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Pathophysiology - Hematology > Hemostasis > Flashcards

Hemostasis Flashcards

1
Q

How large are platelets, how long is their lifespan, and what organelle are they missing?

A

10 fL (about 1/10 size of an RBC), last 7-10 days, they lack nuclei but contain mRNA and all other organelles so they can make proteins

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2
Q

What hormone mediates the production of platelets and where is it produced?

A

Thrombopoietin, produced in liver and kidneys

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3
Q

What are the two types of granules in platelets and what do they release?

A

Delta = Dense = Dark -> release 4 things: ATP, ADP, serotonin, Ca+2

Alpha granules - light colored, release all the rest

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4
Q

What is the first step in primary hemostasis?

A

Reflex vasoconstriction -> from neural stimulation and endothelin release

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5
Q

Where is vWF made and what does it bind (binds two things)?

A

vWF - made in alpha granules and Weibel Palade bodies of endothelial cells

Binds Gp1b receptor on platelets when insoluble due to binding of subendothelial collagen

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6
Q

What is the most important function of the gpIIb/IIIa receptor? And can platelets directly bind collagen?

A

gpIIb/IIIa receptors attach platelets together by binding either side of fibrinogen

Platelets CAN directly bind collagen, via the gpIa or gp6 receptors.

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7
Q

What are the optimal levels of calcium and cAMP for platelet adhesion and activation? How does production of TXA2 help this?

A

Ca+2 - high, acts as a cofactor for many of the clotting factor conversions

cAMP - low

TXA2 blocks adenylate cyclase to keep cAMP levels low, while PGI2 increases adenylate cyclase activity

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8
Q

How does ADP improve hemostasis?

A

Binding of P2Y12 ADP receptor -> upregulates expression of GpIIb/IIIa receptors which improves platelet aggregation

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9
Q

What is the secondary function of vWF other than binding subendothelial collagen + platelets?

A

Also holds factor VIII and protects it from degradation (think of 8-ball in sketchy)

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10
Q

What is the first step of the coagulation cascade (secondary hemostasis), and which part of the pathway is most important?

A

Tissue factor (thromboplastin) binds factor VII when tissue damage occurs, which begins activity of the common pathway (10(5)-2-1)

-> amplification of intrinsic pathway by thrombin is most important and does majority hemostasis

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11
Q

How will a factor XIII deficiency show up in normal labs?

A

It won’t -> just functions to cross-like fibrin

  • > thrombin activates 13a
  • > it is past the common pathway, and will just lead to weaker clotting overall
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12
Q

How does thrombin and factor 13 actually work?

A

Thrombin -> cleaves two fibrinopeptides off of fibrinogen to make fibrin -> these will associated together but not be crosslinked

Factor 13 is activated by thrombin and induces the crosslinking of adjacent fibrin sticks

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13
Q

What is tPA / what makes it? How are fibrin split products generated?

A

tPA is made normal endothelium, (plasminogen activator inhibitor made if damaged). It converts plasminogen to plasmin. Plasmin cleaves cross-linked fibrin which produces “D-dimers” and “fragment E”

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14
Q

What type of bleeding occurs in disorders of primary hemostasis and why?

A

Primary hemostasis - blood vessel / platelet problem - bleeding from skin or mucous membranes (no initial plugs are formed), i.e. petechiae, ecchymoses and easy bruising

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15
Q

What type of bleeding occurs in disorders of secondary hemostasis and why?

A

Secondary hemostasis - cross-linking problem -> deeper bleeding problems with joints with lots of motion -> hemarthrosis, deep tissue bleeding, and rebleeding after surgical procedures

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16
Q

What is the most common cause of defective platelet function?

A

Aspirin and NSAID use

  • > single dose causes defect for 7-10 days
  • > inhibits TXA2 productionn
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17
Q

What is the definition of thrombocytopenia and thrombocytosis?

A

Thrombocytopenia: <150k/uL platelets

Thrombocytosis: >450k/uL platelets

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18
Q

How does platelet volume vary with platelet count?

A

Inversely

As platelet count increases, platelets get smaller

As platelet count gets lower, platelets get larger

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19
Q

What is the use in morphological evaluation of platelets on peripheral smear? When would you use EM?

A

Can look for granule problems, large platelets, or possible clumping which may have caused machine to misread the platelet count

Use EM to diagnose a granule storage pool deficiency

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20
Q

What is bleeding time used to assess and what is the normal range?

A

Normal range is 3-8 minutes, only used to assess disorders of platelets

Poor predictor of bleeding during surgery

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21
Q

What is the platelet aggregation assay / how does it work?

A

Take platelet-rich plasma, measure the optical density with spectrophotometer

  • > add an agonist
  • > as platelets begin to clot, the optical density of the solution falls (reduced turbidity)
  • > release of ADP by activated platelets also contributes
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22
Q

What agonists are used to detect defects in GPIIb/IIIa and fibrinogen via the platelet aggregation assay? What disease may see a defect in this?

A

ADP, epinephrine, collagen, and thromboxane A2

Glanzmann thrombasthenia may be detected (GPIIb/IIIa deficiency) -> glassman saying 2 be or not 2b

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23
Q

What agonist is used to detect defects in GP1b and vWF via the platelet aggregation assay? What diseases might see defects in this?

A

Ristocetin -> activates vWF to bind GP1b in vitro
-> should catalyze clumping of platelets if there’s no defects in both

von Willebrand disease (defect in vWF with qualitative / quantitative changes)

Bernard-Soulier syndrome - genetic GPIb deficiency

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24
Q

What machine has now supplanted the bleeding test, and what drugs extend the coagulation time with Epinephrine and with ADP as an agonist?

A

Platelet function analyzer-100

Collagen + epi: Prolonged by aspirin

Collagen + ADP: prolonged by clopidogrel

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25
Q

What clotting factors are measured by the prothrombin time (PT) and what are frequent causes of prolonged PT?

A

Factors 1, 2, 7, 9, 10

Frequent:

  1. Vitamin K deficiency (fat malabsorption, premature infants, warfarin)
  2. Liver disease - decreased clotting factor production
  3. DIC - Fibrin / fibrinogen degradation products consumed
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26
Q

What are the two primary uses for aPTT?

A
  1. Monitoring of heparin and 2. factor replacement therapy in patients with hemophilia

(thrombin has a much larger effect on the intrinsic pathway)

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27
Q

What are some common causes of prolonged aPTT?

A
  1. Heparin - inhibits Xa and IIa
  2. Fibrin or fibrinogen degradation products / increased consumption - DIC
  3. Antiphospholipid / anticardiolipin antibodies - Lupus anticoagulant
  4. Liver disease
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28
Q

What is the value of a mixing study? How do you run one?

A

Can assess if a prolonged PT or aPTT is due to a clotting factor deficiency or presence of an inhibitor

Mix an equal amount of normal control plasma (with known PT / aPTT) and patient’s plasma, and measure the new PT / aPTT

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29
Q

What are the two possible results of the mixing study and what do they mean?

A
  1. Patient’s PTT / PT value is correct -> factor deficiency was the problem
  2. Patient PT/PTT value is not corrected -> an inhibitor like an antibody is binding clotting factors and rendering them useless. Also bind clotting factors in the control plasma
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30
Q

Give an example of a specific and a nonspecific inhibitor.

A

Specific - antibody against a clotting factor

Nonspecific - lupus anticoagulant - just binds anything

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31
Q

What is the TT and what does it measure? What are some causes of prolongation?

A

Thrombin Time
Thrombin-induced conversion of fibrinogen to fibrin, while bypassing all other factors
-> qualitative or quantitative defects in fibrin
-> thrombolytic therapy or heparin / thrombin inhibitor use

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32
Q

What vascular disease is also known as Osler-Weber-Rendu syndrome and what are its symptoms? Inheritance pattern?

A

Hereditary hemorrhagic telangiectasia - autosomal dominant

Dilated microvascular swellings (telangiectasias) which start in chidhood and increase in adulthood

  • > recurrent bleeding of nose, skin, GI tract, and kidney
  • > can lead to iron deficiency anemia and GI hemorrhage
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33
Q

What are the two most characteristic symptoms of Ehlers-Danlos syndrome and what causes it?

A
  1. Bleeding diathesis (Easy bruising, delayed wound healing)
  2. Joint hyperextensibility

Due to collagen defect

34
Q

Give four acquired causes of easy bruising / spontaneous bleeding from small vessels (vascular disorders).

A
  1. Scurvy
  2. Senile purpura
  3. Purpura associated with infection
  4. Henoch-Scholein syndrome
35
Q

What is senile purpura and what does it have in common with scurvy?

A

Purpura caused by atrophy of supporting tissue of cutaneous blood vessels
-> makes those purple spots you see on old people

Scurvy is different because it causes perifollicular petechiae, but tends to present in old people as well

36
Q

What are some infectious causes of purpura?

A

Viral and bacterial infections
i.e. dengue fever, measles

Especially meningococcal septicemia (DIC caused by N. meningitidis)

37
Q

What is Henoch-Schonlein syndrome and how is it acquired? Triad?

A

Most common childhood systemic vasculitis - follows acute URI

Triad: skin + GI + IgA nephropathy

Skin: palpable purpura on buttocks and lower legs
GI: abdominal pain
IgA nephropathy: hematuria and renal failure

Can also cause arthralgias

38
Q

At what platelet count in thrombocytopenia will you actually get symptoms?

A

<50k / uL, whenever there is surgery or trauma

<20k / uL may cause spontaneous hemorrhage

39
Q

How can the spleen be related to low platelet count?

A

In splenomegaly, up to 90% of platelets may be sequestered in the spleen

40
Q

What are the two forms of Immune thrombocytopenic purpura (ITP) and who tends to get it?

A

Acute - in children weeks after a viral infection or immunization, usually self-limited

Chronic - seen more in adult women, often idiopathic but can be seen with other autoimmune disorders (i.e. SLE, HIV, HL)

41
Q

What will labs and bone marrow biopsy show for ITP?

A

Labs - isolated thrombocytopenia

Bone marrow biopsy - megakaryocytic hyperplasia to compensate

42
Q

What is the pathogenesis and treatment for ITP?

A

IgG antibodies are made to platelet receptors, and platelets are rapidly eaten by splenic macrophages

Treatment: Steroids, IVIG to distract macrophages, Rituximab to slow AB production, and splenectomy if refractory (removes site of removal)

43
Q

What is TTP and what causes it?

A

Thrombotic Thrombocytopenic Purpura

Generally due to an autoantibody against but sometimes hereditary deficiency of ADAMTS13 -> metalloprotease which breaks down vWF multimers

Large vWF multimers induce platelet aggregation and thrombosis

44
Q

What are the pentad of symptoms seen in TTP?

A
  1. Fever
  2. Thrombocytopenia
  3. Microangiopathic hemolytic anemia (with schistocytes)
  4. Renal symptoms (worse in HUS)
  5. NEUROLOGIC symptoms - i.e. involving CNS vessels
45
Q

What is the treatment for TTP and what therapy is contraindicated?

A

Plasmapheresis using fresh frozen plasma with ADAMTS13
-> removes autoantibodies and ultralarge vWF multimers and replaces enzyme

Platelet transfusion contraindicated as it will cause more thrombosis

46
Q

How tends to get hemolytic uremic syndrome and what are the clinical symptoms?

A

Especially children, those with exposure to E.coli O157:H7

Clinical symptoms:
Similar to TTP, except limited to renal insufficiency (involving vessels of kidney)

-> platelet replacement still contraindicated

47
Q

What is Gabali’s mnemonic for TTP vs HUS?

A

Increased LDH (hemolysis) + adult+ thrombocytopenia + neurological symptoms = TTP

Increased LDH + kid + thrombocytopenia + renal symptoms = HUS

48
Q

What causes post tranfusion purpura?

A

Either autoimmune reaction to donor platelet antigens, or simple dilution out of blood by adding only RBCs + saline -> drops the relative platelet count

49
Q

What is Glanzmann thrombasthenia / inheritance pattern?

A

Autosomal recessive failure of platelet aggregation due to fibrinogen receptor deficiency (GpIIb/IIIa)

-> Think of glassman saying 2b or not 2b

50
Q

How will platelets in Glanzmann thrombasthenia coagulate differently when given ADP/epi/collagen as agonist vs ristocetin?

A

ADP/epi/collagen - decreased platelet aggregation

Ristocetin - utilizes vWF receptors and Gp1b -> normal platelet aggregation

51
Q

What disease is marked by an autosomal recessive deficiency in Gp1b receptors? What disease is it clinically similar to?

A

Bernard-Soulier syndrome

Similar to Von Willebrand disease

vONE is ONE Big Sucker (BS, 1b receptor)

52
Q

What is the platelet count and appearance in Bernard Soulier syndrome?

A

Mild thrombocytopenia + platelets appear large

53
Q

How will platelets in Bernard-Soulier syndrome coagulate differently when given ADP/epi/collagen as agonist vs ristocetin?

A

ADP/epi/collagen - normal platelet aggregation

Ristocetin - no response -> failure to aggregate (Gp1b receptor absent)

54
Q

How do you tell von Willebrand Disease and Bernard Soulier apart?

A

Bernard-Soulier - bleeding tendency + thrombocytopenia + LARGE platelet size + no response to ristocetin

vWD - bleeding tendency + NO thrombocytopenia + NORMAL platelet size + no response to ristocetin

55
Q

What anomaly is associated with thrombocytopenia in Alport syndrome?

A

May-Hegglan anomaly

-> Autosomal dominant mutation in myosin heavy chain gene

56
Q

What is seen in peripheral smear in May-Hegglan anomaly?

A

Giant platelets, Dohle bodies in WBC, thrombocytopenia

57
Q

What is absent in grey platelet syndrome and what can be seen in peripheral blood smear?

A

Alpha granules (light granules)

  • > storage pool disorder
  • > large platelets with no granules
58
Q

How does kidneey dysfunction affect platelet function?

A

Uremia - associated with disrupted adhesion and aggregation

59
Q

What is the most common clotting factor deficiency and what are the symptoms associated?

A

Factor 8 - Hemophilia A - X-linked

Joint and soft tissue bleeds, infants may have profuse hemorrhages.

Painful hemarthroses can lead to joint deformity

60
Q

What are the lab findings of Hemophilia A, PT / aPTT, bleeding time

A 
Prolonged aPTT
Normal bleeding time (platelets not affected)
Normal PT (factor 8 is cofactor for 9 in intrinsic pathway)
61
Q

What is the treatment for hemophilia A and when do you need to be more aggressive?

A

Factor 8 replacement therapy + desmopressin (releases vWF from WP bodies which holds factor 8 / improves halflife)

be more aggressive when patient is having major surgery -> prevents bleeding (restore to 100% levels)

62
Q

What is Christmas disease and what is the treatment? What is deficient?

A

Hemophilia B

  • Factor 9 is deficient
  • Treatment is recombinant factor 9
63
Q

What is the most common inherited bleeding disorder and its inheritance pattern? What is the shared theme between the different types?

A

Von Willebrand disease

  • autosomal dominant, except for a couple rare types
  • > caused by defect or reduced production of vWF factor
64
Q

Does von Willebrand disease look more like a platelet problem or clotting factor problem? What will happen to the bleeding time and thrombocyte count?

A

Although vWF carries Factor 8, prolongation of the aPTT is rare (but can be misdiagnosed as hemophilia of A in some types).

Looks like platelet problem -> mucosal and superficial bleeding
-> prolonged bleeding time from impaired platelet plug formation via the Gp1b receptor to vWF

Thrombocyte count is normal

65
Q

What are the three broad types of von Willebrand disease?

A

Type 1 - All vWF multimer sizes present, but at low levels
Type 3 - All multimers absent
Type 2 - decrease in one particular multimer size

66
Q

What are the primary treatments for vWD?

A

Type 1 - DDAVP - increase vWF release

Factor 8 concentrates which contain vWF

67
Q

What is the definition of DIC and what are the laboratory findings? Include PT, PTT, and TT, fibrinogen / platelets, D-dimers, and peripheral smear.

A

Widespread microthrombi with consumption of coagulation factors and platelets due to procoagulant release or widespread endothelial damage

PT, PTT and TT all prolonged
Fibrinogen / platelets - decreased
D-dimers - elevated
Peripheral blood: microangiopathic hemolytic anemia leads to schistocytes

68
Q

What are common causes of DIC?

A

Sepsis - endotoxins and cytokines induce endothelial cells to make tissue factor
Obstetric complications - thromboplastin in amniotic fluid
Malignancies - i.e. adenocarcinoma (mucin) and acute promyelocytic leukemia (Auer rods)

69
Q

What is the treatment for DIC?

A

Treat the underlying cause, support care with cryoprecipitate with coagulation factors as necessary

70
Q

What is the classic presentation for an acute hypercoagulable state? How should you test them in the acute phase and why?

A

Classic presentation is recurrent DVTs or DVTs at a young age

Test them with DNA-based tests since the acute-phase response and anticoagulant therapy can affect test results
-> use schematic testing for inherited thrombophilia based on most common disorders

71
Q

What is the most common inherited hypercoagulability disorder in Caucasians and what causes it?

A

Factor V Leiden - single base pair polymorphism switches arginine to glutamine

  • > factor V is resistant to cleavage by protein C
  • > inheritance is co-dominant (worse when homozygous)
72
Q

What is the second most common inherited hypercoagulability disorder in Caucasians and what causes it?

A

Prothrombin G->A Mutation

  • > point mutation in 3’-UTR what causes overexpression of prothombin
  • > increased prothrombin levels leads to hypercoagulability
73
Q

What is the inheritance pattern of protein C / S deficiency and its claim to fame?

A

Autosomal dominant with variable penetrance

Causes skin necrosis due to dermal vessel thrombosis when treated with warfarin (both factors are vitamin K dependent)

74
Q

What heritable hypercoagulability disorder is associated with decreased response to heparin? How can you acquire this disorder as well?

A

Antithrombin deficiency (no change in PT/aPTT, but heparin is ineffective since it holds antithrombin III)

Disorder is acquired in patients with renal failure / nephrotic syndrome -> loss of AT3 in urine

75
Q

Increased levels of ______ in blood are associated with increased risk for both venous and ARTERIAL thrombosis.

A

Homocysteine

76
Q

What are the causes of homocystinuria?

A
  1. Cystathione synthase deficiency or decreased affinity for B6 - requires B6 as a cofactor
  2. Methionine synthase deficiency
  3. Methylene tetrahydrofolate reductase deficiency -> requires B9 and B12 supplementation
77
Q

How does estrogen increase thrombosis risk?

A

Estrogen therapy induces production of coagulation factors, increasing risk of thrombosis

It also tends to reduce the production of proteins C, S, and antithrombin III
->procoagulant state

78
Q

What is the definition of antiphospholipid syndrome and what is it commonly seen in? What two antibodies are normally seen?

A

Arterial or venous thrombosis or recurrent miscarriage in association with evidence of persistent antiphospholipid antibodies

  • > commonly seen as lupus anticoagulant syndrome (anticardiolipin antibodies)
  • > Two antibody types: anticardiolipin and anti-Beta2 glycoprotein
79
Q

What are the lab findings in antiphospholipid syndrome for PTT and mixing tests?

A

PTT - actually prolonged, since the antibodies bind the phospholipids needed for clotting in the lab (opposite occurs in vivo)

No correct with 50/50 mixes - antibodies react with donor plasma
-> can be corrected with excess phospholipid

80
Q

How can children get antiphospholipid antibodies and are they associated with increased risk of bleeding?

A

Children get them post some viral infections (varicella, adenovirus) or juvenile autoimmune conditions (SLE, AIHA, JIA)

Prolonged PTT but NO increased risk of bleeding -> surgery OK

Pathophysiology - Hematology (14 decks)

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