Autosomal Dominant Bleeding Disorders: Beyond HHT and Type 2 von Willebrand Disease
No, Hereditary Hemorrhagic Telangiectasia (HHT) and Type 2 von Willebrand Disease are not the only autosomal dominant bleeding disorders to consider in clinical practice. There are several autosomal dominant bleeding disorders that should be evaluated when assessing patients with suspected hereditary bleeding tendencies.
Hereditary Hemorrhagic Telangiectasia (HHT)
- HHT is an autosomal dominant rare bleeding disorder with an estimated prevalence of approximately 1 in 5000 persons worldwide 1
- Characterized by vascular malformations (VMs) that result in chronic bleeding, epistaxis, and complications from shunting through these malformations 2
- In 97% of patients with a definite clinical diagnosis of HHT, a causative mutation is identified in one of these genes: endoglin (ENG, HHT type 1), activin receptor-like kinase-1 (ACVRL1, HHT type 2), and SMAD4 (juvenile polyposis-HHT overlap) 2
- Most common symptom is epistaxis (nosebleeds), occurring in more than 90% of adults with the condition 2
- Diagnosis is based on the Curaçao criteria, which include family history of HHT, recurrent spontaneous epistaxis, mucocutaneous telangiectasia, and visceral lesions 2
Von Willebrand Disease (VWD)
- VWD is the most common inherited bleeding disorder, affecting up to 1% of the U.S. and world populations 2
- Type 2 VWD (qualitative deficiency) has four subtypes (2A, 2B, 2M, 2N) and is characterized by dysfunctional von Willebrand factor 2
- Type 2 VWD is inherited in an autosomal dominant pattern, except for Type 2N which is autosomal recessive 2
- Clinical manifestations include easy bruising, mucosal bleeding, gastrointestinal bleeding, and heavy menstrual bleeding in women 2
- Laboratory diagnosis includes initial hemostasis tests (CBC, PT, aPTT) followed by specific VWF testing 2
Other Autosomal Dominant Bleeding Disorders
- Type 1 von Willebrand Disease is also autosomal dominant and accounts for approximately 75% of all VWD cases, characterized by partial quantitative deficiency of VWF 2
- Factor XI deficiency can be inherited in an autosomal dominant pattern in some families 1
- Platelet function disorders such as Bernard-Soulier syndrome and some forms of Glanzmann thrombasthenia can be inherited in an autosomal dominant pattern 1
- Some forms of hereditary fibrinogen disorders (dysfibrinogenemia) follow autosomal dominant inheritance 1
- Factor VII deficiency can present with autosomal dominant inheritance in some cases 1
Clinical Considerations
- Recent research indicates that HHT may actually cause more significant morbidity in women than VWD, with higher odds of iron infusion dependence (17-fold), requirement for red cell transfusion (3-fold), and hemostatic surgical procedures (8-fold) 3
- Women with HHT experience more recurrent epistaxis and gastrointestinal bleeding compared to women with VWD (odds ratio 32.73 and 5.69 respectively) 3
- When evaluating patients with suspected autosomal dominant bleeding disorders, a comprehensive bleeding assessment should be performed, including questions about epistaxis, easy bruising, mucosal bleeding, and family history 2
- Genetic testing is increasingly important for accurate diagnosis and family screening in autosomal dominant bleeding disorders 2, 1
Management Approaches
- Management of HHT has evolved significantly with the introduction of antiangiogenic therapies to eliminate bleeding telangiectasias and achieve hemostasis 2
- Systemic therapies including antiangiogenics (bevacizumab) and antifibrinolytics (tranexamic acid) are now recommended as standard treatment options for bleeding in HHT 2, 4
- For VWD, treatment approaches include desmopressin, VWF replacement therapy, antifibrinolytics, and hormonal treatments for menorrhagia 2
- Management of other autosomal dominant bleeding disorders depends on the specific factor deficiency or platelet dysfunction 1
When evaluating patients with suspected hereditary bleeding disorders, it's important to consider the full spectrum of autosomal dominant conditions beyond just HHT and Type 2 VWD to ensure appropriate diagnosis and management.