Genetic work together in a series of complex

 Genetic causes of hemophilia and its impactson body functioning” Clotting factors are proteins in the blood that control bleeding. Whena blood vessel is injured, the walls of the blood vessel contract to limit the flowof blood to the damaged area. Then, small blood cells called platelets stick tothe site of injury and spread along the surface of the blood vessel to stop thebleeding. At the same time, chemical signals are released from small sacsinside the platelets that attract other cells to the area and make them clumptogether to form what is called a platelet plug.On the surface of theseactivated platelets, many different clotting factors work together in a seriesof complex chemical reactions to form a fi brin clot.

. Coagulation factors are identified with Roman numerals.(1)Factor VIII an essential blood coagulation protein, is a keycomponent of the fluid phase blood coagulation system. Human factor VIII is asingle chain of about 300 kDa consisting of domains described as A1-A2-B-A3-C1-C2. In patients with haemophilia  thelong-term consequences of repeated haemarthrosis include cartilage damage andirreversible arthropathy, resulting in severe impairments in locomotion.Quantifying the extent of joint damage is therefore important in order toprevent disease progression and compare the efficacy of treatment strategies. Numerouschallenges confront adult hemophilia patients with inhibitors, includingdifficulty in controlling bleeding episodes, deterioration of joints, arthriticpain, physical dis­ability, emotional turmoil, and social issues.INTRODUCTION Hemophilia A is an X-linked bleeding disorder affectingapproximately 1 in 5,000 males, and is caused by deficiency of factor VIII, acofactor in the activation of factor X by factor Ixa(36)Clotting factors are proteins in theblood that control bleeding.

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When a blood vessel is injured, the walls of theblood vessel contract to limit the flow of blood to the damaged area The clot acts like a mesh to stopthe bleeding. Coagulation factors circulate in the blood in an inactive form.When a blood vessel is injured, the coagulation cascade is initiated and eachcoagulation factor is activated in a specifi c orderto lead to the formation ofthe blood clot.The protein undergoes processing priorto secre­tion into blood resulting in a heavy chain of 200 kDa (A1-A2-B) and alight chain of 80 kDa (A3-C1-C2) linked by metal ions.

The role of factor VIIIis to increase the catalytic efficiency of factor IX a in the activation offactor X. Variants of these factors lead frequently also to severe bleedingdisorder.The human factor VIII procoagulant protein(VIUC) was purified fromthe VIUC-factor VIII-related antigen complex in commercial factor VIIIconcentrate by immunoadsorbent chromatography with a monoclonal anti-VIURAg antibodybound to Sepharose.

 Combined factor V and factor VIII deficiency is an inherited bleedingdisorder that is caused by low levels of factors V and VIII. Because the amountof these factors in the body is lower than normal, the clotting reaction isblocked prematurely and the blood clot does not form. The combined defi ciencyis completely separate from factor V deficiency and factor VIII deficiency.

Combined factor V and factor VIII deficiency is an autosomal recessivedisorder, which means that both parents must carry the defective gene in orderto pass it on to their child. It also means that the disorder affects bothmales and females. The defi ciency is very rare, but like all autosomalrecessive disorders, it is found more frequently in areas of the world wheremarriage between close relatives is common.

 Most cases are found around the Mediterranean Sea, especially inIsrael, Iran, and Italy. Normally the disorder is caused by a single genedefect that affects the body’s ability to transport factor V and factor VIIIoutside the cell and into the bloodstream, and not by a problem with the gene foreither factor. Deficiencies of factor VIII and factor IX are known ashemophilia A and B, respectively.

Rare clotting factor defi ciencies arebleeding disorders in which one or more of the other clotting factors (i.e.factors I, II, V, V,VIII,VII, X, XI, or XIII) is missing or not workingproperly. While bypassing agents can achieve an effective levelof control for most bleeding episodes in hemophilia patients with inhibitors,their hemostatic efficacy is not equiva­lent to that of factor replacement inpatients without inhibitors and bleeding is harder to control.(2) Patients withinhibitors have worse treatment-related outcomes, including greater incidenceof joint abnormalities, more rapid progression of arthropathy, more chronicjoint pain,(3-6) and an increased incidence of intracranial hemorrhage thanpatients without inhibitors.

(7)Coagulationfactor VIII is a glycoprotein synthesized mainly in hepatocytes, but also inkidneys, endothelial cells and lymphatic tissue. It is one of the largestcoagulation factors  present in the blood­streamin association with von Willebrand factor  in a non-covalent complex (8). The vWFprotects factor VIII from premature proteolysis and transfers it to sites ofendothelial injury. The half-life of coagulation factor VIII is about 12 hours.

The active form of factor VIII is a non-enzymatic cofactor for the prothrom­binaseand tenase complex in the intrinsic coagulation pathway that accelerates factorX activation induced by activated factor IX in the presence of phospho­lipidsand calcium ions.  The gene forfactor VIII is located on the X chromo­some. A mutation in this gene that codesfor co­agulation factor VIII results in congenital bleeding disorder, i.e.hemophilia A. This mutation almost exclusively occurs in male germ cells. Theeffect of the mutation is absent or decreased synthesis of factor VIII orsynthesis of abnormal protein (9).

Hemophilia A isdiagnosed in 1 of 5000 male new­borns. In Poland, frequency of hemophilia isestimated at 1 : 12 300 inhabitants. In approximately 30–50% of af­fectedpatients mutation occurs spontaneously and their family history is negative. Treatment ofbleedings in course of hemophilia and related disorders consists ofsupplementation of miss­ing coagulation factor i.e. its substitution (10).

HISTORICAL OVERVIEW The first lyophilizedfactor VIII concentrates appeared on the market in the late 1960s and sincethat time they have been the basis of hemophilia A treatment. Unfor­tunately,quite quickly, substitutive therapy was found to be also associated with somevery serious side effects for patients. The concentrates produced from pooledplas­ma received from thousands of donors were sources of hepatitis B virus,and since 1989 also of hepatitis C vi­rus. In the early 1980s, in a very shorttime, 60–80% of hemophilia patients became infected by human immuno­deficiencyvirus that was contained in lyophilized concentrates. There are several types of Haemophilia: haemophilia A, haemophilia B, haemophilia C, parahaemophilia,and acquired haemophilia A.(47-50).Haemophilia A affects about 1 in 5,000–10,000, whilehaemophilia B affects about 1 in 40,000, males at birth.

(47-50) Anotherbreakthrough in hemophilia treatment start­ed with the discovery of humanfactor IX and factor VIII genes in 1982 and 1984, respectively (11). Soon afterthese discoveries some research groups proved that mammalian cells transfectedwith human factor VIII cDNA were able to synthesize that factor. Recombinantfactor VIII manufactured using genetic en­gineering technology became availablein the early 1990s (12). In the 1990s,when recombinant factor VIII became available for patients, it was predicted toreplace human plasma derived concentrates. Unfortunately, at present only insome countries, for example Canada and Ireland, 100% of affected patientsreceive recombinant factor VIII. In The United States that percentage is about65% and in many rich and highly developed countries of the European Union thisratio is significantly lower.

In Poland, onlycoagulation factor concentrates manu­factured from human plasma are used. Thereason for that is very high production cost of recombinant factor VIII (13). So far, all available recombinant factor VIII formula­tions havebeen produced in mammalian cells: Common symptomsnosebleeds (epistaxis)easy bruisingheavy or prolonged menstrual bleeding (menorrhagia)bleeding in the mouth, particularly afterdental surgery or tooth extractionbleeding in the head (newborns)heavy bleeding at circumcisionOther reported symptomsbleeding in the gut (gastrointestinal bleeding)(1) BIOCHEMICALCHARACTERIZATION OF COAGULATION FACTOR VIII Human coagulation factorVIII is a glycoprotein en­coded by a gen of 186 000 base-pairs (bp) comprising26 exons. It is synthesized as a single polypeptide chain containing 19signaling peptides. Factor VIII consists of 2332 amino acids forming sixdomains described as A1-A2-B-A3-C1-C2 . Although brain haemorrhage and bleeding into internal organsrepresent major threats to the life of PWH, approximately 80%–90% of bleedingepisodes occur in the musculoskeletal system, especially in the large synovial joints,aswell as in themuscles, thus constituting the principal health problem. Thisinduces progressive cartilage damage,leading to joint destruction andsubsequent severe functional limitation.

 Treatment and, ideally, the prevention of musculoskeletal  are the main challenges in PWH. The adequateprevention of musculoskeletal system  complicationsrequires the early detection of the first signs of joint impairment inrelatively asymptomatic patients as well as the efficient followup of musculoskeletalsystem complications already present. Appropriate treatment, whetherhaemostatic or orthopedic, is only possible if we have reliable assessment toolsat our disposal which can make it possible to quantify the benefits of suchtreatment. The musculoskeletal system  assessmenthas traditionally been evaluated using both radiological and clinical jointscoring systems(14-17).

Information obtained from these scores is regularly usedin clinical practice to evaluate the effects of different  treatments on the progression of arthropathy,includingclotting factor prophylaxis, physical therapy, and surgical procedures(18).There are two C domains within the FVIII struc­ture —C1 and C2. The C1 and C2 domain comprise 153 and 160 amino acids, respectively.Crystal structure of the C2 domain consists of ?-sandwich forming the internaldomain structure, and attached ?-hairpins and loops forming a hydrophobicsurface.COAGULATION FACTOR VIII ACTIVATIONCoagulation factor VIII is proteolytically activated bythrombin. Activation results from cleavage of the heavy chain in: Arg372 (A1 —A2 domain linkage) and Arg740 (A2 — B domain linkage) amino acid sites andcleav­age of the light chain in amino acid site(28-31)Catastrophizing is a coping strategy used by hemophiliapatients who lack a personal sense of psychosocial well-being, and strongpositive correlations have been described between the use of this copingmechanism and pain and dis­ability in these patients.

(19) Aserious consequence of progressive joint disease that can­not be surgicallycorrected in all patients with hemophilia is chronic pain; often, this painpersists despite the patient’s and medical team’s best efforts to control jointbleeding and dis­ease progression.(20,21) Gene mutations re­sult in absent or decreased factorVIII synthesis or ab­normal protein expression (33-35).ControlThe medication desmopressin maybe used in those with mild haemophilia A.

(41) Studies of gene therapy arein early human trials.(42). In 2017 agene therapy trial on nine people with haemophilia A reported that high dosesdid better than low doses. 43,44) Haemophilic arthropathy ischaracterized by chronic proliferative synovitis and cartilage destruction.(46) A healthy diet and regular exercise keep the body healthy and strong.Exercise can also help reduce stress, anxiety and depression,and reduce thefrequency and severity of joint bleeds.People who are overweight placeadditional stress on the joints such as particularly the knees and ankles,leaving them increasingly susceptible to bleeds.

Several strategies are important in the management ofevolving joint disease in patients with inhibitors, including exercise,physical therapy, orthopedic interventions, and pain management.(22) Inaddition, recent studies(23-25).suggest that the prevention of joint bleedingmay be possible with the regular use of secondary prophylaxis with bypassingagents, a therapeutic modality that could be helpful in interrupting theprogression of joint disease if started early in patients who are experiencingrepeated bleeding in a particular joint.Discussion and ConclusionClottingfactors are proteins in the blood that control bleeding. When a blood vessel isinjured, the walls of the blood vessel contract to limit the flow of blood tothe damaged area. Then, small blood cells called platelets stick to the site ofinjury and spread along the surface of the blood vessel to stop the bleeding.At the same time, chemical signals are released from small sacs inside theplatelets that attract other cells to the area and make them clump together toform what is called a platelet plug.Haemophilia is an inherited bleeding disorder where blood doesn’tclot properly.

It is caused when blood does not have enough clotting factor.A clotting factor is a protein in blood that controls bleeding.There are twotypes of haemophilia .Both have the same symptoms.

Haemophilia A is the mostcommon form and is caused by having reducedlevels of clotting factor VIII Haemophilia B, also known asChristmas Disease, is caused by having reduced levels of clotting factor IX..Haemophiliais not contagious. Coagulationfactor VIII is a protein involved in the blood coagulation process.

Its absenceor low blood ac­tivity causes haemophilia A. The treatment of haemo­philia-relatedbleedings and related bleeding disorders consists of coagulation factor VIIIsubstitution. Nowa­days few types of substitutes are used worldwide. The mostcommonly used therapeutics are plasma-derived products. Even though no patientinfections have been observed lately, it cannot be excluded that they are com­pletelyfree of any infectious particles.

The latest re­searche is directed atdevelopment of coagulation factor that can effectively overcome immunologicalresponse or has increased half-time but it is still not free from viraltransmission risk. The next step in haemophilia treatment development would beobtaining recombinant coagulation factor VIII by less expensive prokaryoticexpression system. That would allow significant lowering of production costs,shortening of production time, better product availabil­ity, and — first of all— elimination of the risk of infec­tion.  Musculoskeletal impairmentsin PWH may stem from structural and functional abnormalities, which havetraditionally been evaluated radiologically or clinically  Referances1.www.

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