Antiphospholipid Syndrome (Clinical)

Overview

Definition^[1,10,7]

Antiphospholipid syndrome Antiphospholipid syndrome Antiphospholipid syndrome (APLS) is an acquired autoimmune disorder characterized by the persistent presence of antiphospholipid antibodies, which create a hypercoagulable state. These antibodies are most commonly discovered during a workup for a thrombotic event or recurrent pregnancy loss, which are the 2 most common clinical manifestations. Antiphospholipid Syndrome (APS) is an autoimmune phenomenon that presents with thrombotic events and/or adverse pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care outcomes related to the presence of persistent antiphospholipid antibodies Antiphospholipid antibodies Autoantibodies directed against phospholipids. These antibodies are characteristically found in patients with systemic lupus erythematosus, antiphospholipid syndrome; related autoimmune diseases, some non-autoimmune diseases, and also in healthy individuals. Antiphospholipid Syndrome ( aPL APL An acute myeloid leukemia in which abnormal promyelocytes predominate. It is frequently associated with disseminated intravascular coagulation. Acute Myeloid Leukemia), 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 APL An acute myeloid leukemia in which abnormal promyelocytes predominate. It is frequently associated with disseminated intravascular coagulation. Acute Myeloid Leukemia: autoantibodies Autoantibodies Antibodies that react with self-antigens (autoantigens) of the organism that produced them. Blotting Techniques directed against phospholipid-binding proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis
• Primary APS: APS occurring due to isolated aPLs APLS Antiphospholipid syndrome (APLS) is an acquired autoimmune disorder characterized by the persistent presence of antiphospholipid antibodies, which create a hypercoagulable state. These antibodies are most commonly discovered during a workup for a thrombotic event or recurrent pregnancy loss, which are the 2 most common clinical manifestations. Antiphospholipid Syndrome
• Secondary APS: APS occurring in the setting of underlying systemic autoimmune disease (most commonly 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))

Epidemiology^{[7,10,13–15]}

In the United States:

• Incidence Incidence The number of new cases of a given disease during a given period in a specified population. It also is used for the rate at which new events occur in a defined population. It is differentiated from prevalence, which refers to all cases in the population at a given time. Measures of Disease Frequency: approximately 5 cases per 100,000 persons per year
• Prevalence Prevalence The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. Measures of Disease Frequency: 
  • Approximately 50 cases per 100,000 persons
  • 1%–5% of healthy individuals are suspected to have aPLs APLS Antiphospholipid syndrome (APLS) is an acquired autoimmune disorder characterized by the persistent presence of antiphospholipid antibodies, which create a hypercoagulable state. These antibodies are most commonly discovered during a workup for a thrombotic event or recurrent pregnancy loss, which are the 2 most common clinical manifestations. Antiphospholipid Syndrome (i.e., 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: Types and Functions are present without causing clinical manifestations).
  • Prevalence Prevalence The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. Measures of Disease Frequency 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: Approximately 35% of 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 patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship have positive aPLs APLS Antiphospholipid syndrome (APLS) is an acquired autoimmune disorder characterized by the persistent presence of antiphospholipid antibodies, which create a hypercoagulable state. These antibodies are most commonly discovered during a workup for a thrombotic event or recurrent pregnancy loss, which are the 2 most common clinical manifestations. Antiphospholipid Syndrome, and 10% of 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 patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship have APS.
• Typical age affected: young to middle-aged adults
• Sex Sex The totality of characteristics of reproductive structure, functions, phenotype, and genotype, differentiating the male from the female organism. Gender Dysphoria incidence Incidence The number of new cases of a given disease during a given period in a specified population. It also is used for the rate at which new events occur in a defined population. It is differentiated from prevalence, which refers to all cases in the population at a given time. Measures of Disease Frequency: females > males
• Associated with aPL APL An acute myeloid leukemia in which abnormal promyelocytes predominate. It is frequently associated with disseminated intravascular coagulation. Acute Myeloid Leukemia are:
  • 6%–9% of pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care losses (50,000 annually)
  • 14% of strokes (110,000 annually)
  • 11% of myocardial infarctions (100,000 annually)
  • 10% of deep vein thrombosis Thrombosis Formation and development of a thrombus or blood clot in the blood vessel. Epidemic Typhus (30,000 annually)

Classification^[7,10,15]

Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with APS are classified based on their clinical manifestations.

Etiology and Pathophysiology

The prothrombotic state of APS is related to the presence of aPLs APLS Antiphospholipid syndrome (APLS) is an acquired autoimmune disorder characterized by the persistent presence of antiphospholipid antibodies, which create a hypercoagulable state. These antibodies are most commonly discovered during a workup for a thrombotic event or recurrent pregnancy loss, which are the 2 most common clinical manifestations. Antiphospholipid Syndrome.

Etiology^[13,14]

• 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: Types and Functions
  • Due to mutations in HLA-DR7, DR4, DQw7, and/or C4 
• Secondary (50%):
  • Other rheumatologic diseases:
    • 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 Arthritis Acute or chronic inflammation of joints. Osteoarthritis (RA)
    • Sjögren syndrome Sjögren Syndrome Rheumatoid Arthritis ( SS SS Scleroderma (systemic sclerosis) is an autoimmune condition characterized by diffuse collagen deposition and fibrosis. The clinical presentation varies from limited skin involvement to diffuse involvement of internal organs. Scleroderma)
    • 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)
  • Infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease:
    • HIV HIV Anti-HIV Drugs
    • Hepatitis C Hepatitis C Hepatitis C is an infection of the liver caused by the hepatitis C virus (HCV). 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 can cause both acute and chronic hepatitis, ranging from a mild to a serious, lifelong illness including liver cirrhosis and hepatocellular carcinoma (HCC). Hepatitis C Virus virus Virus Viruses are infectious, obligate intracellular parasites composed of a nucleic acid core surrounded by a protein capsid. Viruses can be either naked (non-enveloped) or enveloped. The classification of viruses is complex and based on many factors, including type and structure of the nucleoid and capsid, the presence of an envelope, the replication cycle, and the host range. Virology ( 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)
    • 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
  • Medications:
    • Procainamide Procainamide A class ia antiarrhythmic drug that is structurally-related to procaine. Class 1 Antiarrhythmic Drugs (Sodium Channel Blockers)
    • Quinidine Quinidine An optical isomer of quinine, extracted from the bark of the cinchona tree and similar plant species. This alkaloid dampens the excitability of cardiac and skeletal muscles by blocking sodium and potassium currents across cellular membranes. It prolongs cellular action potentials, and decreases automaticity. Quinidine also blocks muscarinic and alpha-adrenergic neurotransmission. Class 1 Antiarrhythmic Drugs (Sodium Channel Blockers)
    • Phenytoin Phenytoin An anticonvulsant that is used to treat a wide variety of seizures. The mechanism of therapeutic action is not clear, although several cellular actions have been described including effects on ion channels, active transport, and general membrane stabilization. Phenytoin has been proposed for several other therapeutic uses, but its use has been limited by its many adverse effects and interactions with other drugs. First-Generation Anticonvulsant Drugs
    • Chlorpromazine Chlorpromazine The prototypical phenothiazine antipsychotic drug. Like the other drugs in this class chlorpromazine’s antipsychotic actions are thought to be due to long-term adaptation by the brain to blocking dopamine receptors. Chlorpromazine has several other actions and therapeutic uses, including as an antiemetic and in the treatment of intractable hiccup. First-Generation Antipsychotics
    • Others

Pathophysiology^[1–7,15]

• 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: Types and Functions against phospholipid-binding proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis: 
  • Anticardiolipin
  • Anti-β₂-glycoprotein I 
  • Lupus anticoagulant Lupus anticoagulant An antiphospholipid antibody found in association with systemic lupus erythematosus, antiphospholipid syndrome; and in a variety of other diseases as well as in healthy individuals. In vitro, the antibody interferes with the conversion of prothrombin to thrombin and prolongs the partial thromboplastin time. In vivo, it exerts a procoagulant effect resulting in thrombosis mainly in the larger veins and arteries. It further causes obstetrical complications, including fetal death and spontaneous abortion, as well as a variety of hematologic and neurologic complications. Antiphospholipid Syndrome
• 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: Types and Functions result in:^[2,3,15]
  • 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: Histology, promoting thrombosis Thrombosis Formation and development of a thrombus or blood clot in the blood vessel. Epidemic Typhus
  • Inactivation of anticoagulant factors ( proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis C and S), promoting thrombosis Thrombosis Formation and development of a thrombus or blood clot in the blood vessel. Epidemic Typhus
  • Increased complement activity toward the trophoblasts, resulting in recurrent pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care loss
• Transient aPL APL An acute myeloid leukemia in which abnormal promyelocytes predominate. It is frequently associated with disseminated intravascular coagulation. Acute Myeloid Leukemia are common, especially following an acute illness.
  • Diagnosis of APS 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: Types and Functions.

Clinical Presentation

Antiphospholipid syndrome Antiphospholipid syndrome Antiphospholipid syndrome (APLS) is an acquired autoimmune disorder characterized by the persistent presence of antiphospholipid antibodies, which create a hypercoagulable state. These antibodies are most commonly discovered during a workup for a thrombotic event or recurrent pregnancy loss, which are the 2 most common clinical manifestations. Antiphospholipid Syndrome tends to present in young to middle-aged women with either thromboembolic events and/or pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care complications. Other autoimmune conditions may be present.

Thromboembolic presentations^[1,2,15]

• Deep vein thrombosis Thrombosis Formation and development of a thrombus or blood clot in the blood vessel. Epidemic Typhus ( 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 Swelling Inflammation and/or pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways in the extremity
    • Pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways 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: Anatomy
  • DVTs of the upper extremities
  • Pulmonary embolism Pulmonary Embolism Pulmonary embolism (PE) is a potentially fatal condition that occurs as a result of intraluminal obstruction of the main pulmonary artery or its branches. The causative factors include thrombi, air, amniotic fluid, and fat. In PE, gas exchange is impaired due to the decreased return of deoxygenated blood to the lungs. 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 Thrombosis Formation and development of a thrombus or blood clot in the blood vessel. Epidemic Typhus
  • Hepatic and portal vein Portal vein A short thick vein formed by union of the superior mesenteric vein and the splenic vein. Liver: Anatomy thrombosis Thrombosis Formation and development of a thrombus or blood clot in the blood vessel. Epidemic Typhus
  • Renal vein Renal vein Short thick veins which return blood from the kidneys to the vena cava. Glomerular Filtration thrombosis Thrombosis Formation and development of a thrombus or blood clot in the blood vessel. Epidemic Typhus
  • Adrenal vein thrombosis Thrombosis Formation and development of a thrombus or blood clot in the blood vessel. Epidemic Typhus
• Superficial vein thrombosis Thrombosis Formation and development of a thrombus or blood clot in the blood vessel. Epidemic Typhus
• Arterial thrombosis Arterial Thrombosis Hypercoagulable States:
  • Stroke (most common arterial thrombosis Arterial Thrombosis Hypercoagulable States) 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 Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways
    • 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 Thrombosis Formation and development of a thrombus or blood clot in the blood vessel. Epidemic Typhus
  • Nephropathy due to vaso-occlusion in the small renal vessels:
    • Renal failure Renal failure Conditions in which the kidneys perform below the normal level in the ability to remove wastes, concentrate urine, and maintain electrolyte balance; blood pressure; and calcium metabolism. Renal insufficiency can be classified by the degree of kidney damage (as measured by the level of proteinuria) and reduction in glomerular filtration rate. Crush Syndrome
    • Proteinuria Proteinuria The presence of proteins in the urine, an indicator of kidney diseases. Nephrotic Syndrome in Children
    • 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^[1,2]

• Recurrent miscarriages Recurrent Miscarriages Antiphospholipid Syndrome
• Fetal loss/stillbirth
• Preterm delivery of an anatomically normal infant < 34 weeks gestation due to either:
  • Severe preeclampsia Preeclampsia A complication of pregnancy, characterized by a complex of symptoms including maternal hypertension and proteinuria with or without pathological edema. Symptoms may range between mild and severe. Pre-eclampsia usually occurs after the 20th week of gestation, but may develop before this time in the presence of trophoblastic disease. Hypertensive Pregnancy Disorders or eclampsia Eclampsia Onset of hyperreflexia; seizures; or coma in a previously diagnosed pre-eclamptic patient (pre-eclampsia). Hypertensive Pregnancy Disorders
  • Features consistent with placental insufficiency Placental Insufficiency Failure of the placenta to deliver an adequate supply of nutrients and oxygen to the fetus. Neonatal Polycythemia:
    • 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 Amniotic fluid A clear, yellowish liquid that envelopes the fetus inside the sac of amnion. In the first trimester, it is likely a transudate of maternal or fetal plasma. In the second trimester, amniotic fluid derives primarily from fetal lung and kidney. Cells or substances in this fluid can be removed for prenatal diagnostic tests (amniocentesis). Placenta, Umbilical Cord, and Amniotic Cavity)
    • Low birth weight
    • Non-reassuring or abnormal fetal surveillance Surveillance Developmental Milestones and Normal Growth testing (e.g., non-stress tests, biophysical profile Biophysical Profile Obstetric Imaging, Doppler Doppler Ultrasonography applying the doppler effect, with frequency-shifted ultrasound reflections produced by moving targets (usually red blood cells) in the bloodstream along the ultrasound axis in direct proportion to the velocity of movement of the targets, to determine both direction and velocity of blood flow. Ultrasound (Sonography) studies)

Other findings^[1,2,15]

Some additional findings may include:

• Hematologic findings:
  • 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
  • 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 AIHA 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)
  • Thrombotic microangiopathic 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 and Types
• Cardiac findings: if present, almost always involve the valves
  • Murmurs on exam:
    • Most commonly involve the mitral and aortic valves
    • May lead to regurgitation Regurgitation Gastroesophageal Reflux Disease (GERD), and less commonly stenosis Stenosis Hypoplastic Left Heart Syndrome (HLHS)
  • Thickening of the valve leaflets
  • Nodules/non-bacterial vegetations ( Libman-Sacks endocarditis Libman-Sacks Endocarditis Systemic Lupus Erythematosus)
• Dermatologic findings:
  • Livedo reticularis Livedo reticularis A condition characterized by a reticular or fishnet pattern on the skin of lower extremities and other parts of the body. This red and blue pattern is due to deoxygenated blood in unstable dermal blood vessels. The condition is intensified by cold exposure and relieved by rewarming. Chronic Kidney Disease: a red-blue netlike, reticulated pattern occurring due to compromised blood flow Blood flow Blood flow refers to the movement of a certain volume of blood through the vasculature over a given unit of time (e.g., mL per minute). Vascular Resistance, Flow, and Mean Arterial Pressure in medium-sized vessels
  • Ulceration Ulceration Corneal Abrasions, Erosion, and Ulcers and/or gangrene Gangrene Death and putrefaction of tissue usually due to a loss of blood supply. Small Bowel Obstruction of the digits
  • Splinter hemorrhages Splinter hemorrhages Endocarditis
• 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 Fatigue The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. Fibromyalgia

Diagnosis

Diagnostic criteria^[1–3]

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

aPL APL An acute myeloid leukemia in which abnormal promyelocytes predominate. It is frequently associated with disseminated intravascular coagulation. Acute Myeloid Leukemia testing

Indications:^[1,4,5]

• Any patient meeting the clinical diagnostic criteria for APS-associated pregnancy-morbidity 
• Any of the following thrombotic events in patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship < 50 years of age:
  • Unprovoked venous thromboembolism Thromboembolism Obstruction of a blood vessel (embolism) by a blood clot (thrombus) in the blood stream. Systemic Lupus Erythematosus ( VTE VTE Obstruction of a vein or veins (embolism) by a blood clot (thrombus) in the bloodstream. Hypercoagulable States)
  • Ischemic stroke Ischemic Stroke An ischemic stroke (also known as cerebrovascular accident) is an acute neurologic injury that occurs as a result of brain ischemia; this condition may be due to cerebral blood vessel occlusion by thrombosis or embolism, or rarely due to systemic hypoperfusion. Ischemic Stroke, TIA TIA Transient ischemic attack (TIA) is a temporary episode of neurologic dysfunction caused by ischemia without infarction that resolves completely when blood supply is restored. Transient ischemic attack is a neurologic emergency that warrants urgent medical attention. Transient Ischemic Attack (TIA), or other evidence of brain ischemia Brain Ischemia Localized reduction of blood flow to brain tissue due to arterial obstruction or systemic hypoperfusion. This frequently occurs in conjunction with brain hypoxia. Prolonged ischemia is associated with brain infarction. Ischemic Stroke
  • Arterial thrombosis Arterial Thrombosis Hypercoagulable States
• Any of the following thrombotic events in patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship at any age:
  • VTE VTE Obstruction of a vein or veins (embolism) by a blood clot (thrombus) in the bloodstream. Hypercoagulable States at unusual sites
  • Microvascular thrombosis Thrombosis Formation and development of a thrombus or blood clot in the blood vessel. Epidemic Typhus
  • Recurrent VTE VTE Obstruction of a vein or veins (embolism) by a blood clot (thrombus) in the bloodstream. Hypercoagulable States unexplained by malignancy Malignancy Hemothorax or subtherapeutic anticoagulation Anticoagulation Pulmonary Hypertension Drugs
• 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
• Consider testing in:
  • Immune 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
  • Livedo reticularis Livedo reticularis A condition characterized by a reticular or fishnet pattern on the skin of lower extremities and other parts of the body. This red and blue pattern is due to deoxygenated blood in unstable dermal blood vessels. The condition is intensified by cold exposure and relieved by rewarming. Chronic Kidney Disease
  • Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship < 50 years of age with valvular heart disease and evidence of other autoimmune diseases Autoimmune diseases Disorders that are characterized by the production of antibodies that react with host tissues or immune effector cells that are autoreactive to endogenous peptides. Selective IgA Deficiency
  • Unexplained prolonged aPTT (incidental finding)

Serologies and titer levels:^[1,2,4–6]

• Lupus anticoagulant Lupus anticoagulant An antiphospholipid antibody found in association with systemic lupus erythematosus, antiphospholipid syndrome; and in a variety of other diseases as well as in healthy individuals. In vitro, the antibody interferes with the conversion of prothrombin to thrombin and prolongs the partial thromboplastin time. In vivo, it exerts a procoagulant effect resulting in thrombosis mainly in the larger veins and arteries. It further causes obstetrical complications, including fetal death and spontaneous abortion, as well as a variety of hematologic and neurologic complications. Antiphospholipid Syndrome:
  • 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.
  • False positive False positive An FP test result indicates that a person has the disease when they do not. Epidemiological Values of Diagnostic Tests or false negative False negative An FN test result indicates a person does not have the disease when, in fact, they do. Epidemiological Values of Diagnostic Tests results can occur during/in the presence of:
    • Acute-phase reactants Acute-Phase Reactants Inflammation (including factor VIII Factor VIII Factor VIII of blood coagulation. Antihemophilic factor that is part of the factor viii/von Willebrand factor complex. Factor VIII is produced in the liver and acts in the intrinsic pathway of blood coagulation. It serves as a cofactor in factor X activation and this action is markedly enhanced by small amounts of thrombin. Hemostasis and C-reactive protein (CRP), which may be present after acute VTE VTE Obstruction of a vein or veins (embolism) by a blood clot (thrombus) in the bloodstream. Hypercoagulable States)
    • Pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care
    • Anticoagulation Anticoagulation Pulmonary Hypertension Drugs
• Anticardiolipin antibodies Anticardiolipin antibodies Antiphospholipid antibodies found in association with systemic lupus erythematosus, antiphospholipid syndrome; and in a variety of other diseases as well as in healthy individuals. The antibodies are detected by solid-phase immunoassay employing the purified phospholipid antigen cardiolipin. Antiphospholipid Syndrome:
  • Detected by ELISA ELISA An immunoassay utilizing an antibody labeled with an enzyme marker such as horseradish peroxidase. While either the enzyme or the antibody is bound to an immunosorbent substrate, they both retain their biologic activity; the change in enzyme activity as a result of the enzyme-antibody-antigen reaction is proportional to the concentration of the antigen and can be measured spectrophotometrically or with the naked eye. Many variations of the method have been developed. St. Louis Encephalitis Virus or automated solid-phase assay systems
  • Considered elevated if > 99th percentile of normal controls
  • Note: Anticardiolipin antibodies Anticardiolipin antibodies Antiphospholipid antibodies found in association with systemic lupus erythematosus, antiphospholipid syndrome; and in a variety of other diseases as well as in healthy individuals. The antibodies are detected by solid-phase immunoassay employing the purified phospholipid antigen cardiolipin. Antiphospholipid Syndrome can result in a false positive False positive An FP test result indicates that a person has the disease when they do not. Epidemiological Values of Diagnostic Tests 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 Rapid plasma reagin test Treponema.
• 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: Types and Functions
  • Detected by ELISA ELISA An immunoassay utilizing an antibody labeled with an enzyme marker such as horseradish peroxidase. While either the enzyme or the antibody is bound to an immunosorbent substrate, they both retain their biologic activity; the change in enzyme activity as a result of the enzyme-antibody-antigen reaction is proportional to the concentration of the antigen and can be measured spectrophotometrically or with the naked eye. Many variations of the method have been developed. St. Louis Encephalitis Virus or automated solid-phase assay systems
  • Considered elevated if > 99th percentile of normal controls
• Note: All 3 primary aPLs APLS Antiphospholipid syndrome (APLS) is an acquired autoimmune disorder characterized by the persistent presence of antiphospholipid antibodies, which create a hypercoagulable state. These antibodies are most commonly discovered during a workup for a thrombotic event or recurrent pregnancy loss, which are the 2 most common clinical manifestations. Antiphospholipid Syndrome should be tested for, since triple-positive patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship are at increased risk for thrombosis Thrombosis Formation and development of a thrombus or blood clot in the blood vessel. Epidemic Typhus and pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care morbidity Morbidity The proportion of patients with a particular disease during a given year per given unit of population. Measures of Health Status.

Timing:^[4,5]

• Ideally, 2 tests ≥ 12 weeks apart (both should be positive to confirm the diagnosis)
• In patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship after a thrombotic event: no consensus on best timing
• In patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship on anticoagulation Anticoagulation Pulmonary Hypertension Drugs:^[5]
  • Low-molecular-weight heparin (LMWH):
    • 12 hours after last dose
    • Simultaneously, check anti-Xa activity levels.
  • Direct oral 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 (DOAC):
    • 48 hours after last dose
    • Simultaneously, check the DOAC level.
  • Vitamin K Vitamin K A lipid cofactor that is required for normal blood clotting. Several forms of vitamin K have been identified: vitamin K 1 (phytomenadione) derived from plants, vitamin K 2 (menaquinone) from bacteria, and synthetic naphthoquinone provitamins, vitamin K 3 (menadione). Vitamin k 3 provitamins, after being alkylated in vivo, exhibit the antifibrinolytic activity of vitamin k. Green leafy vegetables, liver, cheese, butter, and egg yolk are good sources of vitamin k. Fat-soluble Vitamins and their Deficiencies antagonists (VKA): consider switching to LMWH and testing 1–2 weeks after last dose
• In reproductive-aged women:
  • Best if performed when not pregnant
  • If tested during pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care, repeat testing postpartum (≥ 6 weeks, but ideally 3 months after delivery).

Other laboratory testing

• 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:^[2,5,12,15]
  • Lupus anticoagulant Lupus anticoagulant An antiphospholipid antibody found in association with systemic lupus erythematosus, antiphospholipid syndrome; and in a variety of other diseases as well as in healthy individuals. In vitro, the antibody interferes with the conversion of prothrombin to thrombin and prolongs the partial thromboplastin time. In vivo, it exerts a procoagulant effect resulting in thrombosis mainly in the larger veins and arteries. It further causes obstetrical complications, including fetal death and spontaneous abortion, as well as a variety of hematologic and neurologic complications. Antiphospholipid Syndrome may interact with the assay and artificially prolong the aPTT.
  • PT may also be abnormal in some cases.
  • Does not represent any degree of anticoagulation Anticoagulation Pulmonary Hypertension Drugs
  • Importance of baseline 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:
    • If aPTT is prolonged, it cannot be used to monitor anticoagulation Anticoagulation Pulmonary Hypertension Drugs during management.
    • Would need to use alternative assays that are not affected by the presence of aPLs APLS Antiphospholipid syndrome (APLS) is an acquired autoimmune disorder characterized by the persistent presence of antiphospholipid antibodies, which create a hypercoagulable state. These antibodies are most commonly discovered during a workup for a thrombotic event or recurrent pregnancy loss, which are the 2 most common clinical manifestations. Antiphospholipid Syndrome (e.g., check anti-factor Xa activity for heparin monitoring)
• CBC may show:^[2,15]
  • 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 and Types (hemolytic, microangiopathic)
  • 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:
    • 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: Histology are consumed in procoagulant states
    • Can be difficult to differentiate from other causes of 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 (e.g., 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, DIC DIC Disseminated intravascular coagulation (DIC) is a condition characterized by systemic bodywide activation of the coagulation cascade. This cascade results in both widespread microvascular thrombi contributing to multiple organ dysfunction and consumption of clotting factors and platelets, leading to hemorrhage. Disseminated Intravascular Coagulation)
• Complement studies:^[7,10]
  • May show ↓ complement levels (e.g., C3 or C4)
  • Can be observed in both primary and secondary APS

Other assessments^[14]

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

• Imaging:
  • Doppler Doppler Ultrasonography applying the doppler effect, with frequency-shifted ultrasound reflections produced by moving targets (usually red blood cells) in the bloodstream along the ultrasound axis in direct proportion to the velocity of movement of the targets, to determine both direction and velocity of blood flow. Ultrasound (Sonography) 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. 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 Thrombophilia A disorder of hemostasis in which there is a tendency for the occurrence of thrombosis. Hypercoagulable States 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 Thrombosis Formation and development of a thrombus or blood clot in the blood vessel. Epidemic Typhus in APS

Management may vary depending on practice location. The following information is from US, UK, and European literature and clinical guidelines. Expert consultation (e.g., hematology) is recommended to assist with management.

The mainstay of therapy for both primary and secondary APS is anticoagulation Anticoagulation Pulmonary Hypertension Drugs. Overall management of acute thrombosis Thrombosis Formation and development of a thrombus or blood clot in the blood vessel. Epidemic Typhus in APS is similar to management in patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship without APS, though warfarin Warfarin An anticoagulant that acts by inhibiting the synthesis of vitamin K-dependent coagulation factors. Warfarin is indicated for the prophylaxis and/or treatment of venous thrombosis and its extension, pulmonary embolism, and atrial fibrillation with embolization. It is also used as an adjunct in the prophylaxis of systemic embolism after myocardial infarction. Warfarin is also used as a rodenticide. Anticoagulants is typically preferred over direct oral 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 ( DOACs DOACs Anticoagulants).

Assess and address the ABCs:

• Airway Airway ABCDE Assessment: ensure airway Airway ABCDE Assessment is open and protected
• Breathing/respiratory support:
  • Ensure adequate oxygenation 
  • May require supplemental O₂, mechanical ventilation Ventilation The total volume of gas inspired or expired per unit of time, usually measured in liters per minute. Ventilation: Mechanics of Breathing, etc ETC The electron transport chain (ETC) sends electrons through a series of proteins, which generate an electrochemical proton gradient that produces energy in the form of adenosine triphosphate (ATP). Electron Transport Chain (ETC).
• Circulation Circulation The movement of the blood as it is pumped through the cardiovascular system. ABCDE Assessment/hemodynamic support:
  • Ensure stable blood pressure and heart rate Heart rate The number of times the heart ventricles contract per unit of time, usually per minute. Cardiac Physiology 
  • May require IV fluids IV fluids Intravenous fluids are one of the most common interventions administered in medicine to approximate physiologic bodily fluids. Intravenous fluids are divided into 2 categories: crystalloid and colloid solutions. Intravenous fluids have a wide variety of indications, including intravascular volume expansion, electrolyte manipulation, and maintenance fluids. Intravenous Fluids, vasopressors Vasopressors Sepsis in Children, cardiac drugs, etc ETC The electron transport chain (ETC) sends electrons through a series of proteins, which generate an electrochemical proton gradient that produces energy in the form of adenosine triphosphate (ATP). Electron Transport Chain (ETC).

Factors that affect anticoagulation Anticoagulation Pulmonary Hypertension Drugs management:

• Hemodynamic stability
• Location and extent of the thrombosis Thrombosis Formation and development of a thrombus or blood clot in the blood vessel. Epidemic Typhus/embolism
• Bleeding risk
• Age and comorbidities Comorbidities The presence of co-existing or additional diseases with reference to an initial diagnosis or with reference to the index condition that is the subject of study. Comorbidity may affect the ability of affected individuals to function and also their survival; it may be used as a prognostic indicator for length of hospital stay, cost factors, and outcome or survival. St. Louis Encephalitis Virus 
• Whether or not they are currently (or actively trying to become) pregnant

Therapeutic anticoagulation Anticoagulation Pulmonary Hypertension Drugs in nonpregnant individuals: 

• Preferred option: heparin overlapped with warfarin Warfarin An anticoagulant that acts by inhibiting the synthesis of vitamin K-dependent coagulation factors. Warfarin is indicated for the prophylaxis and/or treatment of venous thrombosis and its extension, pulmonary embolism, and atrial fibrillation with embolization. It is also used as an adjunct in the prophylaxis of systemic embolism after myocardial infarction. Warfarin is also used as a rodenticide. Anticoagulants^[7,15,16]
  • LMWH is typically the medication of choice.
  • Heparin is continued until the INR is in the therapeutic range for 2 consecutive days. 
  • Heparin can then be discontinued, while warfarin Warfarin An anticoagulant that acts by inhibiting the synthesis of vitamin K-dependent coagulation factors. Warfarin is indicated for the prophylaxis and/or treatment of venous thrombosis and its extension, pulmonary embolism, and atrial fibrillation with embolization. It is also used as an adjunct in the prophylaxis of systemic embolism after myocardial infarction. Warfarin is also used as a rodenticide. Anticoagulants is continued indefinitely for ongoing prophylaxis Prophylaxis Cephalosporins.
  • Goal INR on warfarin Warfarin An anticoagulant that acts by inhibiting the synthesis of vitamin K-dependent coagulation factors. Warfarin is indicated for the prophylaxis and/or treatment of venous thrombosis and its extension, pulmonary embolism, and atrial fibrillation with embolization. It is also used as an adjunct in the prophylaxis of systemic embolism after myocardial infarction. Warfarin is also used as a rodenticide. Anticoagulants: typically, 2–3
  • For arterial thrombosis Arterial Thrombosis Hypercoagulable States:
    • Consider adding low-dose aspirin Aspirin The prototypical analgesic used in the treatment of mild to moderate pain. It has anti-inflammatory and antipyretic properties and acts as an inhibitor of cyclooxygenase which results in the inhibition of the biosynthesis of prostaglandins. Aspirin also inhibits platelet aggregation and is used in the prevention of arterial and venous thrombosis. Nonsteroidal Antiinflammatory Drugs (NSAIDs) to standard warfarin Warfarin An anticoagulant that acts by inhibiting the synthesis of vitamin K-dependent coagulation factors. Warfarin is indicated for the prophylaxis and/or treatment of venous thrombosis and its extension, pulmonary embolism, and atrial fibrillation with embolization. It is also used as an adjunct in the prophylaxis of systemic embolism after myocardial infarction. Warfarin is also used as a rodenticide. Anticoagulants therapy.
    • Alternative: higher-dose warfarin Warfarin An anticoagulant that acts by inhibiting the synthesis of vitamin K-dependent coagulation factors. Warfarin is indicated for the prophylaxis and/or treatment of venous thrombosis and its extension, pulmonary embolism, and atrial fibrillation with embolization. It is also used as an adjunct in the prophylaxis of systemic embolism after myocardial infarction. Warfarin is also used as a rodenticide. Anticoagulants (goal INR 3–4)
  • Note: Warfarin Warfarin An anticoagulant that acts by inhibiting the synthesis of vitamin K-dependent coagulation factors. Warfarin is indicated for the prophylaxis and/or treatment of venous thrombosis and its extension, pulmonary embolism, and atrial fibrillation with embolization. It is also used as an adjunct in the prophylaxis of systemic embolism after myocardial infarction. Warfarin is also used as a rodenticide. Anticoagulants is contraindicated in pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care.
• Alternative option is DOACs DOACs Anticoagulants:^[7,9]
  • Examples:
    • Rivaroxaban Rivaroxaban A morpholine and thiophene derivative that functions as a factor Xa inhibitor and is used in the treatment and prevention of deep-vein thrombosis and pulmonary embolism. It is also used for the prevention of stroke and systemic embolization in patients with non-valvular atrial fibrillation, and for the prevention of atherothrombotic events in patients after an acute coronary syndrome. Anticoagulants
    • Apixaban Apixaban Anticoagulants
    • Dabigatran Dabigatran A thrombin inhibitor which acts by binding and blocking thrombogenic activity and the prevention of thrombus formation. It is used to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. Anticoagulants
  • DOACs DOACs Anticoagulants may be insufficient to prevent thrombosis Thrombosis Formation and development of a thrombus or blood clot in the blood vessel. Epidemic Typhus in APS.
  • Indications: may be considered in patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with non–high-risk APS with single- or double-positive aPLs APLS Antiphospholipid syndrome (APLS) is an acquired autoimmune disorder characterized by the persistent presence of antiphospholipid antibodies, which create a hypercoagulable state. These antibodies are most commonly discovered during a workup for a thrombotic event or recurrent pregnancy loss, which are the 2 most common clinical manifestations. Antiphospholipid Syndrome who have previously done well on DOACs DOACs Anticoagulants (with good adherence)^[9]
  • Contraindications Contraindications A condition or factor associated with a recipient that makes the use of a drug, procedure, or physical agent improper or inadvisable. Contraindications may be absolute (life threatening) or relative (higher risk of complications in which benefits may outweigh risks). Noninvasive Ventilation ( Warfarin Warfarin An anticoagulant that acts by inhibiting the synthesis of vitamin K-dependent coagulation factors. Warfarin is indicated for the prophylaxis and/or treatment of venous thrombosis and its extension, pulmonary embolism, and atrial fibrillation with embolization. It is also used as an adjunct in the prophylaxis of systemic embolism after myocardial infarction. Warfarin is also used as a rodenticide. Anticoagulants is preferred over DOACs DOACs Anticoagulants in APS, especially in “high-risk” patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship.):^[7,9,16]
    • Triple aPL APL An acute myeloid leukemia in which abnormal promyelocytes predominate. It is frequently associated with disseminated intravascular coagulation. Acute Myeloid Leukemia positivity
    • Arterial thrombosis Arterial Thrombosis Hypercoagulable States
    • Small-vessel thrombosis Thrombosis Formation and development of a thrombus or blood clot in the blood vessel. Epidemic Typhus
    • Organ involvement
    • Heart valve disease
    • Recurrent thrombosis Thrombosis Formation and development of a thrombus or blood clot in the blood vessel. Epidemic Typhus
  • Note: The European Medicines Agency (EMA) states that DOACs DOACs Anticoagulants are not recommended in APS and the US FDA has endorsed these recommendations.^[7]

Therapeutic anticoagulation Anticoagulation Pulmonary Hypertension Drugs in pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care:^[1,15,16]

• LMWH preferred
• Warfarin Warfarin An anticoagulant that acts by inhibiting the synthesis of vitamin K-dependent coagulation factors. Warfarin is indicated for the prophylaxis and/or treatment of venous thrombosis and its extension, pulmonary embolism, and atrial fibrillation with embolization. It is also used as an adjunct in the prophylaxis of systemic embolism after myocardial infarction. Warfarin is also used as a rodenticide. Anticoagulants is contraindicated owing to its teratogenicity.
• Antiplatelet therapy with aspirin Aspirin The prototypical analgesic used in the treatment of mild to moderate pain. It has anti-inflammatory and antipyretic properties and acts as an inhibitor of cyclooxygenase which results in the inhibition of the biosynthesis of prostaglandins. Aspirin also inhibits platelet aggregation and is used in the prevention of arterial and venous thrombosis. Nonsteroidal Antiinflammatory Drugs (NSAIDs) is recommended to reduce obstetric morbidity Morbidity The proportion of patients with a particular disease during a given year per given unit of population. Measures of Health Status.

Thrombolytic/reperfusion therapy in arterial thrombosis Arterial Thrombosis Hypercoagulable States:^[15,16] 

• Management is the same as in individuals without APS.

Catastrophic APS:^[15,16] 

• Prompt recognition and management is crucial.
• Consult hematology for assistance.
• Often includes a combination of therapies, such as:
  • Anticoagulation Anticoagulation Pulmonary Hypertension Drugs
  • 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 (e.g., IV methylprednisolone Methylprednisolone A prednisolone derivative with similar anti-inflammatory action. Immunosuppressants 250–1,000 mg for 3 days)
  • Plasma exchange Plasma exchange Removal of plasma and replacement with various fluids, e.g., fresh frozen plasma, plasma protein fractions (ppf), albumin preparations, dextran solutions, saline. Used in treatment of autoimmune diseases, immune complex diseases, diseases of excess plasma factors, and other conditions. Thrombotic Thrombocytopenic Purpura
  • IV immunoglobulins IV immunoglobulins Immunoglobulin preparations used in intravenous infusion, containing primarily immunoglobulin g. They are used to treat a variety of diseases associated with decreased or abnormal immunoglobulin levels including pediatric aids; primary hypergammaglobulinemia; scid; cytomegalovirus infections in transplant recipients, lymphocytic leukemia, chronic; kawasaki syndrome, infection in neonates, and idiopathic thrombocytopenic purpura. DiGeorge Syndrome ( IVIG IVIG Dermatomyositis)

Prevention of thrombosis Thrombosis Formation and development of a thrombus or blood clot in the blood vessel. Epidemic Typhus^[7,15,16]

• Smoking Smoking Willful or deliberate act of inhaling and exhaling smoke from burning substances or agents held by hand. Interstitial Lung Diseases cessation
• Avoiding estrogen-containing contraceptives → instead, consider:^[1,8]
  • IUD (preferred)
  • Progestin-only contraceptives (less effective)
• Managing hyperlipidemia/ 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
• For patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship who have never had a thrombotic event (i.e., primary prevention):^[7,16]
  • Consider low-dose aspirin Aspirin The prototypical analgesic used in the treatment of mild to moderate pain. It has anti-inflammatory and antipyretic properties and acts as an inhibitor of cyclooxygenase which results in the inhibition of the biosynthesis of prostaglandins. Aspirin also inhibits platelet aggregation and is used in the prevention of arterial and venous thrombosis. Nonsteroidal Antiinflammatory Drugs (NSAIDs) (evidence is limited; consider entire clinical picture).
    • Consider individual risk factors for arterial thrombosis Arterial Thrombosis Hypercoagulable States or VTE VTE Obstruction of a vein or veins (embolism) by a blood clot (thrombus) in the bloodstream. Hypercoagulable States.
    • Weigh against individual risks for bleeding and upper GI reflux.
  • Optimize modifiable risk factors.
  • If pregnant/planning to become pregnant:
    • Not well studied
    • Consider observation versus anticoagulation Anticoagulation Pulmonary Hypertension Drugs to prevent thrombosis Thrombosis Formation and development of a thrombus or blood clot in the blood vessel. Epidemic Typhus. 
    • Preferred agents: LMWH (prophylactic dose) plus aspirin Aspirin The prototypical analgesic used in the treatment of mild to moderate pain. It has anti-inflammatory and antipyretic properties and acts as an inhibitor of cyclooxygenase which results in the inhibition of the biosynthesis of prostaglandins. Aspirin also inhibits platelet aggregation and is used in the prevention of arterial and venous thrombosis. Nonsteroidal Antiinflammatory Drugs (NSAIDs)
• For patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with a history of thrombosis Thrombosis Formation and development of a thrombus or blood clot in the blood vessel. Epidemic Typhus:
  • In patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship who do not desire pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care: warfarin Warfarin An anticoagulant that acts by inhibiting the synthesis of vitamin K-dependent coagulation factors. Warfarin is indicated for the prophylaxis and/or treatment of venous thrombosis and its extension, pulmonary embolism, and atrial fibrillation with embolization. It is also used as an adjunct in the prophylaxis of systemic embolism after myocardial infarction. Warfarin is also used as a rodenticide. Anticoagulants therapy with target INR 2–3
  • In patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship who do desire pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care: LMWH and aspirin Aspirin The prototypical analgesic used in the treatment of mild to moderate pain. It has anti-inflammatory and antipyretic properties and acts as an inhibitor of cyclooxygenase which results in the inhibition of the biosynthesis of prostaglandins. Aspirin also inhibits platelet aggregation and is used in the prevention of arterial and venous thrombosis. Nonsteroidal Antiinflammatory Drugs (NSAIDs) ( warfarin Warfarin An anticoagulant that acts by inhibiting the synthesis of vitamin K-dependent coagulation factors. Warfarin is indicated for the prophylaxis and/or treatment of venous thrombosis and its extension, pulmonary embolism, and atrial fibrillation with embolization. It is also used as an adjunct in the prophylaxis of systemic embolism after myocardial infarction. Warfarin is also used as a rodenticide. Anticoagulants is teratogenic)
• For patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with aPL APL An acute myeloid leukemia in which abnormal promyelocytes predominate. It is frequently associated with disseminated intravascular coagulation. Acute Myeloid Leukemias but who do not meet diagnostic criteria for APS, antithrombotic medication is not recommended (may be considered on case-by-case basis with risk factors, such as 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).^[7,16]

Prophylaxis Prophylaxis Cephalosporins during pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care^[1,4,8,15]

• Anticoagulation Anticoagulation Pulmonary Hypertension Drugs:^[1,8,16]
  • aPL-positive, but no obstetric or thrombosis Thrombosis Formation and development of a thrombus or blood clot in the blood vessel. Epidemic Typhus history:
    • Anticoagulation Anticoagulation Pulmonary Hypertension Drugs not recommended
    • Aspirin Aspirin The prototypical analgesic used in the treatment of mild to moderate pain. It has anti-inflammatory and antipyretic properties and acts as an inhibitor of cyclooxygenase which results in the inhibition of the biosynthesis of prostaglandins. Aspirin also inhibits platelet aggregation and is used in the prevention of arterial and venous thrombosis. Nonsteroidal Antiinflammatory Drugs (NSAIDs) (81–100 mg) is conditionally recommended.
  • History of thrombotic APS:
    • Aspirin Aspirin The prototypical analgesic used in the treatment of mild to moderate pain. It has anti-inflammatory and antipyretic properties and acts as an inhibitor of cyclooxygenase which results in the inhibition of the biosynthesis of prostaglandins. Aspirin also inhibits platelet aggregation and is used in the prevention of arterial and venous thrombosis. Nonsteroidal Antiinflammatory Drugs (NSAIDs) plus therapeutic-dose LMWH
    • Anticoagulation Anticoagulation Pulmonary Hypertension Drugs should be continued throughout the entire pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care and for 6 weeks postpartum.
    • Transition to warfarin Warfarin An anticoagulant that acts by inhibiting the synthesis of vitamin K-dependent coagulation factors. Warfarin is indicated for the prophylaxis and/or treatment of venous thrombosis and its extension, pulmonary embolism, and atrial fibrillation with embolization. It is also used as an adjunct in the prophylaxis of systemic embolism after myocardial infarction. Warfarin is also used as a rodenticide. Anticoagulants after 6 weeks postpartum.
  • History of obstetric APS:
    • Aspirin Aspirin The prototypical analgesic used in the treatment of mild to moderate pain. It has anti-inflammatory and antipyretic properties and acts as an inhibitor of cyclooxygenase which results in the inhibition of the biosynthesis of prostaglandins. Aspirin also inhibits platelet aggregation and is used in the prevention of arterial and venous thrombosis. Nonsteroidal Antiinflammatory Drugs (NSAIDs) plus prophylactic-dose LMWH
    • Continue through 6–12 weeks postpartum
• Indicated to reduce morbidity Morbidity The proportion of patients with a particular disease during a given year per given unit of population. Measures of Health Status due to APS, including:
  • Pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care loss (at any point)
  • Placental insufficiency Placental Insufficiency Failure of the placenta to deliver an adequate supply of nutrients and oxygen to the fetus. Neonatal Polycythemia, which may lead to:
    • Fetal growth restriction Fetal growth restriction Fetal growth restriction (FGR), also known as intrauterine fetal growth restriction (IUGR), is an estimated fetal weight (EFW) or abdominal circumference < 10th percentile for gestational age. The term small for gestational age (SGA) is sometimes erroneously used interchangeably with FGR. Fetal Growth Restriction
    • 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
    • Preeclampsia Preeclampsia A complication of pregnancy, characterized by a complex of symptoms including maternal hypertension and proteinuria with or without pathological edema. Symptoms may range between mild and severe. Pre-eclampsia usually occurs after the 20th week of gestation, but may develop before this time in the presence of trophoblastic disease. Hypertensive Pregnancy Disorders/ eclampsia Eclampsia Onset of hyperreflexia; seizures; or coma in a previously diagnosed pre-eclamptic patient (pre-eclampsia). Hypertensive Pregnancy Disorders 
    • 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
• Fetal surveillance Surveillance Developmental Milestones and Normal Growth:
  • Insufficient data for clear guidelines
  • Many experts recommend serial ultrasonography and antepartum testing Antepartum Testing The primary goals of antepartum testing and monitoring are to assess fetal well-being, identify treatable situations that may cause complications, and evaluate for chromosomal abnormalities. These tests are divided into screening tests (which include cell-free DNA testing, serum analyte testing, and nuchal translucency measurements), and diagnostic tests, which provide a definitive diagnosis of aneuploidy and include chorionic villus sampling (CVS) and amniocentesis. Antepartum Testing and Monitoring in the 3rd trimester.
• Adjunctive therapies whithatch may help improve obstetric outcomes (should be guided by specialist recommendations):
  • 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
  • Hydroxychloroquine Hydroxychloroquine A chemotherapeutic agent that acts against erythrocytic forms of malarial parasites. Hydroxychloroquine appears to concentrate in food vacuoles of affected protozoa. It inhibits plasmodial heme polymerase. Immunosuppressants (in patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with refractory thrombosis Thrombosis Formation and development of a thrombus or blood clot in the blood vessel. Epidemic Typhus)

Other management points

Immunomodulatory agents:^[1,7,15]

• May be considered in some patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with:
  • Recurrent thrombosis Thrombosis Formation and development of a thrombus or blood clot in the blood vessel. Epidemic Typhus despite adequate anticoagulation Anticoagulation Pulmonary Hypertension Drugs
  • 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)
  • 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
• Limited evidence to guide use, though theoretically helpful because APS is an autoimmune disease
• Agents to consider:
  • Hydroxychloroquine Hydroxychloroquine A chemotherapeutic agent that acts against erythrocytic forms of malarial parasites. Hydroxychloroquine appears to concentrate in food vacuoles of affected protozoa. It inhibits plasmodial heme polymerase. Immunosuppressants (especially in 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): reverses aPL-induced platelet activation Platelet activation A series of progressive, overlapping events, triggered by exposure of the platelets to subendothelial tissue. These events include shape change, adhesiveness, aggregation, and release reactions. When carried through to completion, these events lead to the formation of a stable hemostatic plug. Hemostasis and has beneficial effects on cholesterol Cholesterol The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. Cholesterol Metabolism
  • Rituximab Rituximab A murine-derived monoclonal antibody and antineoplastic agent that binds specifically to the cd20 antigen and is used in the treatment of leukemia; lymphoma and rheumatoid arthritis. Immunosuppressants: monoclonal antibody against many B-cell precursors

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:^[15]

• Many patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with APS have mild thrombocytopenia Mild Thrombocytopenia 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.
• Very difficult to distinguish from immune 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
• Anticoagulation Anticoagulation Pulmonary Hypertension Drugs should be continued while the platelet count is > 50,000/µL. 

Statins Statins Statins are competitive inhibitors of HMG-CoA reductase in the liver. HMG-CoA reductase is the rate-limiting step in cholesterol synthesis. Inhibition results in lowered intrahepatocytic cholesterol formation, resulting in up-regulation of LDL receptors and, ultimately, lowering levels of serum LDL and triglycerides. Statins:^[7,15]

• Have antithrombotic and antiinflammatory properties on endothelial cells
• Consider adding in patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with:
  • aPLs APLS Antiphospholipid syndrome (APLS) is an acquired autoimmune disorder characterized by the persistent presence of antiphospholipid antibodies, which create a hypercoagulable state. These antibodies are most commonly discovered during a workup for a thrombotic event or recurrent pregnancy loss, which are the 2 most common clinical manifestations. Antiphospholipid Syndrome and hyperlipidemia
  • Refractory thrombotic APS

Prognosis Prognosis A prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas^[1,15]

• Risk of VTE VTE Obstruction of a vein or veins (embolism) by a blood clot (thrombus) in the bloodstream. Hypercoagulable States in asymptomatic, nonpregnant patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with aPLs APLS Antiphospholipid syndrome (APLS) is an acquired autoimmune disorder characterized by the persistent presence of antiphospholipid antibodies, which create a hypercoagulable state. These antibodies are most commonly discovered during a workup for a thrombotic event or recurrent pregnancy loss, which are the 2 most common clinical manifestations. Antiphospholipid Syndrome: < 1% per year
• Risk of recurrent thrombosis Thrombosis Formation and development of a thrombus or blood clot in the blood vessel. Epidemic Typhus in untreated patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with APS: 25% per year
• Risk of thrombosis Thrombosis Formation and development of a thrombus or blood clot in the blood vessel. Epidemic Typhus during pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care/puerperium in patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with APS: 5%–12% per year

Clinical Relevance

Differential diagnosis for recurrent thrombosis Thrombosis Formation and development of a thrombus or blood clot in the blood vessel. Epidemic Typhus

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: 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 Thrombophilias 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 are defined by an increased risk of clot formation or thrombosis Thrombosis Formation and development of a thrombus or blood clot in the blood vessel. Epidemic Typhus. 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 Factor V Leiden Hypercoagulable States 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.

Common presentations of recurrent thrombosis Thrombosis Formation and development of a thrombus or blood clot in the blood vessel. Epidemic Typhus

• Deep vein thrombosis Thrombosis Formation and development of a thrombus or blood clot in the blood vessel. Epidemic Typhus ( 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 Thrombosis Formation and development of a thrombus or blood clot in the blood vessel. Epidemic Typhus 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 Doppler Ultrasonography applying the doppler effect, with frequency-shifted ultrasound reflections produced by moving targets (usually red blood cells) in the bloodstream along the ultrasound axis in direct proportion to the velocity of movement of the targets, to determine both direction and velocity of blood flow. Ultrasound (Sonography) 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 Pulmonary Embolism Pulmonary embolism (PE) is a potentially fatal condition that occurs as a result of intraluminal obstruction of the main pulmonary artery or its branches. The causative factors include thrombi, air, amniotic fluid, and fat. In PE, gas exchange is impaired due to the decreased return of deoxygenated blood to the lungs. Pulmonary Embolism (PE): a medical emergency in which an embolus blocks part of the pulmonary arterial system, resulting in acute shortness of breath Shortness of breath 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 and impaired ventilation Ventilation The total volume of gas inspired or expired per unit of time, usually measured in liters per minute. Ventilation: Mechanics of Breathing/perfusion. About 30% of these patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship 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 Angiography Radiography of blood vessels after injection of a contrast medium. Cardiac Surgery ( CTPA CTPA Pulmonary Function Tests) scan and/or a V/Q. Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship 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.