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 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, or a decrease in fibrinolysis. There are both inherited and acquired causes, with factor V Leiden being the most common inherited cause. Clinically, hypercoagulable states present with thrombotic events, which cause vessel occlusion and can lead to organ damage. Thrombotic disorders can be fatal if not treated, and management usually involves 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.

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

Table of Contents

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Overview

Definition

Hypercoagulability, also referred to as a thrombophilia, refers to the increased tendency for blood to form clots, known as thrombi. Hypercoagulable states can be inherited or acquired.

Epidemiology

Prevalence of inherited thrombophilias:

Table: Prevalence and risk of venous thromboemolism (VTE) in inherited thrombophilias
Condition Prevalence Risk of VTE
Factor V Leiden 3%–7% 4.3%
Prothrombin G20210A 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 1%–3% 1.9%
Protein C deficiency (heterozygous) 0.02%–0.05% 11.3%
Protein S deficiency (heterozygous) 0.01% 32.4%
Antithrombin deficiency 0.02%–0.04% 17.5%

Most common acquired hypercoagulable states:

  • 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: most common
  • Malignancy: 2nd most common

Clinical impact:

  • VTE is 2nd only to 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 as the most common cardiovascular disorder.
  • Up to 4% of strokes are attributable to hypercoagulability disorders.
  • Thrombosis risk factors are identified in over 80% of patients with thrombotic events.

Virchow’s triad

Thrombotic events occur under 3 primary conditions, which make up Virchow’s triad. These 3 conditions are:

  1. Endothelial injury/subendothelial exposure:
    • Initiates formation of the platelet plug and the coagulation cascade
    • Factors involved in initiating thrombosis: 
      • Tissue factor
      • von Willebrand factor
      • Collagen 
  2. Stasis of 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:
    • Allows more time for platelet aggregation and clot formation
    • Slows the removal of coagulation factors
  3. Hypercoagulable states (alteration in blood constituents): 
    • May result from:
      • An increase in procoagulants
      • A decrease in 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
      • A decrease in fibrinolysis 
    • Balance is tipped to favor thrombosis.
Vichows triad

Virchow’s triad

Image by Lecturio.

Etiology and Pathophysiology

Hypercoagulable states may be primary (inherited) or secondary (acquired).

Primary (inherited) causes of hypercoagulable states

Table: Etiology and pathophysiology of primary (inherited) hypercoagulable states
Condition Inheritance pattern Pathophysiology
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
  • 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 substitutes glutamine for arginine at position 506 in the F5 gene, which codes for factor V.
  • Results in resistance to factor Va degradation by protein C
  • ↑ Factor Va available → enhanced thrombin formation
Prothrombin G20210A (also known as factor II 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) Autosomal recessive
  • Transposition at the promoter region of the prothrombin gene
  • Results in overtranslation of prothrombin
  • ↑ Thrombin precursor → enhanced thrombin formation
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
  • Antithrombin inactivates thrombin (and is augmented by heparin)
  • Deficiency of antithrombin leads to:
    • ↑ Levels of thrombin and factor Xa
    • Resistance to heparins
  • Can also be acquired through antithrombin protein loss ( 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) or decreased antithrombin production ( liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver disease)
Protein C or S 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 (rare; can be recessive)
  • Protein C inactivates factors Va and VIIIa using protein S as a cofactor.
  • Deficiencies of either result in overactivity of factors Va and VIIIa.
  • ↑ Activity of Va and VIIIa → enhances thrombin formation
  • Can also be acquired in 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 and liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver disease
Sticky platelet syndrome 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
  • 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 hyperaggregable.
  • When platelets are activated, they induce a hypercoagulable state.
Overview of the physiologic thrombolytic pathway

Overview of the physiologic thrombolytic pathway:
Several hypercoagulable disorders occur because of abnormalities at the following locations.
Mutations at 1: Factor V Leiden makes factor Va resistant to degradation by activated protein C.
Mutations at 2: Prothrombin 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 produces an increased amount of prothrombin, leading to excess thrombin formation.
Mutations at 3: Antithrombin deficiency leads to reduced inactivation of thrombin and factors Xa and IXa.
Mutations at 4: Protein C or S deficiency leads to reduced inactivation of factors Va and VIIIa.

Image by Lecturio.

Secondary (acquired) causes of hypercoagulable states

  • 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
    • Antibodies form against phospholipid-binding proteins.
    • Antibodies result in:
      • Activation of inflammatory cells, endothelial cells, and platelets, promoting thrombosis
      • Inactivation of anticoagulant factors (proteins C and S)
    • Antibodies may form spontaneously due to genetic predispositions or in association with other disorders, such as:
      • 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
      • Sjögren syndrome
      • 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
  • Antithrombin deficiency
  • Protein C or S deficiencies
  • Malignancy:
    • Tumor cells can release procoagulants: tissue factor and cancer procoagulant
    • Tumors may also cause vessel compression → stasis
    • Most common with adenocarcinomas (especially lung, pancreatic, and colorectal)
  • Increased 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 exposure:
    • Estrogens cause a hypercoagulable state by: 
      • ↑ Concentration of procoagulants: prothrombin, fibrinogen, factor VII, and factor X
      • ↓ Antithrombin levels
    • States associated with ↑ 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:
      • Pregnancy
      • Use of 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
      • Hormone replacement therapy Hormone Replacement Therapy Estrogen and progesterone are the sex hormones produced by the ovaries in premenopausal women. They are used to treat hypogonadism (primary ovarian insufficiency), menopausal symptoms, and gender dysphoria in transgender women. Noncontraceptive Estrogen and Progestins

Other conditions that increase thrombotic risk

Many other conditions and states increase thrombotic risk by affecting components of Virchow’s triad (typically, stasis, endothelial injury, or both) in ways that promote thrombosis. These conditions include:

  • General risk factors (many are cardiovascular risk factors):
    • Prior history of a VTE
    • Older age (≥ 65 years)
    • Obesity Obesity Obesity is a condition associated with excess body weight, specifically with the deposition of excessive adipose tissue. Obesity is considered a global epidemic. Major influences come from the western diet and sedentary lifestyles, but the exact mechanisms likely include a mixture of genetic and environmental factors. Obesity
    • Diabetes mellitus Diabetes mellitus Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus
    • Immobilization (e.g., cast, stroke patient, post–knee surgery, long flight)
    • Current/recent hospitalization
    • Family history
    • Smoking
  • Related to surgery or procedures:
    • Surgery, especially orthopedic, vascular, neurologic, and cancer surgeries
    • Recent trauma
    • Presence of a vascular prosthesis (e.g., central venous catheter Central Venous Catheter Central venous catheters are IV lines placed into the large central veins for monitoring of central venous pressure (CVP), prolonged drug administration, or administration of parenteral nutrition. The most common sites of insertion are the internal jugular and subclavian veins. Central Venous Catheter: Technique)
  • Cardiovascular conditions:
    • Heart failure
    • Chronic venous insufficiency Chronic venous insufficiency Chronic venous disease is a spectrum of disorders characterized by venous dilation and/or abnormal vein function in the lower extremities resulting from venous hypertension. "Chronic venous insufficiency" refers to the more severe forms of chronic venous disease. Skin changes typically distinguish chronic venous insufficiency from milder forms of venous disease. Chronic Venous Insufficiency
    • Congenital heart disease
    • Vasculitis
    • Atherosclerosis Atherosclerosis Atherosclerosis is a common form of arterial disease in which lipid deposition forms a plaque in the blood vessel walls. Atherosclerosis is an incurable disease, for which there are clearly defined risk factors that often can be reduced through a change in lifestyle and behavior of the patient. Atherosclerosis
  • Renal conditions:
    • Chronic renal disease, especially end-stage renal disease
    • Nephrotic syndrome
    • Renal transplantation
  • Hematologic/oncologic conditions:
    • Myeloproliferative neoplasms:
      • Essential thrombocythemia Essential thrombocythemia Essential thrombocythemia (ET) is a type of myeloproliferative neoplasm characterized by the clonal thrombocytosis linked to somatic mutations involving Janus kinase 2 (JAK2), calreticulin (CALR), and myeloproliferative leukemia virus oncogene (MPL). Patients can be asymptomatic or present with vasomotor symptoms. Essential Thrombocythemia
      • 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
    • 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 (PNH)
    • Hypogammaglobulinemias associated with hyperviscosity:
      • Waldenström’s macroglobulinemia
      • Multiple myeloma Multiple myeloma Multiple myeloma (MM) is a malignant condition of plasma cells (activated B lymphocytes) primarily seen in the elderly. Monoclonal proliferation of plasma cells results in cytokine-driven osteoclastic activity and excessive secretion of IgG antibodies. Multiple Myeloma
  • Autoimmune and inflammatory conditions:
    • 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
    • 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
    • Inflammatory bowel disease (Crohn’s disease and ulcerative colitis Ulcerative colitis Ulcerative colitis (UC) is an idiopathic inflammatory condition that involves the mucosal surface of the colon. It is a type of inflammatory bowel disease (IBD), along with Crohn's disease (CD). The rectum is always involved, and inflammation may extend proximally through the colon. Ulcerative Colitis)
    • Infection/ sepsis Sepsis Organ dysfunction resulting from a dysregulated systemic host response to infection separates sepsis from uncomplicated infection. The etiology is mainly bacterial and pneumonia is the most common known source. Patients commonly present with fever, tachycardia, tachypnea, hypotension, and/or altered mentation. Sepsis and Septic Shock
  • Medications:
    • Estrogen- and testosterone-containing drugs
    • Tamoxifen
    • Bevacizumab
    • 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
    • Antidepressants
    • Drugs known to induce 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 (e.g., hydralazine, procainamide, phenothiazines)

Clinical Presentation

The primary clinical presentation of a hypercoagulable state will be a thrombotic event or an asymptomatic family member of a patient with a known primary hypercoagulable condition presenting for evaluation.

Thromboembolic presentations

  • Superficial vein thrombosis (rarely severe)
  • Deep venous 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, redness, 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 distal to a 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 upper extremities
    • 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 ( Budd-Chiari syndrome Budd-Chiari syndrome Budd-Chiari syndrome is a condition resulting from the interruption of the normal outflow of blood from the liver. The primary type arises from a venous process (affecting the hepatic veins or inferior vena cava) such as thrombosis, but can also be from a lesion compressing or invading the veins (secondary type). The patient typically presents with hepatomegaly, ascites, and abdominal discomfort. Budd-Chiari Syndrome)
    • Renal vein thrombosis
    • Adrenal vein thrombosis
  • 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
    • 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
    • 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
  • 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
  • Recurrent thromboembolic events
Pitting oedema of right leg

Pitting edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema with swelling of the right leg Leg The lower leg, or just "leg" in anatomical terms, is the part of the lower limb between the knee and the ankle joint. The bony structure is composed of the tibia and fibula bones, and the muscles of the leg are grouped into the anterior, lateral, and posterior compartments by extensions of fascia. Leg due to a deep venous thrombosis

Image: “Pitting oedema of right leg Leg The lower leg, or just "leg" in anatomical terms, is the part of the lower limb between the knee and the ankle joint. The bony structure is composed of the tibia and fibula bones, and the muscles of the leg are grouped into the anterior, lateral, and posterior compartments by extensions of fascia. Leg” by Department of medicine (ward 45), the National hospital of Sri Lanka, (Regent Street), Colombo, (00800), Sri Lanka. License: CC BY 2.0

Additional specific findings associated with hypercoagulable states

Factor V Leiden and prothrombin G20210A mutations do not have any unique presentations beyond recurrent thrombotic events. Several specific findings may be noted in:

  • Protein C or S deficiency:
    • Neonatal purpura fulminans:
      • Purpuric lesions developing at many different sites during the 1st 72 hours of life
      • Lesions enlarge and produce hemorrhagic bullae with subsequent necrosis and black eschar formation.
    • Warfarin-induced skin necrosis:
      • Diffuse necrosis of the skin and/or subcutaneous tissue due to thrombosis
      • Occurs during the 1st few days of warfarin administration
  • Antithrombin deficiency:
    • Heparin resistance: There is no ↑ in the aPTT with heparin administration.
  • 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 may present with obstetric complications, including:
    • 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 (i.e., miscarriage)
    • Premature birth
    • Placental insufficiency
  • Other medical conditions: 
    • Many additional clinical findings related to an underlying condition associated with hypercoagulability may be present.
    • For example:
      • Weight loss and loss of appetite → can be seen in malignancy
      • Rash, joint 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, and fatigue → 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
      • Characteristic skin changes associated with chronic venous insufficiency
      • Splenomegaly Splenomegaly Splenomegaly is pathologic enlargement of the spleen that is attributable to numerous causes, including infections, hemoglobinopathies, infiltrative processes, and outflow obstruction of the portal vein. Splenomegaly → myeloproliferative disorders

Diagnosis

Basic evaluation

These studies should be performed in most patients with suspected thrombotic events.

  • CBC and peripheral blood smear may reveal clues to the underlying etiology, for example:
    • ↑ Hematocrit → polycythemia
    • ↓ Hematocrit → PNH
    • 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 → thrombocytosis/thrombocythemia
    • Abnormal lymphocytes Lymphocytes Lymphocytes are heterogeneous WBCs involved in immune response. Lymphocytes develop from the bone marrow, starting from hematopoietic stem cells (HSCs) and progressing to common lymphoid progenitors (CLPs). B and T lymphocytes and natural killer (NK) cells arise from the lineage. Lymphocytes on smear → bone marrow Bone marrow Bone marrow, the primary site of hematopoiesis, is found in the cavities of cancellous bones and the medullary canals of long bones. There are 2 types: red marrow (hematopoietic with abundant blood cells) and yellow marrow (predominantly filled with adipocytes). Composition of Bone Marrow malignancy
  • D-dimer: 
    • A fibrin-degradation product that will be ↑ in the presence of a 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
    • Multiple conditions can ↑ the D-dimer level, but a 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 is highly unlikely if the D-dimer level is normal.
  • 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:
    • ↑ PT/INR may suggest underlying liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver disease
    • ↑ aPTT in antiphospholipid syndrome (1 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, lupus anticoagulant, acts as an anticoagulant in vitro, but it promotes thrombosis in vivo)
  • Chemistries: to evaluate liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver and kidney function
  • Age-appropriate screening for malignancy: 
    • Pap smear test
    • Mammography
    • Prostate Prostate The prostate is a gland in the male reproductive system. The gland surrounds the bladder neck and a portion of the urethra. The prostate is an exocrine gland that produces a weakly acidic secretion, which accounts for roughly 20% of the seminal fluid. Prostate and other Male Reproductive Glands specific antigen (PSA) test
    • Stool Hemoccult and/or colonoscopy
  • Imaging:
    • CT pulmonary angiography and/or V/Q for suspected PE
    • Duplex ultrasonography of the limbs for 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; findings of 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 include:
      • Noncompressible lumen
      • Hyperechoic mass
      • Decreased/absent 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
    • Other imaging may be indicated based on clinical presentation (e.g., chest X-ray for suspected malignancy).
Ct of saddle pulmonary embolism

CT angiogram of the chest showing a saddle pulmonary embolus

Image: “Large saddle pulmonary embolism” by Rhode Island Hospital, Brown University School of Medicine, 2 Dudley Street, Providence, RI, USA. License: CC BY 2.0

Indications for a thrombophilia workup

Consider ordering additional specific tests to screen for an inherited thrombophilia if patients meet any of the following criteria:

  • Recurrent thrombosis
  • Thrombosis in patients < 40 years old
  • Idiopathic venous thrombosis: thrombosis without any obvious risk factors 
  • Family history of a thrombophilia
  • Thrombosis at unusual sites
  • Arterial thrombosis
  • 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
  • History of warfarin-induced skin necrosis

Testing for specific conditions

If patients meet any of the above criteria for a thrombophilia workup, the following tests can be ordered to screen for specific inherited thrombophilias:

  • Factor V Leiden: activated protein C resistance assay
  • Prothrombin gene 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: molecular analysis of the prothrombin gene
  • Antithrombin: antithrombin–heparin cofactor assay 
  • Proteins C: functional assay to detect quantitative and qualitative defects
  • Protein S: 
    • Free protein S antigen assay
    • Protein S functional assay
  • 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: serologies to detect the presence of 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
    • 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
    • β2-glycoprotein 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: Acute thrombosis and/or 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 may reduce plasma concentrations of antithrombin, protein C, and protein S.

Management

Management prior to a 1st thrombotic event

In patients with known inherited thrombophilias or who have risk factors for thrombosis:

  • Encourage smoking cessation.
  • Avoid 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.
  • Early mobilization after surgery
  • Manage underlying medical conditions (e.g., 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, 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).
  • Consider low-dose aspirin (evidence is limited; consider entire clinical picture).
  • For patients with deficiencies 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 (antithrombin or protein C or S): Replace missing factors.
  • For patients with a temporary ↑ risk of thrombosis (e.g., postsurgery, 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): anticoagulation for 3–6 months or until the risk factor is no longer present

Management for acute thrombotic events

Anticoagulation is the mainstay of therapy for thrombotic events. Options for initial anticoagulation include:

  • Unfractionated heparin (UFH)
  • Subcutaneous low-molecular-weight heparin (LMWH)
  • Subcutaneous fondaparinux (indirect factor Xa inhibitor)
  • Oral rivaroxaban or apixaban (direct factor Xa inhibitors)
  • Note: Warfarin (vitamin K antagonist) should not be used as monotherapy for initial treatment:
    • The half-lives of the 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 are much shorter than those of the vitamin K–dependent procoagulants → warfarin causes an initial period of hypercoagulability
    • Warfarin may be started in combination with other agents (e.g., LMWH).
    • Useful for maintenance therapy

Duration of therapy:

  • Should be started immediately on diagnosis
  • Typically continue for 3–6 months, sometimes longer.

Prophylaxis after a thrombotic event

  • Patients who typically require ongoing prophylactic anticoagulation:
    • Inherited thrombophilia and history of a thrombotic event 
    • Nonmodifiable causes of hypercoagulability (e.g., malignancy)
  • For 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, options include: 
    • Warfarin therapy (goal INR, 2–3)
    • Rivaroxaban or apixaban
  • For 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 contraindications to anticoagulation (e.g., severe bleeding diathesis, planned surgeries with high bleeding risk): Place an inferior vena cava Inferior vena cava The venous trunk which receives blood from the lower extremities and from the pelvic and abdominal organs. Mediastinum and Great Vessels ( IVC IVC The venous trunk which receives blood from the lower extremities and from the pelvic and abdominal organs. Mediastinum and Great Vessels) filter.

References

  1. Bauer, K. (2020). Evaluating adult patients with established venous thromboembolism for acquired and inherited risk factors. Retrieved May 1, 2021, from https://www.uptodate.com/contents/evaluating-adult-patients-with-established-venous-thromboembolism-for-acquired-and-inherited-risk-factors
  2. Bauer, K. (2021). Overview of the causes of venous thrombosis. Retrieved May 1, 2021, from  https://www.uptodate.com/contents/overview-of-the-causes-of-venous-thrombosis
  3. Lip, G. (2020). Overview of the treatment of lower extremity deep vein thrombosis (DVT). Retrieved May 1, 2021, from  https://www.uptodate.com/contents/overview-of-the-treatment-of-lower-extremity-deep-vein-thrombosis-dvt
  4. Lip, G. (2021). Selecting adult patients with lower extremity deep venous thrombosis and pulmonary embolism for indefinite anticoagulation. Retrieved May 1, 2021, from https://www.uptodate.com/contents/selecting-adult-patients-with-lower-extremity-deep-venous-thrombosis-and-pulmonary-embolism-for-indefinite-anticoagulation
  5. Thomas, R.H. (2001). Hypercoagulability syndromes. Arch Intern Med 161:2433–2439.
  6. Schick, P. (2020). Hereditary and acquired hypercoagulability. Medscape. Retrieved May 4, 2021, from https://emedicine.medscape.com/article/211039-overview

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