Vascular Bleeding Disorders
Bleeding may result from abnormalities in
- Coagulation factors
- Blood vessels
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.
Marfan syndrome (also called Marfan’s syndrome or Marfans syndrome) is a condition that affects the connective tissue. Connective tissue holds the body together and provides support to many structures throughout the body. In Marfan syndrome, the connective tissue isn’t normal. As a result, many-body systems are affected, including the heart, blood vessels, bones, tendons, cartilage, eyes, nervous system, skin, and lungs.
Although some patients with Marfan syndrome complain of easy bruising there is no increased vascular fragility of capillaries or of small and middle-size arteries or veins. This can be explained by the fact that patients with Marfan syndrome may have thinner skin, and less subcutaneous fat, and hence less protective cushioning for minor traumata. Also, joint laxity and poor visual acuity may contribute to a predisposition to contusions in some patients. Some patients with Marfan syndrome present mild hyperextensibility of the skin, reminiscent of EDS. However, the most common skin manifestations of Marfan syndrome are the striae atrophicae or stretch marks, which usually present on the back, the shoulders, and the thighs.
Inheritance of Marfan syndrome is autosomal dominant. About 75% of the time, the condition is inherited from a parent with the condition, while 25% of the time it is a new mutation. The basic molecular defect results from mutations in the gene encoding the glycoprotein fibrillin-1 (FBN1), which is the main component of microfibrils and helps anchor cells to the extracellular matrix. The principal structural defect involves the cardiovascular, musculoskeletal, and ocular systems. The pulmonary system and central nervous system are also affected. There are many different manifestations of the genetic mutation that causes Marfan syndrome; however, it is typically recognized by the constellation of long limbs, aortic root dilation, and dislocated lenses.
Marfan syndrome is fairly common, affecting 1 in 10,000 to 20,000 people. It has been found in people of all races and ethnic backgrounds.
Symptoms and signs of Marfan syndrome:
Sometimes Marfan syndrome is so mild, few if any, symptoms occur. In most cases, the disease progresses with age, and symptoms of Marfan syndrome become noticeable as changes in connective tissue occur.
Major findings include:
Most severe complications result from pathologic changes in the aortic root and ascending aorta. The aortic media is affected preferentially in areas subject to the greatest hemodynamic stress. The aorta progressively dilates or acutely dissects, beginning in the coronary sinuses, sometimes before 10 years of age. The aortic root dilates in 50% of children and in 60 to 80% of adults and can cause aortic regurgitation, in which case a diastolic murmur may be heard over the aortic valve.
Redundant cusps and chordae tendineae may lead to mitral valve prolapse or regurgitation; mitral valve prolapse may cause a systolic click and a late systolic murmur or, in severe cases, a holosystolic murmur. Bacterial endocarditis may develop in affected valves.
Severity varies greatly. Patients are taller than average for age and family; arm span exceeds height. Arachnodactyly (disproportionately long, thin digits) is noticeable, often by the thumb sign (the distal phalanx of the thumb protrudes beyond the edge of the clenched fist). Sternum deformity—pectus carinatum (outward displacement) or pectus excavatum (inward displacement)—is common, as are joint hyperextensibility (but usually small flexion contractures to the elbows), genu recurvatum (backward curvature of the legs at the knees), pes planus (flat feet), kyphoscoliosis, and diaphragmatic and inguinal hernias. Subcutaneous fat usually is sparse. The palate is often high-arched.
People with Marfan syndrome are often very tall and thin. Their arms, legs, fingers, and toes may seem out of proportion, too long for the rest of their body. Their spine may be curved and their breastbone (sternum) may either stick out or be indented. Their joints may be weak and easily become dislocated. Often, people with Marfan syndrome have a long, narrow face and the roof of the mouth may be higher than normal, causing the teeth to be crowded.
Findings include ectopia lentis (subluxation or upward dislocation of the lens) and iridodonesis (tremulousness of the iris). The margin of the dislocated lens can often be seen through the undilated pupil. High-grade myopia may be present, and spontaneous retinal detachment may occur.
Cystic lung disease and recurrent spontaneous pneumothorax may occur. These disorders can cause pain and shortness of breath.
Central nervous system
Dural ectasia (widening of the dural sac surrounding the spinal cord) is a common finding and most frequently occurs in the lumbosacral spine. It may cause headache, lower back pain, or neurologic deficits manifested by bowel or bladder weakness.
Diagnosis of Marfan syndrome:
- Genetic testing
- Echocardiography/MRI (measurement of the aortic root, detection of valve prolapse)
- Slit-lamp examination (lens abnormalities)
- X-rays of the skeletal system (hand, spine, pelvis, chest, foot, and skull for characteristic abnormalities)
- MRI of the lumbosacral spine (dural ectasia)
Diagnosis of Marfan syndrome can be difficult because many patients have only a few typical symptoms and signs and no specific histologic or biochemical changes. Considering this variability, diagnostic criteria are based on constellations of clinical findings and family and genetic history.
Nonetheless, diagnosis is uncertain in many partial cases of Marfan syndrome.
Homocystinuria can partially mimic Marfan syndrome but can be differentiated by detecting homocystine in the urine. Genetic testing for FBN1 mutations can help establish the diagnosis in people who do not meet all clinical criteria, but FBN1 mutation-negative cases exist. Prenatal diagnosis by analysis of the FBN1 gene is hampered by poor genotype/phenotype correlation (> 1700 different mutations have been described).
Standard imaging of the skeletal, cardiovascular, and ocular systems is done to detect any clinically relevant structural abnormalities and to provide information contributing to the diagnostic criteria (eg, echocardiography to identify aortic root enlargement).
In addition to the criteria established within organ systems, family history (1st-degree relative with Marfan syndrome) and genetic history (presence of the FBN1 mutation known to cause Marfan syndrome) are considered major criteria.
Prognosis for Marfan syndrome:
Advancements in therapy and regular monitoring have improved quality of life and reduced mortality. Median life expectancy increased from 48 years in 1972 to near normal in people receiving appropriate medical care. However, life expectancy is still reduced for the average patient, primarily because of the cardiac and vascular complications. This decreased life expectancy can take an emotional toll on an adolescent and the family.
Treatment of Marfan syndrome:
- Induction of precocious puberty in tall girls
- Elective aortic repair and valve repair
- Bracing and surgery for scoliosis
Treatment of Marfan syndrome is focused on prevention and treatment of complications.
For very tall girls, inducing precocious puberty by age 10 with estrogens and progesterone may reduce potential adult height.
All patients should routinely be given beta-blockers (eg, atenolol, propranolol) to help prevent cardiovascular complications. These drugs lower myocardial contractility and pulse pressure and reduce the progression of aortic root dilation and the risk of dissection. In people who are unable to take beta-blockers due to asthma or side effects, a calcium channel blocker, such as verapamil, is recommended. Angiotensin II receptor blockers also may be given.
Prophylactic surgery is offered if the aortic diameter is > 5 cm (less in children). Pregnant women are at especially high risk of aortic complications; elective aortic repair before conception should be discussed. Severe valve regurgitation is also surgically repaired. Bacterial endocarditis prophylaxis before invasive procedures is not indicated except in patients who have prosthetic valves or who previously had infective endocarditis.
Scoliosis is managed with bracing as long as possible, but surgical intervention is encouraged in patients with curves of 40 to 50°.
Cardiovascular, skeletal, and ocular findings (including echocardiography) should be reevaluated annually. Appropriate genetic counseling is indicated.
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