.

Thromboembolic presentations

  • Deep vein thrombosis ( DVT DVT Deep vein thrombosis (DVT) usually occurs in the deep veins of the lower extremities. The affected veins include the femoral, popliteal, iliofemoral, and pelvic veins. Proximal DVT is more likely to cause a pulmonary embolism (PE) and is generally considered more serious. Deep Vein Thrombosis):
    • DVTs of the lower extremities (most common DVTs):
      • Unilateral swelling and/or pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain in the extremity
      • Pain with dorsiflexion of the foot Foot The foot is the terminal portion of the lower limb, whose primary function is to bear weight and facilitate locomotion. The foot comprises 26 bones, including the tarsal bones, metatarsal bones, and phalanges. The bones of the foot form longitudinal and transverse arches and are supported by various muscles, ligaments, and tendons. Foot
    • DVTs of the upper extremities
    • Pulmonary embolism (PE):
      • Dyspnea Dyspnea Dyspnea is the subjective sensation of breathing discomfort. Dyspnea is a normal manifestation of heavy physical or psychological exertion, but also may be caused by underlying conditions (both pulmonary and extrapulmonary). Dyspnea
      • Acute respiratory distress
      • Pulmonary hypertension Pulmonary Hypertension Pulmonary hypertension (PH) or pulmonary arterial hypertension (PAH) is characterized by elevated pulmonary arterial pressure, which can lead to chronic progressive right heart failure. Pulmonary hypertension is grouped into 5 categories based on etiology, which include primary PAH, and PH due to cardiac disease, lung or hypoxic disease, chronic thromboembolic disease, and multifactorial or unclear etiologies. Pulmonary Hypertension
    • Cerebral sinus thrombosis
    • Hepatic and portal vein Portal vein A short thick vein formed by union of the superior mesenteric vein and the splenic vein. Liver thrombosis
    • Renal vein thrombosis
    • Adrenal vein thrombosis
  • Superficial vein thrombosis
  • Arterial thrombosis:
    • Stroke (most common arterial thrombosis) and transient ischemic attacks (TIAs):
      • Focal neurologic findings
      • Cognitive deficits
    • MI MI MI is ischemia and death of an area of myocardial tissue due to insufficient blood flow and oxygenation, usually from thrombus formation on a ruptured atherosclerotic plaque in the epicardial arteries. Clinical presentation is most commonly with chest pain, but women and patients with diabetes may have atypical symptoms. Myocardial Infarction:
      • Chest pain Chest Pain Chest pain is one of the most common and challenging complaints that may present in an inpatient and outpatient setting. The differential diagnosis of chest pain is large and includes cardiac, gastrointestinal, pulmonary, musculoskeletal, and psychiatric etiologies. Chest Pain
      • Dyspnea Dyspnea Dyspnea is the subjective sensation of breathing discomfort. Dyspnea is a normal manifestation of heavy physical or psychological exertion, but also may be caused by underlying conditions (both pulmonary and extrapulmonary). Dyspnea on exertion
    • Retinal thrombosis
    • Nephropathy due to vaso-occlusion in the small renal vessels:
      • Renal failure
      • Proteinuria
      • Hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension
  • Recurrent thromboembolic events

Obstetric presentations

  • Recurrent miscarriages
  • Preterm delivery of an anatomically normal infant < 34 weeks gestation due to either:
    • Severe preeclampsia or eclampsia
    • Features consistent with placental insufficiency:
      • Oligohydramnios Oligohydramnios Oligohydramnios refers to amniotic fluid volume less than expected for the current gestational age. Oligohydramnios is diagnosed by ultrasound and defined as an amniotic fluid index (AFI) of ‰¤ 5 cm or a single deep pocket (SDP) of < 2 cm in the 2nd or 3rd trimester. Oligohydramnios (low amniotic fluid)
      • Low birth weight
      • Non-reassuring or abnormal fetal surveillance testing (e.g., non-stress tests, biophysical profile, Doppler studies)

Other findings

Some additional findings may include:

  • Hematologic findings:
    • Thrombocytopenia
    • Autoimmune hemolytic anemia Autoimmune Hemolytic Anemia Autoimmune hemolytic anemia (AIHA) is a rare type of hemolytic anemia characterized by antibody production against self RBCs, leading to destruction of these cells in the spleen and other reticuloendothelial tissues. The disease is generally categorized as warm or cold, depending on the thermal reactivity of the autoantibodies. Autoimmune Hemolytic Anemia (AIHA)
    • Thrombotic microangiopathic anemia
  • Cardiac findings: if present, almost always involve the valves
    • Murmurs on exam:
      • Most commonly involve the mitral and aortic valves
      • May lead to regurgitation, and less commonly stenosis
    • Thickening of the valve leaflets
    • Nodules/non-bacterial vegetations (Libman-Sacks endocarditis Endocarditis Endocarditis is an inflammatory disease involving the inner lining (endometrium) of the heart, most commonly affecting the cardiac valves. Both infectious and noninfectious etiologies lead to vegetations on the valve leaflets. Patients may present with nonspecific symptoms such as fever and fatigue. Endocarditis)
  • Dermatologic findings:
    • Livedo reticularis: a red-blue netlike, reticulated pattern occurring due to compromised blood flow Flow Blood flows through the heart, arteries, capillaries, and veins in a closed, continuous circuit. Flow is the movement of volume per unit of time. Flow is affected by the pressure gradient and the resistance fluid encounters between 2 points. Vascular resistance is the opposition to flow, which is caused primarily by blood friction against vessel walls. Vascular Resistance, Flow, and Mean Arterial Pressure in medium-sized vessels
    • Ulceration and/or gangrene of the digits
    • Splinter hemorrhages
  • Rheumatologic findings: consistent with an associated rheumatologic disorder
    • Rashes Rashes Rashes are a group of diseases that cause abnormal coloration and texture to the skin. The etiologies are numerous but can include irritation, allergens, infections, or inflammatory conditions. Rashes that present in only 1 area of the body are called localized rashes. Generalized rashes occur diffusely throughout the body. Generalized and Localized Rashes
    • Arthralgias
    • Fatigue
Livedo reticularis

Livedo reticularis

Image: “Livedo reticularis in a patient with DADA2” by Roberta Caorsi et al. License: CC BY 4.0

Diagnosis

Diagnostic criteria

To meet the diagnostic criteria for APLS, a patient must meet both clinical and laboratory criteria.

Table: Diagnostic criteria for APLS
Criteria Events which satisfy the criteria
Clinical criteria Need to have a history of at least one of the following:
  • Vascular thrombosis:
    • ≥ 1 deep vein, arterial, or small vessel thrombosis in any organ or tissue
    • Superficial venous thrombosis does not satisfy this criteria.
  • Pregnancy morbidity:
    • ≥ 3 consecutive, spontaneous pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-HCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care losses at < 10 weeks gestational age (WGA)
    • ≥ 1 pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-HCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care loss of a morphologically normal fetus at ≥ 10 WGA
    • ≥ 1 premature delivery at < 34 WGA due to severe preeclampsia/eclampsia, or placental insufficiency
Laboratory criteria Need at least one positive antibody finding, on at least 2 separate occasions, at least 12 weeks apart:
  • Lupus anticoagulant (positive = present)
  • Anti-cardiolipin antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins (positive = ↑ IgG and/or IgM titers)
  • β2-glycoprotein-I antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins (positive = ↑ IgG and/or IgM titers)

Laboratory assessment

  • Serologies and titer levels for aPL: 
    • Anticardiolipin antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins:
      • Note: Anticardiolipin antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins can result in a false positive test for syphilis Syphilis Syphilis is a bacterial infection caused by the spirochete Treponema pallidum pallidum (T. p. pallidum), which is usually spread through sexual contact. Syphilis has 4 clinical stages: primary, secondary, latent, and tertiary. Syphilis because they react with the cardiolipin reagent in the rapid plasma reagin test.
    • Anti-β2-glycoprotein I antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins
    • Lupus anticoagulant:
      • Note: Despite being called an “anticoagulant,” this factor is actually prothrombotic.
      • Its name comes from the fact that it functions as an anticoagulant in some lab tests.
  • CBC and coagulation studies Coagulation studies Coagulation studies are a group of hematologic laboratory studies that reflect the function of blood vessels, platelets, and coagulation factors, which all interact with one another to achieve hemostasis. Coagulation studies are usually ordered to evaluate patients with bleeding or hypercoagulation disorders. Coagulation Studies may show:
    • Anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview (hemolytic, microangiopathic)
    • Thrombocytopenia ( platelets Platelets Platelets are small cell fragments involved in hemostasis. Thrombopoiesis takes place primarily in the bone marrow through a series of cell differentiation and is influenced by several cytokines. Platelets are formed after fragmentation of the megakaryocyte cytoplasm. Platelets are consumed in procoagulant states)
    • Prolonged aPTT (due to Lupus anticoagulant)
  • Complement studies: may show complement levels (e.g., C3 or C4), can be observed in both primary and secondary APLS

Other assessments

Other testing may be clinically indicated based on presentation. For example:

  • Imaging:
    • Doppler studies for a suspected DVT DVT Deep vein thrombosis (DVT) usually occurs in the deep veins of the lower extremities. The affected veins include the femoral, popliteal, iliofemoral, and pelvic veins. Proximal DVT is more likely to cause a pulmonary embolism (PE) and is generally considered more serious. Deep Vein Thrombosis
    • CT for a suspected stroke
  • ECG ECG An electrocardiogram (ECG) is a graphic representation of the electrical activity of the heart plotted against time. Adhesive electrodes are affixed to the skin surface allowing measurement of cardiac impulses from many angles. The ECG provides 3-dimensional information about the conduction system of the heart, the myocardium, and other cardiac structures. Normal Electrocardiogram (ECG) for suspected MI MI MI is ischemia and death of an area of myocardial tissue due to insufficient blood flow and oxygenation, usually from thrombus formation on a ruptured atherosclerotic plaque in the epicardial arteries. Clinical presentation is most commonly with chest pain, but women and patients with diabetes may have atypical symptoms. Myocardial Infarction
  • Thrombophilia workup (e.g., if only presenting symptom is an unprovoked DVT DVT Deep vein thrombosis (DVT) usually occurs in the deep veins of the lower extremities. The affected veins include the femoral, popliteal, iliofemoral, and pelvic veins. Proximal DVT is more likely to cause a pulmonary embolism (PE) and is generally considered more serious. Deep Vein Thrombosis)
  • Rheumatologic workup (e.g., if patient has findings consistent with SLE SLE Systemic lupus erythematosus (SLE) is a chronic autoimmune, inflammatory condition that causes immune-complex deposition in organs, resulting in systemic manifestations. Women, particularly those of African American descent, are more commonly affected. Systemic Lupus Erythematosus)

Management

Management of acute thrombosis in APLS

The mainstay of therapy for both primary and secondary (i.e., associated with SLE SLE Systemic lupus erythematosus (SLE) is a chronic autoimmune, inflammatory condition that causes immune-complex deposition in organs, resulting in systemic manifestations. Women, particularly those of African American descent, are more commonly affected. Systemic Lupus Erythematosus) APLS is anticoagulation.

  • Thrombotic and obstetric APLS:
    • Initiate anticoagulation with heparin overlapped with warfarin. 
    • Low-molecular-weight heparins (LMWHs) are typically the drug of choice.
    • Heparins are continued until the INR is in the therapeutic range for 2 consecutive days. 
    • Heparins can then be discontinued, while warfarin is continued indefinitely for ongoing prophylaxis.
  • Catastrophic APLS: 
    • Anticoagulation
    • IV glucocorticoids Glucocorticoids Glucocorticoids are a class within the corticosteroid family. Glucocorticoids are chemically and functionally similar to endogenous cortisol. There are a wide array of indications, which primarily benefit from the antiinflammatory and immunosuppressive effects of this class of drugs. Glucocorticoids
    • Plasmapheresis
    • IV immunoglobulins Immunoglobulins Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins (IVIG)
  • Arterial thrombosis (e.g., MI MI MI is ischemia and death of an area of myocardial tissue due to insufficient blood flow and oxygenation, usually from thrombus formation on a ruptured atherosclerotic plaque in the epicardial arteries. Clinical presentation is most commonly with chest pain, but women and patients with diabetes may have atypical symptoms. Myocardial Infarction, stroke): managed the same as patients without APLS

Prevention of thrombosis

  • Smoking cessation
  • Avoiding estrogen Estrogen Compounds that interact with estrogen receptors in target tissues to bring about the effects similar to those of estradiol. Estrogens stimulate the female reproductive organs, and the development of secondary female sex characteristics. Estrogenic chemicals include natural, synthetic, steroidal, or non-steroidal compounds. Ovaries-containing contraceptives
  • Managing hyperlipidemia/hypertension
  • For patients who have never had a thrombotic event (i.e., primary prevention): 
    • Consider low-dose aspirin (evidence is limited; consider entire clinical picture).
    • Optimize modifiable risk factors.
  • For patients with a history of thrombosis:
    • In patients who do not desire pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-HCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care: warfarin therapy
    • In patients who do desire pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-HCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care: LMWH and aspirin (warfarin is teratogenic)
  • For patients with aPL but who do not meet diagnostic criteria for APLS, antithrombotic medication is not recommended.

Other management points

  • Immunomodulatory agents:
    • May be considered in some patients with:
      • Recurrent thrombosis despite adequate anticoagulation
      • Hematologic manifestations (e.g., thrombocytopenia Thrombocytopenia Thrombocytopenia occurs when the platelet count is < 150,000 per microliter. The normal range for platelets is usually 150,000-450,000/µL of whole blood. Thrombocytopenia can be a result of decreased production, increased destruction, or splenic sequestration of platelets. Patients are often asymptomatic until platelet counts are < 50,000/µL. Thrombocytopenia or thrombotic microangiopathies)
    • Limited evidence to guide use, though theoretically helpful because APLS is an autoimmune disease
    • Agents to consider: hydroxychloroquine, rituximab
  • Thrombocytopenia:
    • Many patients with APLS have mild thrombocytopenia Thrombocytopenia Thrombocytopenia occurs when the platelet count is < 150,000 per microliter. The normal range for platelets is usually 150,000-450,000/µL of whole blood. Thrombocytopenia can be a result of decreased production, increased destruction, or splenic sequestration of platelets. Patients are often asymptomatic until platelet counts are < 50,000/µL. Thrombocytopenia.
    • Cause of the thrombocytopenia Thrombocytopenia Thrombocytopenia occurs when the platelet count is < 150,000 per microliter. The normal range for platelets is usually 150,000-450,000/µL of whole blood. Thrombocytopenia can be a result of decreased production, increased destruction, or splenic sequestration of platelets. Patients are often asymptomatic until platelet counts are < 50,000/µL. Thrombocytopenia should still be investigated.
    • Anticoagulation should be continued while the platelet count is > 50,000/µL. 
  • Screening ECGs: 
    • Despite an increased risk for cardiac valvulopathies, routine ECGs are generally not recommended.
    • ECGs should be performed for new murmurs or symptoms.

Clinical Relevance

Differential diagnosis for recurrent thrombosis

Hypercoagulable states Hypercoagulable states Hypercoagulable states (also referred to as thrombophilias) are a group of hematologic diseases defined by an increased risk of clot formation (i.e., thrombosis) due to either an increase in procoagulants, a decrease in anticoagulants, or a decrease in fibrinolysis. Hypercoagulable States: hypercoagulable Hypercoagulable Hypercoagulable states (also referred to as thrombophilias) are a group of hematologic diseases defined by an increased risk of clot formation (i.e., thrombosis) due to either an increase in procoagulants, a decrease in anticoagulants, or a decrease in fibrinolysis. Hypercoagulable States states or thrombophilias are defined by an increased risk of clot formation or thrombosis. The cause may be inherited or acquired; both lead to the production of clots that may cause occlusion of vessels in major organs, which can be fatal. Factor V Leiden is the most common inherited cause. Management usually involves the use of anticoagulants Anticoagulants Anticoagulants are drugs that retard or interrupt the coagulation cascade. The primary classes of available anticoagulants include heparins, vitamin K-dependent antagonists (e.g., warfarin), direct thrombin inhibitors, and factor Xa inhibitors. Anticoagulants.

Table: Causes of a hypercoagulable Hypercoagulable Hypercoagulable states (also referred to as thrombophilias) are a group of hematologic diseases defined by an increased risk of clot formation (i.e., thrombosis) due to either an increase in procoagulants, a decrease in anticoagulants, or a decrease in fibrinolysis. Hypercoagulable States state
Type Disease Description
Primary or inherited Factor V Leiden
  • Autosomal dominant Autosomal dominant Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal dominant diseases are expressed when only 1 copy of the dominant allele is inherited. Autosomal Recessive and Autosomal Dominant Inheritance with incomplete penetrance
  • Most common inherited thrombophilia in caucasians
  • Caused by a point mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations substituting guanine for adenine
  • Results in resistance to factor V degradation by protein C
Prothrombin 20210A or factor II mutations
  • Autosomal dominant Autosomal dominant Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal dominant diseases are expressed when only 1 copy of the dominant allele is inherited. Autosomal Recessive and Autosomal Dominant Inheritance
  • 2nd most common inherited thrombophilia
  • Point mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations leads to ↑ prothrombin function.
Antithrombin deficiency
  • Autosomal dominant Autosomal dominant Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal dominant diseases are expressed when only 1 copy of the dominant allele is inherited. Autosomal Recessive and Autosomal Dominant Inheritance (or can be acquired)
  • Antithrombin normally inhibits thrombin and factor Xa.
  • Antithrombin deficiency leads to:
    • ↑ Thrombin and factor Xa
    • Resistance to LMWH
Protein C or S deficiency
  • Proteins C and S are vitamin K-dependent anticoagulants Anticoagulants Anticoagulants are drugs that retard or interrupt the coagulation cascade. The primary classes of available anticoagulants include heparins, vitamin K-dependent antagonists (e.g., warfarin), direct thrombin inhibitors, and factor Xa inhibitors. Anticoagulants.
  • Deficiencies result in overactivity of factors V and VIII.
Secondary or acquired Venous stasis
  • Immobility (cast, stroke patients, post-knee surgery, long flights)
  • Varicose veins Veins Veins are tubular collections of cells, which transport deoxygenated blood and waste from the capillary beds back to the heart. Veins are classified into 3 types: small veins/venules, medium veins, and large veins. Each type contains 3 primary layers: tunica intima, tunica media, and tunica adventitia. Veins
  • Hyperviscosity (e.g., polycythemia vera Polycythemia vera Polycythemia vera (PV) is a chronic myeloproliferative neoplasm characterized by the overproduction of RBCs. In addition, the WBC and platelet counts are also increased, which differentiate PV from erythrocytosis seen with chronic hypoxia and other chronic conditions. Polycythemia Vera)
Endothelial injury
  • Malignancy
  • Vasculitis
  • Instrumentation
Acquired hypercoagulability
  • Oral contraceptive pills
  • Antiphospholipid syndrome
  • Nephrotic syndrome Nephrotic syndrome Nephrotic syndrome is characterized by severe proteinuria, hypoalbuminemia, and peripheral edema. In contrast, the nephritic syndromes present with hematuria, variable loss of renal function, and hypertension, although there is sometimes overlap of > 1 glomerular disease in the same individual. Nephrotic Syndrome
  • Paroxysmal nocturnal hemoglobinuria Paroxysmal Nocturnal Hemoglobinuria Paroxysmal nocturnal hemoglobinuria (PNH) is a rare but serious acquired hemolytic anemia with periodic exacerbations. This anemia is caused by nonmalignant clonal expansion of ≥ 1 hematopoietic stem cells that have acquired a somatic mutation of the phosphatidylinositol N-acetylglucosaminyltransferase subunit A (PIG-A) gene. Paroxysmal Nocturnal Hemoglobinuria
  • Inflammatory bowel disease

Common presentations of recurrent thrombosis

  • Deep vein thrombosis ( DVT DVT Deep vein thrombosis (DVT) usually occurs in the deep veins of the lower extremities. The affected veins include the femoral, popliteal, iliofemoral, and pelvic veins. Proximal DVT is more likely to cause a pulmonary embolism (PE) and is generally considered more serious. Deep Vein Thrombosis): thrombosis of the deep venous systems found in the lower limb. The condition is a clinical manifestation of hypercoagulable Hypercoagulable Hypercoagulable states (also referred to as thrombophilias) are a group of hematologic diseases defined by an increased risk of clot formation (i.e., thrombosis) due to either an increase in procoagulants, a decrease in anticoagulants, or a decrease in fibrinolysis. Hypercoagulable States states and requires management acutely to prevent the development of pulmonary emboli. Diagnosis is typically made using Doppler ultrasonography. The condition is treated with anticoagulants Anticoagulants Anticoagulants are drugs that retard or interrupt the coagulation cascade. The primary classes of available anticoagulants include heparins, vitamin K-dependent antagonists (e.g., warfarin), direct thrombin inhibitors, and factor Xa inhibitors. Anticoagulants.
  • Pulmonary embolism (PE): a medical emergency in which an embolus will block the pulmonary trunk/artery, resulting in acute shortness of breath and impaired ventilation/perfusion. About 30% of these patients have a concurrent DVT DVT Deep vein thrombosis (DVT) usually occurs in the deep veins of the lower extremities. The affected veins include the femoral, popliteal, iliofemoral, and pelvic veins. Proximal DVT is more likely to cause a pulmonary embolism (PE) and is generally considered more serious. Deep Vein Thrombosis. Diagnosis can be made on a CT pulmonary angiography (CTPA) scan and/or a V/Q. Patients are treated with anticoagulants Anticoagulants Anticoagulants are drugs that retard or interrupt the coagulation cascade. The primary classes of available anticoagulants include heparins, vitamin K-dependent antagonists (e.g., warfarin), direct thrombin inhibitors, and factor Xa inhibitors. Anticoagulants.

References

  1. Urkan, D, Ortel, T. (2020). Clinical manifestations of antiphospholipid syndrome. Viewed Retrieved Apr 18, 2021, from https://www.uptodate.com/contents/clinical-manifestations-of-antiphospholipid-syndrome
  2. Urkan, D, Ortel, T. (2020). Diagnosis of antiphospholipid syndrome. Retrieved Apr 18, 2021, fromhttps://www.uptodate.com/contents/diagnosis-of-antiphospholipid-syndrome 
  3. Urkan, D, Ortel, T. (2020). Treatment of antiphospholipid syndrome. Retrieved Apr 18, 2021, from https://www.uptodate.com/contents/treatment-of-antiphospholipid-syndrome
  4. Bustamante, J. (2020). Antiphospholipid syndrome. In Singhal, M. (Ed.) StatPearls. Retrieved April 23, 2021, from https://www.statpearls.com/articlelibrary/viewarticle/17705/ 
  5. Movva, S. (2020). Antiphospholipid syndrome. In Diamond, H. (Ed.) Medscape. Retrieved April 23, 2021, from https://emedicine.medscape.com/article/333221-overview

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