Hypocoagulable Conditions

Hypocoagulable conditions, also known as bleeding disorders or bleeding diatheses, are a diverse group of diseases that result in abnormal hemostasis Hemostasis Hemostasis refers to the innate, stepwise body processes that occur following vessel injury, resulting in clot formation and cessation of bleeding. Hemostasis occurs in 2 phases, namely, primary and secondary. Primary hemostasis involves forming a plug that stops the bleeding temporarily. Secondary hemostasis involves the activation of the coagulation cascade. Hemostasis. Hemostasis is the innate, stepwise process resulting in bleeding cessation from a damaged blood vessel. Physiologic hemostasis Hemostasis Hemostasis refers to the innate, stepwise body processes that occur following vessel injury, resulting in clot formation and cessation of bleeding. Hemostasis occurs in 2 phases, namely, primary and secondary. Primary hemostasis involves forming a plug that stops the bleeding temporarily. Secondary hemostasis involves the activation of the coagulation cascade. Hemostasis is dependent on the integrity of endothelial cells and subendothelial matrix, 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, and coagulation factors. The hypocoagulable states result from abnormalities in one or more of these contributors, resulting in ineffective thrombosis and bleeding.

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

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Overview

Definition

Hypocoagulable conditions, also known as bleeding disorders or bleeding diatheses, are a diverse group of diseases that result in abnormal hemostasis Hemostasis Hemostasis refers to the innate, stepwise body processes that occur following vessel injury, resulting in clot formation and cessation of bleeding. Hemostasis occurs in 2 phases, namely, primary and secondary. Primary hemostasis involves forming a plug that stops the bleeding temporarily. Secondary hemostasis involves the activation of the coagulation cascade. Hemostasis and increased bleeding risk.

Physiologic hemostasis Hemostasis Hemostasis refers to the innate, stepwise body processes that occur following vessel injury, resulting in clot formation and cessation of bleeding. Hemostasis occurs in 2 phases, namely, primary and secondary. Primary hemostasis involves forming a plug that stops the bleeding temporarily. Secondary hemostasis involves the activation of the coagulation cascade. Hemostasis is dependent on normal structure and function of: 

  • Vessel walls, made up of:
    • Endothelial cells
    • Subendothelial matrix
    • Extravascular connective tissue Connective tissue Connective tissues originate from embryonic mesenchyme and are present throughout the body except inside the brain and spinal cord. The main function of connective tissues is to provide structural support to organs. Connective tissues consist of cells and an extracellular matrix. Connective Tissue 
  • Platelets 
  • Coagulation factors

Review of hemostasis Hemostasis Hemostasis refers to the innate, stepwise body processes that occur following vessel injury, resulting in clot formation and cessation of bleeding. Hemostasis occurs in 2 phases, namely, primary and secondary. Primary hemostasis involves forming a plug that stops the bleeding temporarily. Secondary hemostasis involves the activation of the coagulation cascade. Hemostasis

The following is a summary of the process:

  • Constriction of the blood vessel limits 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 to the area.
  • Formation of the platelet plug: the initial, temporary plug formed via the following steps:
    • Adhesion: Exposed von Willebrand factor (VWF) binds to the glycoprotein (Gp) Ib receptors on 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.
    • Aggregation: GpIIb/IIIa receptors on 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 bind fibrinogen.
    • Secretion: Substances are released that stimulate further platelet activation and aggregation and initiation of the coagulation cascade.
  • Activation of the coagulation cascade: forms a more stable fibrin clot
    • Extrinsic pathway: 
      • Primarily responsible for initiation of the cascade
      • Involves (in order): tissue factor, factor VII, and factor X
    • Intrinsic pathway: 
      • Primarily involved in amplification of the cascade
      • Can also be directly activated by vessel injury
      • Involves (in order): factors XII, XI, IX, VIII, and X
    • Common pathway: 
      • The extrinsic and intrinsic pathways join together when factor X is activated to form the final common pathway.
      • Involves (in order): factors X, V, II (thrombin), I (fibrin), and XIII
  • Inhibition of clotting and the fibrinolytic phase: 
    • Stops clotting and breaks down the clot once it is no longer necessary
    • Involves: 
      • Plasmin Plasmin A product of the lysis of plasminogen (profibrinolysin) by plasminogen activators. It is composed of two polypeptide chains, light (b) and heavy (a), with a molecular weight of 75, 000. It is the major proteolytic enzyme involved in blood clot retraction or the lysis of fibrin and quickly inactivated by antiplasmins. Hemostasis
      • Antithrombin
      • Proteins C and S
Formation of the temporary hemostatic plug

Formation of the temporary hemostatic plug:
The disrupted endothelial surface exposes von Willebrand Factor (vWF) to the passing blood. Platelets bind to the vWF via their GpIb receptors and are activated. Platelet activation triggers them to secrete adenosine diphosphate (ADP), which stimulates the expression of the GpIIb/IIIa receptors on the 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. The GpIIb/IIIa receptors bind to fibrinogen, which is able to bind a platelet on each end, causing 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 to aggregate. As more 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 bound to one another, the platelet plug is generated. As the coagulation cascade is activated, thrombin converts the weaker fibrinogen into the stronger fibrin, creating a much more stable clot.

Image by Lecturio.

Etiology

The following conditions can lead to a hypocoagulable state.

Table: Etiologies of hypocoagulable conditions
Inherited conditions Acquired conditions
Vessel wall disorders
  • Hereditary hemorrhagic telangiectasia (Osler–Weber–Rendu disease)
  • Ehlers–Danlos syndrome
  • Age-related thinning of the skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin
  • Chronic glucocorticoid use
  • Vitamin C deficiency
  • Henoch–Schönlein purpura
Platelet disorders
  • Wiskott–Aldrich syndrome
  • Fanconi 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
  • Bernard–Soulier syndrome
  • Glanzmann thrombasthenia
  • Idiopathic thrombocytopenic purpura
  • Thrombotic thrombocytopenic purpura Thrombotic thrombocytopenic purpura Thrombotic thrombocytopenic purpura (TTP) is a life-threatening condition due to either a congenital or an acquired deficiency of ADAMTS-13, a metalloproteinase that cleaves multimers of von Willebrand factor (VWF). The large multimers then aggregate excessive platelets resulting in microvascular thrombosis and an increase in consumption of platelets. Thrombotic Thrombocytopenic Purpura
  • Hemolytic uremic syndrome
  • Splenic sequestration
  • Aplastic anemia Aplastic Anemia Aplastic anemia (AA) is a rare, life-threatening condition characterized by pancytopenia and hypocellularity of the bone marrow (in the absence of any abnormal cells) reflecting damage to hematopoietic stem cells. Aplastic anemia can be acquired or inherited, however, most cases of AA are acquired and caused by autoimmune damage to hematopoietic stem cells. Aplastic Anemia
  • Bone marrow infiltration
  • Myelosuppression: drug-induced, radiation-induced
  • 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 cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic parenchymal necrosis and scarring (fibrosis) most commonly due to hepatitis C infection and alcoholic liver disease. Patients may present with jaundice, ascites, and hepatosplenomegaly. Cirrhosis can also cause complications such as hepatic encephalopathy, portal hypertension, portal vein thrombosis, and hepatorenal syndrome. Cirrhosis
  • Chronic kidney disease Chronic Kidney Disease Chronic kidney disease (CKD) is kidney impairment that lasts for ≥ 3 months, implying that it is irreversible. Hypertension and diabetes are the most common causes; however, there are a multitude of other etiologies. In the early to moderate stages, CKD is usually asymptomatic and is primarily diagnosed by laboratory abnormalities. Chronic Kidney Disease
  • Viral infections
  • Vitamin B12 and folate Folate Folate and vitamin B12 are 2 of the most clinically important water-soluble vitamins. Deficiencies can present with megaloblastic anemia, GI symptoms, neuropsychiatric symptoms, and adverse pregnancy complications, including neural tube defects. Folate and Vitamin B12 deficiencies
  • 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-associated conditions: gestational 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, HELLP syndrome
Coagulation disorders Hemophilias A, B, and C
  • Development of clotting factor autoantibodies
  • Vitamin K deficiency
Mixed disorders Von Willebrand disease Von Willebrand disease Von Willebrand disease (vWD) is a bleeding disorder characterized by a qualitative or quantitative deficiency of von Willebrand factor (vWF). Von Willebrand factor is a multimeric protein involved in the plate adhesion phase of hemostasis by forming a bridge between platelets and damaged portions of the vessel wall. Von Willebrand Disease Disseminated intravascular coagulation Disseminated intravascular coagulation 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
Medications
  • Antiplatelet drugs: aspirin, NSAIDs, clopidogrel, ticlopidine
  • 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: warfarin, heparin
  • Factor inhibitors:
    • Argatroban (inhibits thrombin)
    • Rivaroxaban (inhibits factor Xa)
  • Myelosuppressive chemotherapeutic agents

Clinical Presentation

A hypocoagulable state may present in the following ways:

  • Cutaneous bleeding:
    • Petechiae 
    • Purpura 
    • Ecchymosis and easy bruising  
  • Mucosal bleeding: 
    • Gingival bleeding: with brushing, flossing, and/or dental procedures
    • GI mucosal bleeding: gross blood in stool or on fecal occult blood testing
    • Nasopharyngeal bleeding: prolonged or recurrent epistaxis 
    • Menstrual bleeding: prolonged or heavy periods 
    • Urinary tract Urinary tract The urinary tract is located in the abdomen and pelvis and consists of the kidneys, ureters, urinary bladder, and urethra. The structures permit the excretion of urine from the body. Urine flows from the kidneys through the ureters to the urinary bladder and out through the urethra. Urinary Tract bleeding: gross or microscopic hematuria
  • Internal bleeding: 
    • Hemarthrosis 
    • Intramuscular hematoma
    • Intracranial hemorrhage 
    • Retroperitoneal hematoma 
  • Iron deficiency anemia Iron Deficiency Anemia Iron deficiency anemia is the most common type of anemia worldwide. This form of anemia is caused by insufficient iron due to a decreased supply, an increased loss, or an increased demand. Iron deficiency anemia is seen across all ages, sexes, and socioeconomic strata; however, children, women of childbearing age, and patients from lower socioeconomic strata are at higher risk. Iron Deficiency Anemia (if significant blood loss occurs):
    • Fatigue
    • Conjunctival pallor
    • Pica Pica Pica is an eating disorder characterized by a desire or recurrent compulsion to eat substances that are nonnutritive and not food. These compulsions and ingested substances are inappropriate for age or culture. Pica
  • Genetic/inherited bleeding disorders:
    • Symptomatic bleeding early in infancy/childhood 
    • Other findings consistent with an inherited disorder
Table: Usual clinical presentation according to the cause
Cutaneous bleeding Mucosal bleeding Internal bleeding Onset of bleeding after trauma
Platelet disorders Early (immediately)
Vessel disorders
Disorders of the coagulation cascade Late (minutes to hours)

Disorders of the Vessel Wall

Overview

Bleeding disorders may stem from abnormalities of the vessel wall.

  • Abnormalities may be in any component of the vessel walls, which are made up of:
    • Endothelial cells
    • Subendothelial matrix
    • Extravascular connective tissues
  • Disorders may be inherited or acquired.
  • Usually present with the spontaneous appearance of petechiae and ecchymoses in the skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin and mucous membranes or after a minor trauma 
  • Coagulation and bleeding studies are usually normal.

Inherited disorders of the vessel wall

Inherited disorders of the connective tissue Connective tissue Connective tissues originate from embryonic mesenchyme and are present throughout the body except inside the brain and spinal cord. The main function of connective tissues is to provide structural support to organs. Connective tissues consist of cells and an extracellular matrix. Connective Tissue matrix can cause vascular fragility, leading to frequent vessel injury.

  • Hereditary hemorrhagic telangiectasia (Osler–Weber–Rendu 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 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 in endoglin (an integral collagen protein)
    • Presents with:
      • Telangiectasias in skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin, mucous membranes, and internal organs
      • Epistaxis
      • GI bleeding
      • Iron deficiency anemia Iron Deficiency Anemia Iron deficiency anemia is the most common type of anemia worldwide. This form of anemia is caused by insufficient iron due to a decreased supply, an increased loss, or an increased demand. Iron deficiency anemia is seen across all ages, sexes, and socioeconomic strata; however, children, women of childbearing age, and patients from lower socioeconomic strata are at higher risk. Iron Deficiency Anemia
      • Arteriovenous malformations in the lungs Lungs Lungs are the main organs of the respiratory system. Lungs are paired viscera located in the thoracic cavity and are composed of spongy tissue. The primary function of the lungs is to oxygenate blood and eliminate CO2. Lungs, liver, and brain
  • Ehlers–Danlos syndrome:
    • A genetic disorder affecting the synthesis and/or processing of collagen 
    • Multiple phenotypes, but generally characterized by:
      • Skin hyperextensibility
      • Joint hypermobility
      • Tissue fragility
    • The vascular type in particular has ↑ risk for spontaneous vascular or visceral rupture with potentially life-threatening bleeding.
Mucocutaneous telangiectases

Hereditary hemorrhagic telangiectasia

Image: “Clinical manifestations of HHT” by Latino et al. License: CC BY 4.0, cropped by Lecturio.

Acquired disorders of the vessel wall

The following acquired conditions may lead to vascular fragility and increase vessel injury:

  • Age-related thinning of the skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin
  • Long-term topical glucocorticoid use may cause atrophy of supporting connective tissue Connective tissue Connective tissues originate from embryonic mesenchyme and are present throughout the body except inside the brain and spinal cord. The main function of connective tissues is to provide structural support to organs. Connective tissues consist of cells and an extracellular matrix. Connective Tissue.
  • Vitamin C deficiency (scurvy): 
    • Vitamin C is essential for collagen synthesis and integrity.
    • Presentation: 
      • Cutaneous signs: petechiae, perifollicular hemorrhage, and bruising
      • Gingivitis
      • Arthralgias
      • Impaired wound healing Wound healing Wound healing is a physiological process involving tissue repair in response to injury. It involves a complex interaction of various cell types, cytokines, and inflammatory mediators. Wound healing stages include hemostasis, inflammation, granulation, and remodeling. Wound Healing
  • Henoch–Schönlein purpura: 
    • Postinfectious IgA-mediated small vessel vasculitis in children and young adults
    • Classical presentation:
      • Purpura on extensor surfaces
      • Arthralgias
      • Abdominal 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
      • Renal disease/hematuria

Platelet disorders

Overview

  • Hypocoagulable platelet disorders may be due to: 
    • Decreased number ( 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) 
      • Increased destruction/clearance
      • Decreased production
    • Abnormal function 
  • Laboratory findings:
    • Bleeding time: prolonged
    • PT, INR, and PTT: not affected by pure platelet disorders

Thrombocytopenias

  • 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):
    • IgG 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 against 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, leading to their destruction 
    • May be primary or secondary 
    • Secondary 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 may be caused by:
      • Viral infections (see below)
      • CLL CLL Chronic lymphocytic leukemia (CLL) is a hematologic malignancy characterized by excess production of monoclonal B lymphocytes in the peripheral blood. When the involvement is primarily nodal, the condition is called small lymphocytic lymphoma (SLL). The disease usually presents in older adults, with a median age of 70 years. Chronic Lymphocytic Leukemia
      • 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)
      • 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
      • Common variable Variable Variables represent information about something that can change. The design of the measurement scales, or of the methods for obtaining information, will determine the data gathered and the characteristics of that data. As a result, a variable can be qualitative or quantitative, and may be further classified into subgroups. Types of Variables immune deficiency (CVID)
  • Thrombotic thrombocytopenic purpura Thrombotic thrombocytopenic purpura Thrombotic thrombocytopenic purpura (TTP) is a life-threatening condition due to either a congenital or an acquired deficiency of ADAMTS-13, a metalloproteinase that cleaves multimers of von Willebrand factor (VWF). The large multimers then aggregate excessive platelets resulting in microvascular thrombosis and an increase in consumption of platelets. Thrombotic Thrombocytopenic Purpura (TTP):
    • Deficiency of ADAMTS13 metalloproteinase (congenital or autoimmune)
      • This protein is responsible for cleaving the large VWF multimers.
      • Deficiencies lead to large VWF multimers that strongly adhere to 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 and increase platelet aggregation.
      • These platelet plugs damage the flowing RBCs → hemolytic anemia Hemolytic Anemia Hemolytic anemia (HA) is the term given to a large group of anemias that are caused by the premature destruction/hemolysis of circulating red blood cells (RBCs). Hemolysis can occur within (intravascular hemolysis) or outside the blood vessels (extravascular hemolysis). Hemolytic Anemia
      • Limits 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 to the brain and kidneys Kidneys The kidneys are a pair of bean-shaped organs located retroperitoneally against the posterior wall of the abdomen on either side of the spine. As part of the urinary tract, the kidneys are responsible for blood filtration and excretion of water-soluble waste in the urine. Kidneys
    • Classic presentation (pentad): 
      • Thrombocytopenia 
      • Hemolytic 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
      • Acute renal failure
      • Neurologic symptoms
      • Fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever
    • Modern presentation (now often diagnosed prior to the classic presentation of more severe disease; fever, especially, is uncommon):
      • Fatigue, weakness
      • Bleeding, petechiae, or purpura
      • GI symptoms
      • Neurologic findings: stroke, seizure, headache, confusion
  • Hemolytic uremic syndrome:
    • Primarily an acquired condition, typically in children
      • 90% occur after Shiga toxin–producing Escherichia coli Escherichia coli The gram-negative bacterium Escherichia coli is a key component of the human gut microbiota. Most strains of E. coli are avirulent, but occasionally they escape the GI tract, infecting the urinary tract and other sites. Less common strains of E. coli are able to cause disease within the GI tract, most commonly presenting as abdominal pain and diarrhea. Escherichia coli infection.
      • Hereditary forms involving mutations in complement and coagulation pathway proteins are possible.
    • Classic presentation (triad): 
      • Thrombocytopenia
      • Hemolytic 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
      • Acute renal failure 
    • Usually follows bloody diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea   
  • Hypersplenism (splenic sequestration of 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): 
    • Thrombocytopenia is typically mild.
    • Bleeding abnormalities are rare.
  • 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 cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic parenchymal necrosis and scarring (fibrosis) most commonly due to hepatitis C infection and alcoholic liver disease. Patients may present with jaundice, ascites, and hepatosplenomegaly. Cirrhosis can also cause complications such as hepatic encephalopathy, portal hypertension, portal vein thrombosis, and hepatorenal syndrome. Cirrhosis: 
    • Decreased liver production of thrombopoietin → ↓ platelet production
    • Portal hypertension Portal hypertension Portal hypertension is increased pressure in the portal venous system. This increased pressure can lead to splanchnic vasodilation, collateral blood flow through portosystemic anastomoses, and increased hydrostatic pressure. There are a number of etiologies, including cirrhosis, right-sided congestive heart failure, schistosomiasis, portal vein thrombosis, hepatitis, and Budd-Chiari syndrome. Portal Hypertension →  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  → splenic sequestration
  • Viral infections:
    • Mechanisms:
      • Splenic sequestration
      • Viral infection → hepatitis → ↓ platelet production
      • Secondary 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
      • Direct platelet destruction
    • Viruses most likely to cause 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:
      • HIV
      • Epstein–Barr 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: Overview
      • Cytomegalovirus Cytomegalovirus CMV is a ubiquitous double-stranded DNA virus belonging to the Herpesviridae family. CMV infections can be transmitted in bodily fluids, such as blood, saliva, urine, semen, and breast milk. The initial infection is usually asymptomatic in the immunocompetent host, or it can present with symptoms of mononucleosis. Cytomegalovirus
      • Rubella Rubella Rubella (also known as German measles or three-day measles) is caused by a single-stranded, positive-sense RNA virus of the Togaviridae family. Rubella only infects humans and spreads prenatally via vertical transmission or postnatally via droplet contact. Congenital rubella is associated with a classic triad of symptoms: cataracts, cardiac defects, and deafness. Infection in children and adults may be mild and present with constitutional symptoms along with a viral exanthem. Rubella Virus
      • Varicella
      • Mumps Mumps Mumps is caused by a single-stranded, linear, negative-sense RNA virus of the family Paramyxoviridae. Mumps is typically a disease of childhood, which manifests initially with fever, muscle pain, headache, poor appetite, and a general feeling of malaise, and is classically followed by parotitis. Mumps Virus/Mumps
      • Parvovirus
      • 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
  • Bone marrow suppression:
    • Aplastic anemia Aplastic Anemia Aplastic anemia (AA) is a rare, life-threatening condition characterized by pancytopenia and hypocellularity of the bone marrow (in the absence of any abnormal cells) reflecting damage to hematopoietic stem cells. Aplastic anemia can be acquired or inherited, however, most cases of AA are acquired and caused by autoimmune damage to hematopoietic stem cells. Aplastic Anemia
      • A life-threatening failure of the 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 causing pancytopenia 
      • Due to injury of the multipotent hematopoietic stem cells
    • Fanconi 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
      • An inherited type of aplastic 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
      • Associated with an increased risk for malignancy, developmental delay, café-au-lait spots, and VACTERL (Vertebral defects, Anal atresia, Cardiac defects, Tracheo-Esophageal fistula, Renal anomalies, and Limb abnormalities) association anomalies
    • Myelodysplasia
    • Drug-induced myelosuppression (e.g., chemotherapy)
    • Radiation-induced myelosuppression
    • Toxic chemicals (e.g., arsenic, benzene)
  • Vitamin deficiencies: 
    • B12
    • Folic acid 
  • Conditions associated with pregnancy:
    • Gestational 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
    • HELLP syndrome

Disorders of platelet function

Inherited disorders:

  • Bernard–Soulier syndrome:  
    • Autosomal recessive Autosomal recessive Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal recessive diseases are only expressed when 2 copies of the recessive allele are inherited. Autosomal Recessive and Autosomal Dominant Inheritancecondition 
    • Abnormal platelet adhesion due to low GpIb
    • Large 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 on smear 
  • Glanzmann thrombasthenia: 
    • Autosomal recessive Autosomal recessive Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal recessive diseases are only expressed when 2 copies of the recessive allele are inherited. Autosomal Recessive and Autosomal Dominant Inheritancecondition 
    • Abnormal platelet aggregation due to low GpIIb/IIIa
    • Presents with mucocutaneous bleeding without 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 
  • Wiskott–Aldrich syndrome (WAS): 
    • X-linked recessive disorder caused by mutations in the WAS protein
    • Presentation (classic triad): 
      • Immunodeficiency
      • Thrombocytopenia
      • Eczema Eczema Atopic dermatitis, also known as eczema, is a chronic, relapsing, pruritic, inflammatory skin disease that occurs more frequently in children, although adults can also be affected. The condition is often associated with elevated serum levels of IgE and a personal or family history of atopy. Skin dryness, erythema, oozing, crusting, and lichenification are present. Atopic Dermatitis (Eczema)
    • Mixed B- and T-cell deficiency results in immunodeficiency.
    • Abnormal platelet development causes:
      • Severely dysfunctional 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
      • Thrombocytopenia
      • Abnormal bleeding

Acquired conditions:

  • Uremic platelet dysfunction:
    • Chronic renal failure leads to abnormal 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 (mechanisms not fully understood).
    • Presentation: bruising, epistaxis, GI and genitourinary bleeding
  • Myeloproliferative disorders:
    • Bleeding complications vary (incidence: 3%–59%).
    • Presentation: bruising, epistaxis, gingival hemorrhage, and GI bleeding 
  • Use of antiplatelet agents Antiplatelet agents Antiplatelet agents are medications that inhibit platelet aggregation, a critical step in the formation of the initial platelet plug. Abnormal, or inappropriate, platelet aggregation is a key step in the pathophysiology of arterial ischemic events. The primary categories of antiplatelet agents include aspirin, ADP inhibitors, phosphodiesterase/adenosine uptake inhibitors, and glycoprotein IIb/IIIa inhibitors. Antiplatelet Agents
    • NSAIDs
    • Aspirin
    • Clopidogrel

Disorders of the Coagulation Cascade

Overview

  • Hypocoagulable disorders may be due to: 
    • Decreased number of coagulation factors (referred to as “factor deficiency”)
    • Abnormal function of coagulation factors
  • Laboratory findings:
    • PT and/or PTT will be prolonged by pure coagulation factor disorders.
    • Platelet count and bleeding time will not be affected.

Inherited conditions

  • Hemophilia Hemophilia The hemophilias are a group of inherited, or sometimes acquired, disorders of secondary hemostasis due to deficiency of specific clotting factors. Hemophilia A is a deficiency of factor VIII, hemophilia B a deficiency of factor IX, and hemophilia C a deficiency of factor XI. Patients present with bleeding events that may be spontaneous or associated with minor or major trauma. Hemophilia A:
    • X-linked recessive disorder 
    • Factor VIII deficiency 
    • Presents with:
      • Easy bleeding and bruising as an infant
      • Bleeding into the joints, muscles, and GI tract when older
    • Treated with prophylactic factor VIII infusions
  • Hemophilia Hemophilia The hemophilias are a group of inherited, or sometimes acquired, disorders of secondary hemostasis due to deficiency of specific clotting factors. Hemophilia A is a deficiency of factor VIII, hemophilia B a deficiency of factor IX, and hemophilia C a deficiency of factor XI. Patients present with bleeding events that may be spontaneous or associated with minor or major trauma. Hemophilia B:
    • X-linked recessive disorder 
    • Factor IX deficiency 
    • Less common
  • Hemophilia Hemophilia The hemophilias are a group of inherited, or sometimes acquired, disorders of secondary hemostasis due to deficiency of specific clotting factors. Hemophilia A is a deficiency of factor VIII, hemophilia B a deficiency of factor IX, and hemophilia C a deficiency of factor XI. Patients present with bleeding events that may be spontaneous or associated with minor or major trauma. Hemophilia C:

Acquired conditions

  • Development of factor inhibitors (autoantibodies against specific clotting factors):
    • Manifests clinically as hemophilia 
    • Often difficult to treat
  • Vitamin K deficiency: 
    • Malabsorption Malabsorption Malabsorption involves many disorders in which there is an inability of the gut to absorb nutrients from dietary intake, potentially including water and/or electrolytes. A closely related term, maldigestion is the inability to break down large molecules of food into their smaller constituents. Malabsorption and maldigestion can affect macronutrients (fats, proteins, and carbohydrates), micronutrients (vitamins and minerals), or both. Malabsorption and Maldigestion 
    • Malnutrition Malnutrition Malnutrition is a clinical state caused by an imbalance or deficiency of calories and/or micronutrients and macronutrients. The 2 main manifestations of acute severe malnutrition are marasmus (total caloric insufficiency) and kwashiorkor (protein malnutrition with characteristic edema). Malnutrition in children in resource-limited countries (e.g., alcohol abuse)
  • Anticoagulation therapy:
    • Heparins: 
      • Bind to antithrombin and increase its activity 
      • Lead to faster inactivation of coagulation factors (thrombin, factor Xa)
    • Warfarin:
      • Inhibits the vitamin K epoxide reductase in the liver, which prevents gamma-carboxylation of the vitamin K–dependent coagulation factors
      • Vitamin K–dependent procoagulants: factors II (thrombin), VII, IX, and X 
      • Vitamin K–dependent anticoagulants: proteins C and S

Mixed Platelet and Coagulation Disorders

  • Disseminated intravascular coagulation Disseminated intravascular coagulation 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 ( 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):
    • Cause: systemic thrombi formation throughout the microcirculation caused by systemic activation of coagulation due to:
      • 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
      • Malignancy
      • Trauma
      • Obstetric complications: preeclampsia, postpartum hemorrhage Postpartum hemorrhage Postpartum hemorrhage is one of the most common and deadly obstetric complications. Since 2017, postpartum hemorrhage has been defined as blood loss greater than 1,000 mL for both cesarean and vaginal deliveries, or excessive blood loss with signs of hemodynamic instability. Postpartum Hemorrhage, retained deceased fetus
      • Acute hemolytic transfusion reaction
    • Results: Platelets and coagulation factors are consumed, leading to bleeding diathesis. 
    • Presentation: spontaneous bleeding from mucous membranes
  • Von Willebrand disease Von Willebrand disease Von Willebrand disease (vWD) is a bleeding disorder characterized by a qualitative or quantitative deficiency of von Willebrand factor (vWF). Von Willebrand factor is a multimeric protein involved in the plate adhesion phase of hemostasis by forming a bridge between platelets and damaged portions of the vessel wall. Von Willebrand Disease
    • The most common inherited bleeding disorder 
    • 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 inheritance
    • Results from quantitative or qualitative deficiency of VWF
    • Functions of VWF:
      • VWF binds to and stabilizes factor VIII (affects the intrinsic pathway).
      • VWF is present on injured vessel walls and binds the GpIb receptor on 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 (initial adhesion of 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).
    • Clinical presentations:
      • Asymptomatic 
      • Spontaneous bleeding from mucous membranes (e.g., epistaxis)
      • Menorrhagia 
      • Bleeding from wounds

References

  1. Rajendran, P., Rengarajan, T., Thangavel, J., Nishigaki, Y., Sakthisekaran, D., Sethi, G., Nishigaki, I. (2013). The vascular endothelium and human diseases. International Journal of Biological Sciences 9(10):1057–1069. https://doi.org/10.7150/ijbs.7502
  2. Zehnder, J. (2020).  Clinical use of coagulation tests. Retrieved March 3, 2021, from https://www.uptodate.com/contents/clinical-use-of-coagulation-tests
  3. Ma, A. (2021). Approach to the adult with a suspected bleeding disorder. In Tirnauer, J.S. (Ed.), UpToDate. Retrieved March 18, 2021, from https://www.uptodate.com/contents/approach-to-the-adult-with-a-suspected-bleeding-disorder
  4. Longo, D., Fauci, A., Kasper, D., Hauser, S., Jameson, J., Loscalzo, J. (2012). Harrison’s Manual of Medicine, 18th ed. McGraw-Hill Professional, pages 2159–2178.
  5. Arnold, D.M., Cuker, A. (2021). Diagnostic approach to the adult with unexplained thrombocytopenia. In Tirnauer, J.S. (Ed.), UpToDate. Retrieved March 30, 2021, from https://www.uptodate.com/contents/diagnostic-approach-to-the-adult-with-unexplained-thrombocytopenia

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