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Cardiovascular & Respiratory Medicine > Haemostasis > Flashcards

Haemostasis Flashcards

1
Q

What is haemostasis?

A

“the cellular and biochemical processes that enables both the specific and regulated cessation of bleeding in response to vascular insult”

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2
Q

Why is haemostasis important?

A

Needed for the:
- Prevention of blood loss from intact vessels
- Arrest bleeding from injured vessels
- enable tissue repair

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3
Q

Describe the mechanism of haemostasis following injury to endothelial cell lining

A
  1. Vessel constriction:
    Vascular smooth muscle cells contract locally
    Limits blood flow to injured vessel
  2. PRIMARY HAEMOSTASIS: Formation of an unstable platelet plug:
    platelet adhesion
    platelet aggregation
    Limits blood loss + provides surface for coagulation
  3. SECONDARY HAEMOSTASIS: Stabilisation of the plus with fibrin:
    blood coagulation
    Stops blood loss
  4. FIBRINOLYSIS: Vessel repair and dissolution of clot:
    Cell migration/proliferation & fibrinolysis
    Restores vessel integrity
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4
Q

Why do we need to understand haemostatic mechanisms?

A

Diagnose and treat bleeding disorders

Control bleeding in individuals who do not have an underlying bleeding disorder

Identify risk factors for thrombosis

Treat thrombotic disorders

Monitor the drugs that are used to treat bleeding and thrombotic disorders

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5
Q

Normal haemostasis is a delicate balance between what 2 factors?

A
  1. Fibrinolytic factors: anticoagulant proteins (bleeding)
  2. Coagulant factors: platelets (thrombosis)
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6
Q

What can cause the balance of haemostasis to tipp towards bleeding?

A

Increased fibrinolytic factors and/ or Coagulation factor deficiencies:
1. Lack of a specific factor:
- Failure of production: congenital and acquired
- Increased consumption/clearance
2. Defective function of a specific factor:
Genetic
- Acquired: drugs, synthetic defect, inhibition

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7
Q

List the disorders of primary haemostasis associated with the platelets

A
  1. PLATELETS
    - Low numbers: thrombocytopenia
    * Bone marrow failure eg: leukemia, B12 deficiency (bone marrow infiltrated by leukemic cells or megaloblasts in Vit B12 deficiency)
    * Accelerated clearance eg: immune (ITP), Disseminated Intravascular Coagulation (DIC)
    (platelets destroyed in the peripheral circulation)
    *Pooling and destruction in an enlarged spleen
    (splenomegaly)
    - Impaired function
    * Hereditary absence of glycoproteins or storage granules (rare)
    * Acquired due to drugs: aspirin, NSAIDs, clopidogrel (common)
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8
Q

What is Immune Thrombocytopenic Purpura (ITP)

A

Condition where the immune system mistakenly attacks and destroys platelets
- Antiplatelet auto-antibodies bind to platelets -> sensitised platlets
- the sensitised platelets are cleared by the macrophages of the reticulo-endothelial system in the spleen
- ITP is a very common cause of thrombocytopenia

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9
Q

What are the different types of hereditary Platelet defects?

A
  1. Glanzmann’s thrombasthenia= absence of the GPIIbIIa receptor on platelets
  2. Bernard Soulier syndrome= resulting from an absence of GpIb receptors
  3. Storage Pool disease= Refers to reduction in the granular contents of platelets (dense granules)
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10
Q

What antiplatelet therapy is used to treat cardiovasuclar/ cerebrovascular disease?

A
  1. Aspirin
  2. Clopidogrel
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11
Q

Describe the mechanism of action of aspirin

A
  • Inhibits the production of thromboxane A2
  • by irreversibly blocking the action of Cyclo-oxygenase (COX)
  • Resulting in reduction in platelet aggregation
  • Effects of aspirin last for 7 days until most f the platelets present at the time of ingestion have been replaced by new platelets
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12
Q

Describe the mechanism of action of Clopidogrel

A
  • Irreversibly blocks the ADP receptor P2Y12, which is on the platelet cell membrane
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13
Q

List the disorders of primary haemostasis associated with Von Willebrand factor:

A

Von Willebrand disease: (VWF is reduced or defective)
* Hereditary decrease of quantity +/ function (common)
* Acquired due to antibody (rare)
* VWF has two functions in haemostasis:
- Binding to collagen and capturing platelets
- Stabilising Factor VIII (Factor VIII may be low if VWF is very low)
* VWD is usually hereditary (autosomal inheritance pattern):
- Deficiency of VWF (Type 1 or 3)
- VWF with abnormal function (Type 2)

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14
Q

List the disorders of primary haemostasis affecting the vessel walls

A
  1. Inherited (rare) Hereditary haemorrhagic telangiectasia Ehlers-Danlos syndrome and other connective tissue disorders
    - usually caused by abnormalities in collagen
  2. Acquired (common):
  • Steroid therapy (can develop atrophy of the collagen fibres supporting blood vessels in the skin)
  • Ageing (‘senile’ purpura) (dark purple well defined margins which don’t undergo the color changes of a bruise and can take up to 3 weeks to resolve; most commonly distributed on the extensor surfaces of forearms and the dorsal aspects of hands)
  • Vasculitis, Scurvy (Vitamin C deficiency) (leads to defect in collagen synthesis leading to weakening of the capillary walls)
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15
Q

What are the clinical features of disorders of primary haemostasis?

A
  1. Typical primary haemostasis bleeding:
    - Immediate
    - Prolonged bleeding from cuts
    - Nose bleeds (epistaxis):prolonged > 20 mins
    - Gum bleeding: prolonged
    - Heavy menstrual bleeding (menorrhagia)
    - Bruising (ecchymosis), may be spontaneous/”easy bruising”- bruising in response to minimal trauma
    - Prolonged bleeding after trauma or surgery
  2. Thrombocytopenia – Petechiae
  3. Purpura – platelet (thrombocytopenic purpura) or vascular disorders
    (Petechiae and Purpura are caused by bleeding under the skin & Purpura do not blanch when pressure is applied)
  4. Severe VWD – haemophilia-like bleeding (due to low FVIII)
  5. Increased skin elasticity in connective tissue disorders
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16
Q

What are the tests for disorders of primary haemostasis?

A
  1. Platelet count, platelet morphology (need an electron microscope- not visiible under light)
  2. Bleeding time (PFA100 in lab)
  3. Assays of von Willebrand Factor
  4. Clinical observation (e.g high elasticity/ bruising)
  5. Note –coagulation screen (PT, APTT) is normal (in disorders of primary homeostasis, except more severe VWD cases where FVIII is low)
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17
Q

What is the platelet count/ threshold for Thrombocytopenia that result in bleeding?

A
  • 40-100 (x10 to the power 9/L)= No spontaneous bleeding, but bleeding with trauma
  • 10-40 (x10 to the power 9/L)= Spontaneous bleeding common
  • <10 (x10 to the power 9/L)= Severe spontaneous bleeding
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18
Q

What are the treatment options for abnormal haemostasis?

A
  • Failure of production/function
    1. Replace missing factor/platelets e.g. VWF containing concentrates: (this can be given as a preventative measure e.g. for patients with severe VWF disease before an operation OR to treat bleeding)
    i) Prophylactic
    ii) Therapeutic
    2. Stop drugs e.g. aspirin/NSAIDs
  • Immune destruction
    3. Immunosuppression (e.g. prednisolone)
    4. Splenectomy for ITP
  • Increased consumption
    5. Treat cause
    6. Replace as necessary
    7. Desmopressin (DDAVP):
  • Vasopressin analogue
  • 2-5 fold increase in VWF (and FVIII)
  • releases endogenous stores (so only useful in mild disorders)
    8. Tranexamic acid (antifibrinolytic- increases factor 8)
    9. Fibrin glue/ spray
    10. Other approaches e.g hormonal (oral contraceptive pill for menorrhagia- heavy menstrual bleeding)
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19
Q

Describe the general mechanism of action which would lead to disorders in secondary haemostasis

A
  • The role of coagulation is to generate thrombin (IIa), which will convert fibrinogen to fibrin
  • Deficiency of any coagulation factor results in a failure of thrombin generation and hence fibrin formation
20
Q

What can tip the haemostasis balance towards bleeding?

A

Coagulation factor deficiencies (and increase in fibrinolytic factors/ anti-coagulation proteins)

21
Q

What are the different disorders of coagulation?

A
  1. Deficiency of coagulation factor production
    - Hereditary: Factor VIII/IX: haemophilia A/B
    - Acquired:
    * Liver disease
    * Anticoagulant drugs (warfarin, Direct Oral Anticoagulants DOACs)
  2. Dilution
    - Acquired:
    * blood transfusion (lots of RBCs are transfused but with insufficient plasma= dilution of coagulation factors)
  3. Increased consumption
    - Acquired:
    * Disseminated intravascular coagulation (DIC)- common
    * (Immune – autoantibodies – rare)
22
Q

What are the hereditary coagulation disorders for disorders in secondary haemostasis?

A

“Haemophilia: failure to generate fibrin to stabilise platelet plug”
- Haemophilia A (Factor VIII deficiency)
- Haemophilia B (Factor IX deficiency):
* sex linked (X linked)
* 1 in 104 births
- Others are very rare (autosomal recessive)

23
Q

What are the hallmarks for hemophilia?

A
  • Haemarthrosis= spontaneous joint bleeding
  • Occurs when factors 8 or 9 are low
  • Chronic haemarthrosis= Bleeding into a joint
  • Muscle wasting (weakening, shrinking, and loss of muscle)
24
Q

What caution must be taken with patients with haemophilia in terms of the use of medical instruments?

A

Intramuscular injections should be avoided in patients with haemophilia

25
Q

Coagulation factor deficiencies are not all the same, compare the effects of each deficiency

A
  1. Factor VIII and IX (Haemophilia) =
    - Severe but compatible with life
    - Spontaneous joint and muscle bleeding
  2. Prothrombin (Factor II) =
    - Lethal
  3. Factor XI =
    - Bleed after trauma but not spontaneously
  4. Factor XII =
    No bleeding at all
26
Q

What are the acquired coagulation disorders, seen with disorders of secondary haemostasis?

A
  1. Liver failure – decreased production
    - Most coagulation factors are synthesised in the liver (except VWF that is synthesised in the endothelial cells lining blood vessels & factor V- synthesised in platelets)
  2. Anticoagulant drugs
  3. Dilution
    - Red cell transfusions no longer contain plasma
    - Major haemorrhage requires transfusion of plasma as well as red cells and platelets
    (More common in hospital practice)
27
Q

What is meant by the coagulation disorder “increased consumption”?

A
  • Acquired disease
    1. Disseminated intravascular coagulation- common=
  • Generalised activation of coagulation – Tissue factor
  • Associated with sepsis, major tissue damage, inflammation
  • Consumes and depletes coagulation factors
  • Platelets consumed - thrombocytopenia
  • Activation of fibrinolysis depletes fibrinogen – raised D-dimer (a breakdown product of fibrin)
  • Deposition of fibrin in vessels causes organ failure (can also result in shearing of the RBCs that flow through these vessels- leading to red cell fragmentation)
    2. (Immune- auto-antibodies- rare) e.g. ITP
28
Q

What are the clinical features of coagulation disorders?

A
  • superficial cuts do not bleed (platelets working fine/ platelet plug forming as usual- larger blood vessels causes platelet plug to fall apart- which is normal)
  • bruising is common, nosebleeds are rare
  • spontaneous bleeding is deep, into muscles and joints
  • bleeding after trauma may be delayed and is prolonged
  • Bleeding frequently restarts after stopping
29
Q

How can “Increased consumption”- this aquired disorder of secondary haemostasis be prevented?

A

Only way to switch off this process is to treat the underlying cause but it may be necessary to first use supportive treatment (e.g. replacing CFs- giving FFP and platelets)

30
Q

What is the clinical distinction between bleeding due to Platelet vs Coagulation defects?

A

Platelet/Vascular:
- Superficial bleeding into skin, mucosal membranes
- Bleeding immediate after injury
Coagulation:
- Bleeding into deep tissues, muscles, joints
- Delayed, but severe bleeding afterinjury.
- Bleeding often prolonged

31
Q

What are the tests for coagulation disorders?

A
  1. Screening tests (‘clotting screen’):
    - Prothrombin time (PT)
    - Activated partial thromboplastin time (APTT)
    - Full blood count (platelets)
  2. Coagulation factor assays (for Factor VIII etc)
  3. Tests for inhibitors
32
Q

How are “Screening tests” conducted?

A
  1. Measure APTT AND PT
    Aim= to measure the “Activated partial thromboplastin time” (APTT)- measures the ‘Intrinisic’ pathway
    * We trigger this with contact activation using glass, silica acid or ellagic acid
    Aim= to measure the “Prothrombin time” (PT)- measures the ‘Extrinsic’ pathway
    * We trigger this using a form of tissue factor- recombinant
  2. Compare with normal
    PT (9.6-11.6s)
    APTT (26-32s)
  3. interpret
33
Q

What deficiency is likely if PT is high, and APTT is normal?

A

Factor VII deficiency

34
Q

What deficiency is likely if PT is low, and APTT is high?

A

Haemophilia A
Haemophilia B
Factor XI deficiency
Factor XII deficiency

35
Q

What disease is likely if PT is high and APTT is high?

A

Liver disease
Anticoagulant drugs e.g. warfarin
DIC (platelets and D dimer)
Dilution following red cell transfusion

36
Q

What different factor replacement therapies are there for treating missing coagulation factors?

A
  • Plasma (fresh frozen plasma FFP)
  • Contains all coagulation factors
  • Cryoprecipitate
  • Rich in Fibrinogen, FVIII, VWF, Factor XIII
  • Factor concentrates
  • Concentrates available for all factors except factor V.
  • Prothrombin complex concentrates (PCCs) Factors II, VII, IX, X
  • Recombinant forms of FVIII and FIX are available
  • ‘On Demand’ to treat bleeds
  • Prophylaxis to prevent bleeds
37
Q

What are the novel treatment options for haemophilia?

A
  1. Gene therapy (Haem A and B)
  2. Bispecific antibodies (Haem A):
    - Emicizumab
    - Binds to FIXa and FX
    - Mimics procoagulant function of FVIII
  3. RNA silencing (Haem A and B):
    - Targets natural anticoagulant - antithrombin
38
Q

How do disorders of thrombosis present?

A

VENOUS THROMBOSIS: 2 examples
1. Pulmonary embolism (PE)
Tachycardia
Hypoxia
Shortness of breath
Chest pain
Haemopysis
Sudden death
2. Deep vein thrombosis (DVT)
Painful leg
Swelling
Red
Warm
May embolise to lungs
Post thrombotic syndrome
- Most people die with a ‘haemostatic end-point’

39
Q

What are the features of thrombosis?

A

“the formation of a blood clot”
- Intravascular coagulation
- Inappropriate coagulation
- Venous (or arterial)
- Obstructs flow
- May embolise to lungs

40
Q

What is “Virchow’s triad”?

A

Implicates the 3 contributing factors in the formation of thrombosis:
1. Blood: dominant in venous thrombosis
2. Vessel wall: dominant in arterial thrombosis
* Many proteins active in coagulation are expressed on the surface of endothelial cells and their expression altered in inflammation (TM, EPCR, TF)
3. Blood flow: contributes to both arterial and venous thrombosis
* Reduced flow (stasis) increases the risk of thrombosis
e.g. surgery, long haul flight, pregnancy

41
Q

What is thrombophilia?

A

Thrombophilia means blood has an increased tendency to form clots= Increased risk of venous thrombosis
- Can be congenital or acquired

42
Q

How might thrombophilia present?

A

Thrombosis at young age (risk increases with age)
‘spontaneous thrombosis’
Multiple thromboses
Thrombosis whilst anticoagulated

43
Q

What can cause the haemostasis balance to tip towards venous thrombosis?

A

Increased coagulant factors/ platelets:
- Factor VIII
- Factor II
- Factor V Leiden (increase activity due to activated protein C resistance)
- Myeloproliferative disorders (plts increase)

OR

decreased fibrinolytic factors/ anticoagulant proteins:
- Antithrombin
- Protein C
- Protein S

44
Q

Which anticoagulant deficiency has the most powerful effect of causing venous thrombosis?

A

Antithrombin

45
Q

Venous thrombosis is Multi-Causal Arising from Interacting Risk Factors- what type of risk factors:

A
  • Genetic
  • Acquired risk
  • Cumulative risk= people may have always had an underlying genetic risk, but it only manifests later OR when some other environmental factor comes along
  • Risk of ageing
46
Q

What are the treatment options for venous thrombosis?

A
  1. Prevention
    - Assess and prevent risks: (patients receive “thromboprophylaxis- prevents thrombosis unless there’s a reason not to, e.g. high bleeding risk)
    - Prophylactic anticoagulant therapy
  2. If thrombosis does occur, reduce risk of recurrence/extension (embolising):
    - lower procoagulant factors e.g.: warfarin, DOACs
    - increase anticoagulant activity e.g: heparin

Cardiovascular & Respiratory Medicine (14 decks)

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