Haemostasis (part 1: primary haemostasis)

Mind Map by maisie_oj, updated more than 1 year ago
Created by maisie_oj about 7 years ago


Blood Science Mind Map on Haemostasis (part 1: primary haemostasis), created by maisie_oj on 04/30/2013.

Resource summary

Haemostasis (part 1: primary haemostasis)
1 Introduction
1.1 The pysiological response to blood vessel damage that acts to minimise blood loss
1.2 Balance between protecting from haemorrhage and thrombosis
1.3 Primary haemostasis = platelet plug formation
1.4 Secondary haemostasis = fibrin clot formation
1.5 General mechanism
1.5.1 Blood vessel injury Platelet aggregation Platelet activation + + (Neural) vessel constriction Reduced blood flow Stable haemostatic plug (Tissue factor) coagulation cascade Fibrin formation
2 Primary haemostasis players
2.1 Endothelium
2.1.1 Normally the endothelium prevents thrombus formation by actively exhibiting antiplatlet, anticoagulant and profibrinolytic properties Antiplatelet properties The endothelium serves as a barrier between the highly pro-thrombotic ECM and the platelets in circulation Secrete NO (nitric oxide) and prostaglandin I-2 (PGI2) which promotes vasodilation and inhibits the activation of platelets Also expresses adenylate diphosphatase (ADPase) which degrades circulating ADP (an activator of platelets) Anticoagulative The endothelial cells feature membrane-bound thrombomodulin Thrombomodulin binds to thrombin (converting it from a pro-thrombotic to anti-thrombotic protein) This activates protein C (an inhibitor of the coagulation cascade) Protein C (with protein S) inhibits coagulation factors Va and VIIIa Endothelial membrane-bound heparin-like molecules act as cofactors Bind as cofactors to antithrombin(III) Activated antithrombin(III) Inactivates thrombin Inactivates factors IXa and Xa Profibrinolytic Endothelial cells produce t-PA (tissue plasminogen activator) t-PA cleaves plasminogen into plasmin (which degrades fibrin - degrades thrombi)
2.1.2 Prothrombotic qualities (following injury) Loss of endothelium reveals ECM collagen-bound vWF -> platelets biond vWF (via the platelet glycoprotein GPIb) Procoagulative In response to inflammatory cytokines (TNF, IL-1) endothelial cells prodcue tissue factor Tissue factor activates the extrinsic coagulation cascade Anti-fibrinolytic Under the right circumstances (injury etc.) endothelial cells produce inhibitors of plasminogen activator (PAI's) Prevents plasmin-mediated fibrinolysis
2.2 Platelets
2.2.1 Disc-shaped, anucleate cell fragments (from megakaryocytes - about 2-3,000 per megakaryocyte) Function depends on their activation; shape change and degranulation
2.2.2 Feature granules (alpha and delta granules) Alpha-granules feature P-selectins in the membrane (become externalised - adhesion); TGF-beta; PDGF; fibronectin and coagulation factors Clotting factors in alpha-granules = fibrinogen (I); V and VIII Delta-granules contain ADP, ATP, ionised Ca(2+), histamine, seratonin and adrenaline
2.2.3 Normally platelets are inactivated Following vessel endothelial damage ECM (with vWF is exposed) Platelets bind to this via their surface GPIb glycoprotein Also able to bind other ECM components (e.g. fibronectin) Secretion of both alpha and delta-granules Alpha-granule products promote coagulation and adhesion of platelets Delta-granule products activate the coagulation cascade (Ca(+) and ADP also promotes platelet aggregation) Platelet aggregation at the injury site (aided by ADP and thromboxane A2 (TxA2) release This aggregation leads to the formation of the primary haemostatic plug Held together by the interaction between platelets (GPIIb-IIIa - fibrinogen - GPIIb-IIIa) and platelets with the ECM (via ECM vWF - GPIb) This is followed by the activation of the coagulation cacade which ultimately produces fibrin (forms a meshwork around the platelet aggregation) Platelets release coagulation factors (fibrinogen (I), V and VIII) Platelets release pro-coagulative factors (Ca(+)) Activated platelets contract their cytoskeletons to form a tight-knit mass of cells ADP activates other platelets Causes conformational change in a large platelet surface glycoprtein (GPIIb-IIIa) GPIIb-IIIa binds fibrinogen (from alpha-granules) and links activated platelets together Loss = Glanzmann's thrombasthenia (another bleeding disorder) TxA2 is a potent vasoconstrictor Loss of this factor results in von willebrand disease (bleeding disorder) Loss of the GPIb receptor = Bernard-soulier syndrome (bleeding disorder)
3 Testing platelets
3.1 Full blood count (with mean platelet volume (MPV), blood film)
3.2 PFA-100 (platelet function analyser)
3.2.1 Full blood sample is drawn up through a capillary tube towards a membrane with a hole in the end The membrane is coated in collagen with either; ADP or adrenaline If normal platelets -> should be activated by the membrane and form a clot Blood should be inhibited from passing through the hole at the end
3.2.2 Measures high shear haemostasis
3.3 Platelet aggregation assay
3.3.1 In vitro assays Measure platelets clumps in platelet-rich plasma (PRP) or whole blood when exposed to aggregation agonists Collagen, ADP and thrombin all bind to their own specific receptor resulting in activation All receptors are implicated in different diseases (e.g. GPIb, GPIIb-IIIa) Activation = shape change, granule release and aggregation
3.3.2 Activation-induced change depends on the normal platelet function Useful data; lag phase, aggregation rate and amplitude
3.4 Platelet secretion assay
3.4.1 Platelet ADP/ATP release (from delta-granules) can be measured Valuable diagnostic tool Methods: HPLC (high performance liquid chromatography) luminescence; Firefly lantern preps (luminescence due to the ATP concentration)
3.5 Flow cytometry
3.5.1 Uses whole blood (2ul minimum) - therefore its a physiological activity assay Whole blood sample prevents artificially induced platelet aggregation
3.5.2 All blood cell properties can be analysed simultaneously (Not just platelets)
3.5.3 New Ab's or dyes can be easily introduced into samples
3.5.4 High degree of sensitivity Future - aggregation by flow? I have no idea what this means either...
4 Examples of platelet disorders
4.1 Thrombocytopaenia
4.1.1 Signs/symptoms Common Spontaneous skin pupura (/ecchymoses) Mucous membrane bleeding (/epistaxis) Protracted bleeding after trauma/surgery Menorrhagia / postpartum haemorrhage Uncommon Haemorrhages in the following places Intracranial, gastrointestinal, retinal and genitourinary
4.1.2 Causes (aetiology) Drugs Infection DIC Immune
4.2 Glanzmann's thrombasthenia
4.2.1 Loss of platelet GPIIb-IIIa (binds platelets together via fibrinogen bridge) >40 mutations ID'd (most type I involve the GPIIb gene; others = GPIIIa gene)
4.2.2 Bleeding disorder with a normal platelet count
4.2.3 Test results Normal Platelet count Platelet size / morphology and lifespan Very long bleeding time and PFA result
4.2.4 Autosomal recessive Often severe bleeding, but variable phenotype Subtypes (1 = complete IIb-IIIa loss; 2 = partial loss of IIb-IIIa)
4.3 Treatment options in platelet disorders
4.3.1 Specialist care
4.3.2 Avois aspirin, NSAIDs
4.3.3 Hormonal control on menses
4.3.4 Supportive care - tranexamic acid
4.3.5 Platelet transfusion
4.3.6 Recombinant rVIIIa (clotting factor)
4.4 Thrombocytosis (= high concentration of platelets in the blood)
4.4.1 Causes Inflammatory response Fe-deficiency / bleeding Bone marrow disorder (e.g. cancer)
4.4.2 Antiplatelet / anticoagulant agents Heparin (binds antithrombin(III) and inactivates thrombin) Aspirin, NSAIDs (inhibit COX2) Clopidogrel (ADP receptor inhibitor)
5 Von willebrand factor (vWF)
5.1 Large multimeric glycoprotein (exists as a series of multimers)
5.1.1 Extensively processed (multimer assembly) Constituitively expressed
5.2 Functions
5.2.1 Carrier protein for factor VIII (protects VIII against premature proteolytic degradation)
5.2.2 Adhesive protein in primary haemostasis (platelet adhesion)
5.2.3 Binds a number of ligands Collagen; platelet GPIb and GPIIb-IIIa; sulfatides; heparin
5.3 Clinical features
5.3.1 Highly heterogenous phenotypic expression Mild-moderate bleeding tenedency Bruising, epistaxis, gingival haemorrhage, post-surgical/dental bleeding Mucosal bleeding
5.4 Laboratory diagnosis
5.4.1 Screening test Increased bleeding time, increased partial thromboplastin time (doesnt invovle tissue factor)
5.4.2 Specific assay Decreased: factor VIII, vWF (via Ab) and vWF activity
5.5 Criteria
5.5.1 Type 1 vWD (von willebrand disease) Inherited bleeding disorder Diagnosis based on three criterias - symptoms, lab tests and inheritence pattern If all three criteria not met = possible type 1 VWD
Show full summary Hide full summary


Cell adaptations
Acute Inflammation
Rheumatoid Arthritis
Haematopoietic System Malignancies 2
Haemostasis (part 2: secondary haemostasis)
Bone marrow failure syndromes
Blood transfusion and haematopoietic stem cell transplantation
Haemopoietic System Malignancies
Characteristics of major tumour types
Response to cell injury