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M2 Heme/Lymph > Bleeding Disorders - Friedman > Flashcards

Bleeding Disorders - Friedman Flashcards

1
Q

Distinguish between *hemostasis *and thrombosis.

A

Hemostasis: Prevention of blood loss from damaged vessels (split into primary and secondary; entails vasoconstriction)

Thrombosis: pathological formation of fibrinous plug in the absence of bleeding. (review Virchow’s triad)

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2
Q

Name two major receptors found on platelets. What do they bind, and what disease results from their absence?

A

GPIIb/IIIa: Bind fibrinogen; absence = Glanzman’s Thrombasthenia.

GPIba: Bind vWF; absence = Bernard Soulier Disease.

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3
Q

Distinguish between the contents of a dense granule and an alpha granule.

How do they appear on EM?

A

Dense granules contain ADP, ATP, 5-HT and calcium.

Alpha granules contain coagulation proteins, growth factors, and PF4.

Both are dark on EM, but dense granules are denser of course.

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4
Q

What chemical signals can trigger platelet activation?

What does this process entail?

A

ADP, 5-HT, TxA2, Factor IIa

Activation of IP3/DAG pathway, resulting in granule secretion, integrin activation, and shape changes (pseudopods, etc)

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5
Q

In primary hemostasis, how do platelets stick to the site of damage?

A

Damaged endothelium exposes collagen which bounds plasma vWF. vWF in turn binds both platelet receptor GPIb and GPIIb/IIIa.

Note: Transient, braking interactions more GPIb, while activation more GPIIb/IIIa?

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6
Q

How do platelets amplify a clotting response?

Besides platelets, what other component comprises a primary plug?

A

Platelet activation causes degranulation (contents of granules activate more platlets), as well as upregulation of GPIIb/IIIa to increase cohesion.

Fibrin/fibrinogen (bound by GPIIb/IIIa).

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7
Q

What are the initial triggers of the coagulation cascade?

What is “amplification” in the context of this cascade?

What does the coagulation cascade converge on?

A

Tissue Factor/VII activates factors IX and X (extrinsic pathway).

Thrombin (IIa) produced early in the response causes positive feedback to upregulate factors V, VIII, IX (all intrinsic pathway).

Both intrinsic and extrinsic pathways converge upon factors X and II.

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8
Q

What does thrombin activate, asides from fibrinogen??

A

Activates factor XIII, as well as TAFI.

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9
Q

Which factors are dependent on vitamin K for synthesis?

Why does warfarin mimic vitamin K deficiency?

A

2, 7, 9, 10, C, S.

Warfarin inhibits VKORC, which is needed to convert vitamin K into its reduced (usable) form.

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10
Q

What role does factor XIII play in the context of hemostasis?

A

Factor XIII is a transpeptidase; it forms crosslinks to mature a fibrin clot.

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11
Q

Summarize the intrinsic, extrinsic, and common coagulation cascade pathways.

A

Intrinsic: XII > XI > IX > X

Extrinsic: VII > X

Common: X > II (uses V as a cofactor)

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12
Q

Describe the process by which fibrin clots are lysed. Include in your explanation **t-PA, Plasminogen, a2-antiplasmin, **and d-dimers.

A

Tissue plasminogen activator produced from nearly endothelium activates circulating plasminogen to plasmin, which degrades fibrin to yield degradation products including D-dimers. Plasmin is inhibited by a2-antiplasmin, and its activation is inhibited by PAIs.

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13
Q

Besides t-PA, what factors are produced by endothelial cells to prevent clotting?

A

PGI2, NO

Heparan / Antithrombin

Protein C

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14
Q

Try to name 4 categories of bleeding disorders.

(Hint: 3 are hematologic, 1 is vascular)

A

Thrombocytopenias

Thrombocytopathies (platelet defects)

Coagulopathy

Vascular Fragility syndromes (eg ehler-danlos, scurvy)

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15
Q

What is the significance of bleeding in:

Mucosae?

Deep tissues?

Generalized ozzing at venipuncture sites?

A

Mucosae: Platelet defect of vWF deficiency

Deep tissues: Factor deficiencies

Oozing on venipuncture: DIC

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16
Q

What do petechiae indicate on physical exam?

A

Thrombocytopenia.

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17
Q

Recall 5-6 screening test that can assess for bleeding disorders.

A

Platelet count, PFA-100

PT, PTT, Fibrinogen, 1:1 mixing

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18
Q

Thrombocytopenias can generally be split into two categories of pathogenesis. What are they?

A

Decreased production (eg B12 deficiency or marrow infiltration)

Increased destruction (immune or non[DIC?])

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19
Q

What is immune thrombocytopenic purpura?

Distinguish between the adult and childhood forms.

A

Auto-antibodies made against platelet glycoproteins, resulting in thrombocytopenia.

Childhood abrupt, more often virally associated, with good recovery. Adult insidious, with decreased platelet production and worse recovery.

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20
Q

Heparin-Induced Thrombocytopenia

Describe the etiology & pathophysiology.

What are the consequences?

Lab findings?

A

Heparin-Induced Thrombocytopenia

Antibodies made against the heparin-PF4 complex.

Moderate thrombocytopenia, thrombotic events.

Positive ELISA against PF4-heparin antibody.

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21
Q

Name 5 causes of thrombotic microangiopathy.

A

Prosthetic valves, malignant hypertension, DIC/sepsis, HUS and TTP, and presumably many others…

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22
Q

What is the “pentad” seen in TTP?

What other findings are there?

A

Microangiopathic hemolytic anemia, thrombocytopenia (lab findings needed for Dx)

Organ dysfunction eg Renal failure, mental status changes, and fever.

Schistocytes on smear, high LDH, low haptoglobin, high bilirubin, negative Coomb’s.

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23
Q

What is the etiology of TTP?

What does this show on histology?

A

Congenital loss of or formed antibodies against ADAMTS-13, a protein which cleaves vWF.

Failure of cleavage results in a platelet string which may form a thrombus.

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24
Q

What is a PFA-100? What does it assess?

A

Citrated blood is ran at high pressure through an aperture coated with collagen. Time to form a complete clot (closure time) is measured

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25
Q

What roles do PFA-100 and vWF have in diagnosing bleeding disorders?

A

PFA-100 assesses platelet and vWF function. vWF tests further narrow the differential (VWD vs everything else)

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26
Q

What functions are served by vWF?

How is it assayed?

A

Promote platelet adhesion and stabilize factor 8.

Quantify by immunoassay and cofactor assay.

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27
Q

What are some examples of platelet function defects?

A

Receptor disorders (Glanzman’s, Bernard Soulier)

Drugs (eg Aspirin)

Uremia

Myeloproliferative syndromes (form immature platelets?)

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28
Q

How is PT measured?

Which pathway does this assess?

What role does this play, especially in warfarin management?

A

Plasma is treated with citrate (to remove calcium), then treated with tissue factor, phospholipid and calcium. Time clotting.

Assesses the extrinsic pathway (VII > X)

Calculation of INR (INR is based off of PT, not PTT)

29
Q

How is PTT measured?

Which pathway does it assess?

A

Citrated plasma is treated with surface activator (Kaolin?), phospholipid and calcium. Time clotting.

The intrinsic pathway (XII > XI > IX > X).

30
Q

What is a 1:1 mix assay, and how is it useful?

Give an example of two diseases that could be distinguished using this assay.

A

Patient plasma is mixed with normal plasma, and clotting time measured on the mixed sample. Distinguishes diseases of factor deficiency from those of inhibitors.

eg, Lupus anticoagulant from hemophilia.

31
Q

What is on the differential for an isolated long PTT?

An isolated long PT?

A

Deficiency of factors in the intrinsic pathway (VIII, IX, XI, XII), vWD, heparin, lupus anticoagulant, and “specific factor inhibitors”

Factor VII deficiency, liver disease/vitK deficiency, and lupus/factor inhibitors.

32
Q

What is on the differential for a prolonged PT and PTT?

A

Factor deficiency (of common pathway, or multiple eg liver disease, vitK deficiency), DIC, many inhibitors (direct, lupus, drugs)

33
Q

What factors are not tested by common coagulation screens?

A

Factor XIII, endothelial function, fibrinolysis, and anticoagulants such as AT, Proteins C & S.

34
Q

Give the clotting factor deficiency associated with the following:

  • Hemophilia A
  • Hemophilia B
  • Hemophilia C
A
  • VIII
  • IX
  • XI
35
Q

What is the inheritance pattern of Hemophilia A and Hemophilia B?

Give the lab findings in terms of:

PTT, PT, TT, fibrinogen, PFA-100, clotting factors

What determines the severity of symptoms?

A

X-linked recessive

  • Prolonged PTT (corrects on 1:1 mix)
  • Normal PT, TT, fibrinogen, PFA-100
  • Low factor VIII or IX

Severity: level of deficient clotting factor (<1% = spontaneous bleed episodes)

36
Q

Give the two hallmark symptoms of hemophilia A & B

A

hemarthrosis and deep muscle bleeds

37
Q

What are the two main functions of vWF?

A

Support platelet adhesion

Serve as a carrier for Factor VIII

38
Q

deficient vWF may lead to a deficiency in what other factor?

A

Factor VIII

39
Q

Give the vitamin-K dependent factors

What are some underlying causes of vitamin K deficiency?

What is the treatment?

A

Factors II, VII, IX, X, Protein C, Protein S

Causes: drugs (Warfarin, Abx), malabsorption or dietary deficiency, liver disease, newborns

Treatment: vitamin K replacement (or plasma and PCC in emergencies)

40
Q

Compare PTT and PT in Vitamin K deficiency

A

PTT prolonged (+)

PT very prolonged (++)

41
Q

What factors are affected by liver disease?

A

Factors II, VII, IX, X, V, AT3, Protein C, Protein S

42
Q

Compare PTT and PT in the setting of liver disease

A

PTT: prolonged (+)

PT: very prolonged (++)

43
Q

Give Virchow’s Triad of thrombosis

A

endothelial injury

abnormal blood flow (stasis, turbulence)

hypercoagulability

44
Q

Explain the role of each of the following in coagulation control:

  • Blood flow
  • TFPI
  • Antithrombin
  • Protein C
  • Fibrinolytic system
A
  • blood washes away activated factors (this is part of why stasis is bad)
  • TFPI stops initiation (inactivates VII and X)
  • Antithrombin inactivates IIa and Xa
  • Protein C digests cofactors V and VIII
  • Fibrinolytic system digests fibrin clots, controlling clot proliferation
45
Q

Give three primary hypercoagulable states associated with venous thromboembolism

A
  • Deficiency of control proteins (AT, C, S)
  • Mutations in control mechanisms (factor V leiden)
  • Increased coagulation factor levels (prothrombin gene variation G20210A)
46
Q

AT, Protein C, and Protein S deficiencies account for approximately what percentage of familial thrombosis?

How does the risk of thrombosis evolve throughout life?

What tests might be ordered to identify this problem?

A

5-15%

Risk increases after puberty

Tests to order: functional AT, PC or PS assay; Protein S free antigen

47
Q

Failure of PTT to prolong in response to addition of activated protein C is indicative of what condition?

A

Factor V Leiden

48
Q

What is the mutation seen in Factor V Leiden?

Is the risk of thrombosis primarily arterial or venous?

A

Arg506 replaced with Gln

venous

49
Q

Rank the following in terms of risk of thrombosis:

  1. Homozygous F5L
  2. Heterozygous F5L
  3. Protein C/S or AT3 deficiency
  4. G20210A mutation
A

1 > 3 > 2 ~ 4

50
Q

G20210A gene variation:

Arterial or venous?

Mechanism?

Risk compared to 5FL

A

venous

produces elevated Factor-II levels

Similar risk to heterozygous F5L

51
Q

Venous and arterial thrombosis with recurrent fetal wastage is indicative of what?

Give two major lab findings

A

Antiphosphlipid Antibody syndrome

Labs: evidence of “Lupus-like” anticoagulant (not associated with SLE) and thrombocytopenia

52
Q

What is the “Lupus” anticoagulant?

How is its presence detected on coagulation studies?

A

Antibody not always associated with SLE. Auto-antibody against phospholipid-protein complexes. Generally inhibits phospholipid-dependent in-vitro coagulation studies.

53
Q

Give the lab results of each of the following when the “Lupus-like” anticoagulant is present:

  • dRVVT
  • PTT
  • 1:1 mix study
  • Platelet neutralization assay
  • hexagonal phase assay

If the patient has bleeding, what else should be considered?

A
  • prolonged
  • prolonged
  • failure to correct
  • corrects (lipid-rich assay)
  • corrects (lipid-rich assay)

With bleeding: consider II or VIII deficiency

54
Q

Give the main site of thrombosis (arterial or venous) for each of the following:

  • APLA syndrome
  • Protein C/S deficiency
  • Prothrombin gene (G20210A)
  • Antithrombin deficiency
  • Factor V Leiden
  • Homocysteine deficiency
A
  • arterial and venous
  • venous
  • venous
  • venous
  • venous
  • arterial and venous
55
Q

Give three general acquired predispositions to thrombosis

A
  • Obstruction to flow (prior DVT, pregnancy, etc)
  • Activation of hemostatic mechanisms (sepsis, neoplasm, foreign body, etc)
  • Damaged epithelium (inflammation, atherosclerosis, trauma, etC)
56
Q

List several disease-related factors contributing to a secondary hypercoagulable state

A
  • post-operative state
  • neoplasm or chemotherapy
  • post-DVT
  • MPD
  • PNH
  • auto-immune
  • nephrotic syndrome
  • homocysteinemia
57
Q

List several circumstantial factors contributing to a secondary hypercoagulable state

A
  • immobilization
  • pregnancy
  • oral contraceptive use
  • obesity
58
Q

In DIC, which comes first: bleeding or thrombosis

A

thrombosis first

bleeding later (after exhaustion of clotting system)

59
Q

Define Disseminated Intravascular Coagulation (DIC)

A

Widespread activation of thrombin and plasmin mechanisms, which overwhelms control mechanisms and consumes hemostatic elements (platelets, coagulation proteins, control proteins). Usually presents as either massive thrombosis or bleeding.

60
Q

Give examples of each of the following broad categories of DIC-associated mechanisms:

  • Introduction of extrinsic clot promoting material
  • Intravascular elaboration of procoagulants
  • Vascular injury
A
  • malignancy, amniotic fluid, fat embolism
  • acute hemolytic processes, heparin-induced thrombocytopenia
  • bacterial or viral sepsis, hypotension
61
Q

What is this?

What is it associated with?

A

Purpura Fulminans, due to DIC

Associated with: meningococcal sepsis, severe protein C deficiency in a newborn

62
Q

Give 4 major clinical presentation of DIC

A
  • Bruising and petechiae
  • Bleeding from venupunctures
  • Purpura fulminans
  • Large vessel thrombosis
63
Q

Give the findings of PT and PTT in the setting of DIC

A

Both PT and PTT prolonged

64
Q

Describe the diagnosis of DIC. Are labs useful?

Give the expected findings of the following in DIC:

  • PT
  • PTT
  • Fibrinogen
  • Platelets
  • FDP
  • D-Dimer
  • Control proteins (AT, C, S)
A
  • prolonged (50-75%)
  • prolonged (50-75%)
  • decreased fibrinogen
  • decreased platelets (<30K in 80-90% of cases)
  • elevated (95%)
  • elevated (99%)
  • decreased
65
Q

What are the major effects of DIC on the following organs?

  • Liver
  • Heart
  • CNS
  • Kidneys
  • Adrenals
  • GI
  • Skin
A

Microcirculatory failure underlies all of these organ dysfunctions!

  • disturbed liver function
  • ischemia, release of cardiac enzymes, MI
  • altered mentation (CNS abnormalities)
  • renal insufficiency
  • ARDS
  • adrenal infarction
  • GI mucosal hemorrhage
  • microhemorrhage and infarctive necrosis
66
Q

Describe the treatment approach for DIC

A

Treat the triggering condition

Restore tissue perfusion and acid/base balance

replacement therapy

anticoagulation therapy in patients with thrombosis

67
Q

In the setting of DIC, what three approaches to replacement therapy are used? What is the purpose of each?

A
  • Cryoprecipitate - replace fibrinogen
  • FFP - replace coagulation proteins and anticoagulant proteins
  • Platelet concentrates - replace platelets
68
Q

Differentiate the following

  • DIC
  • Liver failure
  • Vitamin K deficiency
  • Lupus anticoagulant

in terms of:

  • PT
  • PTT
  • Fibrinogen
  • Platelets
  • FDP
  • Key clinical findings
A

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M2 Heme/Lymph (32 decks)

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