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Step 1 Miscellanous > Pathoma Hemostasis and Related Disorders > Flashcards

Pathoma Hemostasis and Related Disorders Flashcards

1
Q

What mediates the transient vasoconstriction of the blood vessel upon vascular injury?

A
  1. Reflex neural stimulation

2. Endothelin - very high yield to know

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2
Q

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

A

vWF - made in alpha (light) granules of platelets and Weibel Palade bodies of endothelial cells

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

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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 “ASC”
-> serotonin is released by activated platelets, think of the smiley face helmet in sketchy

Alpha granules - light colored, release all the rest

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4
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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5
Q

What is meant by adhesion / aggregation of platelets? What other mediator helps with aggregation of platelets other than ADP?

A

Adhesion - initial attachment to von Willebrand factor via the GP1b receptor
-> stimulates platelet activation

ADP as well as TXA2 is released once the platelet is activated
-> TXA2 promotes a reduction in cAMP levels -> improvement in aggregation

Aggregation -> GpIIb/IIIa receptors start making everything stick together via fibrinogen crosslinks

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6
Q

What is the predominant symptom of defects of primary hemostasis and the most severe / feared consequence?

A

Mucosal / skin bleeding, especially epistaxis

Severe thrombocytopenia -> intracranial bleeding

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7
Q

What are petechiae vs purpura vs ecchymoses?

A

Petechiae - pinpoint bleeds 1-2mm - usually NOT seen in qualitative disorders of platelets, but rather quantitative (Thrombocytopenia)
Purpura - >3mm
Ecchymoses - bruises >1cm

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8
Q

What is the most common cause of thrombocytopenia in children and adults? What is the pathogenesis?

A

Immune thrombocytopenic purpura (ITP)

IgG antibodies are made against platelet antigens (usually GP2b/3a)
-> splenic removal of platelets results in thrombocytopenia

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9
Q

What typically happens in children to cause ITP? Prognosis?

A

Usually arises weeks after a viral infection or immunization, and is self-limiting
-> acute form of ITP

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10
Q

Who typically gets chronic ITP?

A

Usually in women of childbearing age

May be primary - idiopathic
or
Secondary - i.e. autoimmune. Commonly seen in SLE (much like you have autoimmune hemolytic anemia, you can have this auto IMMUNE reaction to platelets. NOT thrombotic!!!!!!!!!!!!!!!!!)

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11
Q

What is the worry for women of childbearing age who have ITP?

A

IgG antiplatelet antibodies can cross the placenta and can cause a transient thrombocytopenia in newborns

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12
Q

What is seen on bone marrow biopsy of ITP?

A

Megakaryocytes -> indicating reactive platelet formation (since platelet count usually falls low, i.e. <150K, even <50K)

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13
Q

What is the treatment for ITP?

A

Treatment - corticosteroids, IVIG (short-lived distraction for macrophages), or splenic removal if refractory

Splenic removal -> removes the SOURCE of the antibodies and the SITE of removal

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14
Q

What are the two broad causes of microangiopathic hemolytic anemia? What does this generally mean?

A

Process where platelet microthrombi are formed which cause intravascular hemolysis of platelets

  1. Thrombotic thrombocytopenic purpura (TTP) - deficiency of ADAMTS13
  2. Hemolytic Uremic Syndrome (HUS) - E. coli verotoxin -> platelet microthrombi
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15
Q

Who is TTP classically seen in and what is the pathogenesis?

A

Can be due to genetic deficiency in ADAMTS13 (vWF metalloprotease), but typically due to an autoantibody to ADAMTS13

-> vWF multimers lead to abnormal platelet adhesion

B/c it’s normally due to autoantibody -> usually seen in middle-aged ADULT WOMEN

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16
Q

What are the classic symptoms of HUS vs TTP?

A

HUS - increased LDH + kid + thrombocytopenia + renal insufficiency (Thrombi usually in kidney)

TTP - increased LDH + adult + thrombocytopenia + neurologic symptoms (thrombi usually involve the CNS).

There is some crossover between disorders btw (TTP can involve kidney, HUS can involve CNS)

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17
Q

What happens to the PT/PTT in HUS / TTP?

A

These are PLATELET ONLY microthrombi

  • > no activation of coagulation cascade
  • > PT / PTT are normal
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18
Q

What is the treatment for TTP?

A

Plasmapheresis and corticosteroids

-> decrease auto-antibody production, and plasmapheresis to remove antibodies to ADAMSTS13

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19
Q

What is the pathogenesis of Bernard-Soulier syndrome? What is seen in terms of platelet count and peripheral smear?

A

Qualitative platelet defect in Gp1b, so platelets cannot bind Gp1b. -> defective ADHESION

Mild thrombocytopenia -> defective platelets tend to not live as long
Large platelets -> these are some “big suckers” dude

Just remember “vOne Big-Sucker” for 1b Bernard Soulier.

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20
Q

What is wrong in Glanzmann Thrombasthenia?

A

Genetic Gp2b/3a deficiency - platelet AGGREGATION via fibrinogren is impaired

Glassman - 2b or not to be.

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21
Q

What happens to platelet function in renal failure?

A

Uremia disrupts platelet function -> qualitative platelet defect in adhesion and aggregation

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22
Q

What are the classic clinical findings in problems of secondary hemostasis?

A

Deep tissue bleeding into muscles / joints (hemarthrosis), and rebleeding after surgical procedures (i.e. dental extractions)

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23
Q

What happens at the beginning of the instrinic pathway? Steps to the common pathway?

A

Hageman factor (Factor 12) binds subendothelial collagen, converted from 12 to 12a

12 -> 11 to 11a
11a -> 9 to 9a
Factor 8 is the cofactor for 9a’s conversion of 10 to 10a

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24
Q

When endothelial cells are injured, what three compounds do they begin secreting?

A
  1. von Willebrand Factor - mediates platelet adhesion to ECM
  2. Tissue factor - pro-coagulant for the extrinsic pathway
  3. Anti-fibrinolytic - plasminogen activator inhibitors
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25
Q

How does the extrinsic pathway work and is this the vitamin K dependent pathway or no? Include cofactors as applicable

A

Tissue factor released by injured endothelium converts 7 to 7a and forms a complex

TF-7a complex activates factors IX and X to activate downstream pathways

-> note that activation of factor 9 is a bit of an overlap with the instrinsic pathway for activation of 10

YES - 2, 7, 9, and 10 are extrinsic pathway, depend on vitamin K

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26
Q

What is the most common clotting factor deficiency? What are the lab values? Will patients always have a family history?

A

Factor 8 - Hemophilia A - X-linked, may arise de novo without a family history

Prolonged aPTT
Normal bleeding time (platelets not affected)
Normal PT (factor 8 is cofactor for 9 in intrinsic pathway)
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27
Q

What is the treatment for hemophilia A?

A

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

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

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 corrected -> 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 binds clotting factors in the control plasma)
30
Q

What is the most common coagulation factor inhibitor?

A

Anti-Factor 8 -> similar to Hemophilia AAAAAAAight.

31
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 -> induces aggregation via GpIIb/IIIa

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

32
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

33
Q

What is the most common inherited coagulation disorder?

A

von Willebrand disease

-> Hemophilia A is just the most common factor deficiency

34
Q

What are the lab findings of von Willebrand disease, PT / aPTT, bleeding time? Contrast this to Bernard-Soulier.

A

vWD - platelet adhesion defect

Bleeding time - prolonged, always-> looks like a platelet defect
aPTT - Often elevated vWF is needed to stabilize factor 8 -> factor 8 will be low. Normal in BS.
PT - normal

35
Q

What is the primary treatment of von Willebrand disease?

A

Desmopression -> causes release of vWF from the WP bodies of the endothelium
-> same reason why it can be used for treatment of Hemophilia A (vWF stabilizes factor 8)

36
Q

Why are newborns susceiptible to hemorrhagic disease of the newborn?

A

Newborns lack GI colonization by bacteria that normally synthesize vitamin K
-> reason why you can have clotting defects with longterm antibiotic use as well (disruption of K-producing GI flora).

37
Q

How do you follow the effect of liver failure on coagulation and why?

A

Follow via the PT -> vitamin K epoxide reductase occurs here, and it makes all coagulation factors. Vitamin K related clotting factors are best followed via the PT.

38
Q

What is HIT and what is the mechanism? What types of heparin tend to cause it?

A

Heparin-induced thrombocytopenia, from forming antibodies against heparin + PF4. These antibodies bind and activate platelets, cause a hypercoagulable state and low platelet count

UFH most commonly causes it - think of dad shooting four plates

LMWH can cause it but it is rare - she throws up four plates but doesn’t shoot them

Fondaparinux never causes it

39
Q

What drug is given in the management of HIT?

A

Direct thrombin inhibitors, i.e. espectially argatroban (gator eating thrombeaver)

40
Q

What are common causes of DIC?

A

Sepsis - endotoxins and cytokines (IL-1/TNF) induce endothelial cells to make tissue factor
Obstetric complications - thromboplastin (tissue factor) in amniotic fluid
Malignancies - i.e. adenocarcinoma (mucin, i.e. pancreatic) and acute promyelocytic leukemia (Auer rods)
Nephrotic syndrome - loss of AT3

41
Q

What can venom from a rattlesnake bite cause?

A

Venom can cause DIC

42
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

43
Q

What is the best screening test for DIC?

A

D-dimer -> elevation indicates that their was total activation of the coagulation cascade followed by clot lysis

44
Q

What activates plasmin and what does it cleave?

A

Activated by tPA (plasminogen to plasmin)

It cleaves fibrin (current clots), as well as fibrinogen and coagulation factors. Also inhibits platelet aggregation -> prevents formation of future clots

45
Q

What is the major inhibitor of activated plasmin? What produces it?

A

alpha2-antiplasmin

Produced in the liver.

46
Q

What condition does overactivity of plasmin cause? Give two example causes of this.

A

Disorders of fibrinolysis - plasmin overactivity. Leads to excessive cleavage of serum fibrinogen.

  1. Radical prostatectomy - release of urokinase activates plasmin
  2. Cirrhosis of liver - reduced production of alpha2-antiplasmin
47
Q

How do you differentiate disorders of fibrinolysis from DIC based on labs?

A

PT/PTT will still be elevated - plasmin destroys coag factors
Bleeding time will be elevated - inhibits platelet aggregation
Platelet count will be NORMAL - clots not forming
Fibrinogen split products are increased WITHOUT D-dimers -> plasmin is cleaving fibrinogen without the full maturation of the clotting cascade

48
Q

What is the treatment for disorders of fibrinolysis? When are they contraindicated?

A

Must inhibit the formation of plasmin by inhibiting tPA
-> aminocaproic / tranexamic acid

Contraindicated in ischemic stroke - worsening of clot
Contraindicated in DIC - will cause worsening of thrombosis although bleeding would be controlled.

49
Q

What is Virchow’s triad?

A

The triad of interrelated factors leading to thrombosis, including

  1. Endothelial injury
  2. Abnormal blood flow
  3. Hypercoagulability
50
Q

What direct fibrinolytic agent do healthy endothelial cells release?

A

Tissue-type plasminogen activator (tPA) -> keeps plasmin in proximity

51
Q

What are the defenses against coagulation secreted by endothelial cells?

A
  1. Heparin-like molecules - bind antithrombin 3 to mediate its inhibition of thrombin + others
  2. Thrombomodulin
  3. Tissue factor pathway inhibitor
52
Q

How do thrombomodulin and tissue factor pathway inhibitor (TFPI) work?

A

Thrombomodulin -> binds thrombin, activates protein C and protein S -> degrades factors 5 and 8 which are needed for coagulation pathway

TFPI - inhibits interaction between TF-7a complex and X

53
Q

How does a deficiency in B9 or B12 increase risk for thrombosis?

A

Will lead to decreased conversion of homocysteine to methionine via methionine synthase
-> buildup of homocysteine damages endothelium

54
Q

What does cystathionine synthase do and what is the cofactor?

A

Converts homocysteine + serine to cystathionine
-> cystathionine will be later converted to cysteine

Because it is combining two amino acids, requires B6

55
Q

What does cystathione synthase deficiency cause and what is the treatment?

A

These are causes of homocystinuria:

Deficiency -> treat with decreased methionine (make less homocysteine), increased cysteine (since it becomes essential), increased B6 (keeps whatever residual enzyme functioning) and increased B12/folate (homocysteine -> methionine as much as possible).

56
Q

What are the clinical features of homocystinuria?

A

Vessel thrombosis / atherosclerosis (endothelial damage by homocysteine), mental retardation, and marfanoid habitus (long, slender fingers, INFERIOR lens dislocation)

57
Q

What are the general clinical features of a hypercoagulable state?

A

Increased venous thrombosis - recurrent DVTs or DVT’s at a young age

58
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. I’m gonna R->Q this game!!!!

  • > factor V is resistant to cleavage by protein C
  • > inheritance is co-dominant (worse when homozygous)
59
Q

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

A

Prothrombin gene mutation

  • > point mutation in 3’-UTR what causes overexpression of prothombin
  • > increased prothrombin levels leads to hypercoagulability
60
Q

What is the inheritance pattern of protein C / S deficiency and its claim to fame? Which factors do these inhibits?

A

Autosomal dominant with variable penetrance

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

C/S both inhibit factors 5 and 8

61
Q

What should you be thinking if you give a patient heparin and their PTT doesn’t increase? How can you anticoagulate them?

A

Inherited antithrombin III deficiency since heparin works thru antithrombin III

Can anticoagulate through giving extremely high dose heparin (activates remaining AT3) as bridge therapy for warfarin

62
Q

What is an acquired cause of AT3 deficiency?

A

Nephrotic syndrome -> antithrombin III loss in urine

63
Q

What are the acute and chronic manifestations of gas emboli?

A

Acute:
Bends - joint and muscle pain
Chokes - respiratory vessel involvement

Chronic:
Caisson disease - long bone infarction

64
Q

What is the classical presentation of an amniotic fluid embolus and what will be seen in the lungs?

A

Shortness of breath, neurologic symptoms (like fat emboli), and DIC -> due to tissue factor in amniotic fluid

Emboli composed of squamous cells and keratin debris from fetal skin will be seen in the lungs

65
Q

What is required for a pulmonary embolus to actually cause pulmonary infarction (since it has a dual blood supply)? What type of infarction?

A
  1. Obstruction of a large or medium size artery
  2. Pre-existing cardiopulmonary compromise -> lack of sufficient blood flow around the obstruction

Loosely organized tissue with loose blood supply -> hemorrhagic infarct

Step 1 Miscellanous (40 decks)

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