History

Fact Explanation
Bleeding from trivial wounds Von Willebrand Factor(vWF) serves two functions: it binds to factor VIII in the circulation and prevents its early metabolism and helps platelets adhere to exposed subendothelial collagen at the site of vascular injury. Deficiency or dysfunctions of vWF leads to impaired platelet response and clot formation leading to abnormal, excessive bleeding.[2,3]
Easy bruising Skin bruising commonly found in von Willebrand disease.[2,3]
Epistaxis Deficiency or dysfunction of vWF will lead to impairment in platelet adhesion in response to vascular injury which will give rise to spontaneous nose bleeds which is common in von Willebrand Disease..[2,1]
Oral cavity bleeding Common site of bleeding in von Willebrand Disease.[1,2]
Menorrhagia Found in menstruating females with von Willebrand Disease. Mainly due to disruption of the normal platelet response. [1,2,3]
History of abnormal, excessive bleeding during dental extraction, minor surgery or trauma and post partum hemorrhage. Deep bleeds are due to defective intrinsic coagulation owing to low plasma levels of factor VIII in the absence of von Willebrand factor and mucosal bleeds are due to defective platelet response.[2]
Family history of bleeding disorder Most commonly found (80%) von Willebrand Disease type 1 has an autosomal dominant type transmission across generations. [4,2]
History of lymphoproliferative disorders, monoclonal gammopathies, autoimmune diseases like SLE Acquired von Willebrand disease can be found in these conditiions due to formation of antibodies against vWF and removal of vWF from circulation by aberrant binding to tumor cells.[1,2]
History of cardiac defects such as ventricular septal defect, aortic stenosis There is shear-induced conformational changes in the vWF leading to increased proteolysis of VWF which results low plasma levels.[1,2]
History of hypothyroidism There is a reduction in synthesis of vWF leading to low plasma levels.[1,2]
References
  1. BARBARA P. YAWN. William L. Nichols. Margaret E. Rick. Diagnosis and Management of Von Willebrand Disease: Guidelines for Primary Care. American Family Physician [online]. December 2009, vol.1;80(11):1261-1268. [viewed 10.04.2014] Available from: http://www.aafp.org/afp/2009/1201/p1261.html
  2. BRIAN CROWNOVER. Leslie Sleuwen. Beth Ketterman. Diagnosing Von Willebrand Disease. American Family Physician [online]. June 2010, vol 15;81(12):1415-1418. [viewed 10.04.2014] Available from: http://www.aafp.org/afp/2010/0615/p1415.html
  3. MICHAEL BALLAS. Eric H. Kraut. Bleeding and Bruising: A Diagnostic Work-up. American Family Physician. April 2008, vol 15;77(8):1117-1124. [viewed 10.04.2014] Available from: http://www.aafp.org/afp/2008/0415/p1117.html
  4. MASSIMO FRANCHINI, Giuseppe Lippi. The management of patients with congenital von Willebrand disease during surgery or other invasive procedures: focus on antihemophilic factor/von Willebrand factor complex. Biologics [online]. September 2007, vol 1(3): 285–289. [viewed 13.04.2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2721309/

Examination

Fact Explanation
Conjunctival pallor Due to anemia.[1]
Petechiae and ecchymosis As a result of bleeding under the skin due to minor blood vessel injury.[1,2]
Palpable swellings over muscles and joint swellings Due to muscle hematoma and hemearthrosis which are found in more severe cases.[1,2]
References
  1. BARBARA P. YAWN. William L. Nichols. Margaret E. Rick. Diagnosis and Management of Von Willebrand Disease: Guidelines for Primary Care. American Family Physician [online]. December 2009, vol 1;80(11):1261-1268. [viewed 10.04.2014] Available from: http://www.aafp.org/afp/2009/1201/p1261.html
  2. MICHAEL BALLAS. Eric H. Kraut. Bleeding and Bruising: A Diagnostic Work-up. American Family Physician [online]. April 2008, vol 15;77(8):1117-1124. [viewed 10.04.2014] Available from: http://www.aafp.org/afp/2008/0415/p1117.html

Differential Diagnoses

Fact Explanation
Idiopathic thrombocytopenic purpura (ITP) Characterised by thromnocytopenia due to immune mediated platelet destruction.[2,1]
Thrombotic thrombocytopenic purpura (TTP) In TTP there is deficient regulation of vWF (ADAMTS13 metalloprotease) leading to vWF-platelet aggregation and microvascular thrombus formation affecting the arterioles and capillaries of multiple organs. There is no deficiency or dysfunction of vWF itself like in von Willebrand disease.[3,1]
Platelet glycoprotein disorders (Bernard-Soulier syndrome, Glanzmann thrombasthenia) Surface membrane glycoproteins in platelets also important in platelet response and defect in these glycoproteins also will lead to impaired platelet response and coagulation. These are rarely found disorders and need special investigations to diagnose these conditions. [4]
Hemophilia type A, B or other clotting factor deficiencies Unlike in vWD where patients commonly present with mucosal bleeding unless very severe disease, clotting factor deficinet patients typically present with deep bleeds such as joint or soft-tissue bleeding. Also in hemophilia positive family history of bleeding in men can be found. [1]
Viral (Dengue) infections Consider in patients with acute onset high fever, headache, arthralgia, mayalgia other than bleeding manifestations.[8]
Disseminated intravascular coagulation Found in severly ill patients. Typically bleeding from multiple sites can be seen. Consumptive coagulopathy is the cause for bleeding. So organ dysfunction due to thrombi formation also present.[6]
Purpura simplex Extremely common. Bruising occurs due to increased vascular fragility. Commonly found in women on the upper thighs, buttocks and arms without known trauma. There will be a positive family history. All the investigations will result as normal.[1,5]
Abuse (including child abuse) Consider when there is multiple bruises with different stages of healing, bruises that pattern after objects, bruises in children who are not yet mobile, retinal hemorrhages, history that is inconsistent with the patient's injuries, associated bites, burns and fractures.[7]
Senile purpura Senile purpura is a common, benign condition characterised by recurrent formation of purple ecchymoses (bruises) on the extensor surfaces of forearms following minor trauma.[1]
References
  1. MICHAEL BALLAS. Eric H. Kraut. Bleeding and Bruising: A Diagnostic Work-up. American Family Physician [online]. April 2008, vol 15;77(8):1117-1124. [viewed 10.04.2014] Available from: http://www.aafp.org/afp/2008/0415/p1117.html
  2. AHN YS. Horstman LL. Idiopathic thrombocytopenic purpura: pathophysiology and management. Int Journal of Hematology [online]. August 2002, vol 76 Suppl 2:123-31. [viewed 12.04.2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/12430912
  3. TSAI HM. Pathophysiology of thrombotic thrombocytopenic purpura. Int J Hematol [online]. January 2010, vol 91(1):1-19. [viewed 12.04.2014] Available from: doi: 10.1007/s12185-009-0476-1.
  4. DIZ-KUCUKKAYA R. Lopez JA. Inherited disorders of platelets: membrane glycoprotein disorders. Hematol Oncol Clin North Am[online]. June 2013, vol 27(3):613-27. [viewed 12.04.2014] Available from: doi: 10.1016/j.hoc.2013.03.005.
  5. AMITA V MODI. Spontaneous Bruising in a Family Practice Population How common and how benign is it?.Can Fam Physician [online]. August 1992, vol 38: 1805–1808. [viewed 13.04.2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2145765/
  6. LEVI M, Toh CH, Thachil J, Watson HG. Guidelines for the diagnosis and management of disseminated intravascular coagulation. British Committee for Standards in Haematology. British Journal of Haematology [online]. April 2009, vol 145(1):24-33. [viewed 13.04.2014] Available from: doi: 10.1111/j.1365-2141.2009.07600.x. Epub 2009 Feb 12.
  7. KELLY COLLEEN MCDONALD. Child Abuse: Approach and Management. American Family Physician [online]. January 2007, vol 15;75(2):221-228. [viewed 12.04.2014] Available from: http://www.aafp.org/afp/2007/0115/p221.html
  8. Dengue hemorrhagic fever. A.D.A.M. Medical Encyclopedia [online]. [viewed 13.04.2014] Available from: http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002349/

Investigations - for Diagnosis

Fact Explanation
Ristocetin co-factor activity - vWF:RCoF Von Willebrand Factor (vWF) interacts with the antibiotic ristocetin and platelet glycoprotein Ib and mediates platelet adhesion. In von Willebrand disease this test result will be low.[1,5]
Collagen binding activity - vWF:CBA vWF binds to type I or type III collagen and facilitate platelet adhesion to the subendothelial matrix at the site of vascular injury. In von Willebrand disease this test result will be low.[1,5]
von willebrand factor antigen levels (vWF:Ag) Definetive diagnosis can be made if the antigen levels are less than 30 IU/dL. Antigen levels can fluctuate daily, therefore recommends testing patients on two separate occasions. Conditions such as strenuous exercises which can falsely elevate antigen levels should be avoided before the test.[1]
Factor VIII assay vWF prevents the early metabolism of factor VIII and therefore in von Willebrand disease low factor VIII levels can be found. However, a normal factor VIII level does not rule out VWD.[3]
Bleeding time Can be increased or normal in some patients.[1]
Platelet count To rule out thrombocytopenia.[1]
Prothrombin time To exclude other bleeding disorders due to clotting factor defects.[1]
PTT (partial thromboplastin time) This test will be abnormal only if there is significant reduction in factor VIII level secondary to vWF deficiency, so test will be prolonged in von Willebrand disease type 3 and will be normal in mild disease such as type 1 and some subtypes of type 2.[2]
Platelet Function Analyzer-100 A system for analysing platelet function using platelet agonists (ADP and Epinephrin). Closure times correlate inversely with plasma VWF activity levels, so CT-collagen ADP and EPI results will be high in von willebrand disease. Note: The use of bleeding time to assess platelet function is discouraged; the Platelet Function Analyzer-100 is preferred.[4]
References
  1. BRIAN CROWNOVER. Leslie Sleuwen. Beth Ketterman. Diagnosing Von Willebrand Disease. Am Fam Physician [online]. 2010 Jun 15;81(12):1415-1418. [viewed 10.04.2014] Available from: http://www.aafp.org/afp/2010/0615/p1415.html
  2. The diagnosis, evaluation and management of von Willebrand disease. National Heart, Lung, and Blood Institute [online]. December 2007. [viewed 11.04.2014] Available from: http://www.nhlbi.nih.gov/guidelines/vwd/3_diagnosisandevaluation.htm
  3. BARBARA P. YAWN. William L. Nichols. Margaret E. Rick. Diagnosis and Management of Von Willebrand Disease: Guidelines for Primary Care. Am Fam Physician [online]. 2009 Dec 1;80(11):1261-1268. [viewed 10.04.2014] Available from: http://www.aafp.org/afp/2009/1201/p1261.html
  4. A Practical Guide to Laboratory Haemostasis. Practical-Haemostasis.com [online]. [viewed 10.04.2014] Available from: http://www.practical-haemostasis.com/Platelet/platelet_function_testing_pfa100.html
  5. MANNUCCI PM. How I treat patients with von Willebrand disease. Blood [online]. 2001;97(7):1915–1919. [viewed 11.04.2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/11264151

Investigations - Fitness for Management

Fact Explanation
Hemoglobin level To detect the degree of anemia.
References

Investigations - Followup

Fact Explanation
Serum electrolytes - Na+ Desmopressin is generally administered for short periods in von Willebrand disease type 1 and some of type 2. However, if a longer duration or shorter intervals are required, the patient should be monitored for fluid and electrolyte problems because desmopressin may lead to symptomatic hyponatremia.
References
  1. BARBARA P. YAWN. WILLIAM L. NICHOLS. MARGARET E. RICK. Diagnosis and Management of Von Willebrand Disease: Guidelines for Primary Care. Am Fam Physician [online]. 2009 Dec 1;80(11):1261-1268. [viewed 10.04.2014] Available from: http://www.aafp.org/afp/2009/1201/p1261.html

Management - General Measures

Fact Explanation
Patient and family education Extremely important since it is a hereditary disease and patient will require family support. Must educate to avoid aspirin, other NSAIDs and other platelet inhibiting drugs[1,2]
Immunization - Hepatitis A, B Treatment include transfusion of blood products, so as a preventive measure to overcome the risk of transmission of blood borne infections patients should vaccinated against them.[2]
Restriction of fluids to maintenance levels Should be considered in patients receiving Desmopressin (especially for young children and in surgical settings) to avoid the occurrence of hyponatremia and seizures.[2]
References
  1. MANNUCCI PM. How I treat patients with von Willebrand disease. Blood [online]. 2001;97(7):1915–1919. [viewed 11.04.2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/11264151
  2. Clinical guidelines. The Diagnosis, Evaluation and Management of von Willebrand Disease Management of VWD. National Heart, Lung and Blood Institute [online]. [viewed 11.04.2014] Available from: http://www.nhlbi.nih.gov/guidelines/vwd/4_managementofvwd.htm

Management - Specific Treatments

Fact Explanation
Desmopressin (DDAVP) Used to stop spontaneous bleeding and to prevent bleeding at the time of surgical procedures. Patients with low vWF antigen levels (type 1) may benefit from desmopressin (DDAVP), which increases endothelial release of vWF antigen. [1,2]
Factor replacement therapy - Alphanate (a high-purity concentrate containing factor VIII) and Humate-P Can use if treatment with desmopressin is unsuccessful. Treatment duration varies by procedure.[1] Note: Cryoprecipitate is no longer recommended for VWF or factor VIII replacement.[2]
Oral antifibrinolytic agents (epsilon-aminocaproic acid (Amicar) and tranexamic acid) Antifibrinolytic agents prevent the clot lysis [3] They are very useful for mucous membrane bleeding. [2]
Topical agents, such as bovine or human thrombin and fibrin sealants Use for accessible minor bleeding.[2]
Combined oral contraceptives and the levonorgestrel-releasing intrauterine device (Mirena) Use as the treatment for menorrhagia due to Von Willebrand Disease. They prevent bleeding by acting on endometrium where there is no relation with regards to vWF levels. Note: patient should be informed about the contraceptive benefit and should not be used in females who are trying to become pregnant.[2,3]
Platelet concentrates Used to prevent heavy bleeding.[3]
Referrel to a genetic counselor and to a pediatric hematologist Before or during pregnancy, women with VWD should be referred to a genetic counselor to discuss the inheritance of the disease and also to a pediatric hematologist for evaluation of the infant after delivery.[2]
References
  1. BRIAN CROWNOVER, Leslie Sleuwen, Beth Ketterman. Diagnosing Von Willebrand Disease. Am Fam Physician [online]. 2010 Jun 15;81(12):1415-1418. [viewed 10.04.2014] Available from: http://www.aafp.org/afp/2010/0615/p1415.html
  2. BARBARA P. YAWN. William L. Nichols. Margaret E. Rick. Diagnosis and Management of Von Willebrand Disease: Guidelines for Primary Care. Am Fam Physician [online]. 2009 Dec 1;80(11):1261-1268. [viewed 10.04.2014] Available from: http://www.aafp.org/afp/2009/1201/p1261.html
  3. MANNUCCI PM. How I treat patients with von Willebrand disease. Blood [online]. 2001;97(7):1915–1919. [viewed 10.04.2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/11264151 http://bloodjournal.hematologylibrary.org/content/97/7/1915/T4.expansion.html