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Pathology Block 1 > Block 1 Coagulation > Flashcards

Block 1 Coagulation Flashcards

1
Q

Anti-thrombotic factors produced by endothelial cells

A

PGI2, NO, heparin-like molecule, tPA, thrombomodulin

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2
Q

von Willebrand factor

A

Co-factor for platelet adhesion; produced by platelet a-granules, subendothelial CT, Weibel-Palade bodies of endothelium

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3
Q

Main factors secreted by platelets

A

Serotonin
TXA2
ADP

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4
Q

Fibrinogen

A

Cross-links platelets in primary hemostasis, co-factor for platelet aggregation

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5
Q

How are platelets activated?

A

Exposure to sub-endothelial BM thrombin (factor 2a)

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6
Q

Tissue factor/ extrinsic pathway of clotting cascade

A

Damaged endo = FVII leaves, contact TF, TF-FVIIa -> FXa + FVa -> IIa/ thombin -> fibrin

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7
Q

Contact/ intrinsic pathway of clotting cascade

A

Endothelial damage -> formation of kallikrein-FXII complex my HMWK -> FXIIa -> FXIa -> FIXa + FVIIIa -> FXa + FVa -> IIa/ thrombin -> fibrin

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8
Q

Bleeding time

A

Assesses platelets; 2-9 min nrl, prolonged = defect in platelet # or fxn

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9
Q

Normal platelet count

A

150k-300k/ul

*May appear low d/t post-draw clumping

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10
Q

PT (prothrombin time)

A

Add TF and Ca2+

Measures extrinsic/ TF pathway: FVII, FX, FV, FII, fibrinogen

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11
Q

Normal PT and APTT time

A

PT: 11-14 s
PTT: 25-35 s

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12
Q

APTT (activated partial thromboplastin time)

A

Add surface area and Ca2+

Measures intrinsic/ contact pathway: FXII, HMWK, PK, XI, IX, VIII, X, V, II, fibrinogen

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13
Q

Three main categories of bleeding disorders

A

Increase vessel fragility
Platelets (deficiency or dysfunction)
Coagulation factors

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14
Q

Symptoms of vessel wall abnormalities

A

Non-thrombocytopenic purpura/ petechiae in skin, mucous membranes
Occasionally joint, mm bleeds, menorrhagia, epistaxis, GI bleed, hematuria

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15
Q

Lab values for vessel wall abnormalities

A

Bleeding time, platelet count, PT, APTT all normal

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16
Q

Causes of vessel wall abnormalities

A

Infections -> vasculitis or DIC (meningococcemia, infective endocarditis, Rickettsioses)
Drug rxns -> Ab-Ag complex deposition
Impaired collagen formation (elderly, Cushing syndrome, scurvy, ED syndrome)

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17
Q

Henoch-Schonlein purpura

A

Vessel wall abnormality d/t systemic hypersensitivity of unknown cause
Deposition of Ag-Ab complexes in vessels -> purpuric rash, abdominal pain, polyarthralgia, acute glomerulonephritis

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18
Q

Hereditary hemorrhagic telangiectasia

A

Vessel wall abnormality of AD inheritance; dilated, thin-walled vessels bleed easily, commonly in nose, mouth, tongue, eyes, GI tract

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19
Q

Amyloid

A

Causes vessel wall abnormalities d/t perivascular deposition seen in plasma cell dycrasias -> mucocutaneous petechiae

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20
Q

Thrombocytopenia

A

Platelets

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21
Q

Causes of thrombocytopenia d/t decreased platelet production

A

Generalized BM disease, selective impairment of production, ineffective megakaryopoiesis

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22
Q

Specific causes of BM disease, impaired platelet production, ineffective megakaryopoiesis

A

BM: aplastic anemia, marrow infiltration (leukemia)
Imp: drugs (thiazides, alcohol), infections (HIV, measles)
Mega: megaloblastic anemia, myelodysplastic syndromes

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23
Q

Causes of thrombocytopenia d/t decreased platelet survival

A

Immunologic (auto-Abs and allo-Abs) and non-immunologic (mechanical)

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24
Q

Immunologic causes of thrombocytopenia

A

Ab against platelet membrane GPIIb-IIIa and Ib-IX
Auto-Abs: ITP, SLE, HIT, HIV/mono
Allo-Abs: blood transfusion, pregnancy

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25
Q

Non-immunologic mechanical causes of thrombocytopenia

A

Artificial heart valves, malignant HTN with diffuse narrowing of vessels

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26
Q

Thrombocytopenia d/t sequestration and dilution

A

Seq: hypersplenism (normally stores 30-40%)
Dil: blood stored >24 h has no platelets -> relative dilution w/ transfusion

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27
Q

ITP general characteristics

A

Immune thrombocytopenic purpura
Primary acute or chronic, and secondary
Auto-Abs against GP2a-3b or 1b-9
Long BT, nrl PT/APTT

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28
Q

Mechanism of ITP & histo findings

A

Plasma or bound auto-IgG against GP 2b-3a, Ib-9 -> spleen phago of opsonized platelets
Prominent spleen germ center, increased BM megakaryos (immature, non-lobated nuc), megathrombocytes on PBS

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29
Q

Chronic ITP

A

Women

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30
Q

Acute ITP

A

Children, F=M
Follow viral illness, self-limited to 6 mos
Steroid therapy in severe cases
20% may -> chronic ITP, usually w/o viral prodrome

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31
Q

Secondary ITP

A

Due to a variety of conditions and exposures (e.g. HIT, HIV)

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32
Q

Drug-induced thrombocytopenia

A

Quinine, quinidine, sulfonamide ABs

Heparin: 5% pts (HIT)

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33
Q

Type 1 HIT

A

Occurs rapidly after therapy onset, mild and may resolve spont, d/t direct platelet-aggregating effect of heparin

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34
Q

Type 2 HIT

A

5-14 d post therapy onset, severe, Abs against heparin-platelet factor 4 complex; activated platelets -> thrombus

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35
Q

HIV-induced thrombocytopenia

A

Megakaryos have CD4 receptor, can be infected -> apoptosis = impaired platelet production
Abs cross-rx with HIV-assc GP120 & direct against GP2b-3a complex, acting as opsonins

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36
Q

TTP symptoms

A

Thrombotic thrombocytopenic purpura
Pentad: fever, thrombocytopenia, microangiopathic hemolytic anemia, transient neuro def, renal failure
*Can result in consumption, hemolytic anemia

37
Q

HUS symptoms

A 
Hemolytic uremic syndrome
No neuro symptoms
Prominent acute renal failure
Seen in children
*Can result in consumption, hemolytic anemia
38
Q

Cause, dx, and tx of TTP

A

ADAMTS-13 enzyme def, a vWF metalloprotease -> chains of vWF = microaggregates
PT, APTT normal
Tx: plasma exchange

39
Q

Acquired vs. inherited TTP

A

Ac: have inhibiting antibody
In: have inactivating mutation

40
Q

Cause, dx of HUS

A

Kids: E. coli O157:H7 -> Shiga-like toxin damages endo -> aggregation
*Bloody diarrhea precedes by 2-3 days
Good prognosis with supportive care
Adult: endo damage d/t drugs or radiation; poor prognosis
PT/APTT normal

41
Q

Bernard-Soulier syndrome

A

AR defect in platelet adhesion d/t deficiency of GP1b-9 (vWF receptor)

42
Q

Glanzmann’s thrombasthenia

A

AR defect in platelet aggregation d/t dysfunction GP2b-3a (bridges platelets by binding fibrinogen and vWF)

43
Q

Impaired platelet secretion of TXA and ADP

A

Storage pool disorder/ disorder of secretion = no platelet activation

44
Q

Aspirin & uremia -> thrombocytopenia

A

ASA: irreversible COX inh = no TXA2/PG for platelet aggregation and release rxns
Uremia: not fully understood, several platelet fxn abnormalities

45
Q

Symptoms of clotting factor deficiencies

A

Large post-traumatic ecchymoses, hematomas, or prolonged bleeding
GI, GU, joint bleeding

46
Q

Acquired clotting factor deficiencies

A 
Vit K def (F2, 7, 9, 10)
Liver disease (dec synth factors)
DIC
47
Q

Factor VIII

A

Produced by sinusoidal endothelial cells, Kupffer cells, glomerular and tubular renal epithelium
Circulates with vWF

48
Q

vWF

A

Multimers produced by endothelial cells and megakaryos
In platelet alpha granules
Dep in subendo matrix, promotes platelet adh via GP1b-9
Circulating: promotes platelet agg by binding activated GP2b-3a

49
Q

Von Willebrand disease

A

1% frequency
Mostly AD inheritance
Quant (type 1, 3) and qual deficiencies (type 2)

50
Q

Type 1, 2, 3 vWF disease

A

1: Quant, 70% cases, mild
2: Qual, 25% cases, mild-mod
3: Quant, AR, severe

51
Q

Testing for vWF disease

A

Ristocetin agglutination test: AB promotes intxn vWF and GP1b-9
Types 1, 3 may have 2’ FVIII def = prolonged PTT

52
Q

Hemophilia A

A 
Most common hereditary disorder a/w serious bleeding
X-linked
Reduction amt/act FVIII
PTT prolonged, all else nrl
Deep bleeding: jj, mm, intracranial
53
Q

Hemophilia B/ Christmas disease

A

Factor IX def, X-linked
Clinically indistinguishable from Hemophilia A
PTT prolonged, all else nrl
Tx: recombinant FIX

54
Q

Hemophilia treatment

A

Lyophylized powder reconstituted at home or in hospital for IV admin
Dosed to correct def to specific levels
Prophylaxis to prevent bleeds
Issues: venous access, cost, inhibitors

55
Q

Protective mechanisms against thrombosis

A

Intact endothelium, neutralization of activated factors by circulating anti-coags
Dilution of activated factors by blood flow
Clearance of activated factors by liver
Fibrinolysis

56
Q

Natural circulating anti-coags

A

AT-3, protein C, protein S, TFP-I (tissue factor pathway [extrinsic] inhibitor)

57
Q

Antithrombin 3

A

Interacts with HLM on endo to inactivate thrombin (2), 9, 10, 11, 12

58
Q

Protein C

A

Main circulating anti-coag, complexed to protein S
Affects Vit-K dep factors
Activated by ™ on endo surface, inactivates 5a, 8a

59
Q

TFPI

A

Secreted by endo and other cells, inactivates 10a, 7a

60
Q

Fibrinolysis & testing for it

A

Dissolution of formed thrombi performed by plasmin

Tests: plasminogen level, fibrin degradation products (D-dimer)

61
Q

tPA

A

Tissue-type plasminogen activator
Urokinase-type plasminogen activator
Inhibited by PAIs

62
Q

Causes of thrombosis

A

Damaged endo cells, exposure of blood to subendo, act platelets or coagulation, inhibition of fibrinolysis, stasis

63
Q

Predisposing factors of thrombus

A

Trauma, central catheters, deficiencies circulating anti-coags, endo damage, surgery

64
Q

Acquired defects of endo surface function

A

Vascular injury, atherosclerosis, drug/ foreign substance

65
Q

Thrombophilia

A

Predisposition to thrombus
Features: thrombosis at young age, multiple family members with thrombosis, repeated episodes of thrombosis (esp in odd places)

66
Q

Factor V Leiden mutation

A

2-15% Caucasians

Sub Q for R at position 506 = resistant to cleavage by protein C -> unchecked coagulation

67
Q

Prothrombin mutation

A

1-2% population

G to A in 3’ untranslated region of prothrombin gene -> elevated prothrombin levels

68
Q

Hyperhomocytsteinemia

A

A/w premature atherosclerosis, mild elevations a/w arterial and venous thrombosis
? Due to inh AT3 and endo TM
Gene polymorphisms identified

69
Q

Congenital defects of circulating anti-coags

A 
Plasminogen deficiency
AT3 def (heterozygotes prone, venous thromb is adol/early adult)
Protein C or S def
70
Q

Homozygous protein C/S def symptoms & tx

A

Purpura fulminans (skin necrosis, DIC), immediate recognition and FFP transfusions

71
Q

Heterozygous protein C/S def symptoms & risk factors

A

Venous thrombosis in adol/early adulthood

Compounded by pregnancy or birth control pills

72
Q

Anti-phospholipid syndrome (Lupus anti-coag)

A

Ab against cardiolipin = prolonged PT, APTT
No clinical bleeding, may cause recurrent venous or arterial thrombi, miscarriage, cardiac veg, thrombocytopenia
*False + syphilis test

73
Q

Causes of anti-phospholipid syndrome/ Lupus anti-coag

A

Idiopathic
SLE and other collagen vascular diseases
Post-viral
Medication-induced

74
Q

Features, location, complications of DVT

A

Pain, swelling, discoloration
Extremities, pulmonary vessels, pelvic veins, other
PE, post-phlebitic syndrome, bleeding from anti-coag

75
Q

Managing thrombosis patients

A

Thrombolytic therapy, anti-coag, surgical clot removal, angioplasty, anti-platelet therapy, search for causative factors

76
Q

Thrombolytic therapy

A

Activate fibrinolysis pathway to rapidly resolve thrombi, esp in arterial disease
Risk: hemorrhage
Requires plasminogen

77
Q

Streptokinase/ urokinase

A

Activate plasminogen, like tPA

78
Q

Heparin

A 
Rapid reversible anti-coag b/c IV with short T1/2
Therapy before Coumadin
Works via AT3 to inh 10a, 2a
Target PTT = 1.5 upper normal limit
*Measure hep levels directly
79
Q

Safe heparin use includes:

A

Standard infusion rates
Check AT3 levels
Dedicated IV line
Avoid: ASA, IM injections, trauma

80
Q

LMWH (low mol weight heparin)

A

More specifically inh Xa, may be safer than standard hep

Outpatient therapy admin 1-2/day

81
Q

Warfarin/Coumadin

A

Most common anti-coag
Inhibits gamma carboxylation of 2, 7, 9, 10 (vit K antagonist)
Oral, long T1/2
Metabolism affected by diet, meds

82
Q

INR (international normalized ratio)

A

INR = (patient PT/ avg PT)^ISI
ISI = international sensitivity index assigned to each TF batch
*Corrects for variability in instrumentation and reagents

83
Q

Safe use of Coumadin

A

Monitor INR, adjust every 4-5 days, discontinue heparin when therapeutic levels achieved

84
Q

What drugs modify extrinsic/ TF pathway & intrinsic/ contact pathway?

A

TF: Warfarin (PET is WET), measured by PT
CA: Heparin (PITT is a HIT), measured by PTT

85
Q

Prophylactic ASA

A

Aspiring irreversibly acetylates COX, inhibits primary hemostasis; role in preventing arterial thrombosis

86
Q

DIC

A

Acute, subacute, or chronic thrombohemorrhagic disorder

Activation coag pathway -> microthrombi; consumes platelets, fibrin, coag factors; secondary activation fibrinolysis

87
Q

Mechanisms of DIC: release of tissue factor or thromboplastic substances

A

From placenta, mucus from adenocarcinoma (act FX, chronic), granules from acute promyelo leuk, G- sepsis (endotoxins -> monocytes IL-1, TNF = inc exp TF and dec TM)

88
Q

Mechanisms of DIC: widespread endothelial injury

A

Meningococci, ricketssiae, trauma, burns

89
Q

Symptoms of DIC and tx

A

Fibrin dep -> ischemia; microangiopathic hemolytic anemia; dyspnea, cyanosis, resp failure; convulsions, coma; oliguria, acute renal failure; circulatory failure; shock, death
Tx: treat underlying cause

Pathology Block 1 (12 decks)

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