Von Willebrand Disease

Overview

Definition

Von Willebrand disease (vWD) is a bleeding disorder caused by deficiency or dysfunction of the 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.

Epidemiology

• Most common inherited bleeding disorder
• Affects 1% of the general population
• Equal prevalence Prevalence The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. Measures of Disease Frequency between men and women, but women more likely to be symptomatic (as they experience menstrual bleeding)
• Inherited vWD:
  • Type 1 Type 1 Spinal Muscular Atrophy: 60%–80% of cases
  • Type 2 Type 2 Spinal Muscular Atrophy: 20%–30% of cases
  • Type 3 Type 3 Spinal Muscular Atrophy: < 5% of cases
• Acquired vWD:
  • The true prevalence Prevalence The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. Measures of Disease Frequency is not established.
  • Has been described in 20% of patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with malignancies, with metallic cardiac valves, and on ECMO

Classification and etiology

Pathophysiology

Normal physiology of the 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

• A glycoprotein produced by 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 endothelial cells
• Platelet vWF is stored in α-granules 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.
• Circulating vWF is stored in Weibel-Palade bodies of the endothelium Endothelium A layer of epithelium that lines the heart, blood vessels (vascular endothelium), lymph vessels (lymphatic endothelium), and the serous cavities of the body. Arteries: Histology.
• VWF binds to 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, 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 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, and FVIII.
• Functions:
  • Prevention of the degradation of FVIII
  • 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 to 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 of the exposed subendothelium
  • 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 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 (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)

Pathophysiology of VWF

• Intrinsic pathway Intrinsic pathway The intrinsic pathway is mainly responsible for the amplification of factor X activation Hemostasis coagulation defect: ↓ vWF → ↓ binding to FVIII → ↓ FVIII activity → ↑ PTT
• Defect in platelet plug Platelet plug Hemostasis formation: ↓ vWF → ↓ binding to platelet 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 → ↓ platelet-to-platelet and platelet-to-collagen adhesion Adhesion The process whereby platelets adhere to something other than platelets, e.g., collagen; basement membrane; microfibrils; or other ‘foreign’ surfaces. Coagulation Studies

Clinical Presentation

Clinical presentation varies and depends on the disease subtype. Presentation is mild or even asymptomatic in type 1 Type 1 Spinal Muscular Atrophy, with progressively increasing severity in types 2 and 3.

• Most patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship are asymptomatic.
• Symptomatic individuals develop:
  • Mucocutaneous bleeding:
    • Gum bleeding
    • Epistaxis Epistaxis Bleeding from the nose. Granulomatosis with Polyangiitis
    • Petechiae Petechiae Primary Skin Lesions
    • Recurrent and easy bruising Easy bruising Chédiak-Higashi Syndrome
  • Menorrhagia
  • Excessive bleeding after dental or surgical procedures
  • GI bleeding (usually associated with 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)
  • 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
  • Hemarthrosis Hemarthrosis Bleeding into the joints. It may arise from trauma or spontaneously in patients with hemophilia. Hemophilia (bleeding within the joint cavity that usually presents with pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways, swelling Swelling Inflammation, and a decreased range of motion Range of motion The distance and direction to which a bone joint can be extended. Range of motion is a function of the condition of the joints, muscles, and connective tissues involved. Joint flexibility can be improved through appropriate muscle strength exercises. Examination of the Upper Limbs)
  • Hematomas
  • In the pediatric population:
    • Umbilical stump Umbilical Stump Staphylococcal Scalded Skin Syndrome (SSSS) bleeding
    • Cephalohematomas
    • Cheek hematomas
    • Conjunctival hemorrhage
    • Post-vaccination bleeding
    • Post-circumcision bleeding

Diagnosis

VWD should be suspected in individuals with an increased history of bleeding, positive family history Family History Adult Health Maintenance of vWD or increased bleeding, unexplained mild thrombocytopenia Mild Thrombocytopenia Thrombocytopenia, or unexplained mild prolongation of aPTT. Specific vWF and FVIII blood tests are needed to confirm the diagnosis.

History

• Bleeding history
• Medications that may increase bleeding time Bleeding time Duration of blood flow after skin puncture. This test is used as a measure of capillary and platelet function. Hemostasis
• Family history Family History Adult Health Maintenance of bleeding or hypocoagulable Hypocoagulable Hypocoagulable conditions, also known as bleeding disorders or bleeding diathesis, are a diverse group of diseases that result in abnormal hemostasis. Physiologic hemostasis is dependent on the integrity of endothelial cells, subendothelial matrix, platelets, and coagulation factors. The hypocoagulable states result from abnormalities in one or more of these contributors, resulting in ineffective thrombosis and bleeding. Hypocoagulable Conditions states

Physical exam

• Bruises/hematomas
• Petechiae Petechiae Primary Skin Lesions
• Hemarthrosis Hemarthrosis Bleeding into the joints. It may arise from trauma or spontaneously in patients with hemophilia. Hemophilia
• Spontaneous gingival bleeding

Diagnostic testing

• CBC: Platelets Platelets Platelets are small cell fragments involved in hemostasis. Thrombopoiesis takes place primarily in the bone marrow through a series of cell differentiation and is influenced by several cytokines. Platelets are formed after fragmentation of the megakaryocyte cytoplasm. Platelets: Histology are normal in all types of vWD, except for type 2B.
• Coagulation profile:
  • ↑ Bleeding time Bleeding time Duration of blood flow after skin puncture. This test is used as a measure of capillary and platelet function. Hemostasis
  • Normal PT
  • Normal or ↑ aPTT
• VWF antigen Antigen Substances that are recognized by the immune system and induce an immune reaction. Vaccination (vWF: Ag AG Metabolic Acidosis):
  • Evaluates quantitative defects
  • Decreased in types 1, 2A, 2B, and 3
  • Normal or decreased in type 2M
  • Normal in type 2N
• VWF activity:
  • Evaluates qualitative defects (dysfunction) 
  • Tested through vWF ristocetin cofactor activity (vWF:RCo) assay:
    • Ristocetin promotes vWF binding to GPIb 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 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.
    • The normal range is 50–200 IU/dL.
  • Decreased in types 1, 2A, 2B, and 3
  • Normal or decreased in type 2M
  • Normal in type 2N
• FVIII coagulant assay (FVIII:C):
  • Evaluates the ability of vWF to carry FVIII
  • Decreased in types 2N and type 3 Type 3 Spinal Muscular Atrophy

Management

Inherited von Willebrand disease

• Desmopressin Desmopressin Hemophilia acetate:
  • Stimulates the release Release Release of a virus from the host cell following virus assembly and maturation. Egress can occur by host cell lysis, exocytosis, or budding through the plasma membrane. Virology of vWF from endothelial cells
  • Best initial treatment for mild-to-moderate bleeding
  • Contraindicated in type 2B because it exacerbates 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
  • Not effective in type 3 Type 3 Spinal Muscular Atrophy
• VWF replacement:
  • Considered in cases of severe bleeding
  • Considered when desmopressin Desmopressin Hemophilia acetate is not effective
  • Used as prophylaxis Prophylaxis Cephalosporins before surgery
• Oral contraceptives are used in cases of menorrhagia.
• Antifibrinolytic therapy (e.g., aminocaproic acid, tranexamic acid Tranexamic acid Antifibrinolytic hemostatic used in severe hemorrhage. Hemophilia):
  • Inhibits fibrinolysis by inhibiting the conversion of plasminogen Plasminogen Precursor of plasmin (fibrinolysin). It is a single-chain beta-globulin of molecular weight 80-90, 000 found mostly in association with fibrinogen in plasma; plasminogen activators change it to fibrinolysin. It is used in wound debriding and has been investigated as a thrombolytic agent. Hemostasis into 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
  • Used in mild mucocutaneous bleeding

Acquired von Willebrand disease

• The most effective approach is to treat the underlying disease.
• Desmopressin Desmopressin Hemophilia acetate
• VWF-containing concentrates
• Recombinant factor VIIa replacement therapy is especially effective in patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with vWF autoantibodies Autoantibodies Antibodies that react with self-antigens (autoantigens) of the organism that produced them. Blotting Techniques.
• Intravenous immunoglobulin ( IVIG IVIG Dermatomyositis) therapy and plasmapheresis Plasmapheresis Procedure whereby plasma is separated and extracted from anticoagulated whole blood and the red cells retransfused to the donor. Plasmapheresis is also employed for therapeutic use. Stevens-Johnson Syndrome are effective in lymphoproliferative and autoimmune diseases Autoimmune diseases Disorders that are characterized by the production of antibodies that react with host tissues or immune effector cells that are autoreactive to endogenous peptides. Selective IgA Deficiency.

Differential Diagnosis

• 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: an X-linked X-linked Genetic diseases that are linked to gene mutations on the X chromosome in humans or the X chromosome in other species. Included here are animal models of human X-linked diseases. Common Variable Immunodeficiency (CVID) disorder caused by the deficiency of FVIII. 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 is the most common type of 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. Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship present with hemarthrosis Hemarthrosis Bleeding into the joints. It may arise from trauma or spontaneously in patients with hemophilia. Hemophilia, soft-tissue hematomas, intracranial bleeding, and recurrent bruising. Diagnosis is based on history, physical examination, and evaluation of clotting factor activity. Management includes the replacement of FVIII. Desmopressin Desmopressin Hemophilia acetate may be administered in mild cases.
• 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: an X-linked X-linked Genetic diseases that are linked to gene mutations on the X chromosome in humans or the X chromosome in other species. Included here are animal models of human X-linked diseases. Common Variable Immunodeficiency (CVID) disorder caused by the deficiency of clotting 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. 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 is also called “ Christmas disease Christmas Disease Hemophilia.” Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship present with muscular and soft-tissue hematomas, hemarthrosis Hemarthrosis Bleeding into the joints. It may arise from trauma or spontaneously in patients with hemophilia. Hemophilia, GI bleeding, and recurrent bruising. Diagnosis is based on history, physical examination, and laboratory investigations such as coagulation studies Coagulation studies Coagulation studies are a group of hematologic laboratory studies that reflect the function of blood vessels, platelets, and coagulation factors, which all interact with one another to achieve hemostasis. Coagulation studies are usually ordered to evaluate patients with bleeding or hypercoagulation disorders. Coagulation Studies and factor IX assay. Treatment includes the administration of recombinant factor IX.
• Bernard-Soulier disease: a rare 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 blood clotting disorder caused by mutations in the gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics that codes for 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. The defective 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 results in impaired 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. Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship present with purpura, easy bruising Easy bruising Chédiak-Higashi Syndrome, and mucocutaneous bleeding. Diagnosis is based on peripheral smears that show 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 and 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. No treatment is needed in most cases. Bleeding episodes are treated with antifibrinolytics, platelet transfusions, and desmopressin Desmopressin Hemophilia acetate.
• 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 deficiency: an 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 blood clotting disorder caused by deficiency of the vitamin K-dependent serine Serine A non-essential amino acid occurring in natural form as the l-isomer. It is synthesized from glycine or threonine. It is involved in the biosynthesis of purines; pyrimidines; and other amino acids. Synthesis of Nonessential Amino Acids protease Protease Enzyme of the human immunodeficiency virus that is required for post-translational cleavage of gag and gag-pol precursor polyproteins into functional products needed for viral assembly. HIV protease is an aspartic protease encoded by the amino terminus of the pol gene. HIV Infection and AIDS. Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship present with hemarthrosis Hemarthrosis Bleeding into the joints. It may arise from trauma or spontaneously in patients with hemophilia. Hemophilia, hematomas, and GI and CNS bleeding. Diagnosis is based on history and coagulation studies Coagulation studies Coagulation studies are a group of hematologic laboratory studies that reflect the function of blood vessels, platelets, and coagulation factors, which all interact with one another to achieve hemostasis. Coagulation studies are usually ordered to evaluate patients with bleeding or hypercoagulation disorders. Coagulation Studies that demonstrate increased aPTT, PT, and normal bleeding time Bleeding time Duration of blood flow after skin puncture. This test is used as a measure of capillary and platelet function. Hemostasis (BT). The Russell viper venom time is prolonged. Treatment includes fresh frozen plasma Fresh Frozen Plasma Transfusion Products or prothrombin Prothrombin A plasma protein that is the inactive precursor of thrombin. It is converted to thrombin by a prothrombin activator complex consisting of factor Xa, factor V, phospholipid, and calcium ions. Hemostasis complex concentrates, 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 supplements, and replacement with recombinant 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.