A 17-year-old girl comes to the office for follow-up on anemia. She has taken iron supplements regularly since being diagnosed with iron deficiency anemia 3 months ago. However, the patient still feels fatigued and does not think that the supplements have improved her symptoms. She has occasional gingival bleeding when brushing her teeth. Menses occur every 27-28 days and last 7-8 days with heavy flow, sometimes requiring her to change pads every hour. Platelet count is normal. Further evaluation reveals that the patient's platelets do not agglutinate appropriately in response to ristocetin. When normal plasma is added to the solution of patient platelets and ristocetin, appropriate platelet agglutination occurs. Which of the following is most likely deficient in this patient?
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Von Willebrand factor (vWF) is an important hemostatic glycoprotein (GP) synthesized by endothelial cells and megakaryocytes. Following endothelial damage, vWF binds GP Ib receptors on the platelet membrane and mediates platelet adhesion to subendothelial collagen. Deficiency of vWF impairs platelet adhesion and can lead to easy bruising and prolonged mucocutaneous bleeding (eg, gingival bleeding, heavy menses).
Laboratory workup in vWF deficiency reveals a normal platelet count and an abnormal ristocetin cofactor assay. The ristocetin cofactor assay measures in-vitro, vWF-dependent platelet agglutination (indicative of impaired platelet adhesion in-vivo). Ristocetin activates GP Ib receptors on platelets and makes them available for vWF binding; when the vWF level is decreased, there is poor platelet agglutination in the presence of ristocetin. When normal plasma that contains vWF is added, appropriate platelet agglutination occurs.
VWF also serves as a carrier for factor VIII to prolong its half-life, and vWF deficiency can lead to functional deficiency of factor VIII that further contributes to bleeding complications. PTT may be normal or prolonged depending on the degree of factor VIII impairment.
Combined oral contraceptives are often used for treatment of menorrhagia due to vWF deficiency. Patients can also be treated with desmopressin, which stimulates vWF release from endothelium.
(Choice A) Bernard-Soulier syndrome (hereditary deficiency of GP Ib receptors) is characterized by thrombocytopenia, enlarged platelets, and mucocutaneous bleeding. Platelet agglutination to ristocetin will be abnormal and, because the deficiency is with GP Ib receptors and not vWF, the addition of normal plasma will not correct the agglutination.
(Choice B) Hereditary deficiency of GP IIb/IIIa receptors occurs in Glanzmann thrombasthenia, which manifests with mucocutaneous bleeding. Platelet agglutination in response to ristocetin is normal because the levels of vWF and GP Ib receptors are normal.
(Choice C) Congenital deficiency of factor XII (Hageman) causes marked PTT prolongation; however, it does not cause clinical bleeding complications. Instead, patients may have a tendency for thromboembolic complications for unclear reasons.
(Choice D) Thromboxane A2 deficiency is associated with aspirin treatment due to irreversible inactivation of cyclooxygenase in platelets. The major effect is on GP IIb/IIIa-mediated platelet aggregation rather than GP Ib-mediated platelet adhesion; therefore, platelet agglutination to ristocetin is normal.
Educational objective:
Following endothelial damage, von Willebrand factor (vWF) binds glycoprotein Ib receptors on platelets to mediate platelet adherence. The ristocetin cofactor assay measures platelet agglutination via binding of glycoprotein Ib receptors to vWF; it will be abnormal in vWF deficiency but will correct with the addition of normal (vWF-containing) plasma.