A 40-year-old woman with a history of generalized anxiety disorder presents for evaluation of episodic, mild bruising on her extremities without any inciting trauma. The bruises are always preceded by a prodrome of intense itching and swelling, which resolves after a day, at which point a minor ecchymosis appears and persists for seven to 10 days. She states that she first noticed these symptoms arising after the birth of her first child, and particularly after stressful situations. She takes aspirin for occasional migraines. There is no family history of bleeding or thrombotic disorders. The patient denies gingival bleeding, excessive menstrual bleeding, or bleeding complications with previous surgeries. Laboratory evaluation is as follows.
The correct answer is ...
Given the clinical presentation and the normal laboratory values, the most likely diagnosis is Gardner Diamond syndrome (GDS), also known as psychogenic purpura or autoerythrocyte sensitization syndrome. Gardner Diamond syndrome is a rare condition characterized by recurrent, superficial ecchymoses, which are often preceded by a short prodrome of warmth, pain, swelling, or itchiness in patients without a documented history of a bleeding disorder, often as a reaction to some inciting physical or emotional stressor. While the exact pathophysiology of GDS is still unknown, many patients with GDS also have concomitant psychiatric diagnoses such as depression or personality disorders. Laboratory evaluation in patients with Gardner Diamond syndrome is normal. GDS is a diagnosis of exclusion and requires a thorough hematologic and coagulation workup to rule out other bleeding disorders. Given that GDS is a dermal cutaneous disorder, there is no risk for systemic bleeding and prognosis is excellent.
Aspirin covalently attaches an acetyl group to a serine residue in the active site of the enzyme cyclooxygenase (COX), leading to irreversible COX-1 inhibition, and thereby inhibition of thromboxane A2 synthesis in platelets. This mechanism produces an inhibitory effect on platelet aggregation during the lifetime of the affected platelet (8-9 days). Laboratory values such as the PT and APTT are not affected. Aspirin-induced platelet inhibition can be reflected by a prolonged closure time on the collagen/epinephrine PFA-100 assay, as well as decreased aggregation with arachidonic acid on light transmission platelet aggregometry. Due to the patient having recently taken aspirin for her migraines, PFA-100 and platelet aggregometry testing were not initially performed, but should symptoms continue, they could be pursued at a later date when she has been off aspirin for several days.
Von Willebrand factor (VWF) is a protein that binds to platelets via the GpIb receptor to facilitate platelet adhesion; VWF also protects factor VIII from degradation by proteins C and S in the circulation. Von Willebrand disease (VWD) arises from a deficiency or dysfunction of VWF. It is the most common bleeding disorder in humans. VWD is usually inherited in an autosomal dominant fashion, except in types 2N and 3 VWD, which are autosomal recessive. VWD type 1 is the most common subtype of this disorder and it often presents with mild bleeding symptoms such as easy bruising, epistaxis, gingival bleeding, and heavy menstrual bleeding. Some patients may experience excessive bleeding following hemostatic challenges such as surgery and childbirth. Laboratory evaluation for VWD type 1 often shows a proportional decrease in VWF activity and antigen levels, normal or mildly decreased factor VIII activity, and normal molecular weight multimers with decreased staining intensity.
Acquired inhibitors against factor VIII are uncommon. They can occur postpartum or in association with lymphoproliferative diseases or autoimmune disorders. They may also occur without any associated condition. Acquired hemophilia classically presents with massive soft tissue bleeding and is associated with an increased morbidity and mortality. The most common screening laboratory abnormality seen is an isolated, prolonged APTT that does not correct on mixing study. PT, thrombin time, and platelet count will be normal. A normal factor VIII level and normal PTT rules out factor VIII inhibitor.
Kenneth Wee, D.O.
Resident, Anatomic and Clinical Pathology
William Nichols, M.D.
Consultant, Hematology and Hematopathology
Associate Professor of Laboratory Medicine and Pathology and Associate Professor of Medicine
Mayo Clinic College of Medicine and Science