Clotting factors are components found in plasma that are linked to the blood clotting process. These factors are named and numbered based on their discovery.
-Factor I (fibrinogen) -Factor VIII (antihemophilic factor).
-Factor II (prothrombin) -Factor IX (plasma thromboplastin component)
-Factor III (tissue thromboplastin/tissue factor) -Factor X (Stuart-Prower factor)
-Factor IV (ionized calcium) -Factor XI (plasma thromboplastin antecedent)
-Factor V (labile factor or proaccelerin) -Factor XII (Hageman factor)
-Factor VII (stable factor or proconvertin) -Factor XIII (fibrin-stabilizing factor)
Hemostasis is the process in which bleeding is stopped. Blood clotting occurs in a multi-step process known as “the coagulation cascade”. The blood clotting process is complex and involves many reaction however can be summarized in three steps.
–Blood Vessel Constriction : The body will constrict the blood vessel to control blood loss. It will limit the blood flow to the affected area.
–Activation of platelets : In response to the injury, the body activates platelets. At the same time, chemical signals are released from small sacs in the platelets to attract other cells to the area. They make a platelet plug by forming a clump together in the broken walls of blood vessels. A protein called the Von Willebrand Factor (VWF) helps the platelets to stick together.
-Formation of a blood clot (Fibrin clot) : The clot contains fibers that trap the platelets and is stronger and longer-lasting than the platelet plug.
Hemophilia is an inherited rare bleeding disorder in which blood does not clot normally because body does not produce sufficient blood clotting factors. People with hemophilia do not bleed any faster than normal, but they can bleed for a longer time.
The most common type of hemophilia is Hemophilia A or Classical Hemophilia and is caused by having reduced levels of factor VIII (8). Hemophilia B or Christmas Disease is less common and is caused by having reduced levels of factor IX (9).
Hemophilia occurs predominantly in males with occurrence rate of 1 in 10000. In Nepal, there are around 600 people diagnosed with hemophilia.
|Degree of Hemophilia||Factor activity level in blood||Characteristics|
|Severe||1% or less|
|Frequent spontaneous bleeds.|
Coagulation screening always abnormal.
|Moderate|| 1 – 5% |
(>0.01 – 0.05 IU)
|Few spontaneous bleeds. Bleeding after minor trauma.|
Prolonged partial thromboplastin time.
|Mild|| 5 – 30%|
(>0.05 – 0.3 IU)
|Bleed only after trauma or surgery.|
Coagulation screen tests may be low normal.
|Very Mild|| 30 – 50%|
(>0.3 – 0.5 IU)
|May or may not bleed abnormally.|
Coagulation screen tests often normal.
*About one third of carriers have levels between 15 and 50%.
The signs of Hemophilia A and Hemophilia B are similar. Here are major Symptoms
Where does bleeding occur?
People with hemophilia can bleed inside or outside the body. Most bleeding in hemophilia occurs internally, into the muscles or joints. The most common muscle bleeds occur in the muscles of the upper arm and forearm, the iliopsoas muscle (the front of the groin area), the thigh, and the calf. The joints that are most often affected are the knee(45%), elbow(30%) and ankle(15%).
If bleeding occurs many times into the same joint, the joint can become damaged and painful.
Repeated bleeding can cause other health problems like arthritis. This can make it difficult to walk or do simple activities. However, the joints of the hands are not usually affected in hemophilia (unlike some kinds of arthritis).
|Types of Hemorrhage||Prevalence(%)|
|Joints||70 – 80|
|Other major bleeds||5 – 10|
|CNS (brain) bleeds||<5|
The first step in diagnosis is a detailed personal and family history with specific questions about the occurrence of bleeding episodes in close relatives. In any person with prolonged or unexplained bleeding the possibility of hemophilia should be considered and tests done.
The second step is the performance of tests for hemostatis: bleeding time, activated partial prothrombin time(APTT) and prothrombin time(PT). If the APTT is abnormal or bleeding history is suggestive then specific Factor assays should be performed and these may need to be referred to a more specialized hospital.
If the mother is a known carrier of hemophilia, testing can be done before a baby is born. Prenatal diagnosis can be done at 9 to 11 weeks by chorionic villus sampling (CVS) or by fetal blood sampling at a later stage (18 or more weeks).
Humans have 23 pairs of chromosomes. 22 of these pairs look the same in both males and females. However, the 23rd pair differ between males and females. At the 23rd pair, females have two copies of the X chromosome(XX), while males have one X and one Y chromosome(XY).
The gene with the instructions for making factor is found only on the sex chromosome labeled X. If the gene is faulty the result is hemophilia. This explains why mostly males have hemophilia.
Hemophilia is usually inherited, meaning that it is passed on through a parent’s genes. Sometimes hemophilia can occur when there is no family history of it. About 30% or one third of people with hemophilia did not get it through their parent’s genes. It was caused by a change in the person’s own genes.
Mode of inheritance
– When the father has hemophilia, and the mother does not carry the hemophilia gene.
-when the mother is a carrier of the hemophilia gene, and the father does not have hemophilia.
Hemophilia being genetic disorder, there aren’t any permanent treatments available. Though there are few solutions for treating the bleeds either before occurring or on the demand basis. This treatment products are given intravenously at right doses and intervals as prescribed by hematologists or hemophilia trained physicians.
Bleeding should be treated as quickly as possible. Quick treatment will help reduce pain and damage to the joints, muscles, and organs. If bleeding is treated quickly, less treatment product is needed to stop the bleeding and quick recovery is possible.
Factor concentrates are the treatment of choice for hemophilia. They can be made from human blood (called plasma-derived products) or manufactured using genetically engineered cells that carry a human factor gene (called recombinant products). Factor concentrates are made in sophisticated manufacturing facilities. All commercially prepared factor concentrates are treated to remove or inactivate blood-borne viruses.
Cryoprecipitate is derived from blood and contains a moderately high concentration of clotting factor VIII (but not IX). It is effective for joint and muscle bleeds, but is less safe from viral contamination than concentrates and is harder to store and administer. Cryoprecipitate can be made at local blood collection facilities.
In fresh frozen plasma (FFP) the red cells have been removed, leaving the blood proteins including clotting factors VIII and IX. It is less effective than cryoprecipitate for the treatment of Hemophilia A because the factor VIII is less concentrated. Large volumes of plasma must be transfused, which can lead to a complication called circulatory overload. FFP is still the only product available for treatment of Hemophilia A and B in some countries.
Prophylaxis is the regular infusion of missing clotting factor concentrates in order to prevent bleeding from occurrence. Doctors believed that if they could keep minimum factor levels around 1% with regular infusions of clotting factor concentrates, they may reduce the risk of bleeding and prevent joint damage. Studies have shown that children who receive prophylaxis do have fewer bleeds and healthier joints.
Inhibitors are a serious medical problem that can occur when a person with hemophilia has an immune response to treatment with clotting factor concentrates. In the case of an inhibitor, a person’s immune system reacts to proteins in factor concentrates as if they were harmful foreign substances. When this happens, inhibitors (also called antibodies) form in the blood to fight against the foreign factor proteins. This stops the injected factor concentrates from working.
Inhibitors occur more often in individuals with severe hemophilia than those with moderate or mild hemophilia and more often in Hemophilia A than Hemophilia B. Most patients who develop inhibitors do so within the period of the first 75 exposures to factor concentrates, with the greatest risk occurring between the first 10-20 treatments.
Inhibitors are suspected when the person, family members, or medical staff notice that treatment is less effective than it used to be.
In order to confirm the diagnosis, a Bethesda assay is performed. This test can determine the strength (titer) of the inhibitor. However, the Bethesda is not available in many laboratories because it requires specialized expertise.
Inhibitor levels vary from one individual to another and can also vary within the same person over time. The amount of inhibitors in a person’s blood is measured in Bethesda Units (BU) and referred to as “high titer” (more than 5 BU) or “low titer” (less than 5 BU).
People with inhibitors are more difficult to manage and treat than people without inhibitors. There are few options available in country like ours.
-High-dose factor concentrates: Administering factor concentrates at higher doses and/or more frequent intervals is the preferred treatment for acute bleeding in low titre. The person’s factor level should be measured right after each infusion to make sure that target levels are reached. However, it is vital to take into account that the anamnestic response will get stronger within five to seven days, at which time treatment should be switched to bypassing agents.
– Bypassing agents : Bypassing agents, such as activated prothrombin complex concentrates (APCC, eg: FEIBA) and recombinant factor VIIa (rFVIIa, eg:Novoseven), are used to treat acute bleeding in people with high titer inhibitors. However, these treatment products are expensive and not always available in every country.
Rare clotting factor deficiencies are a group of inherited bleeding disorders caused by a problem with one or several clotting factors . Either of the following factors are missing or not working properly that is Factors I, Factor II, Factor V, Combined (Factor V and Factor VIII), Factor VII, Factor X, Factor XI, or Factor XIII.
Factor I, II, V, Combined (V+VIII), VII, X, XIII deficiency are “Autosomal Recessive Disorder”, which means that both parents must carry the defective gene in order to pass it on to their child. It also means that the disorder affects both males and females.
Factor XI deficiency is also called hemophilia C. Factor XI deficiency is the most common of the rare bleeding disorders and the second most common bleeding disorder affecting women (after Von Willebrand Disease,VWD).
Common treatment for all of the above rare clotting factor deficiencies seems to be Fresh frozen plasma (FFP).
People with VWD have a problem with a protein in their blood called Von Willebrand Factor (VWF) that helps control bleeding. They do not have enough of the protein or it does not work the way it should. It takes longer for blood to clot and for bleeding to stop. VWD is the most common bleeding disorder worldwide. It is estimated that up to 1% of the world’s population suffers from VWD, but because many people have only very mild symptoms, only a small number of them know they have it.
In rare cases, a person can develop hemophilia later in life. The majority of cases involve middle-aged or elderly people, or young women who have recently given birth or are in the later stages of pregnancy. This condition often resolves with appropriate treatment.