Introduction

Haemostasis is the body's response to vascular injury; it aims to minimise blood loss, temporarily repair the damaged vessel and creates a framework for tissue repair.

Haemostasis can be divided into:

 

  • primary haemostasis : This is the stage at which a platelet plug is formed. It involves:Vascular Spasm, Platelet Adhesion, Platelet Release Reaction and Platelet Aggregation. 
  • secondary haemostasis :This is currently explained by the cell based model, although knowledge of the previously accepted cascade model is useful. Both models involve interactions between coagulation factors. The cell based model emphasises the importance of platelets and Tissue Factor (TF) bearing cells. The end result is the activation of fibrin.

 

    Although haemostasis is separated into 2 divisions, it should be noted that these events occur simultaneously and the reactions of primary and secondary haemostasis are intertwined and inter-reliant.

    Haemostasis is clearly a vital mechanism to prevent blood loss and to maintain vascular integrity, but it is also paramount for preventing invasive microorganisms from entering the bloodstream.

    Vascular Spasm

    Immediately after the vessel injury, vascular spasm (contraction of smooth muscle) occurs in the damaged vessel and the surrounding small arteries and arterioles; it lasts for approximately 30 minutes after the injury. Vascular spasm is a local reflex response which is amplified by the release of thromboxane A2 (TXA2) and serotonin by platelets.

    Platelets also accelerate division of endothelial cells, smooth muscle cells and fibroblasts which results in a more rapid repair process.

     

     

    Normal vessel diameter compared to constricted vessel

    Platelet Adhesion

    Vessel wall endothelium plays an important role in blood coagulation.

    In normal vessel endothelium, platelet adhesion and thrombus formation is prevented due to:

    1)       The negative charge of the vessel wall

    2)       Thrombomodulin and heparan sulphate expression

    3)       Synthesis of prostacyclin (PG1a) and Nitric Oxide (NO), which cause vasodilation and inhibits

    platelet aggregation

    4)       The production of plasminogen activator

     

    When vascular damage occurs, subendothelium is exposed and therefore reduces the negative surface charge that repels platelets.

    Also, prostacyclin production is limited and adhering and aggregating platelets release platelet factor IV.

    Platelet factor IV is an antiheparin and restricts the activity of antithrombin III, which inhibits production of thrombin (thrombin is a key component of the coagulation cascade).

    Endothelial synthesis of Tissue Factor (TF) occurs. Activated factor IX and factor VIII and X are released at the injury site, allowing activated factor X to be formed - this leads to thrombin production and formation of the fibrin clot.

     

     

    Platelets can attach to exposed collagen from the vessel directly via platelet receptor GPIa.

    Exposed collagen has receptors for Factor VIII and von Willebrand Factor (vWF). Platelets have receptors for vWF called GPIb and via these receptors become indirectly attached to the vessel wall.

    Following platelet adhesion a physical change in the appearance of a platelet is induced. Platelets become more spherical and develop pseudopodia (cytoplasmic projections) which enhance interaction between adjacent platelets.The contraction of microfilaments and production of pseudopodia facilitate the release of granule contents.

     

    Platelet adhesion

    von Willebrand Factor (vWF)

    von Willebrand Factor (vWF)

    vWF is found in endothelial cells, subendothelium and in platelets.

    It is a glycoprotein and it acts as a carrier molecule for factor VIII; it protects VIII from degradation in blood plasma.

    vWF facilitates platelet adhesion to the blood vessel wall and is also involved in the adhesion of platelets to each other to form the haemostatic plug.

    vWF is large, complex multimeric molecule which consists of numerous subunit chains including dimers and multimers joined by disulphide bonds.

    Coded for by a gene on chromosome 12, vWF is synthesised by endothelial cells and megakarocytes; it is then stored in Weibel-Palade bodies in endothelial cells and in platelet α – granules.

    Release of vWF from Weibel- Palade bodies is stimulated by several hormones; a significant increase in the level of circulating vWF can be due to stress, exercise or infusion of adrenaline or desmopressin(DDAVP).

    High molecular weight forms of vWF are the most effective at platelet adhesion, in particular in small vessels where the shear rate (the rate at which adjacent layer of fluid move with respect to each other) of blood flow is high.

     

    Platelet Release Reaction

    Pseudopodia facilitate the release of granule contents. They are produced by the contraction of microfilaments within the platelet.

    These microfilaments are similar to myosin and actin, because they require calcium ions for activation and contraction.

    Calcium ions are released from the dense tubular system within the platelet when the appropriate platelet receptors are stimulated.

     

     Platelet granule contents include:

    • ADP,
    • ATP,
    • platelet Factor,
    • calcium, 
    • serotonin, 
    • fibrinogen,
    • lysosomal enzymes,
    • β- thromboglobulin,
    • heparin neutralising factor

     

    Calcium ions also stimulate the production of Thromboxane A2 (TXA2). In addition, arachidonate release from the endothelial cell membrane also leads to the formation of thromboxane A₂.

     Thromboxane A₂:

    • Lowers cyclic AMP (High levels of cyclic AMP reduce amount of free calcium ions and vice versa)
    • Potent vasoconstrictor
    • Powerful aggregating agent
    • Enhances aggregation by stimulating more surface receptors when released.
    • Initiates platelet release reaction

     

      Prostaglandin prostacyclin (PGI₂)

      The release reaction is inhibited by any substance which increases the level of platelet cyclic AMP; for example, prostaglandin prostacyclin (PGI₂), which is synthesised by vascular endothelial cells. PGI₂ also causes vasodilation. Cyclic AMP inhibits the release reaction by reducing the amount of free calcium ions available to cause contraction of the microfilaments and therefore the production of pseudopodia, which facilitates α granule content release. Lack of calcium ions also restricts TXA₂ production.

      PGI₂ is important in maintaining the intricate balance between haemostasis promoting and limiting mechanisms as it prevents inappropriate platelet aggregation in normal vessel wall and limits the extent of the thrombus after injury.

      Intact endothelial cells are able to produce PGI₂ by utilising two of the intermediate products of TXA₂ synthesis (PGG₂ and PGH₂).

       

       

      Platelet Aggregation

      Platelet aggregation begins within 15 seconds after the injury has occurred.

      Release of ADP and  thromboxane A₂ induces further platelets to aggregate at the site of injury. ADP causes the platelets to swell and the platelet membranes become more adherent to adjacent platelets. As more and more platelets adhere, more release reactions occur, which increases the amount of ADP and thromboxane A₂ causing secondary platelet aggregation. This is a self perpetuating cycle of positive feedback which leads to the formation of a platelet plug. This unstable primary haemostatic plug is usually sufficient to control bleeding temporarily.

       

      In 2012, Spectre et al. demonstrated that platelets have a crucial role in the initiation of 'thrombo-inflammation'. Activated platelets have been shown to promote lymphocyte adhesion to the extracellular matrix components, reinforcing the theory that thrombotic processes are connected to inflammation and immunity.

       

       

      Platelet aggregation

      The Cell Based Model

      Over the past 15 years, the cascade model has evolved into the currently accepted cell based model. 

      The cascade model explained secondary haemostasis reasonably well under static laboratory conditions. However, it was not a sufficient explanation of how coagulation occurs in reality, where plasma is continually flowing through the vessels, interacting with the vessel wall and cell surfaces.

      The cell based model involves interactions between Tissue Factor (TF) bearing cells and platelets. This model of coagulation functions by a positive feedback mechanism. 3 clear but interdependent and overlapping steps are described by the model:

      1) Initiation

      2) Amplification

      3) Propagation

       

       

      Initiation

      TF found on the plasma membrane of cells outside the vasculature are responsible for initiating coagulation. Inappropriate initiation of coagulation is prevented by TF bearing cells being uncontactable by the components of blood whilst the vessel wall is intact.

      Monocytes, tumour cells and other circulating cells express an inactive form of TF, the purpose of which is currently unknown.

      During injury, blood is exposed to TF bearing cells outside of the vessel, as the vessel wall integrity is compromised. Factor VII is the only coagulation protein that regularly circulates in the blood in both active (1% of total amount Factor VII) and inactive forms. The activated factor VII complexes with TF to start process.

      The Factor VIIa/TF complex activates more Factor VII and small amount of Factor IX and X. 

      Factor Xa binds with cofactor Va creating prothrombinase complexes on the plasma membrane of TF bearing cells. If some Factor Xa dissociates from the TF bearing cell, it is immediately inhibited in the fluid phase by Tissue Factor Pathway Inhibitor (TFPI) and Antithrombin III (ATIII); therefore the effect of Factor Xa is localised to the area where it originated and it is unable to from one cell surface to the next.

      Factor IXa is able to transfer from the TF bearing cell where it was formed to a platelet or other cell surface due to the fact that it is not inhibited by TFPI and is inhibited at a particularly slow rate by ATIII.

      The TF pathway occurs continuously at a low level in the extravascular space. Therefore, it is likely that Factor VII is bound to extravascular TF even without the occurrence of vascular injury. Extravascular Factors IX and X are activated once they are transported through the tissues. In support of this theory, called basal coagulation or idling, is the finding that small amounts activation peptides of coagulation factors are present in the blood in normal individuals. 

      As the principal reactants of coagulation (Factor VIII, platelets and vWF) are isolated within the vessel, basal coagulation does not form a blood clot unnecessarily. A small amount of thrombin is produced in the initiation step, however coagulation does not advance until certain components of the blood leave the vessel and bind to the TF bearing cells in the extravascular space.

       

       

       

       

      Diagram of Initiation Step



      Amplification

      If vascular wall integrity is compromised, large molecules and cells (such as platelets) within the blood are enabled to escape from the vascular space into the extravascular space. The components of the blood are exposed to the small amount of thrombin produced in the initiation step.

      The thrombin completely activates platelets which have adhered to the injured area forming a platelet plug. It also activates cofactors V and VIII on the surface of the activated platelets. In order to activate these factors, VIII/vWF complex is removed, enabling vWF to facilitate further platelet adhesion and aggregation in area of damaged vessel.

      Thrombin generated in the initiation step also activates Factor XI on the surface of the platelet, offering a possible explanation as to why Factor XII, amongst other contact factors, are not always required for coagulation to occur.

      The end result of the amplification phase is that fully activated platelets are coated in activated cofactors and Factor XIa.

       

       

      Amplification Diagram



      Propagation

      Following platelet aggregation, more platelet membrane receptors such as P2Y12 are exposed. Platelet factor 3, provides a surface for 2 phospholipid mediated reactions producing coagulation protein complexes to occur in the presence of Ca2+ ions. The first reaction is tenase formation  and the second reaction is prothrombinase formation.

      Primary haemostasis facilitates secondary haemostasis by providing phospholipid surfaces for these crucial reactions to occur; the phospholipid template is ideal for the concentration and orientation of the coagulation proteins.

      The tenase complexes (Factor VIIIa/Factor IXa) and prothrombinase complexes (Factor Va/Factor Xa) are formed on the surface of activated platelets. This is also the site at which the propagation phase occurs.

      Factor XIa (activated during initiation phase) disperse to the surface of the platelet, it then forms the tenase complex. Platelet-bound Factor XIa can provide additional Factor XIa to form more tenase complexes. 

      Factor Xa is rather immobile from the TF bearing cell, and therefore cannot reach the activated platelet effectively. The tenase complexes must deliver Factor Xa directly to the platelet surface.

      Factor Xa promptly binds with cofactor Va which is activated and attached to the platelet during the amplification phase.  The formation of the prothrombinase complexes causes a surge of thrombin synthesis.

      The key contribution of Factor XIa to coagulation is the fact that it causes an increase in the amount of Xa available, which leads to a heightened amount and rate of thrombin production which causes the removal of fibrinopeptide A from fibrinogen. 

      Once a sufficient amount of thrombin is generated with adequate speed to lead to a critical mass of fibrin, the soluble fibrin molecules polymerize into fibrin strands, producing a insoluble fibrin mass.

       

       

      Propagation Diagram



      Clotting Cascade

      The cascade model was proposed in 1964, and although it does not accurately describe how coagulation occurs in vivo, it is important for interpretation of laboratory results and demonstrates how coagulation works in vitro.

      The coagulation pathway is a series of enzymatic reactions which lead to the degradation of soluble fibrinogen to fibrin. Fibrin is the key component of the blood clot; it is polymerised to create visible strands which incorporate blood cells into the clot and seal the area of damaged vessel.

      It involves interactions between coagulation factors which are nearly all polypeptides found as proenzymes circulating in the blood. They are synthesised by hepatocytes. Once activated most factors acts as serine proteases - they are able to cleave a particular polypeptide substrate at a specific point between two basic amino acid residues.

      There is an established link between blood coagulation and the body's immune system. This seems to be logical, as compromised vessel wall integrity provides an access point to pathogens.

      The body must constantly balance mechanisms that promote haemostasis and mechanisms which restrict hamostasis. When blood coagulation is triggered, a counteracting mechanism is simultaneously activated to control the process; excessive coagulation has the potential to be equally as catastrophic as haemorrhage.

      The coagulation cascade is often divided into the intrinsic and extrinsic pathway. If a defect is present in one pathway, the other cannot compensate; both pathways must be functioning properly for normal haemostasis to occur.

      As the intrinsic/extrinsic pathway model is so widely disseminated in literature and represents a good model to understand coagulation, it is detailed here. The intrinsic and extrinsic pathways are considered as a separate series of reactions that both lead to the activation of Factor X. The intrinsic pathway is the longest route to Factor X activation as it involves more reactions. The common pathway is after the point when Factor X has been activated and it will lead to the formation of a fibrin clot.

      The Intrinsic Pathway

      The intrinsic and extrinsic pathway refer to how Factor X is activated.

      The intrinsic pathway is the least clinically significant pathway. It is initiated when contact is made between blood and negatively charged surfaces.

      The first step of the intrinsic pathway is termed the contact phase. 

      When the vascular endothelium is damaged, collagen and microfilaments are exposed and they bind to Factor XII (also known as Hageman's Factor).

      The binding of Factor XII is important, as it leads to a conformational change revealing its active site.

      Kallikrein activates XII to XIIa. Kallikrein is released from its precursor prekallikrein assisted by the action of enzymes.

      Intriguingly, XIIa releases kallikrein from prekallikrein, which encourages its own production by a positive feedback mechanism.

      Kallikrein also reacts with plasminogen to release plasmin (involved in fibrinolysis).

      In addition to this, kallikrein also cleaves the inert precursor High Molecular Weight Kininogen (HMWK) to form bradykinin.

      Bradykinin increases vasodilation and vascular permeability. 

      Kallikrein enhances an immune response at the site of vascular injury. It does this by attracting neutrophils and monocytes to the area, and thus promoting vascular permeability and promoting migration of phagocytic cells. 

      HMWK, XIIa and prekallikrein are absorbed by negatively charged surfaces which enhances their interactions.

      The key role of Factor XIIa is to activate XI, which is also absorbed by negatively charged surfaces.

      The mechanism which heightens activation amongst these proteins would be potentially hazardous if left to proceed without moderation. There are several inhibitory mechanisms in place.

      After the formation of XIa, the focus of the coagulation shifts from negatively charged surfaces to phospholipid surfaces - the contact is phase is over.

      Carboxyglutamic acid residues of Factor XI bind to Calcium ions which anchor it to phospholipid surfaces.

      Factor XIa cleaves Factor IX in a 2 stage process to produce IXa; it remains attached to the membrane and therefore it can remain in close contact with substrate, Factor X, which is also anchored to the phospholipid surface by carboxyglutamate residues.

      Despite this close contact between Factor IXa and Factor X, Factor X activation proceeds slowly, unless the cofactor VIII is present.

      Factor VIII is comprised of protein VIIIRAg covalently bonded to VIIIc. In the presence of trace amount of thrombin, VIIIc is release from the complex.

      VIIIc then forms a complex with platelet bound Factor IXa, enhancing activation of Factor Xa.

      Overproduction is prevented as Factor Xa inhibits VIIIc activity.

       

       

      The Extrinsic Pathway

      The extrinsic pathway is the shorter and more clinically significant of the 2 pathways. It is initiated at the site of injury in response to the release of Tissue Factor (TF). It is also known as the Tissue Factor Pathway. Tissue Factor is secreted by fibroblasts and muscle, amongst other tissue cells.

      Interactions between the pathways:

      • Factor XIIa enhances Factor VII activity.
      • The VII-TF complexes that form during the extrinsic pathway can activate Factor IX of the intrinsic pathway, and this ability is augmented by the presence of Factor Xa.

       

        TF forms a complex with circulating Factor VII. This brings about a conformational change which promotes proteolytic activity with Factor X. Factor VII can act as an anchor to phospholipid surfaces, thus it can bind platelets in close association with Factor X, which it activates enzymatically to form Factor Xa. 

        Factor Xa increases the affinity of Factor VII for TF and the resulting molecule activates further Factor X more efficiently.

        Continual cleavage of Factor VII inactivates the built up concentration of Factor Xa, this prevents over production of Factor Xa.

        The Common Pathway

         Factor Xa works with cofactor V and Ca2+ ions on phospholipid surface to convert prothrombin to thrombin. Similarly to cofactor VIII, cofactor V is converted to its active form by trace amount of thrombin. It can also be activated by Factor Xa. Factor Va binds with Calcium ions and also to platelet phospholipids. The binding causes Factor Va to form a Factor Xa receptor.

        Factor Xa becomes attached at 2 sites - th Factor Va receptor and its own carboxyglutamic acid region. Prothrombin becomes bound to this complex - known as the prothrombinase complex. 

        The prothrombinase complex is interesting as the close association of its components augments prothrombin formation and yet limits it to the locality of the membrane, which prevents dissemination.

        After some thrombin has ben generated, it can cleave prothrombin.  Thrombin is a serine protease which hydrolyses the peptide bonds of fibrinogen, releasing fibrin monomers to form a loose insoluble fibrin polymer. Thrombin also activates factors V and VIII which are both found in plasma bound to vWF.

        Simultaneously, thrombin activates factor XIII in the presence of Ca2+ ions. Factor XIII stabilises polymers by covalently cross linking adjacent fibrin molecules.

           

           

          Coagulation Factor Table



          Diagram of Cascade Model



          The Fibrinolytic System

          The fibrinolytic system is activated by the formation of fibrin.

          It is crucial to have an accurate balance between haemostasis promoting and inhibitory mechanisms to prevent blood loss and micro-organism invasion, and also to ensure fibrin is not formed inappropriately and does not extend to in tact vascular endothelium.

          The fibrinolytic system is also part of the repair and remodelling process of the damaged vessel wall.

          The liver produces plasminogen , which is activated to form plasmin. Plasmin is the key fibrinolytic enzyme. Most of the principal proteolytic enzymes circulate in the blood in an inactive form. Plasminogen is converted to plasmin by plasminogen activators.

          There are 2 types of plasminogen activators:

          1) Tissue-type plasminogen activator (tPA): synthesised in most tissue cells and in the vascular endothelium.

          2)Urokinase-like plasminogen activators: found in urine, tears and saliva.

          tPA has a specific binding site for fibrin, and therefore is only activated in the presence of fibrin. The main role of tPA is to limit the amount of fibrin remaining in the tissues and circulation. This means that it is more limited than uPAs which can activate plasminogen with or without the presence of fibrin.

          The vascular endothelium also produce plasminogen activator inhibitor (PAI), which counteracts tPA under normal vascular conditions (it limits the activity of tPA to prevent plasmin formation). Activated platelets release PAI at the site of an injury to prevent the fibrin clot being broken down too quickly.

          Kallikrein was a key component of the coagulation cascade, but despite activating coagulation it also facilitates conversion of plasminogen to plasmin - demonstrating the intertwined nature of clot promoting and inhibiting mechanisms.

          Generally, there is a higher rate of fibrinolytic activity in arteries than veins. There is more fibrinolytic activity in deep veins than superficial and increased fibrinolytic activity in upper limbs than the lower.

           

           

           

          Heparin Induced Thrombocytopenia (HIT)

          HIT is a relatively rare complication affecting patients who have undergone heparin therapy. The condition usually presents 5-14 days after first exposure to heparin. HIT is caused by an autoimmune response to the heparin-factor4 complex in the blood. It is often difficult to diagnose HIT as patients receiving heparin therapy are often severely ill and thrombocytopenia can be caused for several other reasons.

           HIT can be caused by all types of heparin but LMW heparin causes HIT less frequently than other types. When HIT is diagnosed, all heparin administration to the patient but be discontinued, however it is still essential to continue with alternative anticoagulant therapy – especially as HIT is usually associated with the treatment of severe thrombosis. Danaparoid (heparinoid) or Hirudin (direct thrombin inhibitor) should be used and if Warfarin should be prescribed, one of these drugs should be given in conjunction, as Warfarin will deplete Protein C levels

           

          Disseminated Intravascular Coagulation (DIC)

          DIC is secondary complication to many different conditions; it occurs when coagulation becomes over-active, unnecessarily creating thrombi in the microvasculature. The presence of the thrombi leads to innate checking process of coagulation becoming active – platelets, fibrin and coagulation factors are degraded or inactivated and fibrinolysis is initiated. This leads to haemorrhage due the depletion of coagulation factors and activation of fibrinolysis.

          2 major mechanisms cause DIC:

          • Tissue Factor (TF)/thromboplastic substance being secreted into the bloodstream

          Thromboplastic substances can originate from:

          -       Major trauma

          -       Extensive surgery

          -       Severe burns

          -       Dead Retained Foetus Syndrome

          -       The placenta and amniotic fluid in pregnant women

          -       Cytoplasmic granules from promylocytic leukaemia cells

          -       Mucus secreted by certain adenocarcinomas (usually lung,pancreas,stomach and colon cancers)

          -       Widespread endothelial damage

          Any condition leading necrosis of the endothelium of blood vessels will expose the subendothelium – this leads to platelet activate and activation of the intrinsic and extrinsic pathway. Hypoxia, acidosis and shock can all cause DIC and these conditions are often present in critically ill patients.

           

          TNF is associated with DIC caused by sepsis. TNF stimulates endothelial cells to express TF on their surfaces and also to down regulate their thrombomodulin expression. TNF is a chemotactic agent for leukocytes, which can be damage endothelial cells by secreting reactive oxygen species and preformed proteases.

           

          Endothelial damage can occur from antigen-antibody complexes, temperature extremes and microoganisms

           

          Main consequences of DIC:

           

          • Occlusion of most severely affected vessels and most fragile organs by microthrombi leads to ischemia and hypoxia in these tissues – presentation of DIC is usually associated with tissue hypoxia and infarction
          • As the microthrombi reduce the amount of space available in the lumen of vessels for RBCs to pass through, the RBCs can become damaged as they squeeze through the small space, leading to microangiopathic haemolytic anaemia.
          • Haemorrhagic diathesis (tendency) is a severe consequence of DIC caused by depletion of platelets, factors and activation of fibrinolysis.

           

          Impact of Massive Transfusion

          Massive blood transfusion is defined as a volume of >8-10 unites of red cells transfused within a 24-hour period. Massive haemorrhage is defined as loss of 50% blood volume within 3 hours or a rate of blood loss exceeding 150mL/min.

           

          1)      Decrease in Temperature

          Packed cells are normally stored at 4ᵒC in a blood bank – this can cause hypothermia, vasoconstriction (causing reduced rate of infusion) and arrhythmias in the recipient during/after transfusion. Blood should ideally be warmed during massive transfusion and for patients at risk of hypothermia.

           

          2)      Coagulopathy

          Stored blood contains a very small amount of platelets or clotting factors. The risk of coagulopathy therefore increased in massive transfusions.

           

          3)      Hypocalaemia

          In stored blood citrate binds to calcium ions, reducing the amount of ionised calcium. When rapidly transfused this can cause myocardial depression and enhance defective coagulation.

           

          4)      Heightened affinity for oxygen

          In stored blood, the oxyhaemoglobin -dissociation curve is shifted to the left as red cells contain less 2,3 disphosphoglycerate. This means that haemoglobin has an increased affinity to uptake oxygen from the blood, and oxygen unloading to the tissues is impaired. This issue usually resolves itself within 12 hours of transfusion.

           

          5)      Hyperkalaemia

          During storage, blood levels of potassium increase. This is a rare complication however, as when the blood becomes warmed in the body after transfusion, the rate of red cell metabolism increases. Therefore the sodium-potassium pumps become active again and normal blood potassium levels are restored.

           

          Massive Haemorrhage Protocol (for adults)



          Factor Deficiencies

          von Willebrand Disease (vWD)

          vWD is the most common bleeding disorder in humans; it can affect suffers with varying degrees of severity. vWD is caused by an absence of normal levels of VIII-von Willebrand Factor or by the inheritance of an abnormal vWF molecule. 

          Genetically, vWD can be inherited in an autosomal dominant or recessive pattern. There are 4 distinct types of the disease which are classified by the particular molecular abnormality.

          vWD suffers are found to be deficient in Factor VIII. This is due to the role of vWF to act as a carrier molecule for VIII, preventing its degradation. vWF is also thought to be involved in the synthesis of Factor VIII. 

          High molecular weight multimers of vWF are found to be the most effective at bringing about platelet adhesion, especially in small vessels where shear rates are high. Bleeding severity can be determined by the amount of high molecular weight vWF - the more high weight multimer available, the less severe the bleeding disorder.

           

          Haemophilia A

          Both haemophilia A and B are of X- linked recessive inheritance. There are cases of acquired Haemophilia A. Haemophilia A is more common than Haemophilia B. 

          Haemophilia A is caused by deficiency of Factor VIIIc. VIIIC is non-covalently bonded to vWF and is responsible for cofactor activity during coagulation. VIII vWF is sythesised by vascular endothelial cells. VIIIc itself is synthesised in the liver by endothelial cells and hepatocytes. 

          The most apparent symtom of Haemophilia A is prolonged bleeding either internally or externally. The severity of the bleeding varies depending on the genes involved.

          Haemophilia A is usually treated by prophylactic drugs such as desmopressin, which is used by mild sufferers. The drugs are a supplement of Factor VIIIc and should be taken regularly, the dose is usually tailored to the individual. A more concentrated supplement is administered to sufferers before surgery or after major trauma.

          Haemophilia B

          Haemophilia B, also known as Christmas disease, is the second most common form of haemophilia. It is caused a deficiency of Factor IX. The cause of this deficiency is usually due to X-linked inheritance.

          The key feature of haemophilia B is that the sufferers bleeding time is significantly increased.

          As with Haemophilia A, there are varying severities of the condition, ranging from mild to severe. 

          Similar to Haemophilia A, treatment is usually Factor IX prophylactic injections.

          Vitamin K deficiency

          Factors VII, IX, X, prothrombin and inhibitory molecules protein C and S require vitamin K for carboxylation of their glutamic residues whilst they are in the liver (where they are sythesised). Carboxylation is a post-translational process which involves molecular oxygen, reduced vitamin K, bicarbonate and membrane bound carboxylase.

          Carboxylation is paramount to the production of a functioning factor, as it enables them to bind to calcium ions and lipid surfaces. If the body is deficient in vitamin K, a factor which is lacking this function is produced.

          Despite both procoagulant and inhibitory molecules being affected, the overall effect is a hypocoagulable state. Warfarin is a vitamin K antagonist and is therefore used as an anticoagulant drug.

          Reasons for deficiencies are dietary deficiency, obstructive jaundice and intestinal malabsorption. Neonates are all moderately deficient in vitamin K. As vitamin K deficiency is very common, often prophylactic vitamin K is administered by injection. Vitamin K deficiency is problematic for neonates born prematurely or of a low birth weight.

           

          References

          • Essentials of Haemostasis & Thrombosis by L.A.Kay
          • Essential Haematology (third edition) by A.V.Hoffbrand and J.E.Pettit
          • Clinical Medicine (eighth edition) by Parveen Kumar and Michael Clark
          • Fundamentals of Anatomy and Physiology (ninth edition) by Martini, Nath and Bartholomew
          • Spectre G, Zhu L, Ersoy M, et al. Platelets selectivelyenhance lymphocyte adhesion on subendothelialmatrix under arterial flow conditions. ThrombHaemost 2012; 108: 328-337
          • Haemophilia A (Factor VIII deficiency) by Dr G Rull, http://www.patient.co.uk/doctor/Haemophilia-A-(Factor-VIII-Deficiency).htm, date of access: 01/09/2012
          • A New Understanding Of The Coagulation Process - The Cell - Based Model by Adelaida L. Ruseva and Anelia A. Dimitrova
          • Robbins and Cotran: Pathological Basis of Disease (Eighth edition) by Kumar, Abbas, Fausto and Aster
          • Algorithm of Management of Massive Haemorrhage in Adults, version 3, produced 14/06/2013. Reproduced with the kind permission of North West Regional Transfusion Committe incorporating North Wales.
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