HEMOPHILIA

Disease

Brief Summary

Hemophilia is typically an inherited bleeding condition in which there is no adequate coagulation of the blood. This can lead to uncontrolled bleeding after injuries or surgery as well as bleeding. There are low levels of either factor VIII (8) or factor IX (9) in people with hemophilia. The severity of hemophilia that an individual has is determined by the amount of blood factor. The smaller the amount of the factor, the more likely it is that there will be bleeding that can lead to serious health problems.

Source

Image:

Hemophilia under a microscope

Frequency

Hemophilia occurs more commonly in males than in females. Hemophilia A is the most common type.

Ten thousand Filipinos are estimated to have hemophilia. Only about 1,500 have been registered with the Philippine Hemophilia Foundation.

Brief Summary

Inheritance

Hemophilia A is an X-linked recessive disorder and usually occurs in males. In familial cases, the affected boy has inherited the mutant gene from his carrier mother, but about 30% of cases arise from a spontaneous mutation Hemophilia A may occur in females because of the inheritance of defective F8 genes from both parents or on the basis of an autosome translocation disrupting the structure of the gene.

Hemophilia B is classically transmitted as an X-linked recessive disorder

History of Disease

John Conrad Otto, a doctor from Philadelphia, was the first to publish a report in 1803 acknowledging that a hemorrhagic bleeding condition mostly afflicted men and ran in some families. In 1720, he traced the illness back to a female ancestor living in Plymouth, New Hampshire. In 1813, a paper was published by John Hay in the New England Journal of Medicine suggesting that affected men might transfer the trait to their unaffected daughters for a bleeding condition. John Otto called the males "bleeders." Then Friedrich Hopff, a student at the University of Zurich, and Dr. Schonlein, his professor, was given the credits with coining the word "haemorrhaphilia" for the condition in 1828, later shortened to "haemophilia."

History of Disease

Pathogenesis

Achondroplasia is caused by a mutation in the FGF3 gene in chromosome 4 at 4p 16.3. This mutation causes a decreased production of fibroblast growth factor receptor 3 which is crucial in the conversion of cartilage into bone which is vital in the proper development of a person. This mutation is inherited in an autosomal dominant manner. More than 80 percent of people with achondroplasia have parents with normal characteristics and are born with achondroplasia due to a recent (de novo) gene modification (mutation).

Pathogenesis

Hemophilia A and B are both caused by a mutation or alteration in one of the genes that provides instructions for producing the proteins required for the clotting factor to form a blood clot. This alteration or mutation will prevent the clotting protein from functioning properly or from being completely absent. These genes responsible are found on the X chromosome .

Hemophilia A - Genetic variations (mutations) in the F8 gene are the cause of hemophilia A. This gene is responsible for producing the protein, Factor VIII, an essential protein that helps to start blood clot formation. F8 gene mutations contribute to decreased or absent blood Factor VIII levels, making it difficult for the body to form blood clots.

Hemophilia B - Hemophilia B is caused by an inherited or acquired mutation in the F9 gene.

Mode of Inheritance - Both Hemophilia A and B are X-linked recessive disorders

The following examples illustrate how it is possible to inherit the hemophilia gene. It is important to remember that 1/3 of people with hemophilia, there is no family history of the disorder.

While hemophilia exists in families, some families have no prior history of family members who have hemophilia. In some families, there are often carrier females, but no affected males, just by chance. However, 1/3 of the time, the baby with hemophilia is the first in the family to be affected by a mutation in the clotting factor gene.

Source

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Mutated chromosome by Hemophilia

Source

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Inheritance pattern of hemophilia

Symptoms

Bleeding of joints

Bleeding into the skin

Bleeding of the mouth and gums

Bleeding after having shots (vaccination)

Blood in the urine or stool

Social Concerns

People with hemophilia often have depression since they tend to be different than the normal person. Sometimes they aren't allowed to do other activities such as engaging in hard exercises or sports. They have the mindset that they cannot be like other people who are free to do anything they want without causing harm to their body. They also become anxious when they go out and live their everyday life, since symptoms can happen anytime as their body is more delicate compared to the average person. Hemophilia replacement therapy is also typically very costly and it appears to be much more costly for patients with inhibitors. This will be a huge blow to the family financially speaking. For patients with inhibitors, it will be very difficult for the family to handle as financial and emotional challenges arises.

Treatment

Examples of Screening Tests

Complete Blood Count (CBC) - measures the amount of hemoglobin, the size and number of RBC and the numbers of different types of WBC and platelets present in the blood. In individuals with hemophilia, the CBC is normal. However, if there is abnormal bleeding or bleeding for a long time in a person with hemophilia, the amount of hemoglobins and RBC can become low.

Activated Partial Thromboplastin Time (APTT) Test - measures the amount of time it takes for blood to coagulate. It tests the capacity of factors 8, 9, 11 and 12 to coagulate. It takes longer than normal for the blood to clot if all of these clotting factors are too poor. The results of this test would show that people with hemophilia A or B have a longer clotting period.

Prothrombin Time (PT) Test - measures the amount of time it takes to clot blood. It primarily tests the ability of factors 1, 2, 5, 7 and 10 to coagulate. It takes longer than average for the blood to clot if either of these variables are too low. In most people with hemophilia A and B, the results of this test will be normal.

Fibrinogen Test - helps doctors determine the capacity of a patient to shape a blood clot. This test is requested either when a patient has an irregular PT or APTT test result, or both, along with other blood clotting tests.

Clotting Factor Tests - also called factor assays, are required to diagnose a bleeding disorder. The type of hemophilia and the severity are indicated by this blood test. In order to develop the right recovery plan, it's crucial to know the form and severity.

Severity Levels of Factor 8 or 9 in the blood

Normal (person who does not have hemophilia) 50% to 100%

Mild hemophilia Greater than 5% but less than 50%

Moderate hemophilia 1% to 5%

Severe hemophilia Less than 1%

Available clinical treatments:

Replacing the missing blood clotting factor so that the blood can clot properly is the safest way to treat hemophilia. Usually, this is achieved by injecting medication products into the vein of an individual, called clotting factor concentrate. For episodic care or prophylactic care, physicians usually prescribe medication items. Episodic therapy is used to prevent bleeding episodes in a patient; prophylactic medication is used to avoid the occurrence of bleeding complications. Today people affected with hemophilia and their families can learn how to provide care products at home with their own clotting factor. Giving home treatment items with the clotting factor means that bleeding can be managed more easily, resulting in less severe bleeding and less side effects.

Treatment Centers - Usually, the best choice for care is at a comprehensive hemophilia treatment center (HTC). An HTC offers the treatment and education of patients to solve all concerns related to the condition. The team consists of doctors (hematologists or blood specialists), nurses, social workers, physiotherapists, and other specialists in the treatment of people with bleeding disorders.

Clotting Factor Products:

Plasma-derived Factor Concentrates - This concentrate is made from human blood which is donated by healthy volunteers and screened for safety. These products have been used by people with hemophilia since the 1970s.

Recombinant Factor Concentrates - This concentrate is genetically modified using DNA technology. In order to eliminate or inactivate bloodborne viruses, commercially prepared factor concentrates are processed. Furthermore, recombinant factors 8 and 9 do not contain plasma or albumin and are thus not capable of transmitting any blood-borne virus.

Other Treatment Products:

Hemlibra® (also known as ACE 910 or emicizumab)

DDAVP® or Stimate® (Desmopressin Acetate)

Amicar® (Epsilon Amino Caproic Acid)

Cryoprecipitate

Source

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Treatment for hemophilia

Clinical Trials

Title:

A Phase III Open Label, Multicenter, Extension Study to Assess the Safety and Efficacy of Recombinant Coagulation Factor VIII (rVIII-SingleChain, CSL627) in Subjects With Severe Hemophilia A

Intervention:

Biological - rVIII-SingleChain

Phase:

Phase 3

Procedure:

This multicenter, open-label, phase 3 extension study will investigate the safety and efficacy of rVIII-SingleChain for prophylaxis and on-demand treatment of bleeding episodes in at least 200 previously treated patients (PTPs) with severe congenital hemophilia A and previous exposure to FVIII products who achieve at least 100 exposure days (EDs) to rVIII-SingleChain in this study, as well as in previously untreated patients (PUPs) with no previous exposure to any FVIII product who achieve at least 50 EDs to rVIII-SingleChain in this study. A substudy (open to both PTPs and PUPs) will investigate the use of rVIII-SingleChain in surgery. A substudy (open to PUPs who develop an inhibitor to rVIII-SingleChain) will investigate the use of rVIII-SingleChain in immune tolerance induction (ITI) therapy.

Goal:

Percentage of major bleeding episodes treated successfully where treatment success for a bleeding episode is defined as a rating of "excellent" or "good" on the investigator's clinical assessment of hemostatic efficacy 4-point scale "excellent, good, moderate or poor/no response". Major bleeding episodes are defined as bleeding episodes for which a subject is required to seek treatment at the hemophilia center or that threatens the subject's life or loss of limb.

Further details at:

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor. Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02172950

Clinical Trials

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