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Year 3 - Haematology > Week 2 > Flashcards

Week 2 Flashcards

1
Q

What are the 4 steps of the normal haemostatic response?

A

Formation of platelet plug (primary haemostasis)

Formation of fibrin clot (secondary haemostasis)

Fibrinolysis

Anticoagulation defences

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2
Q

What large precursor cell do platelets arise from?

A

Megakaryocytes

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3
Q

Do platelets have a nucleus?

How long is a platelet lifespan?

A

They are anucleate

Lifespan is 7-10 days

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4
Q

How does endothelial damage and subsequent exposure of collagen recruit platelets to the site of injury?

A

Exposure of collagen causes release of von Willebrand Factor and other proteins which causes platelet adhesion

Once adhered, platelets secrete various chemicals which leads to further platelet aggregation

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5
Q

Why might a platelet plug fail to form?

A

Vascular reasons - elderly patients/vitamin C deficiency (e.g. alcoholics)

Platelets either reduced in number (thrombocytopoenia), most commonly caused deliberately by iatrogenic intervention e.g. warfarin following MI, or reduced platelet function

Errors with von Willebrand Factor

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6
Q

What might some of the signs be in the event of failure of platelet plug formation?

A

Spontaneous bruising and purpura (most common, esp. in elderly)

Bleeding from mucosal sites (nose, GI, conjunctival, menorrhagia)

Retinal haemorrhages

Intracranial haemorrhage (rare, more severe)

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7
Q

What screening test is performed to assess primary haemostasis?

A

Reminder - primary haemostasis is platelet plug formation

Only one test - platelet count!

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8
Q

What is secondary haemostasis?

A

Formation of the fibrin clot

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9
Q

What coagulation factors are responsible for the initiation of fibrin clot formation?

A

Tissue Factor

Factor VIIa

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10
Q

What coagulation factors are required for the propagation of prothrombin (Factor II) to thrombin (Factor IIa)?

A

Factor V

Factor Xa

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11
Q

What coagulation factors are required for the amplification of thrombin in the formation of the fibrin clot?

A

Factor VIII

Factor IXa

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12
Q

Which coagulation factors are absent in the following forms of haemophilia?

  • Haemophilia A
  • Haemophilia B
  • Haemophilia C
A

Haemophilia A - Factor VIII

Haemophilia B - Factor IX

Haemophilia C - Factor XI

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13
Q

What is the usual cause of a deficiency in a SINGLE clotting factor? Examples?

What is the usual cause of a deficiency of MULTIPLE clotting factors? Examples?

A

Single - usually hereditary e.g. Haemophilia

Multiple - usually acquired e.g. liver cirrhosis, Disseminated Intravascular Coagulopathy (e.g. in the case of major trauma, clotting factors are used up)

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14
Q

Describe the process of fibrinolysis

What marker is an indicator of the degree of fibrinolysis?

A

Plasminogen is converted to Plasmin in the presence of Tissue Plasminogen Activator (tPA)

Plasmin then breaks Fibrin down into Fibrin Degradation Products (FDPs). This can be measured clinically and is known as D-Dimer

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15
Q

What screening tests are there to assess fibrin clot formation? What exactly do they measure?

A

Prothrombin Time - measures Tissue Factor and Factor VIIa

Activated Partial Thromboplastin Time - measures Factor VIII and Factor IXa

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16
Q

Patient comes to you with some symptoms that could suggest a bleeding disorder - what questions do you ask?

A

History - bleeding/bruising (what is normal?), duration (has it been life-long?), any previous surgeries or dental extractions?

Drug history - especially if blood thinners

Family History - could be congenital

Social history - do they smoke or drink? Think about malignancies and liver pathology

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17
Q

What are the body’s naturally occuring anticoagulants and how do they work?

A

Serine protease inhibitors e.g. antithrombin III - switches off clotting process via thrombin inactivation, as well as Factors V/Xa, Tissue Factor and Factor VIIa, and Factors VIII/IXa (clue is in the name!)

Protein C and Protein S - thrombin binds to thrombomodulin which in turn activates PC and PS to swtich off the clotting process via Factors V/Xa and Factors VIII/IXa (thrombin regulates its own clotting!)

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18
Q

What is the name of the hereditary condition that results from a deficiency of naturally occuring anticoagulants?

What presentation does this condition have an increased tendency for?

A

Thrombophilia

Increased tendency for patients to present with Deep Vein Thrombosis/Pulmonary embolism

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19
Q

What are the five signs that could determine if a patient is in shock (described as “windows” in the lecture)?

A

Skin changes - i.e. fixed mottling

Brain changes - confusion, as seen in a drop in GCS

Kidney changes - low urine output

Changes seen on Sidestream Dark Field Microscopy

Raised Lactate (used to confirm)

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20
Q

What are the 4 separate phsyiological mechanisms of shock?

A
  1. Cardiogenic
  2. Obstructive
  3. Hypovolaemic
  4. Distributive
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21
Q

What are the 3 components of Virchow’s Triad?

A

Hypercoagulability

Stasis

Endothelial injury

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22
Q

A MAP above what is required to adequately perfuse organs?

A

Above 50-60 mmHg

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23
Q

Bleeding disorders can arise from each part of the normal haemostatic system (primary and secondary haemostasis, fibrinolysis and anticoagulant defences). What might cause dysfunction of primary haemostasis?

A

Primary haemostasis = formation of the platelet plug

Vascular causes

  • increasing age
  • steroids
  • autoimmune causes (e.g. vasculitis such as Henoch-Schonlein Purpura)
  • vitamin C deficiency (required for collagen)
  • inherited collagen disorders (e.g. Marfan’s)

Platelet causes

  • reduced number (thrombocytopenia - most common cause of primary haemostasis failure)
    • increased destruction
    • reduced production
  • reduced function

von Willebrand Factor problems

  • von Willebrand Disease
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24
Q

Where might you see purpura in a patient with HSP (autoimmune vasculitis)?

A

Lower limbs

Chest

Mouth

Retina

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25
Q

What are some of the causes of peripheral platelet destruction (resulting in thrombocytopenia)?

Which of these is the most common cause?

A

Disseminated Intravascular Coagulopathy (DIC)

Autoimmune - immune thrombocytopenic purpura (ITP) - isolated low platelet count with normal bone marrow and the absence of other causes of thrombocytopenia. Causes characteristic purpuric rash and increased tendency to bleed

Hypersplenism i.e. as a result of liver disease causing build up (portal hypertension) and leaving the blood in the spleen

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26
Q

What common autosomal dominant hereditary condition might result in reduced platelet function?

What clotting factor might also be affected?

A

von Willebrand Disease (vWF deficiency)

vWF also carries around Factor VIII, so when levels of vWF become very low factor VIII may become deficient

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27
Q

Thrombocytopenia is the most common cause of failure of primary haemostasis - what can cause thrombocytopenia?

A

Thrombocytopenia = reduced platelet numbers

Caused by either marrow failure or peripheral destruction (DIC, ITP, hypersplenism secondary to liver disease)

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28
Q

What clotting factors are involved in the extrinsic pathway?

Which screening test measures the function of this pathway?

A

Tissue Factor and Factor VII and VIIa

Go on to activate Factor X to Xa and Factor V

Prothrombin Time measures the effectiveness of this pathway

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29
Q

What clotting factors are involved in the intrinsic pathway?

Which screening test measures the function of this pathway?

A

Factor XII activates to XIIa, which activates Factor XI to XIa

Factor XIa activates Factor IX which with it’s co-factor Factor VIIIa (forming the tenase complex) go on to activate Factor X

VIII/IXa (tenase complex) is measured by the activated Partial Thromboplastin Time (aPTT)

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30
Q

The extrinsic/intrinsic pathway is responsible for initiating the clotting cascade

The extrinsic/intrinsic pathway is then responsible for amplifying the response

A

Extrinsic = initiation

Intrinsic = amplification

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31
Q

Why might the fibrin clot fail to form (secondary haemostasis)?

A

Clotting Factor Deficiency

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32
Q

Deficiency in a single clotting factor is likely due to ____ - example?

Deficiency in multiple clotting factors is likely due to ____ - example?

A

Single clotting factor is likely hereditary e.g. Haemophilia

Multiple clotting factors is likely acquired e.g. Liver disease, Vitamin K deficiency/Warfarin therapy, DIC

33
Q

What are some of the causes of being deficienct in multiple clotting factors?

A

Liver disease

Vitamin K deficiency/Warfarin therapy

Complex coagulopathy e.g. DIC

34
Q

Which clotting factors is Vitamin K required for?

A

II

VII

IX

X

The above factors are carboxylated by Vit. K = essential for function

35
Q

What might cause a Vitamin K deficiency?

A

Dietary insufficiency (lacking leafy vegetables)

Malabsorption (especially things affecting the small intestine e.g. Crohn’s Disease)

Obstructive jaundice as a result of gallstones and bile build up (bile is required for Vitamin K absorption)

Warfarin (vitamin K antagonist)

Haemorrhagic disease of the newborn

36
Q

Why are all newborns given a Vitamin K injection after birth?

A

To prevent Haemorrhagic Disease of the Newborn (bleeding in newborn babies caused by deficiency of factors II, VII, IX and X, as well as protein C and protein S)

37
Q

What parts of the normal haemostatic response are affected by DIC?

What happens in this condition? What causes it?

A

Primary haemostasis, secondary haemostasis and fibrinolysis

Features formation of lots of microvascular thrombi resulting in end organ failure, and a consumption of clotting factors (causing bruising, purpura and generalised bleeding)

Caused essentially anything that brings about large stress on the body e.g. major trauma, sepsis, transfusion reactions, AAAs, PPH etc.

38
Q

How is DIC treated?

A

ABC

Manage the underlying disorder

May need to give platelets, coagulation factors (FFP) and coagulation inhibitors

39
Q

What is the difference between FFP and cryoprecipitate?

A

FFP = all factors of the coagulation system, indicated when the patient has multiple deficiencies and is bleeding. NB - FFP also contains some fibrinogen

Cryoprecipitate = concentrated subset of FFP components including fibrinogen, factor VIII, vWF and factor XIII. Indicated when the patient is lacking fibrinogen, has von Willebrand Disease, or in situations requiring a “fibrin glue”. TL;DR - less factors than FPP but more concentrated and a higher amount of fibrinogen

40
Q

How would the D-dimer levels of a patient with Liver Disease vs a patient with DIC compare?

A

Liver disease - D-dimer would be low because they aren’t synthesizing clotting factors

DIC - D-dimer would be very high because there will be a lot of fibrin breakdown

41
Q

Which is more common - Haemophilia A or B?

How are these conditions inherited?

A

Haemophilia A is 5 times as common

Inherited in an X-linked recessive manner, meaning only males are affected

42
Q

How is Haemophilia (mild-moderate) managed?

A

Sub. cut. injections with factor VIII every 2 days

43
Q

Immune Thrombocytopenic Purpura (ITP) is the immune destruction of platelets, and occurs in both children and adults. How does it present? And how is it diagnosed?

A

Presentation - major haemorrhage is only seen in patients with severe thrombocytopenia. More common in women and associated with other autoimmune diseases e.g. SLE. Easy bruising, purpura, epistaxis and menorrhagia are common. Splenomegaly is rare

Investigations - only blood count abnormality is thrombocytopenia. Detection of platelet autoantibodies can be done but is not essential, diagnosis is one of exclusion

44
Q

What are some of the main differences regarding arterial and venous thrombosis?

A

Arterial - presents in coronary, cerebral and peripheral circulations. High pressure system, clots occur on a background of atherosclerosis and are platelet-rich (“white clots”)

Venous - presents in deep veins or as pulmonary emboli. Low pressure system, platelets aren’t activated and there is an activation of the coagulation cascade, meaning that the clots are fibrin-rich (“red clots”)

45
Q

How are arterial clots managed?

How are venous clots managed?

A

Arterial - aspirin and other anti-platelet drugs (clopidogrel, ticagrelor, prasugrel etc.)

Venous - heparin (immediate, subcutaneous injections), warfarin (long-term, oral, not used as much any more), NOACs (don’t require blood monitoring, e.g. rivaroxaban, dabigatran)

46
Q

What are the components of Virchow’s Triad? Does this concept relate more to arterial or venous clots?

A
  1. Stasis
  2. Hypercoagulability
  3. Endothelial damage

More applicable to venous clots but has relevance to both

47
Q

What can be given to counteract the effects of warfarin?

A

Vitamin K1 (remember that warfarin is a Vitamin K antagonist and is a cause of Vit. K deficiency!)

48
Q

ABO incompatibility is a type __ hypersensitivity reaction

A

Type II

49
Q

In a patient with suspected fluid overload due to transfusion, what drug would you give and why?

A

Furosemide (loop diuretic) to encourage osmotic diuresis (used to treat fluid build-up due to heart failure, liver scarring or kidney disease). Can also be used for hypertension

50
Q

What are some of the risk factors for venous thromboembolism (relating to stasis)?

A

Increasing age

Obesity

Pregnancy

Previous DVT/PE - 25% risk of recurrence

Trauma/surgery

Malignancy

Paralysis

51
Q

What are some of the risk factors for venous thromboembolism (regarding endothelial damage)?

A

Increasing age

Previous DVT/PE

Smoking and obesity

52
Q

What are some of the risk factors for venous thromboembolism (regarding hypercoagulability)?

A

Increasing age

Pregnancy

Puerperium

Oestrogen therapy e.g. oral contraceptive

Trauma/surgery

Malignancy

Infection

Thrombophilia

53
Q

What is thrombophilia and what might it be due to (again, think of the basic mechanisms of haemostasis)?

A

Thrombophilia is either a familial or acquired disorder of the haemostatic mechanism that predisposes the individual to clot formation

Increased coagulation activity (NB - can cause both venous and arterial clots, but venous is more likely)

  • platelet plug formation
  • fibrin clot formation

Decreased fibrinolytic activity

Decreased anticoagulant activity (reduced Protein C/S and antithrombin)

54
Q

Describe the process of fibrinolysis in haemostasis

A

Plasminogen is converted to Plasmin via Tissue Plasminogen Activator (tPA)

Plasmin then cleaves Fibrinto form theFibrin Degradation Products (FDPs)

55
Q

Name some anticoagulant drugs

A

Heparin

Warfarin

NOACs (rivaroxaban, dabigatran)

56
Q

What are the indications for using anticoagulant drugs?

A

Venous thrombosis

Atrial Fibrillation

57
Q

What are some naturally occurring anticoagulants in the human body?

What parts of the coagulation cascade do these target?

A

Serine protease inhibitors i.e. antithrombin III. Targets all parts of the coag. cascade (TF/VIIa, V/Xa. VIII/IXa and thrombin)

Protein C and Protein S. Targets V/Xa and VIII/IXa after being activated by thrombin binding to thrombomodulin

58
Q

How does Heparin work? Does it do this quickly or slowly?

What are the two forms of Heparin?

A

Heparin potentiates antithrombin by securing its binding with protein (either thrombin or factor Xa), and does so with immediate effect (hence why it is used in an acute setting over Warfarin)

Unfractionated Heparin

LMW Heparin (more commonly used)

59
Q

What factors in secondary haemostasis are targeted by a) Unfractionated Heparin and b) LMW Heparin?

A

a) Unfractionated Heparin predominantly targets and switches off thrombin by preventing its interaction with antithrombin III
b) LMW Heparin predominantly targets and switches off the common pathway i.e. Factor V/Xa

60
Q

How is Heparin monitored (both unfractionated and LMWH)?

A

Using activated Partial Thromboplastin Time (aPTT) for UNFRACTIONATED - intrinsic pathway

Anti-Xa assay can be used for LMWH but is generally not used as LMWH response is a lot more predictable

61
Q

How is Warfarin monitored?

A

Using INR (derived from Prothrombin Time)

62
Q

What are some of the complications associated with Heparin use?

A

Bleeding is the main risk

Heparin-induced thrombocytopoenia with thrombosis (HITT) - immune response directed against Heparin/platelet factor 4 complexes that causes platelets to get used up. Very rare but patients may go on to develop further blood clots

Osteoporosis with long-term use

63
Q

How can excessive Heparin be counteracted?

A
  1. Stop the Heparin (very short half-life, especially unfractionated - 30 mins compared to 24 hours for LMWH)
  2. Give Protamine Suplhate - reverses antithrombin effect (complete for unfractionated, partial for LMWH)
64
Q

Vitamin K…

  • is fat soluble/insoluble
  • is absorbed in the upper/lower intestine
  • requires ____ for absorption
  • is required for the carboxylation of factors __, __, __ and __
A

Vitamin K is fat soluble

Vitamin K is absorbed in the upper intestine

Vitamin K requires bile salts to be absorbed

Vitamin K is required for the carboxylation of factors II, VII, IX and X, as well as Protein C and Protein S

65
Q

What is the mechanism of action of Warfarin?

A

Inhibition of Vitamin K

Factors II, VII, IX and X are still made, but are non-functional due to not being carboxylated

66
Q

What are some of the factors that affect Warfarin control?

A

Drugs – macrolides, imidazole antifungals, sulfamethoxazole/trimethoprim, amiodarone, statins, some NSAIDs, St John’s Wort (all increase INR). Antidepressants (SSRIs and SNRIs) also have an antiplatelet effect and should be avoided if possible.

Diet – beetroot, liver, leafy green veg (all decrease INR), cranberry juice (increases INR)

Weight loss/weight gain

Excess alcohol consumption

Acute illness

67
Q

How is Warfarin overdose managed?

How long do these steps take?

A

Dependent on severity of excess (more aggressive towards the bottom…)

  1. No action
  2. Omit warfarin dose(s)
  3. Administer oral vitamin K (if INR >8 or if the patient is bleeding) - takes approx 6 hours to work
  4. Administer clotting factor concentrates (II, VII, IX and X) in case of major haemorrhage - works immediately
68
Q

How does the NOAC Dabigatran work?

A

Targets thrombin

69
Q

How do the NOACs Rivaroxaban and Apixaban work?

A

Target Factor Xa - eliminated through the HPB system, as opposed to the renal system like Dabigatran. Safer as it won’t cause renal failure

70
Q

What type of anticoagulant is now currently used as prophylaxis in elective hip and knee replacement surgery?

A

NOACs (used to be LMWH) - have less drug interactions

71
Q

Mechanism and type of thrombus seen in a) arteries and b) veins?

A

a) Arteries - atherosclerosis and a platelet-rich thrombus (white clot)
b) Veins - Virchow’s Triad and a fibrin-rich thrombus (red clot)

72
Q

How are arterial thrombi managed?

A

Aspirin and other antiplatelet medications (ticagrelor, clopidogrel, prasugrel etc.)

Lifestyle modification

73
Q

What are some of the risk factors for developing an anterial thrombus?

A

Anything that causes damage to the endothelium, increases foamy macrophage numbers and platelet activation…

Hypertension (increased endothelial damage and platelet activation)

Smoking (increased endothelial damage and platelet activation)

High cholesterol

Diabetes mellitus (increased endothelial damage and platelet activation, increased cholesterol)

74
Q

After being exposed via endothelial damage, collagen expresses vWF and recruits platelets which adhere to the site of injury. What chemicals are then secreted by the platelets to lead to further platelet aggregation?

A

Platelets secrete thrombin, thromboxane A2 and ADP to recruit and aggregate further platelets

75
Q

What does aspirin target?

A

Thromboxane A2 - inhibits cyclo-oxygenase which is necessary for TXA2 production

76
Q

What do clopidogrel and prasugrel target?

A

ADP - ADP receptor antagonists. ADP is still produced but it cannot bind to its P2Y12 receptor site

77
Q

What are some of the potential side effects of aspirin therapy?

A

Bleeding

Blocked production of prostaglandins (due to inhibiting cyclo-oxygenase-1) predisposes to GI ulceration and bronchospasms

78
Q

Abciximad also inhibits platelet aggregation - how does it do this?

A

Inhibits GP IIb/IIIa - prevents platelets from being able to attach to each other

79
Q

When admitting a patient for an elective surgery, what needs to be done if they are taking antiplatelet medication?

A

Stop antiplatelet medication 7 days before operation - platelets have a life span of 7-10 days

Year 3 - Haematology (5 decks)

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