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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 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 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 Subendothelial Membranoproliferative Glomerulonephritis 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: Histology, and coagulation factors Coagulation factors Endogenous substances, usually proteins, that are involved in the blood coagulation process. Hemostasis. The hypocoagulable states result from abnormalities in one or more of these contributors, resulting in ineffective thrombosis Thrombosis Formation and development of a thrombus or blood clot in the blood vessel. Epidemic Typhus and bleeding.

Last updated: Jan 16, 2024

Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

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:
  • Platelets Platelets Platelets are small cell fragments involved in hemostasis. Thrombopoiesis takes place primarily in the bone marrow through a series of cell differentiation and is influenced by several cytokines. Platelets are formed after fragmentation of the megakaryocyte cytoplasm. Platelets: Histology 
  • Coagulation factors Coagulation factors Endogenous substances, usually proteins, that are involved in the blood coagulation process. Hemostasis

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 Blood flow Blood flow refers to the movement of a certain volume of blood through the vasculature over a given unit of time (e.g., mL per minute). Vascular Resistance, Flow, and Mean Arterial Pressure to the area.
  • Formation of the platelet plug Platelet plug Hemostasis: the initial, temporary plug formed via the following steps:
    • Adhesion Adhesion The process whereby platelets adhere to something other than platelets, e.g., collagen; basement membrane; microfibrils; or other ‘foreign’ surfaces. Coagulation Studies: Exposed von Willebrand factor von Willebrand factor A high-molecular-weight plasma protein, produced by endothelial cells and megakaryocytes, that is part of the factor VIII/von Willebrand factor complex. The von Willebrand factor has receptors for collagen, platelets, and ristocetin activity as well as the immunologically distinct antigenic determinants. It functions in adhesion of platelets to collagen and hemostatic plug formation. The prolonged bleeding time in von Willebrand diseases is due to the deficiency of this factor. Hemostasis (VWF) binds to the glycoprotein (Gp) Ib receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. 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: Histology.
    • Aggregation Aggregation The attachment of platelets to one another. This clumping together can be induced by a number of agents (e.g., thrombin; collagen) and is part of the mechanism leading to the formation of a thrombus. Coagulation Studies: GpIIb/IIIa receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. 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: Histology bind BIND Hyperbilirubinemia of the Newborn fibrinogen Fibrinogen Plasma glycoprotein clotted by thrombin, composed of a dimer of three non-identical pairs of polypeptide chains (alpha, beta, gamma) held together by disulfide bonds. Fibrinogen clotting is a sol-gel change involving complex molecular arrangements: whereas fibrinogen is cleaved by thrombin to form polypeptides a and b, the proteolytic action of other enzymes yields different fibrinogen degradation products. Hemostasis.
    • Secretion Secretion Coagulation Studies: Substances are released that stimulate further platelet activation Platelet activation A series of progressive, overlapping events, triggered by exposure of the platelets to subendothelial tissue. These events include shape change, adhesiveness, aggregation, and release reactions. When carried through to completion, these events lead to the formation of a stable hemostatic plug. Hemostasis and aggregation Aggregation The attachment of platelets to one another. This clumping together can be induced by a number of agents (e.g., thrombin; collagen) and is part of the mechanism leading to the formation of a thrombus. Coagulation Studies and initiation of the coagulation cascade Coagulation cascade The coagulation cascade is a series of reactions that ultimately generates a strong, cross-linked fibrin clot. Hemostasis.
  • Activation of the coagulation cascade Coagulation cascade The coagulation cascade is a series of reactions that ultimately generates a strong, cross-linked fibrin clot. Hemostasis: forms a more stable fibrin Fibrin A protein derived from fibrinogen in the presence of thrombin, which forms part of the blood clot. Rapidly Progressive Glomerulonephritis clot
    • Extrinsic pathway Extrinsic pathway The extrinsic pathway is the primary physiological mechanism by which clotting is initiated Hemostasis:
      • Primarily responsible for initiation of the cascade
      • Involves (in order): tissue factor, factor VII Factor VII Heat- and storage-stable plasma protein that is activated by tissue thromboplastin to form factor viia in the extrinsic pathway of blood coagulation. The activated form then catalyzes the activation of factor X to factor Xa. Hemostasis, and factor X Factor X Storage-stable glycoprotein blood coagulation factor that can be activated to factor Xa by both the intrinsic and extrinsic pathways. A deficiency of factor X, sometimes called stuart-prower factor deficiency, may lead to a systemic coagulation disorder. Hemostasis
    • Intrinsic pathway Intrinsic pathway The intrinsic pathway is mainly responsible for the amplification of factor X activation Hemostasis:
      • 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 Common pathway Hemostasis:
      • The extrinsic and intrinsic pathways join together when factor X Factor X Storage-stable glycoprotein blood coagulation factor that can be activated to factor Xa by both the intrinsic and extrinsic pathways. A deficiency of factor X, sometimes called stuart-prower factor deficiency, may lead to a systemic coagulation disorder. Hemostasis is activated to form the final common pathway Common pathway Hemostasis.
      • Involves (in order): factors X, V, II ( thrombin Thrombin An enzyme formed from prothrombin that converts fibrinogen to fibrin. Hemostasis), I ( fibrin Fibrin A protein derived from fibrinogen in the presence of thrombin, which forms part of the blood clot. Rapidly Progressive Glomerulonephritis), and XIII
  • Inhibition of clotting and the fibrinolytic phase Fibrinolytic phase Coagulation Studies:
    • 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 Antithrombin Endogenous factors and drugs that directly inhibit the action of thrombin, usually by blocking its enzymatic activity. They are distinguished from indirect thrombin inhibitors, such as heparin, which act by enhancing the inhibitory effects of antithrombins. Anticoagulants
      • Proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis C and S
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. The GpIIb/IIIa receptors bind to fibrinogen, which is able to bind a platelet on each end, causing platelets to aggregate. As more 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 Telangiectasia Permanent dilation of preexisting blood vessels creating small focal red lesions, most commonly in the skin or mucous membranes. It is characterized by the prominence of skin blood vessels, such as vascular spiders. Chronic Venous Insufficiency (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. Skin: Structure and Functions
  • Chronic glucocorticoid use
  • Vitamin C Vitamin C A six carbon compound related to glucose. It is found naturally in citrus fruits and many vegetables. Ascorbic acid is an essential nutrient in human diets, and necessary to maintain connective tissue and bone. Its biologically active form, vitamin C, functions as a reducing agent and coenzyme in several metabolic pathways. Vitamin C is considered an antioxidant. Water-soluble Vitamins and their Deficiencies deficiency
  • Henoch–Schönlein purpura
Platelet disorders
  • Wiskott–Aldrich syndrome
  • Fanconi anemia Fanconi anemia Congenital disorder affecting all bone marrow elements, resulting in anemia; leukopenia; and thrombopenia, and associated with cardiac, renal, and limb malformations as well as dermal pigmentary changes. Spontaneous chromosome breakage is a feature of this disease along with predisposition to leukemia. There are at least 7 complementation groups in Fanconi anemia: fanca, fancb, fancc, fancd1, fancd2, fance, fancf, fancg, and fancl. Aplastic Anemia
  • Bernard–Soulier syndrome
  • Glanzmann thrombasthenia
  • Idiopathic Idiopathic Dermatomyositis 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 Splenic sequestration Severe Congenital Neutropenia
  • 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 Bone Marrow Infiltration Multiple Myeloma
  • Myelosuppression Myelosuppression Oxazolidinones: 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: Anatomy 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 Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease
  • 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-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 HELLP syndrome A severe form of preeclampsia with Hemolysis (with: LDH > 600 IU/L, ↑ Bilirubin, Schistocytes on blood smear, Anemia), ↑ Liver enzymes (with AST and/or AST > 2 times upper limit of normal), ↓ Platelet count, and thrombocytopenia (< 100,000). Hypertensive Pregnancy Disorders
Coagulation disorders Hemophilias A, B, and C
  • Development of clotting factor autoantibodies Autoantibodies Antibodies that react with self-antigens (autoantigens) of the organism that produced them. Blotting Techniques
  • Vitamin K deficiency Vitamin K Deficiency A nutritional condition produced by a deficiency of vitamin K in the diet, characterized by an increased tendency to hemorrhage (hemorrhagic disorders). Such bleeding episodes may be particularly severe in newborn infants. Fat-soluble Vitamins and their Deficiencies
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 Aspirin The prototypical analgesic used in the treatment of mild to moderate pain. It has anti-inflammatory and antipyretic properties and acts as an inhibitor of cyclooxygenase which results in the inhibition of the biosynthesis of prostaglandins. Aspirin also inhibits platelet aggregation and is used in the prevention of arterial and venous thrombosis. Nonsteroidal Antiinflammatory Drugs (NSAIDs), NSAIDs NSAIDS Primary vs Secondary Headaches, clopidogrel Clopidogrel A ticlopidine analog and platelet purinergic p2y receptor antagonist that inhibits adenosine diphosphate-mediated platelet aggregation. It is used to prevent thromboembolism in patients with arterial occlusive diseases; myocardial infarction; stroke; or atrial fibrillation. Antiplatelet Drugs, 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 Warfarin An anticoagulant that acts by inhibiting the synthesis of vitamin K-dependent coagulation factors. Warfarin is indicated for the prophylaxis and/or treatment of venous thrombosis and its extension, pulmonary embolism, and atrial fibrillation with embolization. It is also used as an adjunct in the prophylaxis of systemic embolism after myocardial infarction. Warfarin is also used as a rodenticide. Anticoagulants, heparin
  • Factor inhibitors:
    • Argatroban Argatroban Anticoagulants (inhibits thrombin Thrombin An enzyme formed from prothrombin that converts fibrinogen to fibrin. Hemostasis)
    • Rivaroxaban Rivaroxaban A morpholine and thiophene derivative that functions as a factor Xa inhibitor and is used in the treatment and prevention of deep-vein thrombosis and pulmonary embolism. It is also used for the prevention of stroke and systemic embolization in patients with non-valvular atrial fibrillation, and for the prevention of atherothrombotic events in patients after an acute coronary syndrome. Anticoagulants (inhibits factor Xa)
  • Myelosuppressive chemotherapeutic agents

Clinical Presentation

A hypocoagulable state may present in the following ways:

  • Cutaneous bleeding:
  • Mucosal bleeding Mucosal bleeding Chédiak-Higashi Syndrome
    • Gingival bleeding: with brushing, flossing, and/or dental procedures
    • GI mucosal bleeding Mucosal bleeding Chédiak-Higashi Syndrome: gross blood in stool or on fecal occult blood testing
    • Nasopharyngeal bleeding: prolonged or recurrent epistaxis Epistaxis Bleeding from the nose. Granulomatosis with Polyangiitis 
    • 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: Anatomy bleeding: gross or microscopic hematuria Hematuria Presence of blood in the urine. Renal Cell Carcinoma
  • Internal bleeding: 
    • Hemarthrosis Hemarthrosis Bleeding into the joints. It may arise from trauma or spontaneously in patients with hemophilia. Hemophilia 
    • Intramuscular hematoma Hematoma A collection of blood outside the blood vessels. Hematoma can be localized in an organ, space, or tissue. Intussusception
    • Intracranial hemorrhage Intracranial hemorrhage Subarachnoid hemorrhage (SAH) is a type of cerebrovascular accident (stroke) resulting from intracranial hemorrhage into the subarachnoid space between the arachnoid and the pia mater layers of the meninges surrounding the brain. Most sahs originate from a saccular aneurysm in the circle of willis but may also occur as a result of trauma, uncontrolled hypertension, vasculitis, anticoagulant use, or stimulant use. Subarachnoid Hemorrhage 
    • Retroperitoneal Retroperitoneal Peritoneum: Anatomy hematoma Hematoma A collection of blood outside the blood vessels. Hematoma can be localized in an organ, space, or tissue. Intussusception 
  • Iron Iron A metallic element with atomic symbol fe, atomic number 26, and atomic weight 55. 85. It is an essential constituent of hemoglobins; cytochromes; and iron-binding proteins. It plays a role in cellular redox reactions and in the transport of oxygen. Trace Elements deficiency anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types (if significant blood loss occurs):
    • Fatigue Fatigue The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. Fibromyalgia
    • 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 bleedingdisorders:
    • 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 Mucosal bleeding Chédiak-Higashi Syndrome Internal bleeding Onset of bleeding after trauma
Platelet disorders Early (immediately)
Vessel disorders
Disorders of the coagulation cascade Coagulation cascade The coagulation cascade is a series of reactions that ultimately generates a strong, cross-linked fibrin clot. Hemostasis 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:
  • Disorders may be inherited or acquired.
  • Usually present with the spontaneous appearance of petechiae Petechiae Primary Skin Lesions 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. Skin: Structure and Functions 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: Histology matrix can cause vascular fragility, leading to frequent vessel injury.

  • Hereditary hemorrhagic telangiectasia Telangiectasia Permanent dilation of preexisting blood vessels creating small focal red lesions, most commonly in the skin or mucous membranes. It is characterized by the prominence of skin blood vessels, such as vascular spiders. Chronic Venous Insufficiency (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 Collagen A polypeptide substance comprising about one third of the total protein in mammalian organisms. It is the main constituent of skin; connective tissue; and the organic substance of bones (bone and bones) and teeth (tooth). Connective Tissue: Histology protein)
    • Presents with:
      • Telangiectasias Telangiectasias Ataxia-telangiectasia 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. Skin: Structure and Functions, mucous membranes, and internal organs
      • Epistaxis Epistaxis Bleeding from the nose. Granulomatosis with Polyangiitis
      • GI bleeding
      • Iron Iron A metallic element with atomic symbol fe, atomic number 26, and atomic weight 55. 85. It is an essential constituent of hemoglobins; cytochromes; and iron-binding proteins. It plays a role in cellular redox reactions and in the transport of oxygen. Trace Elements deficiency anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types
      • Arteriovenous malformations Arteriovenous malformations Congenital vascular anomalies in the brain characterized by direct communication between an artery and a vein without passing through the capillaries. The locations and size of the shunts determine the symptoms including headaches; seizures; stroke; intracranial hemorrhages; mass effect; and vascular steal effect. Intracerebral Hemorrhage 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: Anatomy, 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: Anatomy, and brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification
  • Ehlers–Danlos syndrome:
    • A genetic disorder affecting the synthesis Synthesis Polymerase Chain Reaction (PCR) and/or processing of collagen Collagen A polypeptide substance comprising about one third of the total protein in mammalian organisms. It is the main constituent of skin; connective tissue; and the organic substance of bones (bone and bones) and teeth (tooth). Connective Tissue: Histology 
    • Multiple phenotypes, but generally characterized by:
      • 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. Skin: Structure and Functions hyperextensibility
      • Joint hypermobility Joint Hypermobility Ehlers-Danlos Syndrome
      • 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. Skin: Structure and Functions
  • Long-term topical glucocorticoid use may cause atrophy Atrophy Decrease in the size of a cell, tissue, organ, or multiple organs, associated with a variety of pathological conditions such as abnormal cellular changes, ischemia, malnutrition, or hormonal changes. Cellular Adaptation 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: Histology.
  • Vitamin C Vitamin C A six carbon compound related to glucose. It is found naturally in citrus fruits and many vegetables. Ascorbic acid is an essential nutrient in human diets, and necessary to maintain connective tissue and bone. Its biologically active form, vitamin C, functions as a reducing agent and coenzyme in several metabolic pathways. Vitamin C is considered an antioxidant. Water-soluble Vitamins and their Deficiencies deficiency ( scurvy Scurvy An acquired blood vessel disorder caused by severe deficiency of vitamin C (ascorbic acid) in the diet leading to defective collagen formation in small blood vessels. Scurvy is characterized by bleeding in any tissue, weakness, anemia, spongy gums, and a brawny induration of the muscles of the calves and legs. Water-soluble Vitamins and their Deficiencies):
    • Vitamin C Vitamin C A six carbon compound related to glucose. It is found naturally in citrus fruits and many vegetables. Ascorbic acid is an essential nutrient in human diets, and necessary to maintain connective tissue and bone. Its biologically active form, vitamin C, functions as a reducing agent and coenzyme in several metabolic pathways. Vitamin C is considered an antioxidant. Water-soluble Vitamins and their Deficiencies is essential for collagen Collagen A polypeptide substance comprising about one third of the total protein in mammalian organisms. It is the main constituent of skin; connective tissue; and the organic substance of bones (bone and bones) and teeth (tooth). Connective Tissue: Histology synthesis Synthesis Polymerase Chain Reaction (PCR) and integrity.
    • Presentation:
      • Cutaneous signs: petechiae Petechiae Primary Skin Lesions, perifollicular hemorrhage, and bruising
      • Gingivitis Gingivitis Inflammation of gum tissue (gingiva) without loss of connective tissue. Chédiak-Higashi Syndrome
      • 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:

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 Bleeding time Duration of blood flow after skin puncture. This test is used as a measure of capillary and platelet function. Hemostasis: 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 IgG The major immunoglobulin isotype class in normal human serum. There are several isotype subclasses of igg, for example, igg1, igg2a, and igg2b. Hypersensitivity Pneumonitis antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins: Types and Functions against platelets Platelets Platelets are small cell fragments involved in hemostasis. Thrombopoiesis takes place primarily in the bone marrow through a series of cell differentiation and is influenced by several cytokines. Platelets are formed after fragmentation of the megakaryocyte cytoplasm. Platelets: Histology, leading to their destruction 
    • May be primary or secondary 
    • Secondary ITP Secondary ITP Immune Thrombocytopenic Purpura may be caused by:
      • Viral infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease (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 CVID Common variable immune deficiency (CVID), also known as humoral immunodeficiency, is a disorder of the immune system characterized by reduced serum levels of immunoglobulins g, a, and m. Common Variable Immunodeficiency (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 TTP 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):
    • Deficiency of ADAMTS13 metalloproteinase ( congenital Congenital Chorioretinitis 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: Histology and increase platelet aggregation Platelet aggregation The attachment of platelets to one another. This clumping together can be induced by a number of agents (e.g., thrombin; collagen) and is part of the mechanism leading to the formation of a thrombus. Hemostasis.
      • These platelet plugs damage the flowing RBCs RBCs Erythrocytes, or red blood cells (RBCs), are the most abundant cells in the blood. While erythrocytes in the fetus are initially produced in the yolk sac then the liver, the bone marrow eventually becomes the main site of production. Erythrocytes: Histology 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 Blood flow Blood flow refers to the movement of a certain volume of blood through the vasculature over a given unit of time (e.g., mL per minute). Vascular Resistance, Flow, and Mean Arterial Pressure to the brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification 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: Anatomy
    • Classic presentation (pentad):
      • 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 
      • 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
      • Acute renal failure Renal failure Conditions in which the kidneys perform below the normal level in the ability to remove wastes, concentrate urine, and maintain electrolyte balance; blood pressure; and calcium metabolism. Renal insufficiency can be classified by the degree of kidney damage (as measured by the level of proteinuria) and reduction in glomerular filtration rate. Crush Syndrome
      • 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 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, especially, is uncommon):
      • Fatigue Fatigue The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. Fibromyalgia, weakness
      • Bleeding, petechiae Petechiae Primary Skin Lesions, or purpura
      • GI symptoms
      • Neurologic findings: stroke, seizure, headache Headache The symptom of pain in the cranial region. It may be an isolated benign occurrence or manifestation of a wide variety of headache disorders. Brain Abscess, confusion
  • Hemolytic uremic syndrome:
    • Primarily an acquired condition, typically in children
      • 90% occur after Shiga toxin Shiga toxin A class of toxins that inhibit protein synthesis by blocking the interaction of ribosomal RNA; with peptide elongation factors. They include shiga toxin which is produced by Shigella dysenteriae and a variety of shiga-like toxins that are produced by pathologic strains of Escherichia coli such as Escherichia coli o157. Diarrheagenic E. coli–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 Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis are possible.
    • Classic presentation (triad):
      • 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
      • 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
      • Acute renal failure Renal failure Conditions in which the kidneys perform below the normal level in the ability to remove wastes, concentrate urine, and maintain electrolyte balance; blood pressure; and calcium metabolism. Renal insufficiency can be classified by the degree of kidney damage (as measured by the level of proteinuria) and reduction in glomerular filtration rate. Crush Syndrome 
    • Usually follows bloody diarrhea Bloody diarrhea Diarrhea   
  • Hypersplenism Hypersplenism Condition characterized by splenomegaly, some reduction in the number of circulating blood cells in the presence of a normal or hyperactive bone marrow, and the potential for reversal by splenectomy. Splenomegaly ( splenic sequestration Splenic sequestration Severe Congenital Neutropenia 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: Histology):
    • 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 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: Anatomy 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 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: Anatomy production of thrombopoietin Thrombopoietin A humoral factor that stimulates the production of thrombocytes (blood platelets). Thrombopoietin stimulates the proliferation of bone marrow megakaryocytes and their release of blood platelets. The process is called thrombopoiesis. Platelets: Histology → ↓ 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 Splenic sequestration Severe Congenital Neutropenia
  • Viral infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease:
    • Mechanisms:
    • Viruses Viruses Minute infectious agents whose genomes are composed of DNA or RNA, but not both. They are characterized by a lack of independent metabolism and the inability to replicate outside living host cells. Virology 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 HIV Anti-HIV Drugs
      • 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
      • 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 An acute infectious disease caused by the rubella virus. The virus enters the respiratory tract via airborne droplet and spreads to the lymphatic system. 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 Bone marrow The soft tissue filling the cavities of bones. Bone marrow exists in two types, yellow and red. Yellow marrow is found in the large cavities of large bones and consists mostly of fat cells and a few primitive blood cells. Red marrow is a hematopoietic tissue and is the site of production of erythrocytes and granular leukocytes. Bone marrow is made up of a framework of connective tissue containing branching fibers with the frame being filled with marrow cells. Bone Marrow: Composition and Hematopoiesis suppression Suppression Defense Mechanisms:
    • 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 The soft tissue filling the cavities of bones. Bone marrow exists in two types, yellow and red. Yellow marrow is found in the large cavities of large bones and consists mostly of fat cells and a few primitive blood cells. Red marrow is a hematopoietic tissue and is the site of production of erythrocytes and granular leukocytes. Bone marrow is made up of a framework of connective tissue containing branching fibers with the frame being filled with marrow cells. Bone Marrow: Composition and Hematopoiesis causing pancytopenia Pancytopenia Deficiency of all three cell elements of the blood, erythrocytes, leukocytes and platelets. Aplastic Anemia 
      • Due to injury of the multipotent hematopoietic stem cells Hematopoietic stem cells Progenitor cells from which all blood cells derived. They are found primarily in the bone marrow and also in small numbers in the peripheral blood. Bone Marrow: Composition and Hematopoiesis
    • Fanconi anemia Fanconi anemia Congenital disorder affecting all bone marrow elements, resulting in anemia; leukopenia; and thrombopenia, and associated with cardiac, renal, and limb malformations as well as dermal pigmentary changes. Spontaneous chromosome breakage is a feature of this disease along with predisposition to leukemia. There are at least 7 complementation groups in Fanconi anemia: fanca, fancb, fancc, fancd1, fancd2, fance, fancf, fancg, and fancl. Aplastic Anemia:
      • An inherited type of 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
      • Associated with an increased risk for malignancy Malignancy Hemothorax, developmental delay, café-au-lait spots, and VACTERL (Vertebral defects, Anal atresia Atresia Hypoplastic Left Heart Syndrome (HLHS), Cardiac defects, Tracheo-Esophageal fistula Fistula Abnormal communication most commonly seen between two internal organs, or between an internal organ and the surface of the body. Anal Fistula, Renal anomalies, and Limb abnormalities) association anomalies
    • Myelodysplasia Myelodysplasia Non-Hodgkin Lymphomas
    • Drug-induced myelosuppression Myelosuppression Oxazolidinones (e.g., chemotherapy Chemotherapy Osteosarcoma)
    • Radiation-induced myelosuppression Myelosuppression Oxazolidinones
    • Toxic chemicals (e.g., arsenic Arsenic A shiny gray element with atomic symbol as, atomic number 33, and atomic weight 75. It occurs throughout the universe, mostly in the form of metallic arsenides. Most forms are toxic. According to the fourth annual report on carcinogens, arsenic and certain arsenic compounds have been listed as known carcinogens. Metal Poisoning (Lead, Arsenic, Iron), benzene)
  • Vitamin deficiencies: 
    • B12
    • Folic acid 
  • Conditions associated with pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care:
    • 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 HELLP syndrome A severe form of preeclampsia with Hemolysis (with: LDH > 600 IU/L, ↑ Bilirubin, Schistocytes on blood smear, Anemia), ↑ Liver enzymes (with AST and/or AST > 2 times upper limit of normal), ↓ Platelet count, and thrombocytopenia (< 100,000). Hypertensive Pregnancy Disorders

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 Inheritance condition 
    • Abnormal platelet adhesion Adhesion The process whereby platelets adhere to something other than platelets, e.g., collagen; basement membrane; microfibrils; or other ‘foreign’ surfaces. Coagulation Studies 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: Histology 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 Inheritance condition 
    • Abnormal platelet aggregation Platelet aggregation The attachment of platelets to one another. This clumping together can be induced by a number of agents (e.g., thrombin; collagen) and is part of the mechanism leading to the formation of a thrombus. Hemostasis 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 X-Linked Recessive Duchenne Muscular Dystrophy disorder caused by mutations in the WAS protein
    • Presentation (classic triad):
      • Immunodeficiency Immunodeficiency Chédiak-Higashi Syndrome
      • 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
      • 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 Immunodeficiency Chédiak-Higashi Syndrome.
    • 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: Histology
      • 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
      • Abnormal bleeding

Acquired conditions:

  • Uremic platelet dysfunction:
    • Chronic renal failure Renal failure Conditions in which the kidneys perform below the normal level in the ability to remove wastes, concentrate urine, and maintain electrolyte balance; blood pressure; and calcium metabolism. Renal insufficiency can be classified by the degree of kidney damage (as measured by the level of proteinuria) and reduction in glomerular filtration rate. Crush Syndrome 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: Histology (mechanisms not fully understood).
    • Presentation: bruising, epistaxis Epistaxis Bleeding from the nose. Granulomatosis with Polyangiitis, GI and genitourinary bleeding
  • Myeloproliferative disorders:
    • Bleeding complications vary ( incidence Incidence The number of new cases of a given disease during a given period in a specified population. It also is used for the rate at which new events occur in a defined population. It is differentiated from prevalence, which refers to all cases in the population at a given time. Measures of Disease Frequency: 3%–59%).
    • Presentation: bruising, epistaxis Epistaxis Bleeding from the nose. Granulomatosis with Polyangiitis, 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 Drugs:
    • NSAIDs NSAIDS Primary vs Secondary Headaches
    • Aspirin Aspirin The prototypical analgesic used in the treatment of mild to moderate pain. It has anti-inflammatory and antipyretic properties and acts as an inhibitor of cyclooxygenase which results in the inhibition of the biosynthesis of prostaglandins. Aspirin also inhibits platelet aggregation and is used in the prevention of arterial and venous thrombosis. Nonsteroidal Antiinflammatory Drugs (NSAIDs)
    • Clopidogrel Clopidogrel A ticlopidine analog and platelet purinergic p2y receptor antagonist that inhibits adenosine diphosphate-mediated platelet aggregation. It is used to prevent thromboembolism in patients with arterial occlusive diseases; myocardial infarction; stroke; or atrial fibrillation. Antiplatelet Drugs

Disorders of the Coagulation Cascade

Overview

  • Hypocoagulable disorders may be due to:
    • Decreased number of coagulation factors Coagulation factors Endogenous substances, usually proteins, that are involved in the blood coagulation process. Hemostasis (referred to as “factor deficiency”)
    • Abnormal function of coagulation factors Coagulation factors Endogenous substances, usually proteins, that are involved in the blood coagulation process. Hemostasis
  • Laboratory findings:
    • PT and/or PTT will be prolonged by pure coagulation factor disorders.
    • Platelet count and bleeding time Bleeding time Duration of blood flow after skin puncture. This test is used as a measure of capillary and platelet function. Hemostasis will not be affected.

Inherited conditions

  • Hemophilia A Hemophilia A The classic hemophilia resulting from a deficiency of factor VIII. It is an inherited disorder of blood coagulation characterized by a permanent tendency to hemorrhage. Hemophilia:
    • X-linked recessive X-Linked Recessive Duchenne Muscular Dystrophy disorder 
    • Factor VIII Factor VIII Factor VIII of blood coagulation. Antihemophilic factor that is part of the factor viii/von Willebrand factor complex. Factor VIII is produced in the liver and acts in the intrinsic pathway of blood coagulation. It serves as a cofactor in factor X activation and this action is markedly enhanced by small amounts of thrombin. Hemostasis 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 Factor VIII Factor VIII of blood coagulation. Antihemophilic factor that is part of the factor viii/von Willebrand factor complex. Factor VIII is produced in the liver and acts in the intrinsic pathway of blood coagulation. It serves as a cofactor in factor X activation and this action is markedly enhanced by small amounts of thrombin. Hemostasis infusions
  • Hemophilia B Hemophilia B A deficiency of blood coagulation factor IX inherited as an X-linked disorder. (also known as Christmas disease, after the first patient studied in detail, not the holiday.) historical and clinical features resemble those in classic hemophilia, but patients present with fewer symptoms. Severity of bleeding is usually similar in members of a single family. Many patients are asymptomatic until the hemostatic system is stressed by surgery or trauma. Treatment is similar to that for hemophilia A. Hemophilia:
    • X-linked recessive X-Linked Recessive Duchenne Muscular Dystrophy disorder 
    • Factor IX Factor IX Storage-stable blood coagulation factor acting in the intrinsic pathway of blood coagulation. Its activated form, ixa, forms a complex with factor VIII and calcium on platelet factor 3 to activate factor X to Xa. Hemostasis deficiency 
    • Less common
  • Hemophilia C Hemophilia C Hemophilia:
    • 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 Inheritance disorder 
    • Factor XI deficiency 
    • Less common

Acquired conditions

  • Development of factor inhibitors ( autoantibodies Autoantibodies Antibodies that react with self-antigens (autoantigens) of the organism that produced them. Blotting Techniques against specific clotting factors):
    • Manifests clinically as 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 
    • Often difficult to treat
  • Vitamin K deficiency Vitamin K Deficiency A nutritional condition produced by a deficiency of vitamin K in the diet, characterized by an increased tendency to hemorrhage (hemorrhagic disorders). Such bleeding episodes may be particularly severe in newborn infants. Fat-soluble Vitamins and their Deficiencies:
    • Malabsorption Malabsorption General term for a group of malnutrition syndromes caused by failure of normal intestinal absorption of nutrients. 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 use disorder Alcohol use disorder Alcohol is one of the most commonly used addictive substances in the world. Alcohol use disorder (AUD) is defined as pathologic consumption of alcohol leading to impaired daily functioning. Acute alcohol intoxication presents with impairment in speech and motor functions and can be managed in most cases with supportive care. Alcohol Use Disorder)
  • Anticoagulation Anticoagulation Pulmonary Hypertension Drugs therapy:
    • Heparins:
      • Bind BIND Hyperbilirubinemia of the Newborn to antithrombin Antithrombin Endogenous factors and drugs that directly inhibit the action of thrombin, usually by blocking its enzymatic activity. They are distinguished from indirect thrombin inhibitors, such as heparin, which act by enhancing the inhibitory effects of antithrombins. Anticoagulants and increase its activity 
      • Lead to faster inactivation of coagulation factors Coagulation factors Endogenous substances, usually proteins, that are involved in the blood coagulation process. Hemostasis ( thrombin Thrombin An enzyme formed from prothrombin that converts fibrinogen to fibrin. Hemostasis, factor Xa)
    • Warfarin Warfarin An anticoagulant that acts by inhibiting the synthesis of vitamin K-dependent coagulation factors. Warfarin is indicated for the prophylaxis and/or treatment of venous thrombosis and its extension, pulmonary embolism, and atrial fibrillation with embolization. It is also used as an adjunct in the prophylaxis of systemic embolism after myocardial infarction. Warfarin is also used as a rodenticide. Anticoagulants:
      • Inhibits the vitamin K epoxide reductase Vitamin K Epoxide Reductase Anticoagulants in the 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: Anatomy, which prevents gamma-carboxylation of the vitamin K Vitamin K A lipid cofactor that is required for normal blood clotting. Several forms of vitamin K have been identified: vitamin K 1 (phytomenadione) derived from plants, vitamin K 2 (menaquinone) from bacteria, and synthetic naphthoquinone provitamins, vitamin K 3 (menadione). Vitamin k 3 provitamins, after being alkylated in vivo, exhibit the antifibrinolytic activity of vitamin k. Green leafy vegetables, liver, cheese, butter, and egg yolk are good sources of vitamin k. Fat-soluble Vitamins and their Deficiencies–dependent coagulation factors Coagulation factors Endogenous substances, usually proteins, that are involved in the blood coagulation process. Hemostasis
      • Vitamin K Vitamin K A lipid cofactor that is required for normal blood clotting. Several forms of vitamin K have been identified: vitamin K 1 (phytomenadione) derived from plants, vitamin K 2 (menaquinone) from bacteria, and synthetic naphthoquinone provitamins, vitamin K 3 (menadione). Vitamin k 3 provitamins, after being alkylated in vivo, exhibit the antifibrinolytic activity of vitamin k. Green leafy vegetables, liver, cheese, butter, and egg yolk are good sources of vitamin k. Fat-soluble Vitamins and their Deficiencies–dependent procoagulants: factors II ( thrombin Thrombin An enzyme formed from prothrombin that converts fibrinogen to fibrin. Hemostasis), VII, IX, and X 
      • Vitamin K Vitamin K A lipid cofactor that is required for normal blood clotting. Several forms of vitamin K have been identified: vitamin K 1 (phytomenadione) derived from plants, vitamin K 2 (menaquinone) from bacteria, and synthetic naphthoquinone provitamins, vitamin K 3 (menadione). Vitamin k 3 provitamins, after being alkylated in vivo, exhibit the antifibrinolytic activity of vitamin k. Green leafy vegetables, liver, cheese, butter, and egg yolk are good sources of vitamin k. Fat-soluble Vitamins and their Deficiencies–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: proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis C and S

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 Systemic inflammatory response syndrome with a proven or suspected infectious etiology. When sepsis is associated with organ dysfunction distant from the site of infection, it is called severe sepsis. When sepsis is accompanied by hypotension despite adequate fluid infusion, it is called septic shock. Sepsis and Septic Shock
      • Malignancy Malignancy Hemothorax
      • Trauma
      • Obstetric complications: preeclampsia Preeclampsia A complication of pregnancy, characterized by a complex of symptoms including maternal hypertension and proteinuria with or without pathological edema. Symptoms may range between mild and severe. Pre-eclampsia usually occurs after the 20th week of gestation, but may develop before this time in the presence of trophoblastic disease. Hypertensive Pregnancy Disorders, 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 Acute hemolytic transfusion reaction Transfusion Reactions
    • Results: Platelets Platelets Platelets are small cell fragments involved in hemostasis. Thrombopoiesis takes place primarily in the bone marrow through a series of cell differentiation and is influenced by several cytokines. Platelets are formed after fragmentation of the megakaryocyte cytoplasm. Platelets: Histology and coagulation factors Coagulation factors Endogenous substances, usually proteins, that are involved in the blood coagulation process. Hemostasis are consumed, leading to bleeding diathesis Bleeding diathesis Wiskott-Aldrich Syndrome
    • 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 inheritance Autosomal dominant inheritance Autosomal Recessive and Autosomal Dominant Inheritance
    • Results from quantitative or qualitative deficiency of VWF
    • Functions of VWF:
      • VWF binds to and stabilizes factor VIII Factor VIII Factor VIII of blood coagulation. Antihemophilic factor that is part of the factor viii/von Willebrand factor complex. Factor VIII is produced in the liver and acts in the intrinsic pathway of blood coagulation. It serves as a cofactor in factor X activation and this action is markedly enhanced by small amounts of thrombin. Hemostasis (affects the intrinsic pathway Intrinsic pathway The intrinsic pathway is mainly responsible for the amplification of factor X activation Hemostasis).
      • VWF is present on injured vessel walls and binds the GpIb receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. 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: Histology (initial adhesion Adhesion The process whereby platelets adhere to something other than platelets, e.g., collagen; basement membrane; microfibrils; or other ‘foreign’ surfaces. Coagulation Studies 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: Histology).
    • Clinical presentations:

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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