Constituents of the blood: Platelets and plasma Dr D J Hampshire University of Sheffield

Two phases of the blood Cellular component (45%) Fluid component (55%) Red cells White cells Platelets Plasma Fluid component (55%)

Haemostasis Blood inside the vessels remains fluid Blood outside the vessels should clot Balance

Blood is usually fluid inside vessels Haemostasis Blood is usually fluid inside vessels Platelets and proteins of the coagulation cascade circulate in an inactive state Endothelial cells, anticoagulant pathway and fibrinolytic pathway actively keep it fluid

Haemostasis Thrombosis Bleeding Balance Blood clots inside the vessel Blood fails to clot outside the vessel Balance

Platelets Anucleate cells Circulate in an inactive state Responsible for primary haemostasis Image © OpenStax College (http://cnx.org/content/col11496/1.6/) Licensed under a Creative Commons Attribution License 3.0 license

Platelets and primary haemostasis Platelets circulate in an inactive state

Platelets and primary haemostasis Damage to the blood vessel Bind (adhere)

Platelets and primary haemostasis Damage to the blood vessel Bind (adhere) Change shape (activate)

Platelets and primary haemostasis Damage to the blood vessel Bind (adhere) Change shape (activate) Release contents (degranulate)

Platelets and primary haemostasis Aggregate to form a platelet (haemostatic) plug Lack of platelet function leads to bleeding

Thrombocytosis Arterial thrombosis Venous thrombosis Platelet number Normal = 140-400 x 109 / L Reduced Increased Thrombocytopenia ≥80 - <140 x 109 / L Increased bleeding ≥20 - <80 x 109 / L Spontaneous bleeding Thrombocytosis Arterial thrombosis Venous thrombosis

Soluble and in plasma component Proteins Soluble and in plasma component Albumin Immunoglobulins Carrier proteins Coagulation proteins

Albumin Produced in the liver Determines oncotic pressure Keeps intravascular fluid in that space Lack of albumin: Oedema, liver disease, nephrotic syndrome

Immunoglobulins Produced by B lymphocytes Antibodies generated when stimulated by foreign antigens Several classes: IgA, IgE, IgG, IgM Basis of immunity and vaccination

Coagulation proteins IIa Xa Va IIa II V TF VII X IX XIIa TF VIIa XIa IXa VIIIa Xa Va II IIa VIII VWF V Fibrinogen Fibrin Monomer Fibrin Polymer XIII XIIIa Stable Fibres IIa

Coagulation proteins TF VII X IX XIIa TF VIIa XIa XI IXa Series of enzymes that circulate in an inactive state Sequentially activated in a cascade sequence Convert soluble fibrinogen into insoluble fibrin polymer Generate a stable clot VIIIa Xa Va II IIa VIII VWF V Fibrinogen Fibrin Monomer Fibrin Polymer XIII XIIIa Stable Fibres IIa

Why is the coagulation cascade so complicated? Multiple steps allows for biological amplification of the response Multiple steps allows for regulation, not an all or nothing response Response can be graduated depending on the severity of the haemostatic challenge

Coagulation cascade and haemostasis Thrombosis Coagulation proteins are overactive Bleeding Failure of coagulation proteins Balance

Haemophilia Haemophilia A Haemophilia B Severe bleeding into muscles and joints Incidence 1 in 10,000 males Deficiency of factor VIII Treat with recombinant factor VIII Severe bleeding into muscles and joints Incidence 1 in 50,000 males Deficiency of factor IX Treat with recombinant factor IX

von Willebrand disease (VWD) Usually mild bleeding disorder often unrecognised and underdiagnosed Prevalence between 1% and 1 in 10,000 Defect or deficiency in von Willebrand factor (VWF) Binds platelets and factor VIII

VWD types Normal individual: normal VWF Type 1: reduced quantity, essentially normal VWF 69% of cases Type 2: functionally deficient VWF 27% of cases Type 3: virtually no VWF 4% of cases

Muco-cutaneous bleeding Epistaxis Menorrhagia Prolonged bleeding from cuts Easy bruising Bleeding after haemostatic challenge including; tooth extraction, trauma, surgery, childbirth

Acquired bleeding disorders Recent onset; not lifelong and no family history Can manifest as generalised or localised bleeding Medicinal drugs can result in acquired bleeding

Liver disease Often associated with bleeding and prolonged prothrombin time Coagulation factors and fibrinogen are synthesised in the liver

Vitamin K deficiency Manifests as prolonged prothrombin time Vitamin K necessary for correct synthesis of coagulation factors II, VII, X and XI Can be treated with intravenous vitamin K

Disseminated intravascular coagulation (DIC) Breakdown of haemostatic balance Simultaneous bleeding and microvascular thrombosis (life threatening) Cause can be sepsis, obstetric or malignancy Administering plasma and platelets can be considered (if required)

Drugs and bleeding Aspirin and clopidogrel affect platelet function Heparin and warfarin affect the coagulation cascade Steroids make tissues thin causing bruising and bleeding