von willebrand disease von willebrand disease von willebrand disease (vwd) is the most common hereditary blood-clotting disorder in humans. an acquired form can sometimes result from other medical conditions. it arises from a deficiency in the quality or quantity of von willebrand factor (vwf), a multimeric protein that is required for platelet adhesion. it is known to affect several breeds of dogs as well as humans. the three forms of vwd are hereditary, acquired, and pseudo or platelet type. the three types of hereditary vwd are vwd type 1, vwd type 2, and vwd type 3. type 2 contains various subtypes. platelet type vwd is also an inherited condition. von willebrand diseasevon willebrand disease types i and ii are inherited in an autosomal dominant pattern.pronunciation/ˌfʌnˈvɪlɪbrɑːnt/ specialtyhematology in 2008 a new diagnostic category of "low vwf" was proposed to include those individuals whose von willebrand factor levels were below the normal reference range but not low enough to be von willebrand disease (levels in the 30-50 iu/dl range). patients with low vwf can experience bleeding, despite mild reductions in vwf levels. vwd type 1 is the most common type of the disorder, with mild bleeding symptoms such as nosebleeds, though occasionally more severe symptoms can occur. blood type can affect the presentation and severity of symptoms of vwd. vwd type 2 is the second most common type of the disorder and has mild to moderate symptoms. the factor is named after the finnish physician erik adolf von willebrand who first described the condition in 1926. guidelines for the diagnosis and management of vwd were updated in 2021. signs and symptoms the various types of vwd present with varying degrees of bleeding tendency, usually in the form of easy bruising, nosebleeds, and bleeding gums. women may experience heavy menstrual periods and blood loss during childbirth. severe internal bleeding and bleeding into joints are uncommon in all but the most severe type, vwd type 3. genetics the vwf gene is located on the short arm p of chromosome 12 (12p13.2). it has 52 exons spanning 178kbp. types 1 and 2 are inherited as autosomal dominant traits. occasionally, type 2 also inherits recessively. type 3 is inherited as autosomal recessive. however, some individuals heterozygous for type 3 may be diagnosed with vwd type 1, indicating an intermediate inheritance in that cases. vwd occurs in approximately 1% of the population and affects men and women equally. genetic testing is typically not part of the initial workup for von willebrand disease, and is not needed for people diagnosed with type 1 vwd based on clinical history and laboratory tests. it is mainly useful for: evaluating family members of individuals who have known variants. differentiating between type 2b and platelet-type vwd, as well as between type 2n vwd and hemophilia a. pathophysiology for the normal function of the coagulation factor, see von willebrand factor. von willebrand factor is mainly active in conditions of high blood flow and shear stress. deficiency of vwf, therefore, shows primarily in organs with extensive small vessels, such as skin, gastrointestinal tract, and uterus. in angiodysplasia, a form of telangiectasia of the colon, shear stress is much higher than in average capillaries, and the risk of bleeding is increased concomitantly. in more severe cases of type 1 vwd, genetic changes are common within the vwf gene and are highly penetrant. in milder cases of type 1 vwd, a complex spectrum of molecular pathology may exist in addition to polymorphisms of the vwf gene alone. the individual's abo blood group can influence presentation and pathology of vwd. those individuals with blood group o have a lower mean level than individuals with other blood groups. unless abo group-specific vwf:antigen reference ranges are used, normal group o individuals can be diagnosed as type i vwd, and some individuals of blood group ab with a genetic defect of vwf may have the diagnosis overlooked because vwf levels are elevated due to blood group. diagnosis basic tests performed in any patient with bleeding problems are a complete blood count-cbc (especially platelet counts), activated partial thromboplastin time-aptt, prothrombin time with international normalized ratio-ptinr, thrombin time-tt, and fibrinogen level. patients with abnormal tests typically undergo further testing for hemophilias. other coagulation factor assays may be performed depending on the results of a coagulation screen. patients with von willebrand disease typically display a normal prothrombin time and a variable prolongation of partial thromboplastin time. when vwd is suspected, blood plasma of a patient must be investigated for quantitative and qualitative deficiencies of vwf. this is achieved by measuring the amount of vwf in a vwf antigen assay and the functionality of vwf with a glycoprotein (gp)ib binding assay, a collagen binding assay, or a ristocetin cofactor activity (ricof) or ristocetin-induced platelet agglutination (ripa) assays. factor viii levels are also performed because factor viii is bound to vwf which protects the factor viii from rapid breakdown within the blood. deficiency of vwf can then lead to a reduction in factor viii levels, which explains the elevation in ptt. normal levels do not exclude all forms of vwd, particularly type 2, which may only be revealed by investigating platelet interaction with subendothelium under flow, a highly specialized coagulation study not routinely performed in most medical laboratories. a platelet aggregation assay will show an abnormal response to ristocetin with normal responses to the other agonists used: platelet aggregation function by main disorders and agonists further information: platelet § tests of function adpepinephrinecollagenristocetin p2y receptor inhibitor or defect decreasednormalnormalnormal adrenergic receptor defect normaldecreasednormalnormal collagen receptor defect normalnormaldecreased or absentnormal von willebrand disease bernard–soulier syndrome normalnormalnormaldecreased or absent glanzmann's thrombasthenia decreaseddecreaseddecreasednormal or decreased a platelet function assay may give an abnormal collagen/epinephrine closure time, and in most cases, a normal collagen/adp time. type 2n may be considered if factor viii levels are disproportionately low, but confirmation requires a "factor viii binding" assay. additional laboratory tests that help classify sub-types of vwd include von willebrand multimer analysis, modified ristocetin induced platelet aggregation assay and vwf propeptide to vwf propeptide antigen ratio. in cases of suspected acquired von willebrand syndrome, a mixing study (analysis of patient plasma along with pooled normal plasma/pnp and a mixture of the two tested immediately, at one hour, and at two hours) should be performed. detection of vwd is complicated by vwf being an acute-phase reactant with levels rising in infection, pregnancy, and stress. the testing for vwd can be influenced by laboratory procedures. numerous variables exist in the testing procedure that may affect the validity of the test results and may result in a missed or erroneous diagnosis. the chance of procedural errors are typically greatest during the preanalytical phase (during collecting storage and transportation of the specimen) especially when the testing is contracted to an outside facility and the specimen is frozen and transported long distances. diagnostic errors are not uncommon, and the rate of testing proficiency varies amongst laboratories, with error rates ranging from 7 to 22% in some studies to as high as 60% in cases of misclassification of vwd subtype. to increase the probability of a proper diagnosis, testing should be done at a facility with immediate on-site processing in a specialized coagulation laboratory. types pie chart of relative incidences of von willebrand disease types in south africa. platelet-type was <0.5% of cases. the four hereditary types of vwd described are type 1, type 2, type 3, and pseudo- or platelet-type. most cases are hereditary, but acquired forms of vwd have been described. the international society on thrombosis and haemostasis's classification depends on the definition of qualitative and quantitative defects. von willebrand disease type iii (and sometimes ii) is inherited in an autosomal recessive pattern. type 1 type 1 vwd (40-80% of all vwd cases) is a quantitative defect which is heterozygous for the defective gene. it can arise from failure to secrete vwf into the circulation or from vwf being cleared more quickly than normal. decreased levels of vwf are detected at 20-50% of normal, i.e. 20-50 iu. many patients are asymptomatic or may have mild symptoms and not have clearly impaired clotting, which might suggest a bleeding disorder. often, the discovery of vwd occurs incidentally to other medical procedures requiring a blood work-up. most cases of type 1 vwd are never diagnosed due to the asymptomatic or mild presentation of type i and most people usually end up leading a normal life free of complications, with many being unaware that they have the disorder. trouble may, however, arise in some patients in the form of bleeding following surgery (including dental procedures), noticeable easy bruising, or menorrhagia (heavy menstrual periods). the minority of cases of type 1 may present with severe hemorrhagic symptoms. type 2 type 2 vwd (15-50% of cases) is a qualitative defect and the bleeding tendency can vary between individuals. four subtypes exist: 2a, 2b, 2m, and 2n. these subtypes depend on the presence and behavior of the underlying multimers. type 2a the ability of the qualitatively defective von willebrand factors to coalesce and form large vwf multimers is impaired, resulting in decreased quantity of large vwf multimers and low rcof activity. only small multimer units are detected in the circulation. von willebrand factor antigen (vwf:ag) assay is low or normal. type 2b this is a "gain of function" defect. the ability of the qualitatively defective vwf to bind to glycoprotein ib (gpib) receptor on the platelet membrane is abnormally enhanced, leading to its spontaneous binding to platelets and subsequent rapid clearance of the bound platelets and of the large vwf multimers. thrombocytopenia may occur. large vwf multimers are reduced or absent from the circulation. the ristocetin cofactor activity is low when the patient's platelet-poor plasma is assayed against formalin-fixed, normal donor platelets. however, when the assay is performed with the patient's own platelets (platelet-rich plasma), a lower-than-normal amount of ristocetin causes aggregation to occur. this is due to the large vwf multimers remaining bound to the patient's platelets. patients with this subtype are unable to use desmopressin as a treatment for bleeding, because it can lead to unwanted platelet aggregation and aggravation of thrombocytopenia. type 2m type 2m vwd is a qualitative defect of vwf characterized by its decreased ability to bind to gpib receptor on the platelet membrane and normal capability at multimerization. the vwf antigen levels are normal. the ristocetin cofactor activity is decreased and high molecular weight large vwf multimers are present in the circulation. type 2n (normandy) this is a deficiency of the binding of vwf to coagulation factor viii. the vwf antigen test is normal, indicating normal quantity of vwf. the ristocetin cofactor assay is normal. assay for coagulation factor viii will show marked quantitative decrease, equivalent to levels seen in hemophilia a. this has led to some vwd type 2n patients being misdiagnosed as having hemophilia a. type 3 type 3 is the most severe form of vwd (homozygous for the defective gene) and is characterized by complete absence of production of vwf. the von willebrand factor is undetectable in the vwf antigen assay. since the vwf protects coagulation factor viii from proteolytic degradation, total absence of vwf leads to extremely low factor viii level, equivalent to that seen in severe hemophilia a with its clinical manifestations of life-threatening external and internal hemorrhages. the inheritance pattern of vwd type 3 is autosomal recessive, while the inheritance pattern of hemophilia a is x-linked recessive. comparison comparison autosomal inheritancevwf activityripamultimer quantity type 1 dominantdecreasednormal or decreasedsimilar decrease among multimer types type 2 adominant or recessivedecreasedoften decreased at high ristocetin concentrationsdecreased large multimers bdominantdecreasedincreaseddecreased large multimers mdominant or recessivedecreaseddecreased at high ristocetin concentrationssimilar decrease among multimer types nrecessivenormalnormalnormal type 3 recessiveabsent or markedly decreasedabsent or markedly decreasedusually undetectable platelet-type platelet-type vwd (also known as pseudo-vwd) is an autosomal dominant genetic defect of the platelets. the vwf is qualitatively normal and genetic testing of the von willebrand gene and vwf protein reveals no mutational alteration. the defect lies in the qualitatively altered gpib receptor on the platelet membrane which increases its affinity to bind to the vwf. large platelet aggregates and high molecular weight vwf multimers are removed from the circulation resulting in thrombocytopenia and diminished or absent large vwf multimers. the ristocetin cofactor activity and loss of large vwf multimers are similar to vwd type 2b. acquired acquired