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Year 5 Haematology > 2s: Coagulation > Flashcards

2s: Coagulation Flashcards

1
Q

List some pro-coagulation and anti-coagulation factors

A

Pro-coagulation:

  • platelets
  • endothelium
  • vWF
  • COAGULATION CASCADE

Anti-coagulation:

  • anti-thrombin
  • Protein C/S
  • TFPI
  • FIBRINOLYSIS
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2
Q

3 responses to vessel injury

A
  • vasoconstriction = minimise blood loss
  • platelet activation = form primary haemostat plug
  • activation of the coagulation cascade
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3
Q

Components of blood clot formation

A

Vascular endothelium

Platelets

Coagulation proteins

White blood cells

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4
Q

Role of vascular endothelium

A

prevents exposure of pro-coagulant sub endothelial structures

Endothelial damage exposes these pro-coagulant substances which then triggers a haemostat response

The exposure of sub endothelial pro-coagulant factors leads to platelet aggregation at the site of damage

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5
Q

What do endothelial cells produce? (4)

A

Prostaglandins (PGI2)

vWD

Plasminogen activators (activators fibrinolysis)

Thrombomodulin

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6
Q

Where do platelets come from

how long do they last, clinical relevance of this

what are some thrombopoeitic factors

A

Produced in bone marrow and originate from megakaryocytes

Each megakaryocytic can produce up to 4000 platelets

Platelets have a life span of 10 days (anti-platelet drugs halt platelet activity for 10 days)

  • clinical relevance: someone on aspirin needs surgery -→ stop aspirin 7-10 days before surgery

Platelet production is regulated by a range of thrombopoietic factors (e.g. thrombopoeitin, IL-6, IL-12)

These can be given therapeutically to stimulate platelet production

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7
Q

What is the structure of platelets (3)

A

Glycoproteins = cell surface proteins via which platelets interact with the endothelium, vWF, and there platelets

Dense granules = contain energy stores (ATP/ADP)

‘Open canalicular system’ and ‘microtubules and actomyosin’ = expand surface area

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8
Q

Platelet adhesion (2 ways) and migration

A

Adhesion:

  • DIRECT = Glp1a
  • INDIRECT = vWF via Glp1B

Adhesion of platelets to exposed structures → release of ADP and thromboxane A2 → platelet aggregation

Platelets attach to each other via Glp11b/11a i.e. the fibrinogen receptor

ADP receptors are also important for platelet aggregation

  • examples of inhibitors: clopidogrel, ticagrelor
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8
Q

Platelet adhesion (2 ways) and migration

A

Adhesion:

  • DIRECT = Glp1a
  • INDIRECT = vWF via Glp1B

Adhesion of platelets to exposed structures → release of ADP and thromboxane A2 → platelet aggregation

Platelets attach to each other via Glp11b/11a i.e. the fibrinogen receptor

ADP receptors are also important for platelet aggregation

  • examples of inhibitors: clopidogrel, ticagrelor
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9
Q

Coagulation Proteins

Fibrin mesh, Intrinsic pathway, extrinsic pathway, Factor Xa, thrombin

A
  • A fibrin mesh needs to be generated to reinforce the clot
  • Intrinsic pathway = in-vitro during clotting studies
  • Extrinsic pathway = the body
  • Factor Xa is the rate-limiting step for fibrin formation
  • Pathway triggered by trace amounts of thrombin (which is formed following the activation of the platelet plug)
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10
Q

Effects of thrombin aka FIIa (4)

A
  • Activates fibrinogen
  • activates platelets
  • Activates pro-cofactors FV and FVIII
  • Activates zymogens (FVII, XI, XIII)

These all link together to form a prothrombinase complex → activation of prothrombin to thrombin

the most iMPORTANT step of the coagulation cascade is the generation of THROMBIN

  • thrombin will catalyse the breakdown of fibrinogen to FIBRIN which is the final step in the coagulation cascade
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11
Q

3 phases of clotting

A

Initiation

Amplification

Propagation

Factor 10a binds Factor 5a = 1st step of the coagulation cascade

  • Factor 5 Leiden will not be able to bind Factor 5a to Factor 10a

Activated platelet → thrombin burst (convert fibrinogen → fibrin)

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12
Q

Rate of prothrombin activation changes

A
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13
Q

PT vs APTT

A
  • PT = INR = extrinsic pathway
  • APTT = intrinsic pathway
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14
Q

Role of vitamin K

A

PRO-COAGULATION

Biological activation = vitamin K is required as a co-enzyme for the gamma-carboxylation of the clotting factors

Vit-K dependent factors = 2, 7, 9, 10 (produced in the liver)

Important notes:

  • Bacteria help produce vitamin K → taking antibiotics can harm gut flora → reduce your vitamin K absorption
  • Vitamin K is fat soluble so need bile to absorb vitamin K (i.e. bile duct obstruction → deficiency)
  • Most common cause of vitamin K deficiency = WARFARIN
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15
Q

Fibrinolysis inhibitors and stimulators

16
Q

Name 3 physiological anticoagulants

A

Anti-thrombins

Protein C an d S

TFPI

17
Q

Antithrombins (ATs)

A

Antithrombins will bind to thrombin on a 1:1 ratio and it will then be excreted in the urine

There are 5 types of antihrombin but the most active is AT-III

  • Heparin = AT-III portentiator (monitor levels with F Xa assay)

The lack or deficiency of antithrombin is the MOST THROMBOGENIC condition

18
Q

Protein C and S

A

F5A and F8A inactivated → thrombin stopped

Thrombin (from start) activates thrombomodulin

This opens up the receptor for thrombomodulin to bind Protein C through endothelial protein C receptor (EPCR)

  • leads to a activated protein C (APC)
  • APC in the present of protein S will fully activate protein C

Full activation inactivates F5a and F8a

19
Q

2 causes of APC resistance

A

Factor V Leiden → prothrombotic

High levels of Factors 8

20
Q

TFPI

A
  • Inhibit F7a
21
Q

Bleeding disorders

Excessive Bleeding and excess thrombosis

Genetic and Acquired

22
Q

4 disorders of haemostasis

A

Vascular disorders - scurvy, easy bruising

Platelet disorders - low number or abnormal function

Coagulation disorders - factor deficiency

Mixed/consumption - DIC

23
Q

Clinical features of bleeding disorders

A

Local vs general (spontaneous)

Haematoma or joint bleed (associated with haemophilia)

Skin/mucous petechia and purpura (suggestive of platelet deficiency or VWD)

Wound/surgical bleeding

Timing

  • immediate = issue with primary haemostatic plug (platelets, endothelium, vWF)
  • delayed = issue with coagulation cascade
24
Differentiating platelet disorders and coagulation disorders
_Platelet_ = petechiae, purpura _Coagulation_ = haemarthrosis **Microscopy** = always inspect under a microscope because… * **pseudothrombocytopaenia** = platelets clump together creating an erroneously low platelet count * **Grey Platelet Syndrome** = you see large platelets
25
2 types of platelet disorders
decreased number (thrombocytopenia) * decreased production * increased consumption (DIC) * decreased survival (ITP) * dilution Defective platelet function * acquired (e.g. aspirin, ESRF) * congenital (e.g. thrombasthenia) * cardiopulmonary bypass **Clopidogrel** = ADP-R blocker → reduce Glp2b/3a crosslinking **COX inhibitors (aspirin, NSAIDs)** → reduce TXAx production
26
3 genres of thrombocytopenia
Immune-mediated * idiopathic * drugs (e.g. rifampicin, vancomycin) * lymphoproliferative disease (e.g. AML) * sarcoidosis * connective tissue damage (e.g. rheumatoid arthritis, SLE) Non-immune mediated * DIC * MAHA ITP * autoantibodies against plts * plus tagged by antibodies and destroyed in reticuloendothelial system (liver, spleen and bone mwarrow/anywhere with macrophages) * non-blanching petechiae
27
features of acute and chronic ITP
* Childhood ITP is usually ACUTE (usually following a previous illness) * Childhood ITP is usually SEVERE (but it is self-limiting and resolves without any treatment) * In adults, ITP is usually chronic and indolent
28
ITP treatment
Treatment of ITP: * It depends on platelet count and symptoms * IVIG works by competing with the anti-platelet antibodies * Haematomas and subconjunctival haemorrhages are features of thrombocytopaenia * It is important to look at the blood film in patients with thrombocytopaenia because there are various causes of thrombocytopaenia that can be diagnosed from the blood film * Vitamin B12 deficiency * Acute leukaemia (i.e. Auer rods in AML)
29
Coagulation factor disorders: inherited vs acquired
30
Haemophilia
* Congenital deficiency of Factor 8 or 9; **X-linked** * Characterised by deep bleeding into joints and muscles * Caused by isolated abnormality in the **INTRINSIC** pathway: * Prolonged APTT * Normal PT * Treatment = clotting factor replacement is required for life * Clinical Features (A & B are clinically indistinguishable): * Haemarthroses (fixed joints)  most COMMON * Soft tissue haematomas (e.g. _muscle atrophy_, _shortened tendons_) & **ecchymoses** * Other sites of bleeding (e.g. urinary tract, CNS, neck) * Prolonged bleeding after surgery or dental extractions
31
VWD (THE MOST COMMON COAGULATION DISORDER)
mucocutaneous bleeding 1. type 1 = PARTIAL quantitative deficiency 2. type 2 = QUALITATIVE deficiency 3. type 3 = TOTAL QUANTITATIVE deficiency * T3 similar to haemophilia A (strong relationship between vWF and F8) * binding of factor 8 to vWF protects factor 8 being destroyed in the circulation
32
Vit K deficiency sources what does it synthesise causes of deficiency treatment
Sources of Vitamin K ***Reverse warfarin with PCC*** * Green vegetables *(Prothrombinase Complex Concentrate)* * Synthesised by intestinal flora Required for synthesis of: * Factors 2, 7, 9 and 10 * Protein C, S and Z Causes of deficiency: * Malnutrition Biliary obstruction (reduces absorption of Vit-K) * Malabsorption Antibiotic therapy (kills gut flora) * Warfarin Treatment * Vitamin K * FFP * PCC when warfarin is the cause
33
DIC = what is it, causes, mechanism and pathogenesis
coagulation and fibrinolysis BOTH ACTIVATED Causes: * sepsis (MOST COMMON) * trauma (e.g. head injury, fat embolism) * obstetric complications (abruption placentae, amniotic fluid embolism) * malignancy * vascular disorders * reaction to toxin (e.g. snake venom) * immunological disorders (e.g. severe allergic reaction, transplant rejection) Mechanism * Systemic activation of coagulation → deposition of fibrin in small blood vessels (which can cause kidney damage, brain damage and damage to the extremities requiring amputation) * The simultaneous depletion of platelets and coagulation factors leads to increased risk of bleeding Pathogenesis * release of thromboplastic material into the coagulation → activation of thrombin → activates coagulation cascade
34
DIC clotting studies and treatment
* Prolonged APTT Prolonged PT * Prolonged TT Decreased fibrinogen * Increased FDP Decreased platelets * Schistocytes (fragmentation of RBCs as they pass through the fibrin mesh in the small blood vessels) Treatment: * Treatment of underlying disorder Anticoagulation with heparin * Platelet transfusion FFP * Coagulation inhibitor concentrate (Activated Protein C concentrate)
35
Liver disease: how does it lead to bleeding disorders
* Leads to bleeding disorders because: * Decreased synthesis of clotting factors 2, 7, 9, 10, 11 and fibrinogen * Dietary vitamin K deficiency (inadequate intake or absorption) * Dysfibrinogenaemia * Enhanced haemolysis (decreased alpha-2 antiplasmin) * DIC * Thrombocytopaenia due to hypersplenism Management of Haemostatic Defects in Liver Disease * Treatment for prolonged PT/PTT * Vitamin K (usually ineffective) * FFP (immediate but temporary effect) * Treatment for low fibrinogen * Cryoprecipitate (1 unit/10kg body weight) * Treatment for DIC (Elevated D-dimer, low factor VIII, thrombocytopenia * Replacement therapy
36
Managing high INR values and managing high INR values in bleeding patients
37
Novel anticoagulants
Warfarin is on its way out and NOACs/DOACs are coming to the forefront The benefit of warfarin is that we can rapidly reverse the bleeding

Year 5 Haematology (7 decks)

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