Coagulation Disorders Among Potential Blood Donors

Coagulation Disorders Among Potential Blood Donors

Coagulation Disorders – Coagulation is a complex process by which blood forms clots. It is an important part of haemostasis, the cessation of blood loss from damage vessel (www.wikipedia.org). It involves a series of enzymatic reaction involving the proteolytic activation of circulating coagulation factors (zymogen and the activity of co-factors) prothrombin which converts soluble plasma fibrinogen into fibrin which enmeshes the platelet plug forming a stable thrombus to stop bleeding and begining repair of damage vessel. Disorders of coagulation among potential blood donors can lead to an increased risk of bleeding (haemorrhage) or obstructive clotting (thrombosis). coagulation disorder include a number of disorders that is related to defects in the clotting of blood. Deficiencies in any of a minor injuries, In some of these disorder a specific deficiency is due to an inherited defect (lak, et al, 2003).In other words, an acquired pathological condition may be responsible for the deficiency (condition interfering with absorption of vitamin k and severe infection) for common clotting disorders, coagulation is highly conserved throughout the body of mammals (horowitz et al 1999).

In mammals coagulation involves both a cellular (platelet) and protein (coagulation factor component). The system in human has been the most extensively researched and is therefore, best understood. Coagulation begins with almost instantly after an injury to the blood vessel endothelium (lining of the vessel) exposure of the blood to protein such as tissue factor initiates changes to blood platelet and plasma protein fibrinogen, a clotting factor (Brewer, 2006).

Coagulation disorders are inherent deficiencies as a result of the absence or defect in any of the coagulation factor. The causes of coagulation disorder among blood donors include deficiency of coagulation factors, inhibition of coagulation factors, and defects in platelet function. The most important coagulation factor disorders are quantitative rather than acquired (www.coagulation factors disorder, free encyclopedia.htm). The platelets function to immediately form a plug at the site of injury. This is called primary haemostasis, secondary haemostasis occur immediately and simultaneously. Proteins in the blood plasma called coagulation factors or clotting factors responds in a complex cascade to form fibrin strands, which strengthen the platelet plug (Furrie, et al., 2005).

The clotting factors deficiencies are treated with plasma or plasma proteins containing the missing factor. These agents can restore haemostasis function to normal for hours or days and with continued treatment, allow injuries to heal or complicated surgery to be performed. The best known coagulation disorder is haemophilia which is due to an inherited defect transmitted by female but manifested almost exclusively in male. The most common form of haemophilia, haemophilia A, is caused by the absence of coagulation protein factor VIII (antihaemophilic globulin). Approximately 85 percent have factor VIII deficiency (Anwar, et al., 1999). The most common form of haemophilia i.e. haemophilia B is due to deficiency of factor IX (plasma thromboplastin component or PTC). Both factor VIII and IX deficiency have signs and symptoms that are indistinguishable (Halbmayer, et al., 1993), spontaneous bleeding into joints, giving rise to severe chronic arthritis, is a common problem among patients with severe haemophilia. In addition, there is bleeding into the brain and abdominal cavity, as well as marked bruising. In general, the greater the deficiency in either factor VIII or factor IX, the more the severity of the manifestation of the disease (Peyvandi, et al., 2003).

Aims and Objectives                              

1. To evaluate the level of this disorder in some potential blood donors.
2. To find the mean values of haemophilic patient and non haemophilic patient (potential blood donors).
3. To compare the levels of haemophilic patient in male and female.

Justification of the Study

The significance of this study is to create the awareness of the dangers associated with potential blood donors with coagulation disorders, since the essence of donating blood is for the recipient safety.

LITERATURE REVIEW

   History theories of blood coagulation

1.  Theories on the coagulation of blood have exited since antiquity. Physiologist Johannes muller (1801-1858) described fibrin, the substance of a thrombus. Its solve precursor,  fibrinogen, was that named by Rudoff Virchow (1821-1902) and isolated chemically by prosper Sylvain Denis (1799-1863) Alexander Schmidt suggested that the conversion from fibrinogen to fibrin is the result of an enzymatic process and labelled the hypothetical enzyme “thrombin” and its precursor “prothrombin”(Schmidt, 1872)
2. (Schmidt, A (1872). Schmidt, et al., 1892) Arthus discorvered in 1890 that calcium was essential in coagulation (Arthus, et al., 1865, and their function was elucidated by Gicilio Bizzozero in 18882 (Brewer 2006). The theory that thrombin is genernted by the presence of tissue factor was consolidated by paul morauits in 1905 (morawits. 19905) At this stage, it was know that thromobokinale (thromboplastin (factor III) is released by damage tissues, reacting with prothrombin (II) which, together with calcium (iv), forms thrombin, which converts fibrinogen into fibrin (1) 9Giangrande 2003)

 Coagulation Factors

The remainder of the biochemical factors in the process of coagulation was largely discovered the 20^th century. A first due as to the actural complexity of the system of coagulation was the discovery of proaccerlerin (initially and later called factor V) by paul owern (1905-1990) in 1947. He also postulated its function to be the activated form of factor V, hence VI is not now in active use (Giangrande, 2003).

Conversion accelerator or proconvertin, precipitated by baricum sulfate) was discovered in a young female patient in 1949 and 1951 different in the clinically recognized but etiologically elusive hemoplilia A, it was identified in the 1950s and is alternatively called antihaemoplulic globulin due to its capability to correct haemophilia A factor IX was discovered in 1952 in a young patient with hemophilia B name Stephen Christmas (1947-1993) His deficiency was described by Dr. Rosemary Bggs and professor R.G. Macfarlane in oxford, UR the factor is hence called chrismax factor. Christmas lived in Canada and campaigned for blood transfusion satiety unit succumbing to transfusion-related AIDS at age 46. An alternative name for the factor is plasma thromboplatin component, given by an hidependent group in California. The view that the coagulation process is a “cascade” or “waterfall” was enunciated almost simultaneously by Macfarlane (Macfarlane 1964) in the UK and Davie and Ranoff (Davie, et al., 1964) in USA, respectively. AIDS at age 46. An alternative name for the factor is plasma thromboplastin component, given by an independent group in California. The view that the coagulation process is a “cascade” or “waterfall” was enunciated almost simultaneously by MacFarlane (MacFarlane. 1964) in the UK and Davies and Ratnoff (Davie, et al., 1964) in USA, respectively.

Nomenclature of Blood Factor

The usage of Roman numerals rather than the eponyms or systematic names was agreed upon during the annual conferences (starting 1955) of hemostasis experts. In 1962, consensus was achieved on the numbering of factors I-XII (Wright 1962).

This committee evolved into the present day international committee on thrombosis and Hemostasis (ICTH) Assignment of numerals ceased in 1963 after the naming of factor XIII. The names Fletcher factor and Fitzgerald factor were given to further coagulation- related proteins, namely prekallikrein and high-molecular-Weight Kininogen (Giangrande. 2003).

Physiological Nomenclature of Platelet Actuation 

Damage to blood vessel walls exposes subendothelium proteins, most notably von willebrand factor (vwf), present  under the endothelium VWF is a protein secreted  by health endothelium, forming a layer between the endothelium and underlying basement membrane (MacFarlane 1964) when the endothelium is damaged, the normally-isolated, underlying Von Willebrand Factor is exposed to white blood cells and recruits factor VIII, collagen and other clotting factors, circulating platelets binds to collagen with surface collagen specific glycoprotein Ia/IIa  receptor. This adhesion is strengthened further by additional circulating proteins VWF which forms additional link between the platelets glycoprotein Ib/IX/V and collagen fibrils. These adhesions activate the platelets (Brewer, et al. 2006).  Activated platelets release the content of stored granules into the blood plasma. The granules include ADP, serotonin, platelet activating factor (PAF), platelet factor 4, and thromboxane A2 (TXA2), which in turn activate additional platelets (Gene, 2004). The granules content activate a G9- linked protein receptor cascade, resulting in increased calcium concentration in the platelets cytosol. The calcium activates protein kinase C, which in turn activates phospholipase A2 (PLA2), then modifies the integrin membranes glycoprotein IIb/IIIa, increasing its affinity to bind fibrinogen. The activated platelets change shapes from spherical to stellate, and the fibrinogen cross links with glycoprotein IIb/IIIa, aids in aggregation of adjacent platelets (completing primary hemostasis).

 The Coagulation Cascade

The coagulation cascade of secondary hemostasis has two pathways which lead to fibrin formation. These are contact activation pathway (formerly known as the intrinsic pathway (Davie et al., 1964) it was previously thought that coagulation cascade consist of two pathways equal importance formed to a common pathway. It is now know that the primary pathway for the initiation of blood coagulation is the tissue factor pathway (MacFarlane, 1964). The pathways are a series of reactions in which a zymogen (Inactive enzyme precursor) of a serine protease and its glycoprotein co-factor are activated to become active components that can catalyze the next reaction in the cascade, ultimately resulting in cross linked fibrin. Coagulation factors are generally indicated by Roman numerals, with lower case ‘a’ appended to indicate an active form. The coagulation factors generally serine proteases (enzymes). There are some exceptions, for example FVIII and FV are glycoproteins and factor XIII is a transglutaminase. Serine proteases act by cleaving other proteins at specific sites. The coagulation factors circulate as active zymogens. The coagulation cascade is classically divided into three pathways. The tissue factor and contact activation pathways both activate the “final common pathway’’ of factor X, thrombin and fibrin.

Tissue Factor Pathway (Extrinsic)

The main role of the tissue factor pathway is to generate a ‘’thrombin burst’’ a process by which thrombin, the most important constituent of coagulation cascade in terms of its feedback activation role is released instantaneously. FVII circulate in a higher amount than any other activated coagulation factor (MacFarlame 1964).

– following damage to the blood vessel, FVII leaves the circulation and comes into contact with tissue factor (IF)expressed on tissue factor being cells (stroma fibroblast and leucocytes)forming an activated complex FVIIa).

– TF-FVIIa activates FIX and FX.

– FVII is usect activated by thrombin, FXLa, FXII and fxa.

– The activation of FXa by TF-FVIIa is almost immediately inhibited by tissue factor pathway inhibitor (TFPL).

-FXa and its co-factor fla form the prothrombinase complex, which activates prothrombin to thrombin

– thrombin then activates other components of the coagulation cascade, including FV and FVIII (which activates FXI, which, in turn, activates Fix) and activated and release FVIII from being bound to VWF.

– FVIIIa is the co-factor of  FIXa and together they form the ‘’tenase’’ complex, which activates FX and so the cycle continues (tenase’’ is a contraction of ‘’transcutaneous electrical nerve (ten)’’ and the suffix’’ase’’ used for enzymes.

Contact Activation Pathway (Intrinsic)

The contact activation pathway begins with formation of the primary complex on collagen high molecular weight kininogen (HMWK), prekallikein is converted to kallikrein and FXII becomes FXIIa.

FXIIa converts FXIa. Factor XIa activates FX to Fxa. The minor role that the contact activation pathway has in initiating clot jonnation can be lustrated by the fact that patients with server deficiencies of FXII, HMWK, and perkallikein do not have a bleeding disorder; instead, contact activation system seems to be more involved in inflammation. Patient without FxII (Hageman Factor) suffer from constant infections (Morawitz, 2005).

 Final Common Pathway

Thrombin has a wide range of function. its primary role is the activation of fibrinogen to fibrin, the building block of hemostatic plug. In addition, it activated factor VIII and V and their inhibition protein C (in the presence of thrombomodulin) and it activates factor XIII, which form convalent bond that crosslink the fibrin polymers that is form from activated monomers (Halbmayer, et al,2003).

Following activation by the contract factor or tissue factor pathway.the coagulation cascade is maintained in a prothromotic state by the continued activation FVIII and FIX to form the tenase complex, until it is down-regulated by the anticoagulant pathways (menegatti et al,2004)

 COFACTORS

Various substances required for the proper functioning of the coagulation cascade. Calcium and phospholipids (a platelet membrane constituent) are required for the tenase and prothrombinase complexes to function. Calcium mediates the binding of the complexes via the terminal gamma –carboxy residuals on FXa and FIXa to the phospholipid surfaces expressed by platelets, as well as procoagulants microparticle or microvesicles shed from them. Calcium is also required at other point in the coagulation cascade.

Vitamin k is an essential factor to a hepahic gamma- glutamyl carboxylase that adds a carboxyl group to glutamic acid residual on factors II, VII, IX and X as well as protein S, protein C and protein    Z (Oldenburg, et. 2000). In adding the gamma-carboxyl group to glutamate residual on the immature clothing factors, vitamin K is itself oxidized. Another enzyme, vitamin K epoxide reductase, (VKORC) reduces vitamin K back to its active from. vitamin K epoxide reductase is pharmacologically important as a target for anticoagulant  drugs, warfarin and related coumarines such as acenocoumarol, phenprocoumon, and dicumarol (Oldenburg, et al 2000) these drugs creates a deficiency of reduced vitamin K  by block VKORC, by inhibiting maturation of clotting factors, other deficiencies of vitamin K (eg in malabsorption) or disease (hepatocellular carcinoma) impairs the function of the enzyme and leads to the formation of gamma carboxycation and affects the coagulation factors ability to bind to expressed phorpholipid (Brenner, et al 1996).

REGULATION OF COAGULATION CASCADE 

Five mechanisms keep platelet activation and the coagulation cascade in check. Abnormalities can lead to an increased tendency towards thrombosis

Protein C is a major physiological anticoagulant, it is a vitamin K- dependent serine protease enzyme that is activated by thrombin into activated protein C (APC). Protein C is activated in a sequence that starts with protein C and thrombin binding to a cell surface protein thrombomodulin.  B bThrombomodulin binds these protein in a such a way that it activates protein C the activated form, along with protein S and a phospholipid as a co-factor degrades FVa and Fvilla. Quantitative  or qualitative deficiency of either may lead to thrombophila (a tendency to develop thrombosis) impaired action of protein C (activated protein C resistance) for  example by having the “leiden’’ variant of factor V or high levels of Fviii also may lead to a thrombotic tendency.

–         Antithrombin is a serine protease inhibitor (Serpin ) that degrades the serine protease. thrombin, Fxa, Fxia. It is constantly active, but its adhesion to these factors is increased by the presence of heparin sulfate(a glycosaminoglycan

or the administration of heparins (different heparinoids increase affinity to FXa, thrombin or both) Quantitative deficiency of antithrombin (inborn  or acquired eg. in proteinuria) leads to thrombophilia.

–         Tissue factor pathway inhibitors (TFPI)  limits the action of tissue factor (JF). It also inhibits excessive tissue factor mediated activation of FIX  and FX

–         Plasmin is generated by proteolytic cleavage of plasminogen, a plasma protein synthesized in the liver. this cleavage is catalysed by tissue plasminogen activator (t-PA), which is synthesized and secreted by endothelium. plasmin proteolytically cleaves fibrin into fibrin degradation products that inhibits excessive fibrin formation.

–         Prostacyclin (PGL2) is released by endothelium and activated platelet, GS protein –linked receptors in turn, activates adenylylcyclase, which synthesizes  _CAMP. _CAMP inhibits platelet activation by decreasing cytosolic levels of calcium and by so doing inhibits the release of granules that would lead to activation of additional platelet and coagulation cascade (Brenner,  et al. 1996)

FIBRINOLYSIS

          Eventually, blood clots and re-organized and resorbed by a process termed fibrinolysis. The main enzyme responsible for this process (plasmin is regulated by various activation and inhibitors. This involved the process of removal of unwanted, insoluble deposits formed as a result of coagulation (ochei 2000).

DEFECTS OF FIBRINOGEN

          Fibrinogen is a large molecule, made up of two identical halves, each half composed of three protein chains (A alpha, B beta and gamma) these genes for these proteins are located at chromosome 4. Thrombin cleaves fibrinogen  with the release of fibrinopeptides A  and B producing fibrin monomer which then polymerizes and is stabilized by the action  of factor XIII fibrinogen abnormalities may be due to the following

–         Absence of fibrinogen- afibrinogenemia

–         A decrease level of fibrinogen with normal structure – hypofibrinogenemia

–         A structurally abnormal fibrmogen dysfibrinogenemia.

In practice, it may be difficult to distinguish between hypo-and dysfibrinogenemia, mild forms are probably under diagnosed fibrinogen disorders with severe bleeding manifestations are uncommon. Two large case series, one from iran (lak, et al. 1999) and the other from Isreal (fried, et al. 1998) describe umbilical bleeding and mucosa hemorrhage as the most common bleeding problem. Musculoskeletal bleeding was not frequent and cerebral bleeding was reported. There is some evidence of impaired wound healing. Bleeding is less severe in hypofibrinogenemia but may occur following invasive procedures, woman with either afibrinogenemia or hypofibrinogenemia have an increased risk of miscarriage, which  suggests, that fibrinogen has a role in implantation. Prophylaxis with fibrinogen concentrate during pregnancy may improve the outcome and  prevent postpartum hemorrhage (kobayashi, et al. 2000) paradoxically, thromobosis is also reported in some people with afibrinogenemia, unrelated to replacement therapy, the mechanism is not clear. There is little literature on dysfibrinogenemia and what there is mainly consist of case reports  on molecular analysis. The clinical picture is vey variable,a compilation of 250 cases reported  hemorrhage in 26% thrombosis in 21% and no symptoms in 53%. An analysis of patients with dysfibrinogenemia and thrombosis with 26 different mutation (Haverkate, et al. 1995)

Prothrombin Deficiency

Factor II is a vitamin K-dependent carboxylase synthesized in the liver. it is a single chain glycoprotein with four domain. Factor Xa activates it on the surface of platelets releasing an activation peptide (Fragment 1-2)  on cleavage. Factor II deficiency may be hypoprothrombinaemia (reduced level of normal molecule, type I) or dysprothrombinemia (activity reduced but antigen normal, type2. A complete deficiency may be incompatible with life (lethal in knockout mice) only a small number of cases are reported worldwide (Girolamin, at al. 1998) and the largest series (14 patients) is from Iran (peyvandi, et al 1999) severe deficiency was associated with levels of 4-10% and the most common bleeding manifestation were hemarthrosis and muscle hematomata. Life threatening umbilical bleeding occurred in two patients and intracranial hemorrhage (ICH) in one. five other cases of (ICH) are found in the literature the clinical picture in dysprothrombinemia is more variable.

ROLE IMMUNE SYSTEM.

          The coagulation system overlaps with immune system. coagulation can physically trap invading microbes in blood clots. Also, some products of coagulation system can contribute, to vascular permeability and acts as chemotactic agents for phagocyte cells. In addition, some of the products of coagulation system are directly antimicrobial. For example, beta-lysine, a protein produced by platelet during coagulation, can cause lysis of many gram-positive bacteria by acting as a cationic detergent (Gene, 2009.) many acute phase proteins of inflammation are involved the coagulation system. In addition, pathogenic bacteria may secretes agents that alter the coagulation system e. g coagulase and streptokinase.

TESTING OF COAGULATION         

Blood plasma after addition of tissue factor forms a gel-like structure (test for prothrombin time). Numerous tests are used to assess the functions of the coagulation system.

–         Common: a PTT,PT (also used to determine INR) Fibrinogen testing often by the clauses method), platelet count, platelet function testing (often by the PFA-100)

–         Other, TCT,  bleeding time, mixing test (whether an abnormality corrects of the patients plasma is mixed with normal plasma) coagulation factor assays, antiphospholipid  antibodies, D-dimer, genetic test (eg factor V leiden, prothrombin mutation (G20210A) dilute Russell’s viper venom time (dRVVT),, miscellaneous platelet function test, thromboelastograpy (TEG or sonoclot), euglobulin hysis time (ELT). The contact activation (intrinsic) pathway is  initiated by activation of the contact factor of plasma and can be measured by the activated partial  thromoboplastin time test (aPTT)  (perrry, et al. 2002).

The tissue factor (extrinsic) pathway is initiated by release of tissue factor (a specific cellular lipoprotein) and can be measured  by prothrombin time (PT) test. PT results are often reported as ratio (INR value) to monitor closing of oral anticoagulants such as warfarin. The quantitative and qualitative screening of fibrinogen is measured by the thrombin clotting time (T.C.T.) measurement of the exact amount of fibrinogen present in the blood is generally done using clause method for fibrinogen testing. many analyzers are capable of analyzing and measuring a “derived fibrinogen” level from the graph of the prothrombin time clot. If a coagulation factors is part of the activation or tissue factor pathway,  a deficiency of that factor will affect only one of the tests thus hemophilia A, a deficiency of factor VIII, which is part of the contact activation pathway results in an abnormally prolonged aPTT rest but a normal PT test. The exceptions are prothrombin, and some variants of FX that can be detected only by either APTT or PT. If any abnormal PT or aPTT is presence, additional testing will occur to determined  If any of the

factor  present as aberrant concentration deficiencies of fibrinogen

(quantitative or qualitative) will affect all screening tests(Nichols, et al.,

1998)

ROLE IN DISEASES

Problem with coagulation system may dispose one to hemorrhage,

thrombosis and occasionally both, depending on the nature of the pathology.

Platelets disorders

Platelets disorders may be inborn or acquired . Some inborn platelet

pathologies are glanzmann’s  thrombasthenia which is an autosomal recessive disorder that leads to failure of primary platelet aggregation because of the deficiency of membrance GPiib (gene on the chromosome 17), Bernard-soulier syndrome (abnormal glycoprotein ib-IX-V complex) in this disease, the platelets are larger than normal, gray platelet syndrome (deficient alpha granules), and delta storage pool deficiency (deficient dense granules) most  inborn disorders are rare conditions, most inborn platelet pathologies predispose to hemorrhage. von willebrand disease is due to deficiency or abnormal function of von willebrand factor and leads to a similar bleeding pattern. Its milder forms are seen to be more relatively common (Hoffman, et al. 2006).

Decrease platelet numbers may be, due to various causes, including

insufficient production e g in myelodysplastic syndrome or other bone marrow disorder, destruction by the immune system (immune thrombocytopenia purpura ITP) and consumption due to various causes (thrombotic thrombocytopenic purpural TTP) hemolytic-uremic syndrome /HUS, paroxmal nocturnal haemoglobinuria PNH, disseminated intravascular coagulation DIC, heparin-induced thrombocytopenia (HIT) most consumptive conditions lead to platelet activation and some are associated with thrombosis (Neerman, et al., 1998).

Combined Deficiency of Factors v and viii

The combined deficiency of FV and factor VIII is of particular interest as

it is the first coagulation disorder attributable to genes defects outside the coagulation factor genes themselves, as inheritance patterns had suggested the disorder is caused by abnormal transport through the endoplasmic reticulum due to a defect in ERGIC-53 coded on chromosome 18. the factor levels as not usually low so spontaneous bleeding is rare. Bleeding occurs after surgery and dental extractions; women may have hemorrhagic and postpartum hemorrhage.

FACTOR VII DEFICIENCY

Factor VIII is one of the vitamin K dependent glycoprotein and is

encoded on chromosome 13.A mutation data base can be view at the fact that FVIII deficiency occurs 1 in 500,000 of the general population but diagnosis of the heterozygous state is complicated by the considerable variation of level in the normal population, due to both inherited (F7gene polymorphism (perry, et al. 2002) and acquired (dietary fat, age, obesity, etc.) causes. In addition, reagent (thromboplastin source) can markedly affect the assay result. There is a relatively poor correlation between FVII level and the wide variety of bleeding manifestation (peyvandi, et al. 1997) Mucous membrane bleeding, including epistaxis and menorrhagia is common. Some patients with severe deficiency have suffered ICH, often in the neonatal period or  joint bleeding. Occasionally patients have paradoxical thrombosis, which is not understood, (perry, et al. 2002)

  FACTOR X DEFICIENCY

Factor X is a vitamin K-dependent protease and has a key role in the

coagulation pathway, being the first enzyme in the common pathway and the most important activator of prothrombin. In association with factor Va and (phosphohpied membranes, fXa accelerates the conversion of prothrombin to thrombin 280,00 fold. The gene is located on chromosome 13 near FVll gene to which it is closely related. FX is synthesized in the liver. The overall frequency of severe deficiency is estimated to be I in I million of the general population. Although most heterozygote do not have any symptoms, some have a significant bleeding  tendency. Severe FX deficiency (FX< I iuldl) is generally a severe bleeding disorder carries a particular risk of ICH in a neonatal period, therefore, where both parent are know to be heterozygous a delivery management plan should be prepared and the infant watch closely for evidence of ICH. Epistaxis is particularlly common and menorrhagia occurs in 50% of woman. Joint bleeding can result in sever arthropathy. prophylactic treatment for severe FX deficiency should be considered mild. FX deficiency is defined as 6-10 iuldl and my be discovered incidentally. Individuals with more than 10 iuldl and as bleeding history despite hemostatic challenge may not require replacement therapy. (peyrandi, et al 1998)

DEFICIENCY OF VITAMIN K-DEPENDENT FACTOR (II, VII, IX , X)

FII, FVII, FIX and FX requires a critical gammacarboxylation step during synthesis to become activated defects in the carboxylation  steps, caused by enzyme deficiencies, can produce combined deficiency of these four factors. Gene defect have been reported in gamma glutamyl carboxylase and vitamin K epoxide reductase complex (Brenner, et al. 1998) the defect is rare and is inherited as an autosomal recessive disorder. It has been reported in only about 20 kindred with variable severity between them. Severe deficiency is associated with levels of L5 iuldl and may present in the neonatal period (with umbilical cow bleeding or even ICH) at which time it must be distinguished from vitamin K deficiency. Milder types may present with mucocutaneous or post –surgical bleeding. The defect also affects the other vitamin K dependent factors, which are protein C and S. matrix Gla protein and Osteocalcin. Thus, severly deficient children may also have other clinical features, similar to warfarin embryopathy, such as nasal hypoplasia, distal digital hyperplasia epiphyseal slippling and mild conductive hearing loss (Oldenburg, et al. 2000)

FACTOR XI DEFICIENCY

          Factor (IX) is a dimeric serine protease whose function in coagulation is to recruit the intrinsic factor pathway after the tissue factor pathway has generated thrombin. Bleeding tendency may depend upon the levels of other coagulation factors such as FVIII: C and von willebrand factor (VWf) the gene is on chromosome 4, factor xi deficiency is the commonest among the rare disorder.the deficiency is particularly common in Ashkenazi Jews where the carrier rate is 8-9%.In this population,most individuals have one or both of two  particular mutations, a stop codon in exon S (type lll) leading to a reduced secretion of the molecule. In other population, the mutations are more variable, but founder mutations have been noted in English (in as many as 1-2% of the population) and Basgues, Heterozygous with FXI often have a bleeding risk that is not well predicted by the FXI;C level. Woman may have hemorrhage and bleeding after childbirth. Severlly deficient individuals (FXI<10 iuldl) have a mild bleeding tendency after surgery, especially in areas with high fibrinolytic potential such as the mouth,nose and the genitor –urinary tract spontaneous bleeding is rare and hemarrthrosis is not a feature, but bleeding may occur after circumcision (bolton, et al. 1995).

  FACTOR XII DEFICIENCY

Factor XII deficiency does not give rise to a bleeding disorder. FXII

deficiency (heterozygous) is common in the general Caucasian population (2-3 % of blood donors (Halbmager, et al. 1993) and is the most commonest cause of an unexpected prolongation of APTT in pre-surgical screening. Severe FXII deficiency is most common in Asian where it is usually completely asymptomatic. There is the possibility that FXII deficiency is related to thrombotic events, but recent analysis suggest that there is no association (Girolami, et al 2005).

  FACTOR XIII DEFICIENCY

Factor XIII deficiency is rare, estimated at I per million of the general

population. As with other rare disorders, heterozygotes are asymptomatic. factor XIII is a tetramer with two “a” chains (containing the thrombin cleavage site and a calcium binding site) and two “b” chains which are cleaved away when FXIII is activated, in other word, the “b” unit is a carrier of the activated “a” unit. The activated molecule then stabilizes fibrin by cross linking the gamma and the alpha chain by the formation of lysine gutamine links. Apha2-plasma inhibitor is also linked to the “a” chains of fibrin by xllla. Interestingly the submit have different sites of synthesis and location. The “a” submit are localed in the platelets and megakaryocytes, placenta, uterus and macrophages where as the “b” units are synthesized in the liver. Thus liver transplantation changes the “b” submits to that of the donor, heaving the “a” unit unchanged and bone narrow transplantation dose he reverse. The FXII subumit “a” fene is located on the chromosome 6 and “6” gene on the same chromosome. The majority of mutations associated with FXIII deficiency have seen described for the “a” unit the disorder shows considerable molecular heterogeneity and therefore variable clinical severity, which in most cases, affected individuals tend to bleed excessively from umbilical stump and are at risk of ICH, which may occur in neonatal period .extensive skin bursing and bleeding is also common and patients may suffer from muscle and joint bleeding pregnancy is often associated with miscarriage unless prophylaxis is given (Anwar, et al,-1999).

PROCOAGULANTS

Anticoagulants and antiplatelet agents are amount the most commonly

used medication. Anti-platelet agents includes aspirin, clopidogrel, dipyridamole and ticlopidine, the parenteral glycoprotein llb/lla inhibition are used during angioplasty of the anticoagulants, warfarin (and related coumarins) and heparin are the most commonly used. warfarin affects the vitamin K- dependent clotting factors (II, VII, IX, X) where as heparin and related compounds increase the action of antithrombin on thrombin and factor Xa. A newer class of drugs, the directs thrombin inhibitors, is under development some members are already in clinical use (such as hapindin). Also under development are other small molecular compounds that interfere directly with the enzymatic action of particular coagulation factors (e g rivaroxaban, dabigatran, apixaban)  (lak, et al. 1999).