Haemostasis, investigation and disorders Flashcards by Freya Millar

What are the principles of haemotasis?

Platelets- normal number, normal function
Functional coagulation cascade
Normal vascular endothelium

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Describe the ultrastructure of a platelet

Membrane glycoproteins- 
Metabolites
Receptors for primary agonists
Dense granules- ADP/ATP, calcium ion, serotonin
Lysosomal granules
Mitochondria
a-granules- VWF fibrinogen

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What are the three distinct stages involved in the formation of a platelet rich thrombus?

Platelet adhesion
Platelet activation/ secretin
Platelet aggregation

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Describe the process

The conversion of fibrinogen to fibrin by thrombin, and polymerisation of fibrin stabilises the platelet thrombus, resulting in a platelet- fibrin (white) clot

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Describe platelet adhesion and activation

Normal platelets in flowing blood
Platelets adhere to damaged endothelium and undergo activation
Aggregation of platelets into a thrombus

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Describe haemostatic plug formation

Primary= aggregation of platelets- clotting
Secondary= coagulation- thrombin- fibrin
Haemostatic clot

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What is early haemostatic response to injury triggered by?

Exposure to subendothelial collagen and the release of tissue factor

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What are types of platelet defects?

-Reduced number of platelets= thrombocytopenia
-Abnormal platelet function= mostly commonly drugs such as aspirin, clopidogrel, renal failure= uraemia- platelet dysfunction
Give rise to prolonged bleeding time

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What is thrombocytopenia?

Reduced number of platelets
Caused by- bone marrow failure, peripheral consumption (like immune TP disseminated intravascular coagulation- DIC, drug-induced)

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What are types of abnormal vessel walls?

Scurvy
Ehlers Danlos syndrome
Henoch Schonlein purpura
Hereditary Haemorrhagic Telangiectasia

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What is abnormal interaction between platelets and vessel wall?

Von Willebrand disease

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What is scurvy?

Classical findings of peri-follicular haemorrhage

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What is Hereditary Haemorrhagic Telangiectasia?

Also known as Osler Weber Rendu syndrome
Telangiectasia in skin, hut, lungs
Can bleed causing anaemia, blood loss

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Name drugs that inhibit platelet function

Aspirin and COX inhibitors
Reversible COX inhibitors (NSAIDs)
Dipyridamole (inhibits phosphodiesterase)
Thienopyridines (inhibit ADP-mediated activation- clopidogrel)
Integrin GP2b/ 3a receptor antagonsist (abciximab, tirofiban, prevent Fgn binding)

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How does the waterfall theory fail to accurately reflect haemostasis?

Patients with fX2 deficiency do not bleed
Patients with fV2 deficiency bleed abnormally
Patients with fV3 and f1X deficiency have severe haemorrhagic diathesis despite a normal extrinsic coagulation pathway
Patients with fX1 deficiency have a variable and mild bleeding diathesis

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What are the enzyme complexes of the coagulation cascade?

Extrinsic Tenase= V2a+TF
Intrinsic Tenase= V3a+ 1Xa
Prothrombinase= 2+2a

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What steps lead to coagulation?

Initiation
Amplification
Propagation
Termination

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What are the natural inhibitors of the coagulation cascade in regulation?

Tissue factor pathway inhibitor= TF-V2a complex/ fXa inhibited by TFP1
Antithrombin= Thrombin and fXa activity inhibited
Protein C pathway= inhibits fVa and fV3a

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How is Prothrombin time (PT) measured?

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Measured in seconds

Reflects the ‘extrinsic pathway’ and the ‘common pathway’

How is Activated Partial Thromboplastin Time (APTT) measured?

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Measure in seconds

Reflects the ‘intrinsic pathway’ and the ‘common pathway’

How is fibrinogen measured?

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Measured in grams/L

Reflects the functional activity of the fibrinogen protein

How are defects inherited and what is the incidence?

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X11- no bleeding- Autosomal- relatively common
X1- autosomal- rare
1X: Haemophilia B- X-Linked recessive- 1:30,000 live male births
V111: Haemophilia A- X-Linked recessive- 1:5000-8000 live male births
Von Willebrand Disease- autosomal dominant- common
V11- autosomal recessive- very rare
X, V, 11, 1, X111- autosomal recessive, very rare

Describe Haemophilia A

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X-linked recessive disorder= expressed in males, carried in females

1:5-8000 males (30% cases are sporadic mutation)
Deficiency of fV111/ dysfunction
Severity same within different generations

What are the clinical severities of haemophilia A?

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-Clinical severity correlates to fV111 level=
Severe- frequent hemarthroses- less than 1%
Moderate- bleeding after minor trauma- 2-10%
Mild- bleeding after surgical challenge- 11-30%
Normal= 50-150%

What is the traditional management of haemophilia?

- Supportive measures - Replacement of missing clotting protein - Antifibrinolytic agents

What are supportive measures for haemophilia treatment?

Ice Immobilisation Rest

What are missing clotting proteins replaced by in haemophilia treatment?

Coagulation factor concentrates (plasma-derived, recombinant, extended half-life products) Desmopressin (DDAVP)- used to increase factor V111 levels in mild/ moderate haemophilia A Novel therapies- monoclonal antibodies, knock-out AT

What are antifibrinolytic agents in haemophilia treatment?

Tranexamic acid

Clinical presentations of congenital haemophilia

Hemarthroses Muscle bleeds Soft tissue bleeds

Clinical presentations of acquired haemophilia

``` Large haematomas Gross haematuria Retropharyngeal and retroperitoneal haematomas Cerebral haemorrhages Compartment syndromes ```

What types of treatment/ services are involved in haemophilia management?

``` Specialised centres- Comprehensive Care Haemophilia Centre Multidisciplinary Approach Home treatment Patient Education and Social Support Physiotherapy, Psychology Orthopaedic advice and treatment Treat and diagnosis of Liver Disease Specialised management for HIV positive patients Genetic counselling ```

What are the roles of the Von Willebrand Factor?

Promote platelet adhesion to subendothelium at high shear rates Carrier molecule for FV111

Describe Von Willebrand disease

Most common heritable bleeding disorder= mainly autosomal dominant, both sexes Associated with defective primary haemostasis Variable reduction in Factor V111 levels= mucocutaneous bleeding including menorrhagia, post-operative and post partum bleeding

Describe the autosomal dominant inheritance of Von Willebrand Disease

Variable penetrance for mild types | Diagnosis of mild vWD difficult due to confounding factors- blood group O: lowers VWF levels

Describe the management of Von Willebrand Disease

Antifibrinolytics: tranexamic acid DDAVP (for type 1 vWD) Factor concentrates containing vWD= plasma derived; no recombinant concentrates yet available, vaccination against hepatitis A and B Contraceptive pill for menorrhagia

What are the types of causes of acquired coagulation disorders?

Underproduction of coagulation factors Anticoagulants Immune Consumption of coagulation factors

Describe underproduction of coagulation factors

Liver failure Vitamin K deficiency- haemorrhagic disease of the new-born due to liver immaturity, lack of gut bacterial synthesis of vit k2 and fall in coagulation factors if breast fed- haemorrhage at days 2-4 or at 2 months 1mg vit K intramuscular at birth

Name anticoagulants

Warfarin, direct oral anticoagulants

Name immune acquired coagulation disorders

Acquired haemophilia | Acquired VW syndrome

What leads to consumption of coagulation factors?

DIC- Disseminated intravascular coagulation

How does liver disease lead to acquired coagulation disorder?

Reduced hepatic synthesis of clotting factors Thrombocytopenia secondary to hypersplenism (enlarged spleen) Reduced vitamin K absorption due to cholestatic jaundice causing deficiencies of factors 11, V11, 1X AND X Treat with plasma products and platelets to cover procedures and vitamin K

Describe the syndrome DIC

- An acquired syndrome of systematic intravascular activation of coagulation- thrombin explosion - Widespread deposition of fibrin in circulation - Tissue ischaemia and multi-organ failure - Consumption of platelets and coagulation factors to generate thrombin, may induce severe bleeding - To maintain vascular patency, plasmin generated in excess, leads to fibrinogenolysis

Describe the aetiology of DIC

- Sepsis- G+ or -ve sepsis, fungal infection, parasitic infection - Tumour- solid, haematological (Acute Promyelocytic Leukaemia) - Trauma- fat embolism, head injury, burns, lightning strikes - Pancreatitis - Obstetric- amniotic fluid embolism, abruptio placentae, pre-eclampsia/ eclampsia syndrome - Vascular- Kasabach Merritt syndrome (haemangioma) (incidence of DIC is 25%), aortic aneurysm (incidence of DIC 0.5-0%) - Toxic- recreational drugs, snake bites, bugs, bats, caterpillars, creepy crawlies - Transfusion of ABO incompatible cells

What might histology o DIC show?

Patient with metastatic breast cancer- peripheral blood smear, bone marrow aspirate Red cell fragments- examination of the peripheral blood film may show red cell fragments

Describe DIC coagulation parameters

Prolonged prothrombin time (PT) Prolonged activated partial thromboplastin time (APTT) Low fibrinogen =markers of consumption of coagulation factors Raised D-dimers= marker of increased fibrinolysis

Haemostasis, investigation and disorders Flashcards

(45 cards)