Vascular Bleeding Disorders
Bleeding may result from abnormalities in
Vascular bleeding disorders result from defects in blood vessels, typically causing petechiae, purpura, and bruising but, except for hereditary hemorrhagic telangiectasia, seldom leading to serious blood loss. Bleeding may result from deficiencies of vascular and perivascular collagen in Ehlers-Danlos syndrome and in other rare hereditary connective tissue disorders (e.g. pseudoxanthoma elasticum, osteogenesis imperfecta, Marfan syndrome). Hemorrhage may be a prominent feature of scurvy or of immunoglobulin A–associated vasculitis, a hypersensitivity vasculitis common during childhood.
Congenital disorders are either caused by vascular malformations or disorders of connective tissue and acquired disorders have multiple causes such as an increase in vessel fragility, vasculitis, and decreased collagen.
Hereditary Hemorrhagic Telangiectasia
Hereditary hemorrhagic telangiectasia (HHT) is a hereditary disorder of vascular malformation transmitted as an autosomal dominant trait affecting men and women.
HHT is a genetic disorder. Each person with HHT has one gene that is altered (mutated), which causes HHT, as well as one normal gene. It takes only one mutant gene to cause HHT. When someone with HHT has children, each child has a 50% chance to receive the mutant gene from his/her parent, and therefore to have HHT, as well. Each child also has a 50% chance to receive the normal gene and not be affected with HHT. At least five different genes can cause HHT, three of which are known.
More than 80% of patients have mutations in one of the following genes (1):
- Endoglin (ENG) gene, which encodes a receptor for transforming growth factor beta-1 (TGF-β1) and transforming growth factor beta-3
- ACVRL1 gene, which encodes the activin receptor-like kinase (ALK1)
- MADH4 gene, which encodes SMAD4, a protein active in the TGF beta signaling pathway
HHT is a disorder in which some blood vessels do not develop properly. A person with HHT may form blood vessels without the capillaries (tiny blood vessels that pass blood from arteries to veins) that are usually present between arteries and veins. The space between an artery and a vein is often fragile and can burst and bleed much more easily than other blood vessels. Men, women, and children from all racial and ethnic groups can be affected by HHT and experience the problems associated with this disorder, some of which are serious and potentially life-threatening. Fortunately, if HHT is discovered early, effective treatments are available. However, there is no cure for HHT.
Symptoms and Signs of HHT:
The most characteristic lesions of hereditary hemorrhagic telangiectasia are small red-to-violet telangiectatic lesions on the face, lips, oral and nasal mucosa, and tips of the fingers and toes. Similar lesions may be present throughout the mucosa of the gastrointestinal (GI) tract, resulting in recurrent GI bleeding. Patients may experience recurrent, profuse nosebleeds. Some patients have pulmonary arteriovenous malformations (AVMs). These AVMs may cause significant right-to-left shunts, which can result in dyspnea, fatigue, cyanosis, or erythrocytosis. However, the first sign of the presence of AVMs may be a brain abscess, transient ischemic attack, or stroke as a result of infected or noninfected emboli. Cerebral or spinal AVMs occur in some families and may cause subarachnoid hemorrhage, seizures, or paraplegia. Hepatic AVMs may lead to liver failure and high output heart failure. Chronic iron deficiency anemia is commonly present.
Nosebleeds are the most common sign of HHT, resulting from small abnormal blood vessels within the inside layer of the nose. Abnormal blood vessels in the skin can appear on the hands, fingertips, face, lips, lining of the mouth, and nose as delicate red or purplish spots that lighten briefly when touched. Bleeding within the stomach or intestines is another possible indicator of HHT that occurs because of abnormal blood vessels lining the digestive tract. Additional signs of HHT include abnormal artery-vein connections within the brain, lungs, and liver, which often do not display any warning signs before rupturing.
- Clinical evaluation
- Sometimes endoscopy or angiography
- Sometimes genetic testing
Diagnosis of hereditary hemorrhagic telangiectasia is based on the finding of characteristic arteriovenous malformations on the face, mouth, nose, digits, and/or internal organs in the context of epistaxis and family history. The Curaçao criteria include the following:
- Spontaneous recurrent epistaxis
- Multiple telangiectasias in typical locations
- Documented visceral arteriovenous malformations (eg, in the lung, liver, brain, and spine)
- First-degree family member with hereditary hemorrhagic telangiectasia
Hereditary hemorrhagic telangiectasia is definite if 3 of these criteria are met and possible if 2 are met.
Endoscopy or angiography is sometimes needed. Laboratory findings are usually normal except for iron deficiency anemia in many patients.
HHT can be diagnosed by performing genetic testing. Genetic testing can detect a gene mutation in about ¾ of families with signs of HHT, which if found can establish the diagnosis of HHT in individuals and families who are unsure about whether they have HHT. HHT can also be diagnosed by using clinical criteria (presence of signs and a history of signs in a parent, sibling, or child). Testing for the ENG, ACVRL1, and MADH4 mutations may be helpful in some patients with atypical features or for screening asymptomatic family members.
Screening for HHT:
If a family history of pulmonary, hepatic, or cerebral arteriovenous malformations exists, screening at puberty and at the end of adolescence with pulmonary CT, hepatic CT, and cerebral MRI is recommended.
Complications and Treatments of HHT:
The complications of HHT can vary widely, even among people affected by HHT in the same family. Complications and treatment of HHT depend on the parts of the body that are affected by this disorder. Treatment may include controlling bleeding and anemia and preventing complications from abnormal artery-vein connections in the lungs and brain.
- Sometimes laser ablation, surgical resection, or embolization of symptomatic arteriovenous malformations
- Supplemental iron therapy
- Possibly blood transfusions
- Sometimes antifibrinolytic drugs (eg, aminocaproic acid, tranexamic acid)
- Sometimes angiogenesis inhibitors (eg, bevacizumab, pomalidomide, thalidomide)
Treatment for most patients is supportive, but accessible telangiectasias (eg, in the nose or gastrointestinal tract via endoscopy) may be treated with laser ablation. Arteriovenous malformations may be treated by surgical resection or coil embolization.
Repeated blood transfusions may be needed; therefore, immunization with hepatitis B vaccine is important.
Many patients require continuous iron therapy to replace iron lost in repeated mucosal bleeding; many patients require parenteral iron and sometimes erythropoietin.
Treatment with drugs that inhibit fibrinolysis, such as aminocaproic acid or tranexamic acid, may be beneficial.
Treatment with drugs that inhibit angiogenesis such as bevacizumab, pomalidomide, or thalidomide can reduce the number and density of abnormal vessel growth. In addition, bevacizumab has recently been shown to reduce the incidence of nasal and gastrointestinal bleeding.
To avoid paradoxical embolization of particulate matter to the brain through pulmonary arteriovenous malformations, all IV fluids need to be given through a filter.
The Ehlers-Danlos syndromes (EDS) are a group of hereditary disorders of connective tissue that are varied in the ways they affect the body and in their genetic causes. The underlying concern is the abnormal structure or function of collagen and certain allied connective tissue proteins.
They are generally characterized by joint hypermobility (joints that move further than normal range), joint instability (subluxation (partial separation of the articulating surfaces of a joint)) and dislocations (full separation of the surfaces of a joint), scoliosis, and other joint deformities, skin hyperextensibility (skin that can be stretched further than normal) and abnormal scarring, and other structural weakness such as hernias and organ prolapse through the pelvic floor. In the rarer types of EDS, there is also weakness of specific tissues that can lead, for example, to major gum and dental disease, eye disease, cardiac valve and aortic root disorders, and life-threatening abdominal organ, uterine, or blood vessel rupture.
Inheritance is usually autosomal dominant, but Ehlers-Danlos syndrome is heterogeneous. Different gene mutations affect the amount, structure, or assembly of different collagens. Mutations can exist in the genes that encode collagens (eg, type I, III, or V) or collagen-modifying enzymes (eg, lysyl hydroxylase, a collagen-cleaving protease).
There are 6 major types:
- Hypermobility (hEDS)
There are also several rare or hard-to-classify types.
Easy bruising, at sites of trauma, accompanies most forms of EDS including hEDS. This occurs due to increased fragility of dermal blood capillaries and poor structural integrity of the skin rather than a clotting abnormality.
Symptoms and Signs of Ehlers-Danlos Syndrome:
Symptoms and signs of Ehlers-Danlos syndrome vary widely.
Predominant symptoms include hypermobile joints, abnormal scar formation, and wound healing, fragile vessels, and velvety, hyperextensible skin. Skin can be stretched several centimeters but returns to normal when released.
Wide papyraceous scars often overlie bony prominences, particularly elbows, knees, and shins; scarring is less severe in the hypermobility type. Molluscoid pseudotumors (fleshy outgrowths) frequently form on top of scars or at pressure points.
The extent of joint hypermobility varies but may be marked in the arthrochalasis, classic, and hypermobility types.
Bleeding tendency is rare, although the vascular type is characterized by vascular rupture and bruising. Subcutaneous calcified spherules may be palpated or seen on x-rays.
Complications of Ehlers-Danlos syndrome:
Minor trauma may cause wide gaping wounds but little bleeding; surgical wound closure may be difficult because sutures tend to tear out of the fragile tissue. Surgical complications occur because of deep tissue fragility.
Sclera may be fragile, leading to perforation of the globe in the kyphoscoliosis type.
Bland synovial effusions, sprains, and dislocations occur frequently. Spinal kyphoscoliosis occurs in 25% of patients (especially in those with the kyphoscoliosis type), thoracic deformity in 20%, and talipes equinovarus in 5%. About 90% of affected adults have pes planus (flat feet). Developmental dysplasia of the hip (formerly congenital hip dislocation) occurs in 1% (the arthrochalasis type is characterized by bilateral developmental dysplasia of the hip).
Gastrointestinal (GI) hernias and diverticula are common. Rarely, portions of the GI tract spontaneously hemorrhage and perforate, and dissecting aortic aneurysm and large arteries spontaneously rupture.
Valvular prolapse is a common complication in the most severe type (vascular type).
In pregnant women, tissue extensibility may cause premature birth, cervical incompetence, and possibly uterine rupture; if the fetus is affected, the fetal membrane is fragile, sometimes resulting in early rupture. Maternal tissue fragility may complicate episiotomy or cesarean delivery. Antenatal, perinatal, and postnatal bleeding may occur.
Other potentially serious complications include arteriovenous fistula, ruptured viscus, and pneumothorax or pneumohemothorax.
Diagnosis of Ehlers-Danlos Syndrome:
- Clinical evaluation
- Echocardiography and/or other vascular imaging to screen for cardiovascular complications
The initial diagnosis of Ehlers-Danlos syndrome is largely clinical but should be confirmed by genetic testing, which is now available for most subtypes.
Ultrastructural examination of skin biopsy can help in diagnosing the classic, hypermobility, and vascular types.
Echocardiography and other vascular imaging are done to check for heart disorders (eg, valvular prolapse, arterial aneurysm) that are associated with some of the types.
When to consider the diagnosis of EDS?
Ehlers–Danlos syndrome needs to be considered when, in the absence of another explanation, one or more of the following occur:
- late walking with joint hypermobility
- abnormal bruising and bleeding
- unexplained vessel rupture or dissection
- tissue fragility, atrophic scarring or skin hyperextensibility
- symptomatic joint hypermobility± dislocations
- Hollow organ rupture
Prognosis for Ehlers-Danlos Syndrome:
Life span is usually normal with most types.
Potentially lethal complications occur in certain types (eg, arterial rupture in the vascular type).
Treatment of Ehlers-Danlos Syndrome:
- Early recognition and treatment of complications
There is no specific treatment for Ehlers-Danlos syndrome.
Trauma should be minimized. Protective clothing and padding may help.
If surgery is done, hemostasis must be meticulous. Wounds are carefully sutured, and tissue tension is avoided.
Obstetric supervision during pregnancy and delivery is mandatory.
Genetic counseling should be provided.
David J. Kuter, MD, DPhil, Harvard Medical School. Overview of Vascular Bleeding Disorders – Hematology and Oncology – MSD Manual Professional Edition https://www.msdmanuals.com/en-gb/professional/hematology-and-oncology/bleeding-due-to-abnormal-blood-vessels/overview-of-vascular-bleeding-disorders
Shovlin CL, Guttmacher AE, Buscarini E, et al: Diagnostic criteria for hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber syndrome). Am J Med Genet 91(1):66–67, 2000. doi: 10.1002/(sici)1096-8628(20000306)91:1<66::aid-ajmg12>3.0.co;2-p.
Al-Samkari H, Kritharis A, Rodriguez-Lopez JM, Kuter D: Systemic bevacizumab for the treatment of chronic bleeding in hereditary haemorrhagic telangiectasia. J Intern Med 285(2):223–231, 2019. doi: 10.1111/joim.12832. Epub 2018 Oct 9.
Frank Pessler , MD, PhD, Hannover, Germany. Ehlers-Danlos Syndrome – Pediatrics – MSD Manual Professional Edition https://www.msdmanuals.com/en-gb/professional/pediatrics/connective-tissue-disorders-in-children/ehlers-danlos-syndrome
Michael A. Briones. Vascular Bleeding Disorders https://www.sciencedirect.com/science/article/pii/B9780123744326001044
Vascular Bleeding Disorders-Hereditary Hemorrhagic Telangiectasia (HHT) https://www.metropolitan-hospital.gr/en/services/general-services/hereditary-hemorrhagic-telangiectasia-hht
Nicoletta Lanese – What Is Ehlers-Danlos Syndrome? https://www.livescience.com/ehlers-danlos-syndrome.html
Social Security Disability for Ehlers-Danlos. https://www.disabilitylawfirmnc.com/social-security-disability-for-ehlers-danlos/
Marco Castori. “Ehlers-Danlos Syndrome, Hypermobility Type: An Underdiagnosed Hereditary Connective Tissue Disorder with Mucocutaneous, Articular, and Systemic Manifestations“, International Scholarly Research Notices, vol. 2012, Article ID 751768, 22 pages, 2012. https://doi.org/10.5402/2012/751768
Larry Constant Jr. Letter From One Tough Zebra: Navigating the Countless Curves of Kyphoscoliotic Ehlers-Danlos Syndrome with Drive and Determination https://www.ehlers-danlos.com/larrysletter/
Facts About Hereditary Hemorrhagic Telangiectasia (HHT) https://www.cdc.gov/ncbddd/hht/index.html
Kritharis A, Al-Samkari H, Kuter D: Hereditary hemorrhagic telangiectasia: Diagnosis and management from the hematologist’s perspective. Haematologica 103:1433–1443, 2018. doi: 10.3324/haematol.2018.193003.
Geisthoff et al (2011) [Hereditary haemorrhagic telangiectasia (Rendu-Osler-Weber disease) as an example of a rare disease relevant for oto-rhino-laryngology]. Laryngo-Rhino-Otologie, 90, 230–242, with permission from Georg Thieme Verlag KG, Stuttgart, Germany, and Prof. Dr. Günther Schneider, Homburg/Saar, Germany. © 2011, Georg Thieme Verlag KG, Stuttgart, Germany.
Geisthoff, U.W., Nguyen, H.-L., Röth, A. and Seyfert, U. (2015), How to manage patients with hereditary haemorrhagic telangiectasia. Br J Haematol, 171: 443-452. https://doi.org/10.1111/bjh.13606