Conventional And Unconventional Medicine In Treating Rare Diseases-�HAEMOPHILIA

Dr. V. Chandrasekhar, MD, FICP

Professor in General Medicine, Kakatiya Medical College,

Superintendent, Mahatma Gandhi Memorial Hospital,

Warangal, Telangana

What Is Rare Disease?

A rare disease is a health condition of a particularly low prevalence that affects a small number of people compared with other prevalent diseases in the general population.

There is no universally accepted definition of rare diseases and the definitions usually vary across different countries

However, the common considerations in the definitions are primarily, disease prevalence and to varying extent - severity and existence of alternative therapeutic options

• Rare diseases include
• genetic diseases
• rare cancers
• infectious tropic diseases and
• degenerative diseases
• 80% of rare diseases are genetic in origin, and thus are present throughout a person’s life, even if symptoms do not immediately appear

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Definitions Of Rare Disease In Different Countries

Indian Scenario

• India, like many other developing countries, currently has no standard definition of rare diseases and data on prevalence. Thus, there are no figures on burden of rare diseases and morbidity and mortality associated with them.
• So far only about 450 rare diseases have been recorded in India from tertiary care hospitals.
• The most common rare diseases include

Haemophilia, Thalassemia, Sickle-cell Anaemia & Primary Immuno Deficiency (PID) in children

Auto-Immune diseases

Lysosomal Storage Disorders such as Pompe disease, Hirschsprung disease, Gaucher’s disease, Cystic Fibrosis, Hemangiomas and certain forms of Muscular Dystrophies.

HAEMOPHILIA

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• Haemophilia is an inherited condition that causes bleeding for a long time after injury or surgery and painful swelling of the joints either after injury or even without injury.

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• Haemophilia is due to a deficiency of clotting factor, this results in increased bleeding. 

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• There are two types of Haemophilia A (clotting factor VIII deficiency), which is more common and occurs in about 1 in 5,000 births. Haemophilia B (factor IX deficiency) is less common and occurs in around 1 in about 20,000 births.

Prevalence of Hemophilia A

China

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Prevalence of Hemophilia A and Hemophilia B

Case detection rate (prevalence) of Hemophilia A (HA) and Hemophilia B (HB) in five countries reporting the highest global number of patients

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How is it inherited?

• The disease of Haemophilia is X linked and inherited from the mother, though the disease is present in males.
• A family history of maternal uncles or other male affected relatives on the mother’s side are often present.
• Though many cases are due to a new acquired mutation in the genes, and in these families, no family history is present.

What Happens In Haemophilia?

• Patients of haemophilia, bleed for a longer time than others after any injury, injections, operations or tooth extractions. They may bleed inside (internally), and in the joints - knees, ankles, and elbows. This bleeding can damage the joints and internal bleeding (head, abdomen) may be life threatening.
• Haemophilia patients bleed for a very long time after injury, and often have delayed bleeding e.g. after a few days after tooth extraction or trauma. Patients with severe haemophilia they can bleed even without injury-spontaneously, this usually occurs in severe haemophilia patients.

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Are there different types of haemophilia?

• Yes, There are two main types
• Haemophilia A (low levels of factor VIII) and
• Haemophilia B (low levels of factor IX).

Severity of haemophilia A or B is based on the amount of factor present in the blood

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• Severe haemophilia have less than 1 % of factor VIII or IX
• Moderate haemophilia have 1-5%  of factor VIII or IX
• Mild haemophilia have greater than 5 – 40%  of factor VIII or IX

Identification of Patients with Hemophilia

Classification Of Hemophilia Based On Diagnosis

• Fijnvandraat K, Cnossen MH, Leebeek FW, Peters M. Diagnosis and management of haemophilia. Bmj. 2012 May 2;344:e2707.

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Patients with mild hemophilia the plasma factor VIII or factor IX concentration is 0.06-0.04 IU/mL (or 6-40%)

Patients with moderate hemophilia the plasma factor VIII or factor IX concentration is 0.02-0.05 IU/mL (or 2-5%)

Patients with severe haemophilia have no measurable factor VIII or factor IX <0.01 1U/mL (or <1%)

Some important sites of bleeding

• The Iliopsoas (a muscle in the hip), is an important site of bleeding.
• Other sites of bleeding are the main joints e.g. knee, ankle, elbow joints are commonly affected.
• Some patients may have bleeding in the brain, even after a very minor injury.
• Occasionally patients may have blood in the urine.

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How Is Haemophilia Diagnosed?

• Family History
• Physical examination
• Serological tests (PT, APTT, Hemophilia A or B)

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Approximate Frequency Of Bleeding at Different Sites

• Srivastava A, Brewer AK, Mauser‐Bunschoten EP, Key NS, Kitchen S, Llinas A, Ludlam CA, Mahlangu JN, Mulder K, Poon MC, Street A. Guidelines for the management of hemophilia. Haemophilia. 2013 Jan;19(1):e1-47.

Haemophilia A is an X-linked genetic disorder

• Haemophilia A results from mutations/defects in the F8 gene located on the X chromosome (Xq28)
• The vast majority (>99%) of identified PWHA are male^1,2
• sons of mothers who are carriers have a 50% chance of having haemophilia, while daughters have a 50% chance of being carriers
• daughters of fathers with haemophilia A always become haemophilia gene carriers; if their mother is also a carrier, they have a 50% chance of having haemophilia
• About two-thirds of PWHA have inherited F8 gene mutations/defects³
• the remaining cases are caused by spontaneous mutations

PWHA, people with haemophilia A

• 1. WFH. Annual global survey. 2013. Available at: http://www1.wfh.org/publications/files/pdf-1591.pdf [Accessed 04 July 2017] 2. CDC. UDC Report. 2014. Patient demographics. Available at: https://www2a.cdc.gov/ncbddd/htcweb/UDC_Report/UDC_view1.asp?para1=NATION&para2=DEMOH&para3 [Accessed 4 July 2017] 3. WFH. Guidelines for the management of haemophilia. 2012. Available at: http://www1.wfh.org/publications/files/pdf-1472.pdf [Accessed 04 July 2017]

How Is Haemophilia Treated?

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• Factor VIII Or IX Replacement Therapy
• Anti Fibrinolytic Medicines
• Somatic Gene Therapy
• Physical Therapy
• Pain relievers other than aspirin or NSAIDs (Aleve, Motrin, ibuprofen), because they decrease the blood's ability to clot
• Topical medications to control bleeding
• Non Factor Therapy : drug Desmopressin (DDAVP) may be used in mild cases of hemophilia A to stimulate low levels of clotting factor
• Surgical and Other Procedures

Certain types of surgery may become necessary, including:

Joint replacement

Removal of an uncontrollable, expanding hematoma (partially clotted blood under the skin that resembles a bruise)

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Overview Of Prevention And Treatment

• Srivastava A, Brewer AK, Mauser‐Bunschoten EP, Key NS, Kitchen S, Llinas A, Ludlam CA, Mahlangu JN, Mulder K, Poon MC, Street A. Guidelines for the management of hemophilia. Haemophilia. 2013 Jan;19(1):e1-47.

Veins must be treated with care during injections they are the lifelines for a person with hemophilia

Prevention of bleeding can be achieved by pro- phylactic factor replacement

Regular exercise and other measures to stimulate normal psychomotor development should be encouraged to promote strong muscles, develop balance and coordination, and improve fitness

Patients should avoid activities likely to cause

trauma

Drugs that affect platelet function, particularly

acetylsalicylic acid (ASA) and non-steroidal anti-inflammatory drugs (NSAIDs), except certainCOX-2 inhibitors, should be avoided

Good oral hygiene is essential to prevent periodontal disease and dental caries, which predispose to gum bleeding

Comprehensive Care

Comprehensive care promotes physical and psychosocial health and quality of life while decreasing morbidity and mortality

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Priorities in the improvement of health and quality of life of people with hemophilia include:

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Management of complications including:

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• Joint and muscle damage and other sequelae of bleeding

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• Inhibitor development

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• Viral infection transmitted through blood

products

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• Srivastava A, Brewer AK, Mauser‐Bunschoten EP, Key NS, Kitchen S, Llinas A, Ludlam CA, Mahlangu JN, Mulder K, Poon MC, Street A. Guidelines for the management of hemophilia. Haemophilia. 2013 Jan;19(1):e1-47.

Adjunctive Management

• Srivastava A, Brewer AK, Mauser‐Bunschoten EP, Key NS, Kitchen S, Llinas A, Ludlam CA, Mahlangu JN, Mulder K, Poon MC, Street A. Guidelines for the management of hemophilia. Haemophilia. 2013 Jan;19(1):e1-47.

Adjunctive therapies are important, particularly where clotting factor concentrates are limited or not available, and may lessen the amount of treatment product required

Protection (splint), rest, ice, compression, and elevation(PRICE)may be used as adjunctive management for bleeding in muscles and joints

Physiotherapy/rehabilitation is particularly important for functional improvement and recovery after musculoskeletal bleeds and for those with hemophilic arthropathy

Antifibrinolytic drugs (e.g., tranexamic acid,epsilon aminocaproic acid) are effective as adjunctive treatment for mucosal bleeds and dental extractions

Certain COX-2 inhibitors may be used judiciously for joint inflammation after an acute bleed and in chronic arthritis

Prophylaxis prevents bleeding and joint destruction and should be the goal of therapy to preserve normal musculoskeletal function

Patients with repeated bleeding in joints, short-term prophylaxis for 4-8 weeks can be used to interrupt the bleeding cycle.

Treatment For Hemophilia

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• Factor concentrates are either prepared by recombinant DNA technology or derived from pools of human plasma

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• Currently there are several recombinant factor VIII (FVIII) products and two recombinant factor IX (FIX) products available with high specific activities (the amount of desired clotting factor per mg of total protein)

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• Plasma-derived clotting factor products are also available

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Factor Replacement Concentrates And Viral Inactivation

• McDaniel M. Treatment of Hemophilia A and B. National Hemophilia Foundation. 2013:1-9.

Recombinant Clotting Factors

Plasma Derived Factor Concentrates

Treatment For Hemophilia

Types of Products Currently used For Replacement Therapy- Hemophilia A

• Coppola A, Di Capua M, Di Minno MN, Di Palo M, Marrone E, Ieranò P, Arturo C, Tufano A, Cerbone AM. Treatment of hemophilia: a review of current advances and ongoing issues. Journal of blood medicine. 2010;1:183.

Treatment For Hemophilia

Types of Products Currently used For Replacement Therapy- Hemophilia B

• Coppola A, Di Capua M, Di Minno MN, Di Palo M, Marrone E, Ieranò P, Arturo C, Tufano A, Cerbone AM. Treatment of hemophilia: a review of current advances and ongoing issues. Journal of blood medicine. 2010;1:183.

Guidelines for Treatment Of Hemophilia- By World Federation Of Hemophilia

• Srivastava A, Brewer AK, Mauser‐Bunschoten EP, Key NS, Kitchen S, Llinas A, Ludlam CA, Mahlangu JN, Mulder K, Poon MC, Street A. Guidelines for the management of hemophilia. Haemophilia. 2013 Jan;19(1):e1-47.

Factor Replacement Therapy Protocols

Treatment Of Mild Hemophilia Using DDAVP

• Some individuals with mild hemophilia A respond to a non-factor product called desmopressin acetate

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McDaniel M. Treatment of Hemophilia A and B. National Hemophilia Foundation. 2013:1-9.

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DDAVP causes (Von Willebrand Factor) to

be released from the

stores in the endothelial

cells that line the blood vessels.

VWF then binds to FVIII as it is released from the liver, protecting it from degradation

Circulating FVIII and VWF levels may rise approximately three-fold in responsive patients

Transient rises in plasma levels of FVIII in mild to moderate Hemophilia A patients

Treatment Of Hemophilia

Use Of Antifibrinolytic Agents

McDaniel M. Treatment of Hemophilia A and B. National Hemophilia Foundation. 2013:1-9.

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Guidelines for Treatment Of Hemophilia- By World Federation Of Hemophilia

• Paracetamol/acetaminophen

(If not effective)

Strategies For Pain Management In Patients With Hemophilia

• Srivastava A, Brewer AK, Mauser‐Bunschoten EP, Key NS, Kitchen S, Llinas A, Ludlam CA, Mahlangu JN, Mulder K, Poon MC, Street A. Guidelines for the management of hemophilia. Haemophilia. 2013 Jan;19(1):e1-47.

COX-2 inhibitor (e.g., celecoxib, meloxicam,

Nimesulide

Paracetamol/acetaminophen plus codeine

(3–4 times per day)

Morphine: use a slow release product with an escape of a rapid release. Increase the slow release product if the rapid release product is used more than 4 times per day

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Evolution of Hemophilia Therapy

Current and Future Approaches to Hemophilia Care

Molecules in Development

Moroctocog alfa : Science behind the Molecule

The Content of this Presentation is only intended for registered healthcare professionals.

The medical information in this Presentation is provided as an information resource only, and is not to be used or relied on for any diagnostic or treatment purpose. Pfizer (including its parent, subsidiary and affiliate entities) makes no representation or warranties of any kind, expressed or implied; as to the content used in the Presentation and/or the accuracy, completeness of its content.

Clinical Particulars

Moroctocog alfa (AF-CC) XYNTHOPHILIA. LPDXYN022019 Pfizer Products India Private Limited. Accessed on 16^th May 2019

The required dosage is determined using the following formula:

Required units = body weight (kg) x desired factor VIII rise (IU/dL or % of normal) x 0.5 (IU/kg per IU/dL)

Dosing for Bleeding and Surgery

• In the case of the following hemorrhagic events, consideration should be given to maintaining the factor VIII activity at or above the plasma levels (in % of normal or in IU/dL) for the indicated period, as outlined in the following table

Moroctocog alfa (AF-CC) XYNTHOPHILIA. LPDXYN022019 Pfizer Products India Private Limited. Accessed on 16^th May 2019

Pharmacokinetic Properties: Moroctocog alfa versus Advate

Moroctocog alfa (AF-CC) XYNTHOPHILIA. LPDXYN022019 Pfizer Products India Private Limited. Accessed on 16^th May 2019

Results: Pharmacokinetics, pharmacokinetic equivalence and stability

Recht M, Nemes L, Matysiak M, Manco‐Johnson M, Lusher J, Smith M, Mannucci P, Hay C, Abshire T, O’BRIEN A, Hayward B. Clinical evaluation of moroctocog alfa (AF‐CC), a new generation of B‐domain deleted recombinant factor VIII (BDDrFVIII) for treatment of haemophilia A: demonstration of safety, efficacy, and pharmacokinetic equivalence to full‐length recombinant factor VIII. Haemophilia. 2009 Jul;15(4):869-80.

Mean (±SE) factor VIII activity-versus-time profiles following a 50 IU kg^-1 infusion of FLrFVIII or BDDrFVIII based on the central laboratory potency assessment

Complementary and Alternative Therapies

• Complementary medicine is used along with conventional medicine while alternative medicine is used in place of conventional medicine. However, the term alternative medicine is often used more broadly to include complementary treatments.

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• Three important points to keep in mind if you are considering complementary medicine:

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• You should not start any complementary therapy without talking to your physician first.

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• Just because a treatment has not been proven to work in formal clinical testing does not mean it will not work for you.

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• Complementary treatments are not always safer treatments—for example, some herbal supplements can actually interfere with the clotting process.

Types of Complementary Treatments

• Complementary treatment takes many forms, some of which you may not have expected. Generally, they fall into several broad types:
• Natural products. These are often in the form of dietary supplements and include herbal medicines, vitamins, and minerals.
• Mind and Body Medicine. This approach focuses on the interactions among the brain, mind, body, and behavior. It includes meditation, yoga, acupuncture, deep breathing, hypnosis, and more.
• Manipulative and Body-based Practices. This approach focuses on body systems and structures such as the bones, joints, soft tissues, and circulatory system, and includes spinal manipulation and massage.
• Other types of CAM. Many other forms of CAM exist, including movement therapy, music therapy, and treatments based around energy fields.

Complementary and Alternative Therapies

• Haemophilia requires conventional medications.
• Some CAM therapies may be helpful when used with conventional care for certain symptoms. For example, some mind-body therapies may help relieve stress and anxiety, which can reduce bleeding. Studies even suggest that hypnosis may reduce (but not eliminate) the need for blood transfusions.
• Self Hypnosis: may help blood clot better and may reduce the need for blood transfusions
• Nutrition: No significant studies but need to avoid Vitamin E and fish oil supplements in hemophilia, as they increase bleeding time by keeping platelets from clumping. add Vitamin K plays a role in normal clotting and may be useful either from dietary sources or in supplement form.

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• Herbs: People with hemophilia should avoid the following herbs, which tend to make bleeding more severe:
• Ginkgo ( Ginkgo biloba)
• Garlic (Allium sativum)
• Ginger (Zingiber officinale)
• Ginseng (Panax spp.)
• Horse chestnut ( Aesculus hippocastanum)
• Turmeric (Curcuma longa)
• White Willow (Salix alba)
• Since herbs can affect clotting in one way or another, people with hemophilia should take herbs only under a doctor's supervision.

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• Homeopathy: Few studies have examined the effectiveness of specific homeopathic remedies. However, several case reports have found that the following remedies were helpful for people with hemophilia and even reduced their need for blood clotting substances like factor VIII. Before prescribing a remedy, homeopaths take into account a person's constitutional type -- your physical, emotional, and intellectual makeup. An experienced homeopath assesses all of these factors, as well as any current symptoms, when determining the most appropriate remedy for a particular person.

• Arnica -- for internal or external bleeding immediately following an injury. It is helpful for shock or trauma.
• Carbo vegetabilis -- for people with pale skin and weakness who are extremely frail, even listless, but like cold and fresh air.
• Crotalus horridus -- used when there is bleeding into the muscles and when blood appears thin and dark. This remedy is most appropriate for people who are tall, thin, and pale, and have diarrhea and an aversion to warm food and drink. They may also fear being alone and death.
• Hamamelis -- for bleeding from a cut or wound, especially useful in nosebleeds, hemorrhoids, and broken blood vessels in the eye.
• Lachesis -- for heavy bleeding that is dark in color, especially in red-headed individuals who are jealous and depressed.
• Millefolium -- for internal or external wounds with significant bleeding and poor clotting.
• Phosphorus -- for frequent, heavy bleeding. This remedy is most appropriate for people who have cold sweats and desire to drink alcoholic beverages. The person may also feel as though clothing aggravates the throat.
• Secale -- for bleeding that is worsened by heat and lessened by cold.

• Acupuncture: Acupuncture is not recommended for people with hemophilia because of the risk of bleeding. If you choose to try acupuncture, work with a trained, licensed acupuncturist who has experience dealing with hemophilia. Laser acupuncture or acupressure may be better for those with hemophilia.
• Physical Medicine: Regular exercise can build strong muscles and help prevent joint problems. People with hemophilia can exercise safely, although they should avoid contact sports. Physical therapy may also play an important role in reducing joint problems caused by repeated bleeding in those areas. Your physical therapist may recommend the following exercises:
• Stretching
• Movement exercises
• Resistance training (such as weight lifting)
• Work with your health care provider to develop a program that is best for you. You should use the routine for at least 6 - 9 months to treat chronic joint inflammation and to prevent severe bleeding.

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• Prognosis/Possible Complications
• Most people with hemophilia can manage their condition and lead normal lives.
• In people who do not receive factor replacement therapy, however, complications include the destruction of bones and joints, life-threatening cysts, bleeding in the brain, gangrene, bleeding into muscles causing damage to nerves, long-term bruising, and anemia.
• Sudden bleeding can occur with emotional stress.
• Although contracting HIV from blood products is rare, about one third of people with hemophilia (between the ages of 21 to 60) are infected with HIV.
• Elderly patients with hemophilia may have more difficulties with daily living.
• Following Up every 6 to 12 months

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Warangal Chapter�

• Factor VIII - 110
• Factor VIII with VWO - 02
• VWD (Von Willebrand Disease) - 02
• Factor IX - 20
• Other bleeding disorder - 04
• Warangal chapter register PWH - 138

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FACTOR VIII PATIENTS�

• Severity No. Of patients Frequency of Infusion

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• Severe 60 Per month 1-2 times

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• Moderate 20 Once every two months

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• Mild 16 Yearly - 1 to 2 times or

accidents / surgery / dental /

pedicure / vaccination

• Factor VIII with Inhibitors - 13 patients

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• Factor VIII - per episode 1kg x 30IU - BID

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FACTOR IX PATIENTS�Factor IX per episode - 1kg x 60IV – OD�

• Severity No. Of patient Frequency of Infusion

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• Severe 10 monthly 1-2 times

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• Moderate 03 Once in 2-3 months

• Mild 07 Yearly -1 to 2 times

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Factor VIII Prophylaxis:�

• Factor VIII prophylaxis therapy - 6 patients
• Weekly twice - 10IU body weight / 1 kg

Experiences:

• SS, M /9 years prophylaxis started at age of 4 years.

No bleeding, No hemophilia arthopathy, no complications.

• GA, M/16 years prophylaxis started at age of 9 years.

No bleeding, No hemophilia arthopathy, no complications.

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Challenges�

• Carrier detection and Prenatal diagnosis test centres are far away

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• Lack of awareness about hemophilia, among rural and uneducated mass

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• Hemophilia treatment centers are not easily accessible by many PWHs

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• Factor assay and Inhibitor screening tests are not accessible as they are situated in state capitals

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• Quality of life is low and low morale as this affects Education and Job options

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Thank you!

Thank you!

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Contact : +91 9346950500

cvalupadas@gmail.com

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