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Basic Pathology Science Exam > Haematology > Flashcards

Haematology Flashcards

1
Q

What is hyperaemia?

A

Active inflammation of an area to move inflammatory molecules and cells to an injured site

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2
Q

What is the lifespan of a platelet?

A

7-10days

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3
Q

What does endothelium produce to prevent clotting at trest?

A

NO and prostacyclin

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4
Q

What does the plt attach to on endothelial injury?

A

Type II collagen via GPIV

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5
Q

What happens when platlet binds col 2 with GPIV?

A

They activate then adhere more via the vWF receptor. The GPiBIX is important for more sticking. They change shape, and they become negatively charged. Plts then aggregate and form a a plug.

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6
Q

What class of molecule are the proteins of the clotting cascade?

A

Serine proteases

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7
Q

What coagulation factors are Vit K dependent for post-translational activation?

A

II, VII, IX, X, protein C and S`

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8
Q

How is haemophilia A inherited?

A

X linked

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9
Q

What factor is affected by haemophilia A?

A

Factor VIII deficiency

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10
Q

How would Haemophilia A pts present?

A

Almost all men (x - linked)
Family history
Joint bleeding as a baby
Bruising very easily
Long APTT (VIII part of the intrinisc pathway)

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11
Q

How is severe haemophilia A treated?

A

Replacement of factor VIII recurrentyl. Unfortunatley, it’s halflife is only 8-12hrs, so needs to be given every day or two.

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12
Q

What is the role of vWF?

A

Mediates attachment of platelets to ECM, but also stabilises factor VIII and increases its half life.

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13
Q

How is vWD inherited?

A

Well there are 3 types. Classical type I is AD. The others are AR.

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14
Q

How do you treat vWD?

A

With desmopressin - causes more production and release of vWF from platelets. Blood donor derivaed VIII has bound vWF (the recombinant stuff does not).

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15
Q

What is the most common cause of thrombocytopoenia due destruction?

A

Viral (CMV, EBV, HIV)
Drugs (qunine)
Autoimmune (SLE)
Sepsis/DIC
Lymphoproliferative disorders
Idiopathic thrombocytopoenia
Post-transfusional purpura
TTP, HELP, HUS

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16
Q

What are the named disorders of platelet function?

A

Bernard-soulier syndrome
vWD
Glanzmanns disease

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17
Q

What drugs cause platelet dysfunction?

A

Aspirin
Clopidogrel
NSAIDs
Penicillins
Cephalosporins
Herparin
Ethanol

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18
Q

Who should be investigated for thrombophilia?

A

Less than 45
Recurrent events
Spontaneous DVT
Proven family history
Thrombosis in an unusual site
Life threatening/catastrophic clot

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19
Q

What tests are in a thrombophilia screen?

A

Factor V leidien (35-40%)
Protein C deficiency 5-8%
Protein S definiciency 5-8%
ATIII 2-3%
APLS 2-3%
Plasminogen <1%
Fibrinogen <1%

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20
Q

What happens if you treat somone with protein C deficiency with warfarin?

A

Warfarin induced skin necrosis

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21
Q

What are the 3 antiphopholipid anthipodies?

A
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22
Q

What is unique about APLS compared with other thrombophilia syndromes?

A

It predisposes to arterial clotting not just venous clotting. This is why it can lead to stroke at a young age and loss of pregnancy.

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23
Q

What is the half life of unfractionated heparin?

A

6hrs

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24
Q

What is the reversal agent for heparin?

A

Protamine

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25
Q

What do you use to measure the effectiveness of dabigatran?

A

APTT

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26
Q

Which isotype of anti-cardiolipin ab are considered more likely to cause clots?

A

IgG

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27
Q

What is the cause of oedema in heart failure?

A

Impaired venous return to the heart leading to increased hydrostatic pressure. But also, renal perfusion is reduced, leading to increased sodium and water retention, increase blood volume, and increased oedema potential.

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28
Q

What is the cause of ascites during liver cirrhosis?

A

Imparied venous return due to cirrhotic portal vein. This leads to increased hydrostatic pressure in the abdominal veins causing transudate leak into the abdomen.
Additionally, reudced osmotic pressure due to impaired synthesis of albumin contributes.

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29
Q

Why does peripheral oedema occur during constrictive pericarditis?

A

Impaired venous return due to compressed right heart. This leads to increased hydrostatic pressure and oedema.

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30
Q

During prolonged heat exposure or neurohormonal dysregulation - what causes peripheral oedema?

A

Arteriolar dilation

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31
Q

What does oedema appaer like microscopically?

A

Clearing and separation of ECM and subtle cell swelling.

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32
Q

Which vessel type dilates to enable hyperaemia?

A

Arterioles

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33
Q

What is congestion? How does it differ to oedema?

A

It is the passive accumulation of blood in a site. Not necessarily transudate in tissue as is seen in oedema. The tissue turns blue/red due to increased presence of deoxygenated haemaglobin.

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34
Q

What is the natural history of congested tissue?

A

Microhaemorrhages will appear. Oedema can follow. Macrophages scavenging haemoglobin form haemosiderin staining of the surrounding tissue.

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35
Q

How does congested tissue look microscopically?

A

Acutely - engorged capillaries. Chronically - numerous macrophages laden with haemosiderin. Distended interstitial tissues. Necrotic tissues.

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36
Q

What is the very first (hint - nerve related) response to tissue trauma?

A

Arteriole vasoconstriction (reflex) - immediate.

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37
Q

What is endothelin?

A

A potent vasoconstrictor promptly secreted by endothelium when it is injured. Kicks in after neurogeneic artiole vascoconstriction to ensure sustained constriciton.

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38
Q

Where is the von Willebrand factor first encountered during tissue injury?

A

It’s pre-deposited ready to go in the subendothelial tissue.

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39
Q

What do platelets initially bind to and use to activate when the encounter a break in the endothelium?

A

They bind to the exposed subendothelial collagen and von Willebrand Factor (glycoprotein Ib receptor binds vWF)

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40
Q

What moleculres are released by activated platelets onactivation to attract more platelets to form a platelet plug?

A

Thromboxane A2 (COX dependent product of the arachadonic acid pathway) and Adenosine Diphosphate (ADP)

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41
Q

How do platelets bind to fibrin to sure up the plug?

A

Using the glycoprotine IIb-IIIa receptors

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42
Q

What is meant by primary haemostasis (aka the haemostatic plug)?

A

The immediate blockage of vessel void by platelets. The subsequent coagulation cascade leading to extensive fibrin network being laid down is referred to as secondary haemostasis.

43
Q

Which coagulation cascade pathway is activated by exposure to tissue factor (TF)?

A

The extrinsic pathway. TF-VIIa is a X->Xa convertase. And remember Xa is the prothrombin to thrombin (II->IIa) convertase, and that thrombin (IIa) produces fibrin from fibrinogen - critical to secondary haemostais. Thrombin also catalyses the reaction of XIII->XIIIa which is a clot stabiliser.

44
Q

We learned about he P-selectin as it is present on endothelial cells along with E-selectin. But the reason it is called P-selecting is…?

A

Because it is the primary selectin found on platelets. It is also released by granules (alpha-granules) from platelets.

45
Q

Platelets contain two types of granules - what are the called?

A

Alpha-granules and delta (dense) granules of course.

46
Q

What are the alpha granules of platelets made up of?

A

P-selectin, fibrinogen, coagulation factor V, vWF, as well as protein facotrs for healing (fibronectin, platelet factor 4, platelet derived growth factor and transforming growth factor)

47
Q

What are the dense (delta) granules of platelets made up of?

A

ADP
ATP
ionized calcium
Serotonin
Adrenaline

48
Q

Where does the ADP come from needed to attract platelets to the plug and cause them to undergo conformational change?

A

Comes from the dense granules of activated platelets.

49
Q

What do platelets use to adhere to the collagen exposed during endothelial injury?

A

GPIa/IIa. That is, glycoprotein receptor Ia/IIa.

50
Q

Pathological variants of the genes responsible for von-willebrand’s factor lead to von willebrand’s disease - a bleeding disorder due to the failure of vWF to bind the GpIb receptor on platelets. What is the name of the bleeding disorder caused by mutations in GpIb?

A

Bernard-Soulier syndrome.

51
Q

After platelets activate, what happens to their surface to make them ideal places for coagulation?

A

They increase their surface area by taking on a spikey sea urchin shape to increase their ability to bind other objects.
They also invert a large proportion of their phospholipids to produce outward facing negatively charged phosphatidylserine which traps calcium (noting that the later steps of the coagulation cascade are calcium dependent).
Lastly, they induce confirmation changes of glycoprotein IIb/IIIa receptor so that it better binds fibrinogen for use in clot formation.

52
Q

What are the two componenets of ‘platelet activation’

A

The release of granules
The change in platelet shape that occurs

53
Q

What are the main triggers of platelet activation following initial binding to the vWF and collagen? Ligand and receptor

A

ADP - binds P2Y1 and P2Y12 receptors.
Thrombin - binds protease activated receptor -1 (PAR-1)
Thromboxane A2 - TP receptor.

54
Q

If GPIIb/IIIa is receptors bind fibrinogen, how do they assist with platelet aggregation?

A

By binding both ends of the fibrinogen, two platelets become stuck together with fibrinogen in between.

55
Q

Defects in vWF and its receptor GPIb lead to von Willebrands diseases and Bernard-Soulier syndromes respectively. What other platelet receptor defect has a named bleeding disorder associated with it?

A

GP IIb/IIIa receptor (fibrinogren receptor) defects cause a bleeding disorder called Glanzmann thrombasthenia.

56
Q

What are their leukocytes stuck in the haemostatic plugs?

A

P-selectin on the platelets, as it does when expressed on the endothelium, sticks to leukocytes.

57
Q

What does vitamin K do to the coagulation factors it impacts? (protein C/S, factors II, VII, IX, X)

A

It gamma-carboxylates glutamate residues so that they can interact with calcium. Without this step, they can’t interact with calcium and perform their enzymatic function.

58
Q

What does the prothrombin time examine?

A

The tissue factor/extrinsic factor dependent pathway

59
Q

What does the partial thromboplastin time evaluate the function of?

A

The intrinsic (negatively charged surface) pathway, and thus the function of XII, XI, IX, VIII, X, V, II and fibrinogen.

60
Q

Despite its classical depiction as exclusively part of the intrsinsic pathway, what has been shown to be the most important enzyme for the conversion of factor IX to IXa?

A

Extrinsic pathway X->Xa convertase VIIa/TF! Yes, it also converts IX to IXa, which is also a X->Xa convertase when in the IXa/VIIIa complex.

61
Q

Apart from cleaving fibrinogen to form fibrin, what else does thrombin do?

A

Cleaves complement
Binds to platetlet receptors to activate them (PAR-1)
Binds to receptors on other cells (leuckocytes) to enhance their local adhesion and activation.
Activates endothelium near injuries.
Creates an anticoagulant effect when it encounters uninjured endothelium.

62
Q

What is the key anticoagulant agent produced and released by health endothelium adjacent to injured epithelium?

A

Tissue plasminogen activator. Plasminogen circulates in the blood at a predictable concentraction, but when it encounters tPA, it is concerted to plasmin, which degrades polymerised fibrin.

63
Q

Once plasmin degrades fibrin, what are the fibrin breakdown products called?

A

D-dimers

64
Q

After plasmin is generated at the site of a thrombus to dissolve it or limits its spread, what innactivates the plasmin to stop it acting distally?

A

alpha2-antiplasmin - a ciculating subtance that binds and inactivates plasmin.

65
Q

What are the substances produced at rest by health endothelium to prevent coagulation?

A

Prostacyclin (PGI2), NO and ADPase (adenosine diphosphatase)

66
Q

On healthy endothelium, what is the membrane bound protein called that enzymatically activates protein C in the presence of protein S and thrombin?

A

Thrombomodulin.
Active protein C then goes on to inhbit factors Va and VIIIa.

67
Q

What does tissue factor pathway inhibitor (an endothelial cell membrane bound protein) do?

A

It inactivates the IX->IXa and X->Xa convertase VIIa-TF (the key convertase in the tissue factor/extrinsic pathway)

68
Q

What does anti-thrombin III inhibits?

A

On binding with heparin-like moleculre (or heparin in a health care setting), it binds to and inactivates thrombin. It also inhibits IXa and Xa.

69
Q

What bleeding is typical of platelet dysfunction and primary haemostasis?

A

Small bleeds of 1-2mm in diameter (petechiae) or purpura (slighly larger >3mm). May also include GI bleeding, nose bleeds, menhorragia or intracerebral bleeding.

70
Q

How do defects of secondary haemostasis typically present?

A

Bleeding into soft tissues like muscles or joints. Haemarthrosis is particularly characteristic. Sometimes (as with primary haemostasis issues, intracerebral bleeding is possible)

71
Q

What are the three pillars of Virchow’s triad of thrombosis?

A

Endothelial injury
Abnormal flow
Hypercoagulabilty

72
Q

Why is it thought that platelets are primarily responsible for haemostasis in the heart and large blood vessels?

A

The high blood flow and shear stress do not appear to allow the accumulation of coagulation factors.

73
Q

What metabolic changes are thought to cause blood that is hypercoaguable?

A

Hyperhomocystinaemia and hypercholesterolaemia

74
Q

Clots sometimes form in vessels that have not been injured to expose tissue factor, vWF and collagen. This is part thought to be due to the activation of endothelial cells to be more pro-thrombotic (e.g. when exposed to reduced blood flow, toxins, inflammation). What changes to the endothelium (‘activated endothelium’) lead to a procoagulant environment?

A

Down regulation of thrombodulin expression (key modulator of thrombin)
Downregulation of protein C production
Downregulation of tissue factor protein inhibitor
Secretion of PAIs (plasminogen activator inhibitors) - which downregulate t-PA production and limit fibrinolysis.

75
Q

Turbulent flow is an important part of Virchow’s triad. What does it do to create a prothrombotic state?

A

Promotes endothelial activation by damaging it
Allows platelets to settle at the edges of vessels (normally rush through the middle)
Prevent washout and dilatution of active clotting factors

76
Q

Why is clotting risk increased in polycythemia vera and sickle cell anaemia?

A

Polycythemia vera is characterised by clonal and much increased concentration of red blood cells - this increases the blood viscosity which creates turbulent flow and increases clotting.

Sickle cell anaemia causes clotting because the sickle cells get stuck in small vessels and disrupt flow, leading to clot formation.

77
Q

What are the two most common inhertied hypercoaguable state diseases?

A

Factor V Leiden and Prothrombin gener mutations.

78
Q

Why do patients with Factor V mutations (FV Leiden) clot more often?

A

Normally, coagulation is regulated in one way by thrombomodulin/thrombin/protein S activated Protein C. Protein C inhibits VIIIa and factor Va. Patients with factor V mutations in V Leiden produce Va that is resistent to protein C inhibition.

79
Q

How is factor 5 lieden inherited?

A

Autosomal dominant. It’s present in 2-15% of caucasions!

80
Q

Prothrombin gene mutations can cause increased coaguability and venous thromboses. How does this work?

A

A single nucleotide change G20210A (G->A at position 20210) in the 3’ untranslated region of the prothrombin gene leads to increased production of prothrombin (and so increased thrombin concentration) and increased clotting.

81
Q

Hereditary thrombocytopoenia is due to antibodies forming to the complex of heparin and platelet factor 4 (a componenet of the alpha granules released from platelets). This IgG+PF4+Heparin complex then binds via Fc receptor on the platelets back to the platelets which leads to them being destroyed by splenic macrophages when circulating. It also, unfortunately, activates the platelets - causing what?

A

This leads to them rapidly participating in coagulation wherever they are, which further depletes platelet numbers (hence thrombocytopoenia) and leads to areterial and venous thromboses and their complications.

82
Q

What is the possible unifying diagnosis in young female patient presenting with CTEPH, vavlular heart disease, DVT, and postprandial pain?

A

Anti-phospholipid syndrome - leads to chronic thrombosis with aseptic valvular vegetations, chronic microthromboemboli leading to pulmonary hypertension, leads to increased risk of DVT, leads to increased risk of mesenteric artery thrombus, leads to increased risk of miscarriage. Also increased risk of stroke and renovascular disease.

83
Q

What are the phospholipids for which antibodies are implicated in APLS?

A

Cardiolipin
B2-glycoprotein I
‘Lupus anticoagulant’ - the laboratory name for the discovery of an antibody to the phospholipids needed to induce clotting.

84
Q

What about APLS leads to loss of multiple pregnancies?

A

The anti-phopsholipid antibodies directly interfering with the differentiation of trophoblasts, leading to failure of placentation.

85
Q

Which coagulation test do the anti-phospholipid antibodies interfere with?

A

They prolong the aPTT as they interefere with the phospholipids needed for the intrinsic (negative charge) pathway.

86
Q

What infectious disease serology is often falsely positive in the setting of anti-phospholipid antibodies? Why?

A

Syphillis. Cardiolipin is presen in the syphillis serology test, and binds the serum antibody to cardiolipin, leading to a positive result.

87
Q

What are lines of Zahn?

A

Pale, platelet and firbin rich deposits that are elongated. They indicate that a clot formed in flowing blood, and are important in post mortem examination, as clots that form post-mortem do not look like this.

88
Q

What are ‘red thrombi’ or ‘stasis thrombi’?

A

They are usually venous clots. Because of the slow moving nature of venous blood flow, clots here tend to trap many more red blood cells that give them a more red appearance.

89
Q

What are the sterile verrucous like vegetations on heart valves called? What disease are they associated with?

A

Libman-Sacks endocarditis. Associated with SLE.

90
Q

Are most of the pulmonary embolli that occur diagnosed?

A

No, because 60-80% of PEs are tiny and clinically silent.

91
Q

If sudden death results from a PE- what has usually happened?

A

Acute heart failure with cardiovascular collapse. Happens when >60% of the pulmonary circulation is blocked by the embolus.

92
Q

AF classically causes thrombosis. What other cardiac disease causes thromboses that can be sent off via the aorta?

A

MI causes large left ventricular thrombi

93
Q

Where do most systemic emboli end up after they are shot out of the heart?

A

70% end up in the legs. Only 10% in the brain. But they can go anywhere.

94
Q

What are the symptoms of fat embolisation syndrome? Usually rapid onset 1-3 days after a skeletal injury.

A

Respiratory dysfunction
Neurologic symptoms
Anaemia
Thrombocytopoenia - binding to fat and activation, sequestration in spleen.

95
Q

How much air is required for an air embolism to be clinically significant?

A

Usually >100mls and greater than 100mLs per second (a lot!)

96
Q

What is decompression sickness?

A

Nitrogen gas forming bubbles out of solution when there is a rapid move from a high pressure to a low pressure environment. They accumulate in joints and the lungs and cause joint pain ‘the bends’ - inciting local inflammation - and respiratory distress ‘the chokes’

97
Q

Venous occlusion rarely causes infarction as collateral vessels are able to open up to drain blood via alternate routes. This cannot occur where there are not readily available collateral pathways. What are these?

A

Testes, ovaries, brain

98
Q

What is a ‘red infarct’

A

Haemorrhagic (full of blood) infarct. Occurs with venous occlusions (e.g. testicular tosion), loose spongy tissues, in tissues with dual circulations, and when flow is reastablished to a site of infarction afterwords.

99
Q

What are ‘white infarcts?’

A

Occur with arterial occlusions to solid organs with ende arterial circulation and where tissue density limits seepage of blood from adjoining capillary beds.

100
Q

Cytokine release syndrome occurs sometimes during CAR-T therapy. What is this a form of?

A

Systemic inflammatory response syndrome (SIRS) - a shock like state.

101
Q

How can a spinal cord injury cause shock?

A

Rapid vasodilation due to loss of sympathetic input

102
Q

What is Waterhouse-Friderichsen syndrome?

A

DIC induced thrombosis and necrosis of adrenal glands leading to adrenal insufficiency (seen in sepsis)

103
Q

Warm shock and cool shock are thrown around - what do they mean?

A

Septic shock often leads to vasodilation and warm skin, where as hypovolaemic and cardiogenic shock lead to vasoconstriction and cold peripheries.

104
Q
A

Basic Pathology Science Exam (14 decks)

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