Question

Defects of Plasma Clotting Factors

If you could please answer the following to help me with my review

1. The APTT is sensitive to a deficiency of which clotting factor?

2. Which clotting factor is associated with a prolonged PT and APTT?

3. Describe the role of vitamin K with regard to maintaining hemostasis.

4. What laboratory test are performed when diagnosing hemophilia patients?

5. What are the three levels of clotting factor activity in hemophilia?

Answer 1

Bleeding disorders are characterized by defects in hemostasis that lead to an increased susceptibility to bleeding. They are caused either by platelet disorders (primary hemostasis defect), coagulation defects (secondary hemostasis defect), or, in some cases, a combination of both. Coagulation defects may be general or further divided into either intrinsic or extrinsic defects according to the specific pathway of the coagulation cascade that is affected. Bleeding disorders may be inherited or acquired. Although clinical features of inherited and acquired disorders may overlap, mucocutaneous bleeding (e.g., epistaxis, petechiae, gastrointestinal bleeding) is associated more with platelet disorders, while bleeding into potential spaces (e.g., hemarthrosis, muscular bleeding) is more characteristic of coagulation defects. A basic understanding of hemostasis is necessary for properly interpreting laboratory studies in order to accurately diagnose the disorder and ensure appropriate treatment. Coagulation factors may be measured by methods assessing both their presence as antigens and their ability to function as an activity. Inherited coagulation factor deficiencies may be of two types. Type I defects (quantitative) have decreased absolute amounts of the factor, resulting in both decreased activity and antigen levels. Type I defects result from a lack of production or increased clearance of the gene product. Type II defects (qualitative) have a defective gene product, resulting in decreased activity but normal or slightly decreased levels of antigen. Type II defects result from a mutation in the gene or altered post-translational modification. Acquired defects may mimic either type by decreased or faulty production, increased clearance or inactivation, or the presence of a circulating inhibitor, usually an antibody, which reacts with the factor to mask its activity or remove it from the circulation

Clotting factors (II, VII, IX, and X) are dependent on vitamin K which is a fat-soluble vitamin. Vitamin K deficiency, therefore, causes prolongation of the prothrombin time (PT) and activated partial thromboplastin time (aPTT) and will respond to intravenous vitamin K. It should be noted that the PT and aPTT are not good predictors of the bleeding risk of a patient, as some clotting disorders associated with thrombosis (e.g. antiphospholipid antibodies) will cause a prolongation of the aPTT.

Activated partial thromboplastin time (PTT) is a routine coagulation screening test that is sensitive to declines of activities of factors II, V, VIII, IX, XI, XII

Vitamin K helps to regulate the process of blood coagulation by assisting in the conversion certain coagulation factors into their mature forms. Without vitamin K, our bodies would be unable to control clot formation.

Now, to understand the regulation of clot formation, briefly about hemostasis--hemo referring to blood, and stasis meaning to halt or stop.

Hemostasis is divided into two phases: primary and secondary hemostasis.

Primary hemostasis involves the formation of a platelet plug around the site of an injured blood vessel, and secondary hemostasis reinforces the platelet plug with the creation of a protein mesh called fibrin. To get to fibrin, a set of coagulation factors, each of which is enzymes, needs to be activated. These enzymes are activated via a process called proteolysis- which is where a portion of the protein is clipped off. In total, there are twelve coagulation factors numbered factors I-XIII, there’s no factor VI. Most of these factors are produced by liver cells, and it turns out that producing coagulation factors II, VII, IX, and X requires an enzyme that uses vitamin K.

Hemophilia screening tests

Blood tests that are used to determine if the blood is clotting properly are called screening tests. Types of screening tests are complete blood count (CBC), activated partial thromboplastin time (APTT) test, prothrombin time (PT) test, and fibrinogen test.

Complete blood count (CBC)

This test measures the amount of hemoglobin (the red pigment that carries oxygen within the red blood cells), the size and number of red blood cells (RBCs), and the number of white blood cells and platelets in the blood. CBC results are normal in people with hemophilia, but there is a decrease in hemoglobin and RBCs in the case of heavy or prolonged bleeding.

Activated partial thromboplastin time (APTT) test

This test measures the delay in blood clot formation and the clotting ability of factors VIII, IX, XI and XII. If any of the clotting factors are too low, it takes longer for the blood to clot. Patients with hemophilia A or hemophilia B show a longer clotting time in this test.

Prothrombin time (PT) test

This test also measures the time it takes for the blood clot to form. It measures the clotting ability of factors I, II, V, VII, and X. If any of these factors are too low, it takes longer than normal for the blood to clot. The results of this test will be normal for patients with hemophilia A or hemophilia B since these conditions are caused by defects in factors VIII and IX, respectively.

Fibrinogen test

Fibrinogen (also known as clotting factor I) test assesses the patient’s ability to form a blood clot. This test is performed along with other blood clotting tests or when a patient has an abnormal PT or APTT test result.

Clotting factor tests

Clotting factor tests, also called factor assays, are needed to diagnose a bleeding disorder. This blood test is used to identify the type and severity of hemophilia, which is important to create the best treatment plan.

Depending on the levels of clotting factors VIII or IX, hemophilia A and B are classified as mild, moderate or severe. The level of clotting factor is between 50 and 100 percent in healthy people, but it is between 5 and 50 percent in people with mild hemophilia, between 1 and 5 percent in people with moderate hemophilia, and at less than 1 percent in people with severe hemophilia.

The severity of symptoms may sometimes overlap between the categories. For example, patients with mild hemophilia may have bleeding problems similar to those with moderate hemophilia.

Depending on the severity level, hemophilia is classified as mild, moderate or severe.

Mild hemophilia

The clotting factor level in the blood of a patient with mild hemophilia is between 5% and 40% (0.05-0.40 IU/ml). In these cases, bleeding typically occurs only after a trauma, such as surgery or major injury. Otherwise, patients either bleed rarely or may never have a bleeding problem. About 25% of people with hemophilia have the mild form of the disease.

Moderate hemophilia

Patients with moderate hemophilia have between 1% and 5% (0.01-0.05 IU/ml) of clotting factor activity in their blood. They bleed infrequently (perhaps once a month). Prolonged bleeding tends to occur following trauma such as minor surgery or injury, and dental treatment, for example. Spontaneous bleeding episodes, although rare, may occur in patients with this type of hemophilia. About 15% of people with hemophilia have the moderate form of the disease.

Severe hemophilia

Patients with severe hemophilia have less than 1% (0.01 IU/ml) clotting factor activity in their blood. They bleed frequently (sometimes once or twice a week). Bleeding may occur spontaneously into their muscles and joints. Prolonged bleeding occurs following trauma, injury, or surgery, but also may occur spontaneously for no obvious reason.

Variations within severity levels of hemophilia

Regardless of the severity level, the frequency and type of bleeds may vary from one patient to the other. For instance, 10% to 15% of patients with severe hemophilia A have less frequent spontaneous bleeding episodes. This variation in bleeding symptoms within the same severity level may arise due to various reasons, such as the type of mutation within the blood clotting factor genes, mutations in other clotting factor genes, inaccurate clotting factor measurement relative to overall clot formation, variations in the immune system, and environmental factors such as physical activity.