Bleeding disorder

Bleeding disorder also called blood clotting disorder, is when your blood does not clot fast enough. This results in too much bleeding or bleeding that lasts a long time. Bleeding disorders are characterized by extended bleeding after injury, surgery, trauma or menstruation. Sometimes the bleeding is spontaneous, without a known or identifiable cause.

Normal blood clotting is called coagulation. This complex process involves platelets and clotting or coagulation factors. Your body produces 13 clotting factors. If any of them are defective or deficient, blood clotting is affected; a mild, moderate or severe bleeding disorder can result. Platelets are special blood cells. Platelets and coagulation factors clump together to heal broken blood vessels. This helps control bleeding. A person needs the right balance of coagulation factors to have healthy bleeding and clotting. Bleeding can result from either too few or abnormal platelets, abnormal or low amounts of clotting proteins, or abnormal blood vessels.

Blood clotting disorders occur when:

• Clotting factors are missing or damaged.
• The blood has too few platelets.
• Platelets do not work correctly.

Symptoms of a bleeding disorder include:

• Bleeding into joints, muscles and soft tissues
• Excessive bruising
• Prolonged, heavy menstrual periods (menorrhagia)
• Unexplained nosebleeds
• Extended bleeding after minor cuts, blood draws or vaccinations, minor surgery or dental procedures

Bleeding disorders fall into two main categories: inherited and acquired. Inherited bleeding disorders have a genetic predisposition and involve a deficiency of coagulation factors. Acquired bleeding disorders can be caused by conditions that an individual may develop at any point during their lifetime. These can be broader in range and dependent on comorbid conditions.

Some bleeding disorders, such as hemophilia, can be inherited or acquired. Others can occur from such conditions as anemia, cirrhosis of the liver, HIV, leukemia and vitamin K deficiency. They also can result from certain medications that thin the blood, including aspirin, heparin and warfarin.

Treatment for bleeding disorders varies, depending on the condition and its severity. For some bleeding disorders, there are clotting factor concentrates that can be infused prophylactically or on-demand at home, to prevent or treat bleeds. For other bleeding disorders, there are topical products, nasal sprays and fresh frozen plasma, which is administered in a hospital setting.

Bleeding disorder causes

Sometimes a person inherits a bleeding disorder. This means it is genetic and runs in the family. A person may also have bleeding problems caused from illness or treatment with specific drugs.

Blood clotting disorder can be caused by:

• Inherited disorders. Hemophilia and von Willebrand’s disease are 2 types. With hemophilia, blood does not clot normally. With von Willebrand’s disease, clotting factors are missing or do not work well.
• A vitamin K deficiency
• Cancer that begins in or spreads to the liver
• Other liver disorders, including hepatitis and cirrhosis. Hepatitis is an infection of the liver. Cirrhosis is scarring of the liver.
• Long-term use of powerful antibiotics or anticoagulants. Anticoagulants are medications that thin the blood.
• Drugs called angiogenesis inhibitors. These prevent the growth and development of new blood vessels.
• Thrombocytopenia, which is an unusually low level of platelets
• Anemia, which is an unusually low level of red blood cells
• Other disorders unrelated to cancer

Hemophilia is perhaps the most well-known inherited bleeding disorder, although it is relatively rare. Hemophilia affects mostly males. Many more people are affected by von Willebrand disease, the most common inherited bleeding disorder in America caused by clotting proteins. Von Willebrand disease can affect both males and females. Platelet disorders are the most common cause of bleeding disorder and are usually acquired rather than inherited.

Hemophilia

Hemophilia is a rare, x-linked inherited bleeding disorder and occurs in families, but in one-third of cases it appears in families with no previous history of the disorder ¹. Hemophilia can range from mild to severe, depending on how much clotting factor is present in the blood.

There are two types of hemophilia:

• Hemophilia A also called classical hemophilia, is the most common type. It is caused by lack of clotting factor 8 (factor VIII), which results from a mutation in gene F8. Hemophilia A is an X-linked recessive genetic disorder affecting 1 in 5,000 males making it the most common congenital coagulopathy ¹.
• Hemophilia B sometimes called Christmas disease, is caused by lack of clotting factor 9 (factor IX), which results from a mutation in gene F9. Hemophilia B is an X-linked genetic coagulopathy affecting 1 in 30,000 male births ¹.

Hemophilia results from a genetic defect found on the X chromosome. Women have two X chromosomes. Women who have one X chromosome with the defective gene are termed carriers and they can pass the disease onto their sons. Due to random chromosome activation, some women carriers may range from asymptomatic to symptomatic depending on how much of their factor VIII or IX is inactivated. In fact, some women may have “mild hemophilia,” though this is less common. Men have one X and one Y chromosome, so if their X chromosome has the defective gene, they will have hemophilia.

Because blood does not clot properly without enough clotting factor, any cut or injury carries the risk of excessive bleeding. In addition, people with hemophilia may suffer from internal bleeding that can damage joints, organs, and tissues over time.

The main signs of hemophilia are:

• easy bruising from an early age
• internal bleeding for no obvious reason, especially in the joints and muscles
• greater than normal bleeding following injury or surgery
• abnormally heavy bleeding during menstruation or after giving birth

Although bleeding problems often start from a young age, some children don’t have symptoms until they begin walking or running. People with mild hemophilia may not bleed excessively until they get an injury or have surgery.

Hemophilia diagnosis

If hemophilia is suspected, blood tests can measure the levels of clotting factors. These tests can show the type and severity of the disease. Genetic testing can often confirm a diagnosis of hemophilia, although a gene mutation can’t always be found.

Hemophilia treatment

Hemophilia can be complex to manage but it can be managed effectively with appropriate treatment. In the past, people with hemophilia were treated with transfusions of factor VIII obtained from donor blood, but by the early 1980s these products were discovered to be transmitting blood-borne viruses, including hepatitis and HIV. Thanks to improved screening techniques, and a major breakthrough that enabled scientists to create synthetic blood factors in the laboratory by cloning the genes responsible for specific clotting factors, today’s factor-replacement therapies are pure and much safer than ever before.

Living with hemophilia

When someone with hemophilia has a bleeding episode, treatment is needed to help their blood clot and stop the bleeding. This usually involves giving clotting factors by infusion or injection.

Complications of the disease also need to be managed, such as damage to joints and muscles that can result from bleeding into these areas.

Guidelines recommend that people with hemophilia receive care from a multidisciplinary team of health-care professionals, made up of doctors, nurses, medical scientists, physiotherapists, social workers and psychologists. If you are diagnosed with hemophilia, you should discuss with your doctor the benefits of referral to a hemophilia treatment center, where a multidisciplinary team can provide you with comprehensive care.

Von Willebrand disease

Von Willebrand disease also called von Willebrand disorder, is a bleeding disorder passed down in the genes you inherit from your parents that results when the blood lacks functioning von Willebrand factor, a protein that helps the blood to clot and also carries another clotting protein, factor VIII ². Von Willebrand disease is similar to hemophilia, but more common and usually milder than hemophilia and can affect both males and females. If you have von Willebrand disease, you don’t have enough of a clotting factor called von Willebrand factor, or the factor doesn’t work properly. The result is that it takes longer than normal for your blood to clot and for bleeding to stop. Women are especially affected by Von Willebrand disease during their menses.

Von Willebrand disease is classified into three different types (Types 1, 2, and 3), based on the levels of von Willebrand factor and factor VIII activity in the blood. Type 1 is the mildest and most common form; Type 3 is the most severe and least common form.

• Type 1 — factor levels are low (the most common type).
• Type 2 — factor doesn’t work properly.
• Type 3 — factor is missing (the rarest type).

Many people who have von Willebrand disease have no obvious symptoms and are not even aware they have it.

When symptoms of von Willebrand disease show up, they may include:

• bruising easily
• bleeding more than normal, for example after an injury or childbirth, or during menstruation
• frequent or long-lasting nosebleeds or gum bleeds
• blood in your urine or stools
• bleeding into the joints and muscles (in severe cases)

If you have von Willebrand disease, you might experience different symptoms at different times of your life.

Von Willebrand diagnosis

Von Willebrand disease might be suspected if you show symptoms such as easy bleeding or bruising, especially if someone in your family is known to have von Willebrand disease. An actual diagnosis of von Willebrand disease relies on special blood tests. These tests can also help determine the type of von Willebrand disease you have.

Many people go through life unaware they have von Willebrand disease. Some find out only when a problem is picked up on blood testing for other conditions.

With early diagnosis, people with von Willebrand disease can lead normal, active lives. People with mild cases may not require treatment, but should avoid taking drugs that could aggravate bleeding, such as aspirin and ibuprofen, without first consulting with a doctor. More serious cases may be treated with drugs that increase the level of von Willebrand factor in the blood or with infusions of blood factor concentrates. It is important for people with von Willebrand disease to consult with their doctors before having surgery, having dental work, or giving birth, so that proper precautions can be taken to prevent excessive bleeding. You may be referred to a hematologist, a doctor who specializes in the treatment of blood disorders.

Living with von Willebrand disease

Treatment for von Willebrand disease depends on the type of von Willebrand disease and how severe it is. In mild cases, treatment might not be needed at all, unless you have surgery or dental work, or sustain an injury that causes bleeding.

Treatments for von Willebrand disease can be given when needed, including:

• medicines to help your blood clot properly
• treatments to help wounds stop bleeding
• hormones to stimulate the production of von Willebrand factor in your blood

Some minor bleeding can be managed at home, while more serious bleeding may require expert help.

Blood clotting disorder symptoms

People with bleeding disorders may have the following symptoms:

• Cuts that bleed too much
• Unexpected or sudden bruising or easy bruising
• Bleeding gums
• Heavy bleeding from small cuts or dental work
• Unexplained nosebleeds
• Heavy menstrual bleeding or longer than usual in women
• Bleeding into joints
• Excessive bleeding following surgery
• Small purple or red spots under the skin called petechiae
• Blood in vomit that often looks like coffee grounds.
• Black or bloody bowel movements
• Red or pink urine
• Dizziness, headaches, or changes in vision
• Joint pain.

People with bleeding disorders experience external and internal bleeds.

• External Bleeds: External bleeds can occur in the mouth, after biting the mouth, lips or tongue. Recurrent, heavy nosebleeds, or epistaxis, without apparent cause are another symptom. Minor cuts that don’t clot or that stop and then start again also can occur.
• Internal Bleeds: The most frequent sites of internal bleeds are the knee, ankle, elbow and hip joints. At first the joint feels bubbly or tingly. As more blood pools in it and swelling occurs, the joint feels tight, may be hot to the touch and becomes painful to bend. Children may hold or protect the affected joint, or start limping or crawling. Bleeds also can occur in large muscles, such as the iliopsoas muscle in the front of the hip, causing abdominal, hip or back pain. Many women with bleeding disorders experience menorrhagia, long, heavy menstrual bleeding, and cramps. Soft tissue bleeds under the skin can leave a telltale sign—large bruises. Brain bleeds, or intracranial hemorrhage, are serious. They can occur spontaneously or after trauma. Symptoms to be aware of include: painful headache, stiff neck, vomiting, sleepiness, changed behavior, sudden weakness or balance issues, difficulty walking, double vision, convulsions and seizures. Other bleeds that need prompt action include those in the eye, throat or gastrointestinal tract, or that are caused by deep cuts or lacerations. For any of these bleeds, it’s best to call your hemophilia treatment center or head right to the emergency room.

Talk with your doctor about any symptoms you have. In particular, tell them about new symptoms or a change in symptoms.

Bleeding disorder diagnosis

Your doctor will review your medical history, perform a physical exam, and draw blood. The blood may be used for several blood tests including:

• Complete blood count (CBC)
• Tests to check the speed of blood clotting
• Tests to check for blood protein deficiencies

Laboratory testing is essential for diagnosing bleeding disorders. However, the specific panels necessary for an accurate diagnostic evaluation are not standardized and may vary significantly between hospitals and regions ¹. Routine laboratory analysis for clotting disorders starts with platelet count, prothrombin time (PT), partial thromboplastin time (aPTT), the international normalized ratio (INR) and bleeding time. The platelet count should not only have a sufficient quantity (normal = 150000 to 500000/ml) but must also be functional. The bleeding time assesses the function of the platelets. Bleeding times can be delayed in a patient with von Willebrand factor (vWF) deficiency or from specific medications that interfere with platelet function (NSAIDS, aspirin and valproic acid). PT (normal = 11.5 to 14 seconds) represents the function of coagulation factors II, V, VII, and X which are the hepatically synthesized vitamin K dependent factors. The PT and INR will be affected by patients taking warfarin as it interferes with the synthesis of vitamin K dependent factors. The INR (normal= 0.8 to 1.2) is a ratio that is used to estimate the percent of functional clotting factors. For example, an INR of between 2 to 3 correlates approximately to 10% of active clotting factors present. It is necessary to have at least 30% of the clotting factors present for normal coagulation. Partial thromboplastin time (normal = 25 to 40 seconds) measures the efficacy of von Willebrand Factor and factors VIII, IX, XI, and XII ³.

Hemophiliacs will have an elevated aPTT and a normal PT/INR, bleeding time and platelet count. The aPTT, a measure of the intrinsic pathway, will be elevated as a result of low levels of FVIII. An elevated aPTT should prompt investigation by looking at individual factor levels, specifically Factor VIII and IX ⁴. When evaluating specific factor levels, the amount of factor present will determine the severity of the disease. When the diagnosis is suspected, emphasis must also focus on family history including maternal male family members.

Diagnosis of von Willebrand disease is represented by increased bleeding time and a decrease in von Willebrand factor (vWF) levels as measured by the ristocetin cofactor collagen binding, in addition to a history of bleeding and positive family history of von Willebrand disease. The reocmmendation is that patients are tested at least three times before making the official diagnosis as vWF levels are subject to fluctuate, changing with stress, pregnancy, exercise, and inflammatory processes. There are also some subtle differences in vWF levels based on gender and blood type ⁵. Von Willebrand disease requires factor multimer assays to diagnose the specific subtype of the disease. Additionally, the aPTT may be mildly elevated in approximately 50% of patients with von Willebrand disease second to low levels of factor VIII.

Bleeding disorder treatment

Bleeding disorder treatment involves treating the underlying cause, such as cancer or liver disease. Additional treatments may include:

• A vitamin K injection
• Drugs that help blood to clot
• Blood plasma or platelet transfusions

Other medications to treat platelet problems. These include hydroxyurea (Droxia, Hydrea) and oprelvekin (Neumega).

The mainstay treatment of hemophilia is factor replacement, either prophylactically or need-based. Recombinant-derived Factor VIII and IX concentrates are available and prevent the risk of viral transmission ⁶. Recombinant Factor VIII increases the plasma concentration by 2% for every 1 IU/kg, and recombinant factor IX produces an increase of 0.8% for every 1 IU/kg given. The goals of correction are to achieve a 50% plasma value for the management of bleeding risks such as surgery and 100% correction in the setting of major trauma. These levels should be obtained 30 minutes before the onset of surgery and maintained for 2 to 7 days after surgery. The timing of subsequent doses is determined based on factor half-life which is typically 8 to 12 hours.

The treatment of von Willebrand disease consists of desmopressin (DDAVP) or cryoprecipitate. Desmopressin (DDAVP) will enhance the release of vWF in patients with Type 1 von Willebrand disease. DDAVP is a synthetic derivative of antidiuretic hormone that acts on type 2 vasopressin receptors. It works by stimulating the release of vWF from endothelial cells by way of signaling through the cyclic adenosine monophosphate pathway which prompts the release of Weibel-Palade bodies into the endothelial cells and eventually into the plasma ⁷. Additionally, DDAVP works on the renal collecting duct as an anti-diuretic. It reduces the amount of water that is eliminated in the urine potentially causing dilutional hyponatremia; therefore, patients should have fluid restriction maintained while receiving this medication ⁸. DDAVP administered intravenously (0.3mcg/kg) will increase plasma Factor VIII and VWF levels by 3 to 5 times their baseline within 30 to 60 minutes after administration. DDAVP can also be administered subcutaneously (0.3 mcg/kg) or at fixed intranasal doses which is convenient for prophylactic treatment at home. DDAVP administration is expected to raise levels to 30 to 50% in patients with a baseline of 10% factor activity which may be sufficient for low-risk procedures but may require further supplementation to increase vWF to adequate levels needed for trauma or major surgery. Patients with a baseline of 20% factor level receiving DDAVP can see levels rise to 60 to 100% which would be suitable for most surgical procedures. Approximately 10% of patients within the Type 1 category may fail to respond to DDAVP; therefore, the recommendation is that patients undergo a trial of DDAVP administration at diagnosis or before its clinical need. Patients with Type 2 and 3 von Willebrand disease typically require replacement products consisting of Factor VIII and vWF. It is also important to note that patients with Type 2a and 3 will not respond to DDAVP as the former possesses dysfunctional vWF and Type 3 lacks releasable stores of vWF. Type 2b should never be given DDAVP, as it is contraindicated due to its potential thrombogenicity ⁹.

Replacement products

There is a human plasma-derived concentrate of Factor VIII with an even higher concentration of vWF. This product has been the subject of extensive study and deemed to be the safest option for factor replacement as it has undergone a pasteurization process to inactivate any blood-borne viruses. It has approval from the Food and Drug Administration (FDA) for the treatment and prevention of bleeding disorders in adult patients with Hemophilia A, as well as adult and pediatric patients with von Willebrand disease ¹⁰.

Factor VIII replacement with human plasma-derived concentrate of Factor VIII requires a simple weight-based calculation. The patient’s weight (in kg) is multiplied by the desired percent level of Factor VIII, assuming that starting levels are 0. That number then gets multiplied by the volume of distribution, which is approximately 0.5 ¹¹. Thus, the dose of human plasma-derived concentrate of:

• Factor VIII = weight in kg x desired Factor VIII level x 0.5. For a 60kg female, with a target goal of 50% Factor VIII level: 60 x 50 x 0.5 = 1500 units of Factor VIII.

Alphanate is another commercially available, virally inactivated product with Factor VIII and ristocetin cofactor activity essential for vWF support. The FDA has approved its use for both adults and children with Hemophilia A or von Willebrand disease who require treatment or prevention of spontaneous or trauma-related bleeding, including surgery.

Factor IX concentrate is a commercially available product and has been subject to various purification techniques to eliminate the risk of viral transmission during its administration. These products have FDA approval for use in the setting of prevention and control of bleeding in patients with a factor IX deficiency ¹².

• Dosing of Factor IX concentrate = weight in kg x desired factor level x volume of distribution (which is 1 for Factor IX). For a 60kg female with a target goal of 100% Factor IX level: 60 x 100 x 1 = 6000 units.

Allogenic replacement therapy

• Fresh frozen plasma (FFP) contains Factor VIII and vWF, but large volumes are needed to obtain adequate factor levels (20 to 25 mL/kg).
• Cryoprecipitate is a human plasma-derived product containing high levels of Factor VIII, vWF and fibrinogen (Factor I). It comes packaged in small volumes, so multiple bags are often required to obtain the adequate level of the factor desired. Virus inactivation is not routinely applied to these products therefore virally inactivated replacement products are considered a safer alternative to fresh frozen plasma (FFP) and cryoprecipitate. The absence of factor IX in cryoprecipitate negates its use in Hemophilia B.
• Platelet transfusions are necessary when bleeding continues despite normal Factor VIII levels. Platelets can transport and localize the vWF from the site of the vascular injury.

Antifibrinolytic acid therapy

• Aminocaproic acid is a synthetic analog of lysine used to control or prevent hemorrhage. It competitively reduces the conversion of plasminogen to plasmin thereby inhibiting fibrinolysis and promoting clot formation. It is typically administered as an intravenous infusion during a surgical procedure but is also available in an oral form for home use in patients with bleeding disorders. It is available as a mouthwash or a tablet for oral bleeding, recurrent epistaxis or menorrhagia. This agent is FDA approved in the treatment of patients with bleeding disorders and is often useful as an adjunct therapy in patients with coagulopathic potential.
• Tranexamic acid is a synthetic medication made from lysine which acts by competitively inhibiting plasminogen activation and is considered more potent than aminocaproic acid. At higher concentrations, it can act as a non-competitive inhibitor of plasmin. It has ten times the potency of aminocaproic acid and is FDA approved for use in patients with bleeding disorders. It is available in intravenous and oral formulations. The oral preparation can also help in the treatment of recurrent minor bleeding issues that occur at home and in preparation for dental work ¹³.

Hormonal treatments

Oral contraceptives such as oral progestins and depot medroxyprogesterone have been shown to be effective in women with Type 1 von Willebrand disease with menorrhagia by significantly elevating circulating vWF levels. While the exact mechanism of estrogens influence on vWF is not entirely understood, it is hypothesized to occur as a result of its lipophilic nature, allowing it to penetrate the cytoplasm of the nuclear receptors thereby increasing gene transcription of the various clotting proteins ¹⁴.

Bleeding disorder prognosis

Patients living with congenital bleeding disorders can expect to live full, productive lives with appropriate medical treatment, education and a management plan in case of trauma or surgery. Patients should consider wearing a medical identification bracelet so that they can receive proper management in case they are involved in significant trauma or are unable to communicate their medical history verbally.

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