EDUCATIONAL COMMENTARY - api-pt.com

1 EDUCATIONAL COMMENTARY BLEEDING DISORDERS: HEMOPHILIA AND VON WILLEBRAND DISEASE EDUCATIONAL COMMENTARY is provided through our affiliation with the American Society for Clinical Pathology (ASCP). To obtain FREE CME/CMLE credits, click on Earn CE Credits under Continuing Education on the left side of the screen. Learning Outcomes On completion of this exercise, the participant should be able to identify laboratory tests used to diagnose bleeding disorders; discuss the pathogenicity of hemophilia and von Willebrand disease (VWD); analyze coagulation results to distinguish VWD from hemophilia; and describe currently available treatments.

2 Introduction Diagnosing a bleeding disorder requires a multidisciplinary approach. Several tools are utilized before laboratory testing. The first assessment is a complete family history, which includes age when bleeding started, medications, information on additional family members with bleeding symptoms, and location and type of All of this information will help determine if the disorder is acquired or congenital. There are also several standardized bleeding scoring systems that assign a numeric value to symptoms to distinguish the presence or absence of a disorder.

3 The higher the number, the more likely the patient has a bleeding disorder. Physical examination may provide limited information for diagnosing a bleeding disorder, because the presence of bruising or bleeding may be limited at the time of Diagnostic Testing The first line of laboratory testing in a patient with a suspected bleeding disorder of secondary hemostasis should be prothrombin time (PT) and activated partial thromboplastin time (aPTT). These global screening assays provide information on possible coagulation factor deficiencies. A prolongation of only the PT will point to a factor VII (FVII) deficiency, whereas a prolongation of the aPTT indicates that factors VIII, IX, and XI should be investigated further.

4 If both the PT and the aPTT are prolonged, common pathway factors II, V, X, or fibrinogen may be the The aPTT will also be prolonged in a FXII deficiency and in the presence of a lupus anticoagulant; however, these patients do not bleed. When the PT and/or aPTT is prolonged, further investigation will aid in determining the abnormality. To eliminate a prolonged aPTT due to heparin or direct thrombin inhibitors, a thrombin time (TT) should be obtained. If the TT is prolonged, a reptilase test may be performed to distinguish anticoagulation from a fibrinogen deficiency.

5 If the reptilase time is normal, the sample is contaminated with anticoagulant, and no further testing should be performed. If the TT is normal, a mixing study should be the next line of testing to help determine if the prolongation is due to a factor deficiency or the presence of an inhibitor. A American Proficiency Institute 2018 1st Test Event 1 EDUCATIONAL COMMENTARY BLEEDING DISORDERS: HEMOPHILIA AND VON WILLEBRAND DISEASE (cont.) mixing study mixes equal parts of the patient s plasma with pooled normal plasma (PNP). It is important to ensure that the PNP used contains normal levels of all factors.

6 If the patient is deficient in a factor, the PNP will replace the missing factor and the PT or aPTT will normalize. This indicates a factor deficiency. If coagulation times are still prolonged after the mix, it means that something in the patient s plasma is inhibiting the PNP and therefore it is unable to Several criteria are used to determine if a mixing study has corrected. Laboratories may compare results to the PNP and allow results to be within several seconds of the PNP to determine a correction, or they may consider a correction if the mixing study result falls back into the normal range.

7 There are no published guidelines or standards for laboratories to Upon correction of a mixing study, specific factor assays are performed. In the 1-stage factor assay, the patient plasma sample is diluted in buffer and added to factor-deficient plasma along with a PT and/or an aPTT reagent, which contains activators ( , ellagic acid, micronized silica) and phospholipids. The time to clot is measured in seconds and compared with a calibration curve constructed from a standard that contains a known concentration of the factor being Factor VIII and von Willebrand Factor Factor VIII is a macromolecule that is not an enzyme but a cofactor for cleavage of FX to FXa by FIXa.

8 It consists of two non-covalently linked proteins, FVIII and von Willebrand factor (VWF). Factor VIII is unstable and circulates bound to the carrier protein VWF. Von Willebrand factor is a large multimeric adhesive glycoprotein that facilitates the adhesion of platelets to injured vessels and the transport of As a result of the relationship of FVII and VWF, a patient who presents with a prolonged aPTT, a corrected mixing study, and a decreased level of FVIII may have hemophilia or VWD, both of which are congenital bleeding disorders. Hemophilia The incidence of excessive bleeding was first recorded in Jewish writings in approximately the 2nd century (CE).

9 If a family had two baby boys who died as a result of circumcision, no other boy of that family would have to undergo the This genetic disorder affects more than 400,000 people worldwide, mostly males, with hemophilia A accounting for up to 85% of cases (Table 1).7-9 Production of FVIII and FIX procoagulant proteins is governed by genes found on the X chromosome. Women present as mostly carriers of the X-linked disorder, although rarely hemophilia presents in a woman. Hemophilia A is characterized by decreased factor FVIII activity, whereas hemophilia B presents with a decreased American Proficiency Institute 2018 1st Test Event 2 EDUCATIONAL COMMENTARY BLEEDING DISORDERS: HEMOPHILIA AND VON WILLEBRAND DISEASE (cont.)

10 Level of FIX. Hemophilia has been traced through three generations the royal families of England, Germany, Spain, and eventually to Tsar Nicolas II s son Alexei, who was known to have the Recently, DNA analysis confirmed this to be hemophilia B (FIX deficiency). Table 1. Prevalence of congenital bleeding disorders9 Prolonged PT Normal APTT Prolonged aPTT Normal PT Prolonged PT Prolonged aPTT Deficiency of FVII (1:500,000) FVIII (1:5000 10,000) males FI FIX (1:100,000) FII (rarest deficiency) FXI (1:100,000) FV (1:1,000,000) FXII (1:1,000,000) FX (1:500,000) Clinically, patients with hemophilia present with joint bleeds, deep muscle bleeds, and hematomas.