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Clinical Pathology > 9. Blood Coagulation, Haemostasis and its Investigations > Flashcards

9. Blood Coagulation, Haemostasis and its Investigations Flashcards

1
Q

What is haemostasis?

A
  • Protective process evolved in order to maintain a stable physiology
  • Designed to curtail blood loss, restore vascular integrity and ultimately preserve life
  • Normal haemostasis - fibrinolytic factors, anticoagulant proteins = coagulation factors, platelets.
  • Thrombosis - increase in coagulation factors and decrease in fibrinolytic factors
  • Bleeding - increase in fibrinolytic factors and decrease in coagulation factors
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2
Q

Characteristics of chronic venous insufficiency

A
  • Atrophic changes
  • Hyperpigmentation
  • Ulceration
  • Infection
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3
Q

What is ecchymosis?

A

Easy bruising

Virtually all bleeding disorders and often in normals

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4
Q

How is haemostasis a life-preserving process designed to maintain blood flow? and what are the key components?

A
  • Respond to tissue injury
  • Curtails blood loss
  • Restore vascular integrity and promote healing
  • Limits infection

• Four key components:

1) Endothelium
2) Platelets
3) Coagulation
4) Fibrinolysis

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5
Q

What are the components of a blood clot?

A
  • Fibrin mesh
  • Platelets
  • Red blood cells
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6
Q

Expand on primary haemostasis.

A

• Vasoconstriction (immediate) -> to reduce blood loss (via endothelin acting on SMCs or nerve reflex)
• Platelet adhesion (within seconds)
- Endothelial damage exposes sub-endothelial layer, in particular signalling molecules, e.g. sub-endothelial collagen and TF
- Exposed signalling molecules attract platelets to site of injury
- TF -> production of small amount of thrombin, initiation step of coagulation process
- Platelets stick to exposed collagen through Von Willberand Factor (acts like glue for collagen and platelets)
-> Platelets activated
• Platelet aggregation and contraction (within minutes)
- Activated platelets release thromboxane A2 -> attracts more platelets to the site of injury -> aggregation
- Through conformation changes during activation, loose platelet plug contracts to form dense, adherent plug -> contraction
- Activated platelets present substantial area of negatively charged phospholipid membrane at site of injury where process of coagulation (secondary haemostasis) can occur if needed (as primary haemostasis may be enough if injury is relatively minor)
- Extra: processes inhibited by use of COX inhibitor, e.g. aspirin -> blocks activity of Thromboxane A2 (inhibits production) -> problem: uncontrolled bleeding

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7
Q

Expand on secondary haemostasis

A

• Activation of coagulation factors (within seconds)
- Initiation: Occurs when sub-endothelial tissue (site of injury) exposed to circulation -> tissues express tissue factor (TF) -> binds to activated Factor VII (TF-VIIa complex)
- Complex binds small amounts of Factor X and V to exposed endothelial surface -> small amount of thrombin produced
- Thrombin -> activates platelets that are attracted to the site, as well as other plasma-borne clotting factors
- Amplification: Activated factors like VIII and IX enable binding of activated Factor X and V to surface of activated platelets (activation -> conformational change -> exposure of ‘reaction sites’ needed for continuation of process)
- Propagation: Leads to thrombin burst (lots of thrombin produced) -> needed for large-scale production of fibrin -> development of effective clot
• Formation of fibrin (within minutes)
- Fibrin -> stick platelets together
- Traps some RBCs, then more fibrin -> formation of clot

• Formation of haemostatic plug - platelets, fibrin and leucocytes

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8
Q

Expand on platelets.

A
  • ADHESION: VWF binds to extrcellular collagen and Gplb-IX-V complex
  • ACTIVATION: Gplb-III undergoes confromational change ~ various agonists bind to specific surface receptors
  • STRUCTURAL PLATELET shape chanegs and release reaction
  • EXPOSURE NEGATIVELY charged phospholipids and provide pro-coagulant surface
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9
Q

Describe the coagulation cascade

A

• There is the original and revised waterfall hypothesis
• Traditional concept is distinct intrinsic and extrinsic coagulation pathways -> useful in vitro and diagnostic purposes
• But pathways integrated in vivo
- As TF-VIIa complex activates factor IX and factor X
- TF -> crucial to initiation of pro-coagulant system

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10
Q

Describe fibrinolysis

A

• Main function:
- Clot limiting mechanism
- Repair and healing mechanism
• Series of tightly regulated enzymatic steps
- Feedback potentiation and inhibition
• Main key players
- Plasminogen
- Tissue plasminogen activator (t-PA) and urokinase (u-PA)
- Plasminogen activator inhibitor -1 and -2
- Å2-plasmin inhibitor

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11
Q

Describe the activation of fibrinolysis

A
  • Plasminogen is converted into plasmin by tissue plasminogen activator (tPA).
  • D dimers are generated when cross-linked fibrin is degraded. FDP (fibrin degradation products) are generated if non-cross linked fibrin or fibrinogen is broken down
  • tPA and a bacterial activator, streptokinase, are used in therapuetic thrombolysis for myocardial infarction (clot busters)
  • Lysis of the plus happens within hours.
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12
Q

Laboratory evaluation of bleeding

A
  • FBC and film - platelet count, platelet morphology ~ thrombocytopenia (ITP, DIC)
  • Coagulation tests - PT, APTT/KCCT, TT/fibrinogen, mixing studies (50;50 mix), factor assays ~ extrinsic pathway, intrinsic pathway, fibrin formation, common pathway
  • Platelet function - VMF, platelet function analyser (PFA-100), platelet aggregometry ~ platelet defects, Von Willebrand disease
  • Global tests - thromboelastography, thrombin generation
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13
Q

What are the principles of clotting tests?

A

• Performed on citrated venous blood sample
• Designed to mimic normal in vivo processes
• Coagulation screening tests used to show any important haemostatic defects – don’t define precise nature of any defect
• Incubate plasma with reagents necessary for coagulation
- Phospholipid, co-factors
- Trigger or activator
- Calcium
• Measure time take to form fibrin clot

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14
Q

Describe a PT test.

A

• Sensitive to extrinsic pathway and to lesser extent common pathway
• TF driven
• Extra:
- Measures clotting time of plasma with optimal concentration of TF (extrinsic thromboplastin), phospholipid and calcium
- Tests factor VII
- Clot time should be 13-15 seconds normal
- Usually expressed as ratio of test plasma:normal (standardised as INR/International normalised ratio)
- INR – PT patient/PT normal
- Test used in oral anticoagulation (warfarin) monitoring

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15
Q

Describe the APTT (activated partial thromboplastic time) test.

A

• Sensitive to intrinsic pathway and to a lesser extent common pathway
• Contact activated
• Extra:
- Detects abnormalities in clotting factors
- Coag sequence initially activated by contact factor activation (adding contact factor, e.g. Kaolin, Silica) w/o addition of extrinsic thromboplastin
- Phospholipid – mimics surface of activated platelet, added to plasma of patient, triggers thrombin generation (in presence of Ca)
- Clot time normal: 35-45 seconds
- All coag factors needed except extrinsic Factor VII

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16
Q

Describe the TT test (thrombin time)

A

• Sensitive to defects in conversion of fibrinogen to fibrin
• Tests final enzymatic reaction in common pathway for abnormalities: Fibrinogen (substrate for all clotting tests) -> fibrin
• Addition of diluted thrombin to platelet-poor plasma: converts fibrinogen -> fibrin clot
• Time to generate fibrin clot: ~10 secs
• Measures fibrin content of plasma
• Sensitive to interference with reaction, e.g:
- Heparin contamination
- High levels of D-dimers
- Inherited fibrin abnormalities (-> defective fibrin clots)

17
Q

How is a blood sample collected?

A
  • Accuracy of haemostasis lab tests depend on quality of specimen submitted
  • Blue bottle used
  • Blood anticoagulated with 3.2% sodium citrate
  • Most tubes contain 0.3 mL anticoagulant and require 2.7 mLs of blood
  • Underfilling of tube -> inaccurate results
18
Q

What are pre-analytical errors?

A 
• Problems with blue-top tube
- Partial fill tubes
- Vacuum leak and citrate evaporation
• Problems with phlebotomy
- Heparin contamination
- Wrong label
- Slow fill
- Underfill
- Vigorous shaking
- Difficult to bleed
• Biological effects
- Hct ≥ 55 or ≤15
- Lipaemia, hyperbilirubinaemia, haemolysis
• Lab errors
- Delay in testing
- Prolonged incubation at 37 degrees
- Freeze/thaw deterioration
19
Q

Describe coagulation techniques

A

• Manual coagulation
- Sample tube tilt 3 times every 5 seconds on water bath of 37 degrees
• Automated coagulation with machines now used -> greater accuracy

20
Q

What is are mixing studies?

A
  • Test plasma + control plasma = 50:50 mix plasma
  • Repeat abnormal coagulation tests
  • Test normalises means there is a factor deficiency
  • Test remains abnormal means there is an inhibitor (usually antibody)
21
Q

What happens in mixing studies when there is a normal PT and an abnormal APPT?

A
  • Normal mix
    • Test for factor deficiency
  • isolated deficiency in intrinsic pathway (factors VIII, IX, XI)
  • Multiple factor deficiencies (rare)

*Abnormal mix
• Test for inhibitor acitivity:
- Specific: factors VIII, IX, XI
- Non-specific (anti-phopsholipid Ab)

22
Q

What happens in mixing studies when there is an abnormal PT and an normal APPT?

A
  • Normal mix
    • Test for factor deficiency
  • isolated deficiency of factor VII (rare)
  • Multiple factor deficiencies (common)
  • (liver disease, vitamin K deficiency, warfarin, DIC)

*Abnormal mix
• Test for inhibitor acitivity:
- Specific: factor VII (rare)
- Non-specific: anti-phopsholipid (rare)

23
Q

What happens in mixing studies when there is an abnormal PT and an abnormal APPT?

A
  • Normal mix
    • Test for factor deficiency
  • isolated deficiency in common pathway: factors V, X, prothtrombin, fibrinogen
  • Multiple factor deficiencies (common)
  • (liver disease, vitamin K deficiency, warfarin, DIC)

*Abnormal mix
• Test for inhibitor acitivity:
- Specific: factors V, X, II, I (rare)
- Non-specific: anti-phopsholipid (common)

24
Q

What happens in mixing studies when there is a normal PT and a normal APPT?

A
  • Normal mix
  • Von Willebrand’s disease
  • FXIII deficiency
  • Non-coagulation defect (e.g. vascular disorder)
  • Abnormal mix
  • Dysfibrinogenaemia
  • abnormal fibrinolysis (e.g. alpha2 anti-plasmin deficiency)
  • Elevated FDPs
25
Q

What is D-dimer testing?

A
  • Measure of D-dimer, fibrin degradation product
  • Found elevated in situation of enhanced fibrinolysis (thrombosis, DIC)
  • Not specific for thrombosis, also elevated as an acute phase reactant
  • A negative result is useful if clinical suspicion of VTE is low

Clinical Pathology (62 decks)

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