Proconvertin deficiency, congenital

Definition

Bleeding disorders are disruptions in the body's ability to control blood clotting. Patients with these conditions bleed easily for longer periods of time than normal.

Description

Coagulation, or clotting, is a complex process involving at least 20 components of the blood, including various enzymes, messenger chemicals, and proteins. Under normal circumstances, the components necessary for coagulation circulate in the blood. When an injury occurs, they act together in a series of chain reactions to form a clot and prevent uncontrolled bleeding. Several disorders affect the blood's clotting components and diminish normal clotting capability. For people with these disorders, even a small injury could make them bleed to death.

Anatomy of a blood clot

In healthy individuals, clots begins when fibrin, an insoluble protein that forms the skeleton of the clot, forms at the wound site from fibrinogen, a soluble protein present in plasma. This chemical change is made possible by thrombin, an enzyme that itself is only created from the compound prothrombin when an injury occurs. Once fibrin strands are formed at the wound site, they trap platelets that flow past them. Platelets then initiate the contraction of damaged blood vessels so that less blood is lost. They also help plug damaged blood vessels and work with plasma to accelerate blood clotting.

Hemophilia A

Hemophilia A, also known as classic hemophilia, is a genetic disorder carried by females but expressed almost exclusively in males. The disorder is characterized by a lack of factor VIII, a glycoprotein found in blood plasma that, like all coagulation factors, is essential for blood clotting. Hemophilia causes uncontrolled bleeding, often internally, which is not only painful, but can permanently damage muscles and joints. The disease can be mild to severe, depending on how much (or little) factor VIII the body produces. Hemophilia A affects about 20,000 Americans, and is found worldwide in about 1:10,000 males; the most severe form is less common, appearing in 1:16,000 males.

Hemophilia B

This X-linked genetic disorder, sometimes called Christmas disease (after one of the first patients in whom it was recognized) is a deficiency of the blood clotting factor IX, or plasma thromboplastin component, which is normally produced by the liver. Like hemophilia A, patients with hemophilia B bleed uncontrollably when injured, and the disease is carried almost exclusively by females; males are almost exclusively afflicted. The degree of severity depends where on the gene the defect is found. Hemophilia B is relatively rare, occurring in at least 1:50,000 people; some estimates are 1:25,000.

Hemophilia C

Hemophilia C is extremely rare, occurring in about 1:100,00 people; it is the only type of hemophilia that can be expressed equally in either males or females. It is marked by a deficiency of the blood clotting factor XI, although, unlike hemophilia A and B, the level of factor XI does not correspond to the disease's severity. Hemophilia C is especially prevalent (1:10,000) among Ashkenazi Jews; in Israel it is estimated to affect 8% of the population.

Disseminated intravascular coagulation disorder (DIC)

Unlike hemophilia, DIC, also known as consumption coagulopathy or defibrination syndrome, is neither hereditary nor common. It is almost always caused by another disease or condition, which in turn activates abnormal and uncontrolled clotting. This causes many small blood clots to form throughout the body, giving the disease its name. This overproduction of clots depletes the supply of clotting factors and platelets necessary to prevent hemorrhage when an injury (or surgery) occurs. Patients with DIC will bleed abnormally even though there is no history of coagulation disorder.

Thrombocytopenia (TCP)

Thrombocytopenia is a group of bleeding disorders characterized by severely diminished platelet counts, which cause internal bleeding. TCP can occur during pregnancy, as a reaction to certain medications, when the spleen and lymph produce antibodies against platelets, or for no known reason, a type called idiopathic TCP.

Other bleeding disorders

Von Willebrand's disease (vWD), also called pseudohemophilia B, vascular hemophilia, or angiohemophilia, is a hereditary disorder, that, like hemophilia, is connected with a factor VIII deficiency and causes uncontrolled bleeding. Unlike hemophilia, however, the true deficiency is the von Willebrand factor, a blood plasma protein that helps transport and protect factor VIII platelets and also helps platelets adhere to tissue at wound sites and also. A further distinction is that both males and females can be affected, making vWD the most common type of bleeding disorder. There are three types of the disease. The first two are mild; the third is the most severe, and must be inherited from both parents.

Hypoprothrombinemia, or factor II deficiency, is a lack of prothrombin (or factor II) that can lead to hemorrhage. The genetic type of the disorder is very rare, and must be inherited from both parents to emerge. Acquired factor II deficiency can result from vitamin K deficiency, liver disease, and several types of gastrointestinal disorders.

Factor VII deficiency, also called proconvertin deficiency or serum prothrombin conversion accelerator (SPCA) deficiency, can be either congenital or acquired through disease, use of anticoagulants, or malnutrition. The congenital form is often diagnosed when newborns react to the trauma of birth with intracranial bleeding. The disease is quite rare, with 1:500,000 people, both males and females, afflicted.

Causes and symptoms

Hemophilia

Hemophilia A is usually inherited through a complex genetic system that passes a recessive gene on the female chromosome. If a woman carries the hemophila gene, each of her male children has a 50% chance of having hemophilia; each female child has a 50% chance of carrying the gene. About a third of all hemophilia patients develop the disease with no known genetic risk; these cases, called sporadic hemophilia, are assumed to be the result of spontaneous genetic mutation.

Hemophilia A is suspected with when patients exhibit numerous large, deep bruises along with painful and swollen joints caused by internal bleeding. Mild hemophilia may first be discovered when prolonged bleeding follows a surgical procedure. If this involves bleeding into the neck, head, or digestive tract, or of the bleeding is caused by an injury, emergency measures may be required.

Hemophilia B

Hemophilia B is also hereditary but less common than hemophilia A. Its severity varies from mild to severe, although mild cases are more common. Hemophilia B symptoms are similar to those of hemophilia A, including numerous large and deep bruises and prolonged bleeding. The more dangerous symptoms are those that represent possible internal bleeding, such as swollen joints or bleeding into internal organs upon trauma.

Hemophilia C

Nearly 50% of patients with this disorder experience no symptoms, but others may notice blood in their urine, nosebleeds, or bruising. Although joint bleeding seldom occurs, some patients will experience bleeding long after an injury occurs. Some women will experience prolonged bleeding after childbirth.

Disseminated intravascular coagulation

DIC has a number of causes, and it is not thoroughly understood why or how they lead to the coagulation problem. It is known, however, that DIC's underlying causes share factors that affect proteins, platelets, or other clotting factors and processes. For example, uterine tissue can enter the mother's circulation during prolonged labor, thus introducing foreign proteins into the blood; the venom of some exotic snakes can activate one of the clotting factors; severe head trauma can expose blood to brain tissue. No matter the cause, the results are a malfunction of thrombin (an enzyme) and prothrombin (factor II), which activate the fibrinolytic system, releasing clotting factors in the blood. DIC can alternate from hemorrhage to thrombosis, and both can exist, which further complicates diagnosis and treatment.

Symptoms may include minute hemorrhage spots on the skin, and purple patches or hematomas caused by bleeding in the skin. Patients may also bleed from surgery or intravenous injection (IV) sites. Related symptoms include vomiting, seizures, coma, shortness of breath, shock, severe pain in the back, muscles, abdomen, or chest.

Thrombocytopenia

Thrombocytopenia, a defective or decreased production of platelets (thrombocytes), may be acquired or congenital. The most common cause of acquired TCP is medication use-mainly heparin or chemotherapy agents (also some antibiotics). Symptoms include sudden onset of petechia or purpura, or bleeding into mucous membranes (such as nosebleeds). The disorder may also be evident as blood in vomit or stools, or unusually heavy menstrual flow in women. Some patients show none of these symptoms, but complain of fatigue and general weakness.

Thrombocytopenia has several causes, most of which are more commonly acquired as a result of another disorder. Common underlying disorders include leukemia, drug toxicity, or aplastic anemia, all of which lead to decreased or defective production of platelets in the bone marrow. Other diseases, such as severe infection, disseminated intravascular coagulation, and cirrhosis of the liver may destroy platelets outside the marrow. The idiopathic form most commonly occurs in children, and is most likely the result of production of antibodies in the spleen and liver that destroy platelets.

Other bleeding disorders

Von Willebrand's disease is caused by a defect in the von Willebrand clotting factor, a blood chemical that regulates the production and availability of factor VIII. In rare cases, it may be acquired. Symptoms include easy bruising, bleeding in small cuts that stops and starts, abnormal bleeding after surgery, and abnormally heavy menstrual bleeding. Nosebleeds and blood in the stool with a black, tarlike appearance are also signs of von Willebrand's disease.

Hypoprothrombinemia is a very rare deficiency in prothrombin, or factor II, a glycoprotein formed and stored in the liver. Unlike hemophilia, both parents must be carriers for the disease to occur. Under normal conditions, prothrombin is converted to thrombin as part of the clotting cascade, which activates fibrin and begins the process of coagulation. Some patients may show no symptoms while others will suffer severe hemorrhaging. Patients may experience easy bruising, profuse nosebleeds, postpartum hemorrhage, excessively prolonged or heavy menstrual bleeding, and postsurgical hemorrhage. Hypoprothrombinemia may also be acquired rather than inherited, usually as a result of vitamin K deficiency caused by liver diseases, newborn hemorrhagic disease, or a number of other factors.

Factor VII deficiency causes varying types and degrees of bleeding, depending on the severity of the disease. Patients may bleed from the gums or nose, within the skin, or into the joints, stomach, intestine, and urinary tract. Women may experience heavy menstrual bleeding.

Diagnosis

There are hundreds of different tests to detect various bleeding disorders, each one geared to the hallmarks of the specific disease. In addition to blood tests, physicians will compile a medical history and perform a physical examination. In the case of acquired blood coagulation disorders, information such as prior or current diseases and medications will be important in determining the cause of the bleeding disorder.

Hemophilia A

Hemophilia A (factor VIII deficiency) will be diagnosed with laboratory tests detecting presence of clotting factor VIII, factor IX (to distinguish it from hemophilia B), and others, as well as the presence or absence of clotting factor inhibitors.

Hemophilia B

Tests for hemophilia B look for diminished levels of factor IX, along with analyses of prothrombin and thromboplastin.

Hemophilia C

Hemophilia C (factor XI deficiency) is diagnosed with a test to measure the amount of factor XI in the blood.

Disseminated intravascular coagulation

Disseminated intravascular coagulation can be diagnosed through a number of laboratory tests that measure the concentration of platelets and fibrinogen in the blood with normal counts and prolonged prothrombin time. Other supportive data include diminished levels of factors V, VIII, and fibrinogen, hemoglobin, and other chemicals. Since many of the test results also indicate other disorders, the physician may have to put together several results to reach a diagnosis of DIC. Serial tests may also be recommended, because a single examine at one moment in time may not reveal the process that is occurring.

Thrombocytopenia

Tests for thrombocytopenia include coagulation tests revealing a decreased platelet count, prolonged bleeding time, and others. If these tests indicate that platelet destruction is causing the disorder, the physician may order bone marrow examination.

Other bleeding disorders

Von Willebrand's disease will be diagnosed with laboratory tests that show prolonged bleeding time, absent or reduced levels of factor VIII and von Willebrand factor, a normal platelet count, and others.

Hypothrombinemia is diagnosed by medical history and tests that measure deficiencies in vitamin K, prothrombin, and clotting factors V, VII, IX, and X.

Factor VII deficiency can be diagnosed with blood tests that show a diminished level of factor VII in the blood, along with other blood tests showing a prolonged prothrombin time and normal partial thromboplastin time.

Treatment

For mild bleeding disorders, treatment may involve drugs that help the body increase the amount of clotting factors available. In severe cases, however, bleeding may only stop if the missing clotting factor that is replaced through fresh frozen plasma or cryoprecipitate, the blood fraction containing factor VIII. Every care must be taken to ensure that these infusions are free of HIV and other contaminants. Unfortunately, for many patients, this was not always the case, and many hemophiliacs, like Ryan White, contracted AIDS. New bioengineered therapies that rely on recombinant DNA technology should prevent any possibility of transferring HIV/AIDS.

Hemophilia A

Mild-to-moderate forms of hemophilia A may be controlled with desmopressin acetate, a synthetic form of a pituitary hormone that rapidly increases that amount of available factor VIII and von Willebrand factor. This drug is called DDAVP in the injectable form, and Stimate when formulated as a nasal spray. Severe bleeding episodes will require transfusions of human blood clotting factors. Many hemophiliacs, however, have become resistant to this form of treatment and have developed antibodies against it. For these patients, a synthetic protein called factor VIIa (tradename NovoSeven) can increase coagulation or prevent bleeding episodes altogether. Factor VIIa is made with recombinant DNA technology. Fetal tissue implants and gene therapies are also being studied as possible treatments for hemophilia.

Hemophilia B

The treatment for hemophilia B is similar to that for hemophilia A, with the infusion of synthetic and human blood products, such as factor IX concentrate or factor IX complex (prothrombin) concentrate, to promote coagulation.

Hemophilia C

Hemophilia C is most often treated with plasma, since concentrates of factor XI are not universally available in the United States, due to the disease's extreme rarity.

Disseminated intravascular coagulation

Treatment for DIC depends on what other disease is causing it. If the patient is not yet actively bleeding, the underlying cause should be dealt with. This supportive treatment may eliminate the DIC and the need for emergency measures. In some instances, heparin, an anticoagulant, is used to dissolve the small clots throughout the body; given that DIC can result in hemorrhage, this therapy is controversial. If bleeding has begun, however, the patient may need infusions of blood, platelets, plasma, and other blood products. Heparin should not be used to treat DIC caused by heatstroke, snakebite, trauma, mismatched transfusions, and acute problems resulting from obstetrical complications, nor should it be administered to patients with head injuries or central nervous system bleeding.

Thrombocytopenia

Secondary acquired thrombocytopenia is best alleviated by treating the underlying cause or disorder. Sometimes, no treatment is necessary; the condition will resolve by itself. If treatment is required, it will depend on the underlying cause. Platelet transfusions can help alleviate TCP caused by chemotherapy, for example. In other cases, corticosteroids or immune globulin may be given to improve platelet production.

Other bleeding disorders

Von Willebrand's disease often requires no treatment because the bleeding is mild and controllable. DDAVP can help raise levels of the Von Willebrand factor and is the treatment of choice for many cases. However, if trauma or surgery is scheduled there are several methods that will reduce bleeding time and replace factor VIII, which will consequently replace the von Willebrand factor. This may include infusion of cryoprecipitate or plasma,. For severe bleeding, infusions of a viral inactivated factor VIII products such as Humane-P, Alphanate, and Koate DVI may be required.

Hypoprothrombinemia may be treated with concentrates of prothrombin. Acquired cases are often treated with vitamin. In bleeding episodes, the patient may receive plasma products.

Factor VII deficiency patients may be treated with normal plasma or concentrates containing factor VII or the biomedically engineered VIIa.

Prognosis

The prognosis for patients with mild forms of bleeding disorders is good; many lead normal lives and enjoy a normal life expectancy. Untreated bleeding episodes, however, cause severe muscle and joint pain that eventually becomes permanent damage. Any incident that causes blood to collect in the head, neck, or digestive system can be fatal without immediate medical attention.

The clots that form throughout the body with DIC can produce gangrene in the fingers, nose, or genitals, and can even cause strokes. The prognosis depends on early intervention and treatment of the underlying condition.

Health care team roles

Patients must communicate with their health care providers before undergoing procedures or tests that could cause bleeding. The best care is obtained when treatment is coordinated by a health care team with expertise in the field. The Centers for Disease Control and Prevention found that patients with severe or moderate hemophilia had 60% less mortality and morbidity when their treatment was coordinated by a comprehensive hemophilia treatment compared to those not seen by a comprehensive hemophilia treatment center.

Other health care providers, such as counselors, may help patients cope with their conditions or illnesses. Support groups can also be helpful in understanding the specific condition and in achieving goals for personal wellness.

Prevention

It is not always possible to prevent bleeding disorders. Some acquired conditions may be prevented by preventing underlying diseases such as cirrhosis, or discontinuing medications whose side effects cause bleeding. Hereditary disorders can be predicted with prenatal testing and genetic counseling. severe bleeding episodes may be prevented by refraining from activities that could cause injury, such as contact sports.

Key Terms

Blood clot

A clump of blood that forms as a result of coagulation when a blood vessel is injured. Without this process a person would bleed to death from a relatively small wound.

Coagulation

The blood's change from a liquid to a semisolid state through chemical reaction.

Clotting factor

Any of several components normally found in blood that are essential for clotting to occur.

Enzyme

A substance that causes a chemical reaction, usually a protein. Enzymes are secreted by cells.

Hemorrhage

Abnormal, uncontrolled bleeding from the blood vessels, usually internally.

Heparin

An anticoagulant; a drug used to dissolve or prevent the formation of blood clots.

Idiopathic

Refers to a disease of unknown cause.

Petechiae

Small pinpoint bruises caused by bleeding under the skin.

Platelets

Also called thrombocytes, these are small, colorless particles found in the only in mammalian blood that help form clots, keep various body chemicals in circulation, and devour foreign bodies, such as viruses.

Purpura

Purplish discoloration of the skin caused by bleeding into the skin and mucous membranes.

Thrombosis

Formation of a clot that either blocks or partially blocks a blood vessel. The thrombus may lead to infarction, or tissue death.