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<unk>  typically display a normal prothrombin time and a variable prolongation of partial thromboplastin time. When<unk>  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<unk> , 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: 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<unk>  include<unk><unk>  multimer analysis, modified ristocetin induced platelet aggregation assay and VWF propeptide to VWF propeptide antigen ratio . In cases of suspected acquired<unk><unk>  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<unk>  is complicated by VWF being an acute-phase reactant with levels rising in infection, pregnancy, and stress. The testing for<unk>  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<unk>  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<unk>  types in South Africa. Platelet-type was <0.5% of cases. The four hereditary types of<unk>  described are type 1, type 2, type 3, and pseudo- or platelet-type. Most cases are hereditary, but acquired forms of<unk>  have been described. The International Society on Thrombosis and Haemostasis's classification depends on the definition of qualitative and quantitative defects.<unk>  type III (and sometimes II) is inherited in an autosomal recessive pattern. Type 1 Type 1<unk>  (40-80% of all<unk>  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<unk>  occurs incidentally to other medical procedures requiring a blood work-up. Most cases of type 1<unk>  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<unk>  (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<unk><unk>  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.<unk><unk>  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<unk>  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<unk>  type 2N patients being misdiagnosed as having hemophilia A. Type 3 Type 3 is the most severe form of<unk>  (homozygous for the defective gene) and is characterized by complete absence of production of VWF. The<unk><unk>  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<unk>  type 3 is autosomal recessive, while the inheritance pattern of hemophilia A is X-linked recessive. Comparison +Comparison Autosomal inheritance vWF activity RIPA Multimer quantity Type 1 Dominant Decreased Normal or decreased Similar decrease among multimer types Type 2 A Dominant or recessive Decreased Often decreased at high ristocetin concentrations Decreased large multimers B Dominant Decreased Increased Decreased large multimers M Dominant or recessive Decreased Decreased at high ristocetin concentrations Similar decrease among multimer types N Recessive Normal Normal Normal Type 3 Recessive Absent or markedly decreased Absent or markedly decreased Usually undetectable Platelet-type Platelet-type<unk>  (also known as pseudo-VWD) is an autosomal dominant genetic defect of the platelets. The VWF is qualitatively normal and genetic testing of the<unk><unk>  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<unk>  type 2B. Acquired Acquired<unk>  can occur in patients with autoantibodies. In this case, the function of VWF is not inhibited, but the VWF-antibody complex is rapidly cleared from the circulation. A form of<unk>  occurs in patients with aortic valve stenosis, leading to gastrointestinal bleeding (Heyde's syndrome). This form of acquired<unk>  may be more prevalent than is presently thought. In 2003, Vincentelli et al. noted that patients with acquired<unk>  and aortic stenosis who underwent valve replacement experienced a correction of their hemostatic abnormalities, but that the hemostatic abnormalities can recur after 6 months when the prosthetic valve is a poor match with the patient. Similarly, acquired<unk>  contributes to the bleeding tendency in people with an implant of a left ventricular assist device (a pump that pumps blood from the left
Von Willebrand disease
Quebec platelet disorder
Harris platelet syndrome
Acquired haemophilia
Bernard–Soulier syndrome
Haemophilia
Gray platelet syndrome
Congenital afibrinogenemia