HEMOPHILIA WED

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HEMOPHILIA:

HEMOPHILIA BY DR SHASHIDHAR B M H

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Hemophilia is an inherited bleeding disorder in which there is a deficiency or lack of factor VIII (hemophilia A) or factor IX (hemophilia B) B M H

History of Hemophilia:

History of Hemophilia The earliest references to hemophilia can be found in second century Jewish writings. The term " haemophilia " is derived from the term " haemorrhaphilia " which was used in a description of the condition written by Friedrich Hopff in 1828, while he was a student at the University of Zurich. In 1937, Patek and Taylor, two doctors from Harvard, discovered anti-hemophilic globulin. In 1947, Pavlosky , a doctor from Buenos Aires, found haemophilia A and haemophilia B to be separate diseases by doing a lab test. B M H

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Haemophilia has featured prominently in European royalty and thus is sometimes known as "the royal disease". Queen Victoria passed the mutation to her son Leopold and, through several of her daughters, to various royals across the continent, including the royal families of Spain, Germany, and Russia. In Russia, Tsarevic Alexei Nikolaevich , son of Nicholas II, was a descendant of Queen Victoria through his mother Empress Alexandra and suffered from haemophilia . B M H

Queen Victoria passed haemophilia A on to many of her descendants:

Queen Victoria passed haemophilia A on to many of her descendants B M H

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The first attempts to treat hemophilia was by replacing the clotting factory with blood plasma taken from pigs and cows. In the 1970s scientists found two approaches to the disease One that was called prophylaxis required injecting doses of the clotting factor on a regular basis The second was to inject the factor whenever the bleeding occurred B M H

How do you get it?:

How do you get it? Hemophilia is a genetic disease and is passed on by the X chromosome (the chromosome that carries the clotting factor). If a boy gets the X chromosome that carries the hemophilia gene he will become a hemophiliac. If a girl get the gene, she will become the carrier of the gene, not showing symptoms of the disease though she may have a long or heavy menstrual cycle. The carrier has a 50% chance of passing the gene on to her children every time she gets pregnant. B M H

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INHERITANCE:

INHERITANCE Hemophilia A and B are X-linked recessive disorders Hemophilia is typically expressed in males and carried by females Severity level is consistent between family members 30 % of cases of hemophilia are new mutations Affects all races and ethnic groups equally Moderate & mild deficiencies under-diagnosed B M H

Mutations and protein function:

Mutations and protein function It’s been well known that point mutations in the factor VIII gene are responsible for most cases of hemophilia A and only a small proportion of these mutations can be recognized by restriction endonuclease analysis, PCR and denaturing gradient gel electrophoresis (DGGE) were used to characterize single nucleotide substitutions. A GC clamp was attached to the 5-prime PCR primer to allow detection of most single base changes in DNA fragments ranging in size from 249 to 356 bp . B M H

BIOCHEMISTRY:

BIOCHEMISTRY Hemophilia A is a complex of a large inert carrier protein and a noncovalently bound small fragment which contains the procoagulant active site. The factor VIII complex, with a molecular weight in excess of 1 million, has 2 components: (1) factor VIII (molecular weight of 293,000 ) called factor VIII C, when measured by procoagulant activity and factor VIII Ag, when measured immunologically and (2) factor VIII R (the von Willebrand factor or vWF ) has a molecular weight of 220,000. Polymerization leads to the high molecular weight of the factor VIII complex (Levin, 1979). Factor VIII is encoded by the factor VIII gene on Xq28. B M H

The C2 MUTATION DOMAIN:

The C2 MUTATION DOMAIN The crystal structure of the human factor VIII C2 domain at a resolution of 1.5 angstroms was reported in 1999. The structure of this protein shows a beta-sandwich core, from which 2 beta-turns and a loop display a group of solvent-exposed hydrophobic residues. Behind the hydrophobic surface lies a ring of positively charged residues. This motif suggests a mechanism for membrane binding involving both hydrophobic and electrostatic interactions. The structure explains, in part, mutations in the C2 region of factor VIII that lead to bleeding disorders in hemophilia A. B M H

Allelic variants :

Allelic variants .0001 HEMOPHILIA A [F8C, ARG2307TER] HEMOPHILIA A [F8C, EX26DEL] HEMOPHILIA A [F8C, ARG2147TER] HEMOPHILIA A [F8C, NEW SPLICE DONOR, IVS4] HEMOPHILIA A [F8C, GLU272GLY] FACTOR VIII (OKAYAMA) [F8C, ARG372HIS] HEMOPHILIA A [F8C, EX26DEL] HEMOPHILIA A [F8C, 23-BP DEL, FS] B M H

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The gene for factor VIII is composed by 186 kb organized into 26 exons ! The majority of the mutations are point mutations. (C2). However, all these mutations contribute to the alteration and dysfunctional factor VIII which leads to the aberrant phenotype of bleeding disorder. B M H

Coagulation Cascade:

Coagulation Cascade TF-Bearing Cell Activated Platelet Platelet TF VIIIa Va VIIIa Va Va VIIa TF VIIa Xa X II IIa IX V Va II VIII /vWF VIIIa II IXa X IX X IXa IXa VIIa Xa IIa IIa Xa B M H

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TYPES & SEVERITY:

TYPES & SEVERITY Normal factor VIII or IX level 50-150% Mild hemophilia factor VIII or IX level 5-50% Moderate hemophilia factor VIII or IX level 1-5% Severe hemophilia factor VIII or IX level <1% B M H

Clinical classification of hemophilia:

Clinical classification of hemophilia B M H

Incidence:

Incidence Hemophilia A: 1:5000 male births Hemophilia B: 1:30,000 male births B M H

Hemophilia A:

Hemophilia A Hemophilia is a inherited bleeding disorder that is caused by the lack or defect of the proteins that is needed for blood to clot. It is caused by the lack of activity of the plasma protein factor VIII which affects the clotting property of blood. B M H

Symptoms of Hemophilia A:

Symptoms of Hemophilia A Bruising Spontaneous bleeding Blood in the urine or stool Prolonged bleeding Bleeding into joints with pain and swelling Gastrointestinal tract and urinary tract hemorrhage B M H

Signs and Tests:

Signs and Tests Normal bleeding time: test in which in which small blood vessels close off to stop bleeding . Normal fibrinogen level tests the amount of fibrinogen level in the blood . Test on partial thromboplastin time which which measures the intrinsic clotting time in plasma. B M H

Hemophilia B:

Hemophilia B Is also known as Christmas disease . Is also inherited blood clotting disease which is caused by a deficiency of a blood plasma protein called factor IX that affects the clotting property of blood. Because of the lack of factor IX blood gets into the joints and may leave people disabled Hemophilia A is seven times more common than hemophilia B. B M H

Symptoms of Hemophilia B:

Symptoms of Hemophilia B Nose bleeds Bruising Spontaneous bleeding Bleeding in joints Blood in urine or stool Prolonged bleeding from cuts, tooth extraction, and surgery Excessive bleeding following circumcision B M H

Signs and Tests:

Signs and Tests Many of the tests and signs are the same as hemophilia A. One tests that is different from the other tests is the serum factor IX test. This is a blood test that measures the activity of factor IX. B M H

Types of Bleeds:

Types of Bleeds Joint bleeding - hemarthrosis Muscle hemorrhage Soft tissue Life threatening-bleeding Other common bleeding B M H

Joint or Muscle Bleeding:

Joint or Muscle Bleeding Symptoms Tingling or bubbling sensation Stiffness Warmth Pain Unusual limb position B M H

Testing for Hemophilia:

Testing for Hemophilia There are two ways to test for Hemophilia before birth though both may cause a sight risk of a miscarriage One is to take a fragment of tissue from the placenta and look at the genetic structure. The DNA can be examined to see if the child has Hemophilia. Another way is to insert a thin needle though the mother’s abdominal wall. The needle has optical fibers and a system which enables the doctor to see the womb and fetus. With the image, the doctor can insert a needle into the umbilical cord and draw out a small amount of fetal blood. After the child is born, several blood tests may be carried out to determine if the child has it. B M H

Laboratory features:

Laboratory features Prolonged activated partial thromboplastin time ( aPTT ) the aPTT is corrected when hemophilic plasma is mixed with an equal volume of normal plasma Normal prothrombin time, thrombin-clotting time, bleeding time A definitive diagnosis of hemophilia A/B should be based on specific assay for factor VIII/IX coagulant activity B M H

Treatment of Hemophilia:

Treatment of Hemophilia Replacement of missing clotting protein Intravenous infusion On demand Prophylaxis Primary/Secondary B M H

Factor VIII Concentrate:

Factor VIII Concentrate Intravenous infusion IV push Dose varies depending on type of bleeding Ranges from 20-50+ units/kg. body weight Half-life 8-12 hours Each unit infused raises serum factor VIII level by 2 % B M H

DDAVP (Desmopressin acetate) :

DDAVP ( Desmopressin acetate) Synthetic vasopressin Method of action - release of stores from endothelial cells raising factor VIII and vWD serum levels Administration - Intravenous Subcutaneously Nasally ( Stimate ) B M H

Stimate (Desmopressin Acetate Nasal Spray) :

Stimate (Desmopressin Acetate Nasal Spray) Dosing Every 24-48 hours prn not to be used more than three days in a row <50 kg. body weight - 1 spray (150 mcg .) >50 kg. body weight - 2 sprays (300 mcg .) B M H

Factor IX Concentrate:

Factor IX Concentrate Intravenous infusion IV push Dose varies depending on type of bleeding Ranges from 20-100+ units/kg. body weight Half-life 12-24 hours Each unit infused raises serum factor IX level by 1% B M H

Factor VIII replacement therapy:

Factor VIII replacement therapy Factor VIII concentrates : plasma-derived intermediate purity, high purity and ultrapure concentrates after viral inactivation by pasteurization or by exposure to solvent detergent produced by recombinant DNA technics B M H

Factor VIII replacement therapy:

Factor VIII replacement therapy The site and severity of hemorrhage determine the frequency and dose of factor VIII to be infused The dose of factor VIII calculation for practical purpose: 1 unit of factor VIII/kg will raise the circulating f. VIII level about 2% (0.02 U/ml) after the initial dose of f. VIII further doses are based on a half- life of 8 to 12 h B M H

Factor IX replacement therapy:

Factor IX replacement therapy Factor IX concentrates: plasma-derived intermediate purity- prothrombin complex concentrates high purity produced by recombinant DNA technics viral inactivation: dry heat 80 o C, pasteurization, solvent detergent B M H

Factor IX replacement therapy:

Factor IX replacement therapy The dose of factor IX calculation for practical purpose: 1 unit of factor IX/kg will raise the circulating f. IX level about 1% (0.01 U/ml) intravascular recovery of factor IX is about 50% (probably f. IX binds to collagen type IV of the vessel wall) the initial dose of f.IX should be followed by one-half this amount every 12 to 18 h B M H

Doses of factor VIII for treatment of hemorrhage:

Doses of factor VIII for treatment of hemorrhage B M H

Minor Bleeding Episodes:

Minor Bleeding Episodes Early joint bleeds Soft tissue & muscle bleeds Nose & gum bleeding not responding to local measures Treatment of minor bleeding episodes 40 - 50% correction FVIII : 20 - 25 units / kg FIX : 40 - 50 units / kg B M H

Major Bleeding Episodes:

Major Bleeding Episodes Head & neck injuries Advanced soft tissue & muscle bleeds Abdominal bleeding Advanced joint bleeding Treatment of major bleeding episodes 100 % correction FVIII : 50 units / kg FIX : 100 units / kg B M H

Primary Prophylaxis:

Primary Prophylaxis Scheduled infusion therapy at an early age before bleeding has regularly occurred to convert patient from severe deficient state to moderate deficient Goal: suppression of spontaneous bleeding episodes Frequency: 2 to 3 times weekly to keep trough factor VIII or IX levels at 2-3 % Use of IVAD necessary in some patients B M H

Secondary Prophylaxis:

Secondary Prophylaxis Scheduled infusion therapy at any age after bleeding has regularly occurred or after injury to convert patient from severe deficient state to moderate deficient Prior to sports activity Goal: suppression of spontaneous bleeding episodes or rebleeding Frequency: 2 to 3 times weekly to keep trough factor VIII or IX levels at 2-3% Use of IVAD necessary in some patients B M H

Morbidity of Chronic Disease:

Morbidity of Chronic Disease School absenteeism increased in children with severe Hemophilia compared to normal population Difficulty attending to task if in pain Ability to achieve potential and find a productive appropriate place in work force Number of bleeding episodes impacts ability to achieve potential Prophylaxis decrease morbidity of chronic disease B M H

Adjunctive Therapy :

Adjunctive Therapy RICE R est /Replacement I ce/ I mmobilization C ompression E levation Antifibrinolytic Agents Amicar ® (aminocaproic acid) Used for mucocutaneous bleeding Dosing: 50 mg./kg. q. 6 hours po B M H

Complications:

Complications Complications of replacement therapy include: Developing antibodies, act against the clotting factors Develop viral infections from human clotting factors Damage to joints, muscles, or other parts of the body resulting from delays in treatment B M H

Factor VIII prophylactic therapy :

Factor VIII prophylactic therapy It should be considered in all severely affected patients The administration of 20 U factor VIII/kg three times weekly markedly decreases the frequency of hemophilic arthropathy and other long-term effects of hemorrhages episodes B M H

Antifibrynolytic agents:

Antifibrynolytic agents Fibrynolytic inhibitors (epsilon- aminocapric acid (EACA), tranexamic acid) may be given as adjunctive therapy for bleeding from mucous membranes, particularly for dental procedure Doses: tranexamic acid ( Exacyl ) 1g every 6 h EACA 4 g every 6 h B M H

Bleeding Episodes:

Bleeding Episodes B M H

Life-Threatening Bleeding:

Life-Threatening Bleeding Head / Intracranial Nausea, vomiting, headache, drowsiness, confusion, visual changes, loss of consciousness Neck and Throat Pain, swelling, difficulty breathing/swallowing Abdominal / GI Pain, tenderness, swelling, blood in the stools Iliopsoas Muscle Back pain, abdominal pain, thigh tingling/numbness, decreased hip range of motion B M H

Joint Bleeds:

Joint Bleeds Most common bleeding manifestation Most common joint Knees, Ankles, Elbows Collection of blood in joint space may cause joint to feel hot Initial symptoms of “tingling” or “bubbling” sensation Early sign: reluctance to move, swelling and joint pain as bleeding progresses Affected joint held in flexed position Usually no visible cutaneous bruising Treat with replacement factor, rest, ice,compression and immobilization B M H

Advanced Joint Bleed :

Advanced Joint Bleed B M H

Complications Joint Bleeds:

Complications Joint Bleeds Flexion contractures Joint arthritis / arthropathy Chronic pain Muscle atrophy B M H

X-Ray of severe joint damage from recurrent hemarthrosis :

X-Ray of severe joint damage from recurrent hemarthrosis B M H

Muscle Bleeding:

Muscle Bleeding Second common bleeding manifestation Bleeding leg, thigh, calf, forearm, and groin create pressure on nerves Early sign: reluctance to move, swelling and pain as bleeding progresses Affected extremity held in flexed position Usually no visible cutaneous bruising Treat with replacement factor, rest, ice , compression and immobilization B M H

Advanced joint and muscle bleed:

Advanced joint and muscle bleed B M H

Complications Muscle Bleeds:

Complications Muscle Bleeds Compartment syndrome Neurologic impairment B M H

Other Common Bleeds:

Other Common Bleeds Bruises Superficial bleeding into soft tissues Usually raised bruises or hematomas Scrapes, minor cuts and/or Lacerations Mucous-membrane bleeding Bleeding from tissues of mouth or nose Can cause nausea and vomiting if blood swallowed Blood loss can be insidious Bleeding with loss of primary teeth usually not a problem Hematuria B M H

Average life span of people with Hemophilia:

Average life span of people with Hemophilia Year Average age at the time of death Treatments available at time Before 1938 11 none Before 1968 20 Plasma or Whole blood transfusions 1968 Less than 40 Cryoprecipitate 1983 64 Freeze dried clotting factors 1988 40 ( impact of aids) Same 1999 Normal life span Factors produced by genetic engineering B M H

Average life span ctd.:

Average life span ctd . B M H

Gene Therapy for Hemophilia:

Gene Therapy for Hemophilia B M H

Gene Therapy Approaches for Hemophilia::

Gene Therapy Approaches for Hemophilia: Liver-directed Muscle-directed Bone marrow-directed Transplantation of genetically-modified fibroblasts B M H

Ex Vivo vs. In Vivo Transfer into Liver :

Ex Vivo vs. In Vivo Transfer into Liver Ex Vivo : Remove hepatocytes Modify in culture Reinject In Vivo : Inject vector parenterally B M H

Blood Vessels Have Fenestrations of 100 nm in Diameter:

Blood Vessels Have Fenestrations of 100 nm in Diameter

Summary of Success with Different Vectors in the Liver:

Summary of Success with Different Vectors in the Liver AAV (Adenovirus associated virus) Vectors Good expression for hemophilia B Safe Retroviral vectors Good expression for hemophilia A and B Safe Adenoviral vectors Great expression for hemophilia A or B Toxic (caused one death in a human patient with OTC) No stable efficacy in large animals B M H

Clinical Trials in Patients::

Clinical Trials in Patients: IM injection of AAV for hemophilia B IV injection of RV for hemophilia A Implantation of genetically-modified fibroblasts for hemophilia A Hepatic artery injection of AAV for hemophilia A B M H

IV injection of RV for hemophilia A:

IV injection of RV for hemophilia A Based on inconsistent results in animals, in which some animals with high antibody levels had high antigen levels, but no coagulation activity Injected RV IV without a stimulus for hepatocyte replication Activity was less that 1% of normal Trial has been stopped No adverse effects were noted B M H

Transplantation of genetically-modified Fibroblasts:

Transplantation of genetically-modified Fibroblasts B M H

Implantation of Genetically-modified Fibroblasts:

Implantation of Genetically-modified Fibroblasts B M H

Hepatic Artery Injection of AAV Vector for Hemophilia B::

Hepatic Artery Injection of AAV Vector for Hemophilia B: Inject 1/10 of dose in dogs into the hepatic artery No evidence of expression to date AAV was noted in semen for several months due to contaminating WBC Trial recently resumed with a medium dose, but there are concerns about germline transmission B M H

Conclusions:

Conclusions No gene therapy approaches have evidence of long-term efficacy in patients IM injection of AAV is too inefficient Implantation of fibroblasts is very laborious and not very effective Liver delivery of AAV or RV should work B M H

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B M H THANK YOU

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B M H

von Willebrand disease :

von Willebrand disease the most common inherited bleeding disorder in humans results from quantitative or qualitative abnormalities in von Willebrand factor (vWF) von Willebrand factor is a central component of hemostasis, secreted by endothelial cells, that circulates in plasma in multimers, serving both as a carrier for factor VIII and as an adhesive link between platelets and the injured blood vessel wall

von Willebrand disease- epidemiology:

von Willebrand disease- epidemiology The overall prevalence of von Willebrand disease is 1% of the general population The prevalence of clinically significant disease is closer to 1: 1000

Classification of von Willebrand disease:

Classification of von Willebrand disease Type 1 vWD - the most common variant autosomal dominant in inheritance normal vWF in structure and function but decrease in quantity- range 25-50% of normal Type 2 vWD (2A, 2B, 2M, 2N) autosomal dominant in inheritance vWF is abnormal in structure and/or function Type 3 vWD autosomal recessive in inheritance the most severe form characterized by very low or undetectable level of vWF

Clinical symptoms:

Clinical symptoms Mucocutaneous bleeding- the most common symptom epistaxis easy bruising and hematomas menorrhagia gingival bleeding gastrointestinal bleeding spontaneous hemarthroses occur almost exclusively in patients with type 3 vWD

Laboratory features:

Laboratory features Screening tests: bleeding time- normal or prolonged aPTT - prolonged or normal PT- normal The routine tests: activity of factor VIII- decreased vWF antigen- decreased ristocetin cofactor activity assay- decreased agglutination of platelets in the presence of ristocetin analysis of plasma vWF multimers - critical for subclassification of vWD

Therapy:

Therapy Desmopressin a dose 0.3  g per kg i.v or s.c., upper limit 20  g , repeated 3 or 4 times every 24 hours the best results in type 1 vWD- effective in 80% patients many patients with type 2 and nearly all ones with type 3 do not respond to DDAVP vWF replacement therapy vWF-containing factor VIII concentrates: Humate P, Koate HP

Nonreplacement therapy:

Nonreplacement therapy Estrogen or oral contraceptives in treating menorrhagia fibrynolytic inhibitors

The other uncommon inherited deficiencies of coagulation factors:

The other uncommon inherited deficiencies of coagulation factors Bleeding tendencies caused by inherited deficiency of factors I, II, V, VII, X, XI and XIII are rare disorders, distributed worldwide Treatment may be necessary during spontaneous bleeding episodes, during or after surgical procedures In most deficiency states fresh frozen plasma replacement is used, but specific concentrates of factors I, II, VII, X, XI and XIII are also available

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