A 12-year-old female presented with history of heavy menstrual bleeding since menarche. Her past history revealed prolonged bleeding after losing a tooth, a large hematoma on leg secondary to trauma and easy bruising. Physical examination revealed multiple ecchymoses on the dorsum of upper and lower extremities.

Family History included severe nose bleeds, prolonged bleeding from tooth extraction and heavy menstrual bleeding in the patient’s mother leading to anemia, requiring iron therapy and red cell transfusions. Similar history of recurrent nose bleeds and easy bruising was found in the patient’s brother and several maternal relatives. Laboratory evaluation showed normal hemoglobin, normal platelet count and low ferritin of 5 ng/ml.

Following coagulation studies and molecular analysis confirmed the diagnosis of Von Willebrand Disease (VWD).

Coagulation Studies

• Prolonged activated partial thromboplastin time (aPTT) of 39.9 sec (reference value 25-34 sec), normal prothrombin time (PT), and fibrinogen levels.
• Von Willebrand (VW) panel results were consistent with von Willebrand disease (VWD):    

1. VW Factor ristocetin cofactor activity (VWF: RCo): <7 IU/dL (normal range 48-142 IU/dL).
2. VWF antigen: 22 IU/dL (normal range 56-176 IU/dL).                   
3. Factor 8 (FVIII) assay: 26 IU/dL (normal range 47-169 IU/dL).                   
4. VWF activity/antigen ratio: 0.3 (normal range 0.7-1.2).

• VW multimer analysis showed accentuated staining of the lower molecular weight bands, with decreased staining of the high molecular weight (HMW) forms.

Molecular Studies

Von Willebrand exon 28 analysis showed a mutation: Heterozygous 4121G>A which causes replacement of Arginine 1374 by Histidine [R1374H]. This mutation is listed in the VWF database with the majority of reports suggesting that it is associated with type 2A VWD.

Learning Points

• VWD is an inherited bleeding disorder, predominantly transmitted in an autosomal dominant manner and is caused by deficiency or abnormality of VWF. VWF is a key protein involved in blood clotting which is required for platelet adhesion to sub-endothelium and functions as a carrier of FVIII.
• There are 3 types of VWD. Type 1 and 3 VWD are quantitative disorders with partial or complete deficiency of VWF respectively, and type 2 VWD is qualitative disorder with sub-types namely type 2A, 2B, 2M and 2N.

1. Type 2A VWD is characterized by the loss of intermediate and HMW multimers.
2. In type 2B VWD, the abnormal VWF has a heightened ristocetin induced platelet agglutination (RIPA), resulting in mild to moderate thrombocytopenia and the absence of HMW multimers.
3. In type 2M VWD, VWF multimer distribution is normal, but platelet dependent VWF activity is reduced.
4. In Type 2N VWD, disproportionally lower FVIII plasma levels (5–40 U/dL) compared to VWF are caused by VWF mutations impairing the binding to FVIII.

• VWD predominantly presents with mucosal bleeding, heavy menstrual and post-partum bleeding, easy bruising, and post-surgical and post-traumatic bleeding. Large hematoma and joint bleeding may be rarely seen in the severe forms especially Type 3 VWD.
• Diagnosis of VWD is based on personal and/or family history of bleeding phenotype consistent with VWD, and an abnormal VW panel. VW multimer analysis and additional molecular studies aid to confirm diagnosis of the severe type 2 and 3 VWD.
• Von Willebrand disease can also present with low levels of factor VIII, but unlike hemophilia, which mainly affects males, von Willebrand disease affects both males and females. Additionally, in hemophilia, VWF levels are normal.