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Flashcards in Bleeding disorders Deck (42):
1

The process of coagulation requires 


–Functioning platelets
–Functioning endothelium
–Coagulation factors

Balance
–Coagulant vs. anticoagulant factors

Imbalance
–Thrombosis
–Bleeding
 

2

What happens when you cut yourself? 

Blood vessel damage
Disrupt endothelium

Exposure of
–Tissue Factor
–Collagen

Primary haemostasis
–Recruitment of platelets

Secondary haemostasis
–Activation of coagulation factors

Occur simultaneously
 

3

Primary haemostasis 

Cut in the blood vessels exposes collagen and tissue factor 

Also causes the exposure of von willebrand, which atrracts and binds platelets (through glycoprotein 1b_V-IX). 

As platelets adhere to von willebrand, they become activated 

Activation releases granular contents which cause aggregation and further activation of platelets 

 

4

Secondary haemostasis 

Activation of coaguation factors 

Cascade of events: 

-Initation - extrinsic pathway 

-Propagantion- intrinsic pathway 

-thromin generation 

-fibrin producition - the clot 

5

Initiation 

ii- prothrombin 

Prothrombinase complex- Xa + II (requires Va) 

IIa- thrombin

thrombin activates XIII to cause cross linking of fibrin 

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6

Propagation 

Thrombin feedsback to factor XI (becomes activated) 

Interacts with IX and causes activation 

Thrombin also activates factor VIIIa

VIIIa + IXa feedback to the prothrombinase complex and causes further  fibrin to be made 

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7

Regulation 

Antithrombin is a naturally occuring anti-coagulant that downreguates factor (7,10) (9,11) (10 +2) (9a + 2a) 

 Thrombomodulin is found on the endothelium. When thrombin is made it binds to thrombomodulin and then feedbacks and interacts with protein C. Protein C is activated to APC. APC plus another co-factor Protein S. Together these factors downregulate factor 5 and 8. 

Tissue factor pathway inhibitor - downregulates pathway between tissue factor and factor VII

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8

Fibrinolysis 

Plasmin degrades fibrin 

Plasmin comes from plasminogen (fibrin stimulates activation of plasminogen through tPA and uPA) 

This process is regulated by alpha antiplasmin and PAI-1 and 2

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9

Laborator analysis of coagulation 


Assessment of primary haemostasis
–in vivo – Bleeding Time (cut the patient, measure clotting time)
–ex vivo – FBC (platelet count), platelet function

Assessment of secondary haemostasis 
–Prothrombin time (PT)- measures the extrinsic system and the final common pathway- increased with warfarin 
–Activated partial thromboplastin time (APTT)- measures the intrinsic and final common pathway - increased with heparin 
–Thrombin clotting time (TCT) - measures the final part of the common pathway 
–Individual coagulation factor assays
 

10

Samplle requirements 

Plasma sample (blood thats not already clotted) 

Prevent clotting 

- citrate sample (chelates all calcium prevents clotting 

-centrifugation (separates cellular component, add in synthetic phospholipid) 

All results expressed 

-seconds 

-ration to normal plasma 

11

What Clotting factors does PT measure? 

Factors in extrinsic and common pathways 

Factors VII 

Factors X, V, II and fibrinogen 

12

Acticated partial thromboplastin time (APTT) process?

Add
–Patient’s plasma
–Contact factor e.g. Kaolin or silica
–Phospholipid ( ‘partial thromboplastin’ )
Warm to 37°C
Add calcium
Time taken to clot
Normal range 26 - 38 secs
Ratio Patient/Average of 20 normals
 

13

Which clotting factors and clotting pathway does APTT measure?


–Factors in intrinsic and common pathways
–Factors VIII, IX, XI & XII
–and Factors X, V, II & Fibrinogen
 

14

Thrombin clotting time (TCT) process 

Add at 37°C
–Patient’s plasma
–Bovine thrombin
–Less Calcium or phospholipid dependent
Time to clot
Normal 10-16 secs
Ratio Patient TT/Average of 20 normal TTs
 

15

What does TCT depend on and what is it inhibited by?

What does TCT depend on?
–How much fibrinogen is present in plasma
–How well that fibrinogen functions

But will also be prolonged by
–Inhibitors of thrombin (e.g. heparin, dabigatran)
–FDPs
Inhibitors of fibrin polymerisation (paraproteins

16

Simplified patterns of coagulation screen abnormality 

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17

Patterns of coaglation screen abnormality 

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18

Clotting factor disorder definition 

Congeital or acquired conditions that impair the body's ability to control blood clotting resulting in inappropriate bleeding

 

Congenital 

  • haemophillia A 
  • haemophilla B 
  • Von willebrands disease 

Acquired 

  • Liver disease 
  • warfarin 
  • Disseminated intravascular coagulation 

19

Disseminated intravascular coagulation (DIC) definition

Acquired, consumptive process
–Activation of coagulation cascade (Microthrombi)
–Exhaustion of coagulation cascade(Bleeding)
 

20

Causes of disseminated intravascular coagulation (DIC) 


–Sepsis
–Malignancy
–Massive haemorrhage
–Severe trauma
–Pregnancy complications e.g. pre-eclampsia, placental abruption, amniotic fluid embolism
 

21

Pathophysiology of disseminated intravascular coagulation 

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22

Laboratory Investigations DIC

LOOK FOR UNDERLYING CAUSE
–sepsis, trauma, cancer, obstetric disaster

-Coagulation  PT,  APTT,  Fibrinogen
-D-dimers
-FBC + film  platelets, RBC fragments
 

23

Treatment of DIC 


TREAT UNDERLYING CAUSE

FFP +/- platelets if bleeding or high risk for bleeding

? Heparin 300-500u/h if thrombotic phenotype
? AT concentrate  (reduces mortality 56% -> 44%)
? Protein C concentrate  (meningococcal sepsis)
? Activated Protein C
 

24

Two types of clotting factor disorders 

Inherited 

Acquired 

25

Clinical features of Disseminated intravascular coagulation

-pyrexia 

-Acute abdomen 

-Paracolic abscess at laparotomy 

 

Raised PT time 

Raised APTT 

Very elevated D-DImers 

26

How to treat warfarin bleeding ?

Any patients with haemorrhage and a raised INR 

- stop warfarin 

-Give coagulation factors ( II, VII, IX, X)

Prothrombin complex concentrates 

27

Dabigatran 

Direct factor II 

PT- no effect 

APTT- if normal, insifnificant dabigatran effect 

TCT- highly sensitive at very low concentration 

28

Rivaroxaban 

DIrect factor Xa inhibitor 

PT- most sensitive (if normal, minimal rivaroxaban effect) 

APTT not useful s non-linear 

29

Coagulopathy in liver disease 

Liver produces all the coagulation factors except for vWf

liver disease is therefore, associated iwith clotting factor deficiency and poor clearance 

In addition, biliary obstrucion can lead to malabsorption and deficiency of fat-soluble vitamin K 

Portal hypertension can lead to splenomegaly resulting in increased spelnic sequestration of plates - low WBC and plts 

30

Haemophllia A

Deficiency

Pattern of inheritance

Diagnosis

Presentation

Management  

Normal primary haemostasis 

Deficiency of Factor VIII 

Sex linked recessive disorder (X-linked recessive) 

Diagnosos: Prolonged APTT - factors 8, 9 , 11, 12 and decreased factor 8 

Presentation: depends on severity and is often in early life or after surgery/trauma - with bleeds into joints leading to criplling arthropathy and into muscles causing haematomas 

Management: Avoid NSAIDs, IM injections. Minor bleeds- desmopressin, pressure elevation. Major bleeds (e,g haemarthosis) require factor VIII 

 

31

Haemophillia B 

Christmas disease 

- factor IX deficiency 

inherited, x-linked recessive

32

Von willebrand disease 

Pattern of inheritance

Cause :

Clinical features

Diagnosis

Treatment 

Autosomal dominant condition 

Commonest inherited coagulopathy in the UK 

Caused by quantitative or qualitative abnormality of vWF production 

vWF is made on endothelial cells. It is the glue that sticks platelets to damaged subendothelium

Disease manifests with bruising, superficial purpura, menoorhagia, nose bleeds, bleeding from cuts and mucous membranes - think primary haemostatic problem!! 

Diagnosis is made by 

a. low factor VIII;c 

b. low factor vWF: Ag 

c. Prolonged bleeding time 

d. deficient ristocetin-induced platelet aggregation

Treatment is with ddAVP if mld and with vWF concentrate 

 

33

Types of von willebrand factor disease

Type 3- no von willebrand facor 

Type 2-  Qualitative( von willebrand factor present but not functional) 

Type 1- Quantitave (Partial von willebrand functional, other half not) 

34

Thrombophillia types

Congenital 
1. Deficencies of: 

  •  anti-thrombin III 
  • Protein C 
  • Protein S 

2. Abnormal prothrombin molecule (increases prothrombin levels_

3. Dysfibrinogenaemia 

4. Fibrinolytic defects 

5. Factor V leiden mutation (renders factor V less sensitive to APC)

Acquired causes 

1. Polycythaemia Rubra vera and essentiial thrombocythaemia 

2. Lupus anticoagulant/antiphospholipid syndrome 

 

35

Treatment of platelet disorders 

-Pressure
-Tranexamic acid / Desmopressin [DDAVP]
-Platelet transfusion [HLA matched]
-rFVIIa
 

36

Definition of thrombophillia 

Disorders if haemostasis that increase the tendancy of blood to clot 

37

Prolonged APPT test

Inhibits the coagulation process 

Prolonged APTT test 

Give 50:50 diltion (ml patient and ml of normal APTT) 

If factor deficiency is corrected then factor deificency 

If partial correction then inhibitor of APTT process - known as a lupus anticoagulant 

 

38

Lupus anti-coagulant 

-Phospholipid dependent antibody
-Interferes with phospholipid dependent tests i.e. APTT
-APTT prolonged
-If persistent, may be associated with prothrombotic state
-Persisting Lupus anticoagulant + thrombosis [or recurrent fetal loss]    =Antiphospholipid Syndrome

 

39

Testing for lupus anticoagulant 


APTT – often prolonged
APTT 50:50 dilution – only partially corrects
DRVVT ratio prolonged
DRVVT ratio corrects with XS phospholipid
 

40

Warfarin 

  • extrinsic pathway
  • monitor with the INR (international normalized ratio) test
  • vitamin K-dependent pathway (vitamin K is a fat-soluble vitamin essential for the production of factors II, VII, IX and X; it enables the γ-carboxylation of the profactors to their active state)
  • the peak effect of warfarin occurs 48 h after ingestion –
  • warfarin has an early prothrombotic effect action as a result of its effects on proteins C + S (the body’s natural anticoagulants).

41

Heparin Important facts 

  •  intrinsic pathway
  • monitor with the APTT (activated partial thromboplastin time) test
  • heparin potentiates the action of anti-thrombin 3 (which in turn activates thrombin and clotting factors VIII, IX, XI and XII)
  •  half-life 2 h – low-molecular-weight heparins do not prolong the APTT; they have a predictable anticoagulant effect and do not require monitoring unless in long-term use; in this case use the factor Xa assay to assess the degree of anticoagulation
  • heparin-induced thrombocytopenia (HIT) is an immune reaction; it occurs in 5 per cent of patients and presets with thrombosis. Platelet activating arhibodies cause platelets to clump. This causes simultaneous thrombosis and thrombocytopaenia.

42

Thrombophillia definition 

Disorders of haemostasis that increas the tendancy of bloot to clot.