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SADL Haematology > Hemostasis > Flashcards

Hemostasis Flashcards

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1
Q

Hermansky Pudlak Syndrome

A

9mutations
1,4 form a complex. associated with pulmonary fibrosis and colitis
3,5,6 associated with ophtho

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2
Q

Emicizumab NEJM paper results

A

Population: Hemophilia A with high titer inhibitors
Dosing: 3mg/kg/week x 4 weeks, then 1.5mg/kg/week
Results:
- 87% decrease in bleeding events compared to no prophylaxis (2.9 vs 23.3 events/yr)
- 79% decrease in events compared to same patients when they were on bypassing agents
- 63% of emi group had no bleeds
- 5 cases of TMA and thrombosis when given with aPCC over 100U/kg/day
- no inhibitors found

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3
Q

Risk factors for Hemophilia A inhibitor development

A
  1. Severity of hemophilia
  2. Mutation type (null mutations)
  3. Intensity of exposure (RODIN study)
  4. Type of product - Sippet study suggesting early exposure to plasma derived is better than recombinant
  5. Family history - genetic variations in immunity
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4
Q

Factor VII deficiency

A

1:500,000 auto recessive.
FVII activity >0.2 rarely bleed, high risk if <0.1
Heterozygotes have activity 0.4-0.6 (INR usually normal when level >0.5)
Recommended replacement is rFVIIa 15-30ug/kg every 4-6 hours. Plasma half-life is estimated 2-3 hours.
**note dose lower than hemophilia

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5
Q

What is the mechanism of action of steroids in ITP?

A

Inhibits phagocytosis of antibody coated platelets

Inhibits antibody production

Suppress activation of t-cells

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6
Q

Name complications of hemophilia apart from bleeding

A 
Development of inhibitors 
Synovitis
Arthropathy
Pseudotumors
Infection from plasma derived products
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7
Q

What is the average lifespan of a platelet?

A

9-10 days

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8
Q

How are platelets distributed in the body?

A

1/3-in the spleen

2/3-in circulation

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9
Q

How long does it take for NAIT to resolve?

A

usually 2-4 weeks

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10
Q

Describe the pathophysiology of NAIT

A

When fetal platelets express platelet-specific antigens inherited from the father, are the target of maternal alloantibodies (mother doesn’t possess these platelet specific antigens)

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11
Q

What is the most common platelet specific antigen involved in NAIT?

A

HPA-1a accounts for ~75% cases

Another 10-20% are due to HPA-5b-these cases tend to be milder

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12
Q

neonates affected by NAIT have what rate of developing ICH?

A

10-20%

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13
Q

How is NAIT treated?

A

Random donor platelets usually are fine
If no response can use matched donor platelets or maternal platelets
IVIG 1g/kg/day for 1-3 days
Methylprednisone 1mg IV q8h with IVIG (says Lanzokowsky’s)
Head U/S
Follow-up until platelets recover

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14
Q

For neonatal autoimmune thrombocytopenia what pattern do you expect with the platelets?

A

Are near/normal at birth, then fall to a clinically significant nadir over the next 1-3 days, the platelet count will normalize over the next 3-12 weeks

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15
Q

What is the most common platelet antigen target in neonatal autoimmune thrombocytopenia?

A

GPIIB/IIIA or GPIb/IX

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16
Q

Which mothers are at risk of giving birth to a neonate with autoimmune thrombocytopenia?

A 
Hx of previously affected infant
Previously splenectomized for ITP
Currently has thrombocytopenia
Has SLE, hypothyroidism, preeclampsia, HELPP syndrome
Maternal drug ingestion (thiazide)
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17
Q

What platelet characteristics are associated with Bernard-Soulier?

A

Moderate thrombocytopenia

Large platelets-usually the size of a red cell

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18
Q

What causes Bernard Soulier?

A

absence of the GPIb glycoprotein complex

this leads to inability of VWF binding, and significant bleeding (epistaxis)

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19
Q

What triad is associated with WAS?

A

eczema, microthrombocytopenia and immunodeficiency (T-cell function)

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20
Q

What mutation causes CAMT?

A

mutation in c-mpl (the thrombopoietin receptor)

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21
Q

What 4 drugs are most commonly associated with drug-induced thrombocytopenia?

A

heparin
quinine
penicillin
VPA

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22
Q

What causes HIT?

A

antibodies develop that are directed against complexes of heparin and platelet factor 4

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23
Q

What is pots-transfusion purpura

A

MIddle aged women with hx of pregnancy. Allo-antibody results in destruction of endogenous and transfused plt. Severe thrombocytopenia 7-10d post with bronchospasm and hemorrhage

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24
Q

MYH-9 features

A

renal failure
sensorineural hearing loss
cataracts

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25
Abnormal radius with normal thumbs
TAR - high TPO - spontaneously recover at 12-24 m Mutation: RBM8A
26
CAMT gene
c-MPL
27
Grey Platelet syndrome
AR macrothrombocytopenia absent alpha granule assoc. with myelofibrosis
28
Hermansky-Pudlak
- AR - absent dense granules - so no ATP secretion or second wave of aggregation with ADP and epi - occulocutaneous albinism
29
What genetic defect causes Familial platelet syndrome with predisposition to AML? (FPS/AML)
RUNX1-a transcription factor
30
what are the 4 T's of HIT?
thrombocytopenia thrombosis timing-usually 5-10 days after 1st heparin exposure, 3-5 days after subsequent oTher-no other reason for thrombocytopenia
31
What is the pentad of TTP?
``` thromobcytopenia microangiopathic hemolytic anemia renal dysfunction neuro symptoms fever ```
32
What is the cause of both acquired and congenital TTP?
ADAMTS-13 deficiency mediated thrombotic microangiopathy
33
What is the treatment for congenital TTP?
because patients don't have antibodies but instead very low levels of ADAMTS-13, plasma infusion is the treament
34
what is the treatment of acquired TTP?
start plasmapheresis right away! removes the antibodies | platelets don't help, can worsen the coagulopathy
35
What test will diagnose acquired TTP?
ADAMTS13 assay which shows low ADAMTS13 activity (<10%) and also documents the presence of ADAMTS13 IgG autoantibodies shouldn't wait for results before starting plasmapheresis
36
What is the pathophys behind aHUS?
dysregulated alternative complement system there's an increase in formation of C5b-9 MAC attack complex there's also inhibition of the regulatory proteins
37
how does eculizumab work?
its a recombinant humanized monoclonal immunoglobulin targeting C5 to prevent cleavage of C5-C5a and preventing formation of the MAC complex
38
What is a major side effect of eculizumab?
increased risk of infection with encapsulated organisms, N.meningitidis (use the complement system) Be sure are vaccinated ahead of time if possible
39
Why does thrombocytopenia occur in patients with severe cyanotic heart disease?
if there's a high hematocrit (>65%) platelets get stuck in the small vessels. Platelets have difficulty aggregating in hypoxic situations
40
Give a differential dx of thrombocytosis
Nutritional-iron deficiency, Vit E def, megaloblastic anemia Infectious Trauma-surgery, fractures, burns, hemorrhage Splenectomy Autoimmune-Kawasaki, RA, HSP, IBD Drug induced-epi, corticosteroids, vinca alkaloids Neoplastic- CML, PV, ET, lymphoma, leukemia Myelodysplastic states- 5q syndrome, Sideroblastic anemia
41
what are the diagnostic criteria for primary ET?
- persistent thrombocytosis (>450) - bone marrow with megakaryocyte proliferation without increased neutrophil granulopoiesis or erythropoiesis - Absence of criteria for PV, PMF, CML, MDS or myeloid neoplasm - Presence of JAK2V617F or clonal marker - No known cause for reactive thrombocytosis
42
What is the treatment for ET?
asymptomatic patient-observe low risk patients with thrombophilia risk factors-anti-platelet agents such as ASA high risk patients with extreme thrombocytosis or symptoms of thrombosis/bleeding-hydroxyurea or anegrelide hydrochloride
43
Which coag factors are normal/high at birth
FVIII vWF Fibrinogen is normal
44
Which coag factors are made outside of the liver?
FVIII - endothelium (and liver) vWF - endothelium, macrophage Factor V - liver, macrophage Factor XIII - liver, macrophage
45
Name contact factors and which one is associated with bleeding. Bonus: which ethnic group has this genetic deficiency
- HMWK - prekallikrein - Factor XII - Factor XI Factor XI deficiency can have bleeding - Ashkenazi Jewish population
46
Name effects of Thrombin
- activated FV, VIII, XI, converts fibrinogen to fibrin (pro-coag) - activated FXIII, TAFI (anti-fibrinolytic) - binds to thrombomodulin on intact endothelium and activates protein C to inhibit coagulation downstream of injury
47
What receptor is involved in fibrinogen-mediated platelet aggregation?
GPIIb/IIIa | - defect gives Glanzmann's thrombasthenia
48
Baby with umbilical stump bleeding and ICH. Normal PT/PTT - Diagnosis? - Lab testing
FXIII deficiency - clot solubility test (qualitative test) and chromogenic assay (gold standard)
49
what is results is seen on platelet aggregation for a patient with Bernard Soulier?
platelets fail to aggregate with ristocetin, but have normal aggregation with ADP, epi, thrombin and collagen
50
what is the platelet aggregation pattern for Glanzmann's?
Glanzman's is global! No aggregation with ADP, epi, collagen only aggregate with ristocetin
51
What is found inside the alpha granules of a platelet?
Large proteins: VWF, fibrinogen, PF4, PDGF
52
What is found inside the dense granules of a platelet?
small molecules-ADP, ATP, serotonin, calcium
53
What disorders have a dense granule deficiency?
Hermansky-pudlak, Chediak Higashi, WAS, TAR
54
What is the platelet aggregation result for patients with Hermansky Pudlak?
Absent second wave to ADP, Epi and ristocetin | abnormal aggregation to collagen
55
Why do you need to bridge with LMWH when starting warfarin
To avoid warfarin induced skin necrosis (drop in Protein C and S)
56
DDAVP effect
VWF release FVIII increase (more protection from VWF) tPA release
57
Most common mutation in Hemophilia A
Intron 22 inversion
58
what are the 3 components of primary hemostasis?
subendothelium platelets VWF
59
What receptor on the platelet surface allows for binding to VWF?
GP1b
60
what occurs during the activation phase of primary hemostasis ?
platelets change shape to fill the hole in the endothelium. Platelets release ADP, serotonin, thromboxane A2 that cause vasoconstriction
61
which factor has the shortest half life? | the longest half life?
shortest FVII-3-6hrs | longest FXIII 10 days
62
which factor levels are not low at birth?
fibrinogen is normal VIII is normal to high VWF is normal to high rest are all low
63
which factors are made in other places than the liver?
Factor V-also in Megs Factor VIII-also in endothelial cells FActor XIII-also in macrophages VWF-in endothelial cells and megs, NOT in the liver
64
what are the inhibitors of the fibrinolytic system?
PAI-1 inhibits tPA | alpha2antiplasmin inhibits plasmin
65
what do protein C and S inhibit?
VIIIa and Va
66
what issues can happen to a blood sample drawn for PT/PTT before the sample is processed? (pre-analytical)
sample not processed quickly-temp artifact difficult blood draw-milking the vessel leads to the sample starting to clot and consumes factors heparin in the sample
67
What is the PFA-100 test?
assesses flow through a membrane, membrane closure time is measured in response to ADP/collagen and Epi/collagen collagen/epi is run first, only run ADP if epi is prolonged if both prolonged suggests possible plt defect or VWD
68
PT/PTT relies on 9:1 ratio of plasma to citrate What happens if there's too little plasma? Too much plasma?
too little=elevated levels occurs if tube not filled or polycythemia too much=falsely normal levels happens in severe anemia
69
PT tests which pathway? aPTT? PT and aPTT?
PT-extrinsic PTT-intrinsic both-common pathway
70
what 3 clinical scenarios occur when a patient is Vit K deficient?
Early-first 24hrs, because of maternal use of warfarin AEDs Classical-2-7d of life because of low stores Late- day 7-6 months due to disorders that interefere with Vit k-CF, liver disease
71
What is the best way to test for a hemophilia carrier?
genetic testing | Factor levels can rise and fall
72
what is the definition of mild, mod, severe hemophilia?
severe <1% factor, spontaneous bleeds moderate 1-5%, bleeding after mild-mod trauma, seldom spontaneous mild 5-40%, bleeding after mod-severe trauma
73
what is the risk of developing inhibitors in hemophilia A and B?
Severe hemophilia A-25% severe hemophilia B-5% Moderate hemophilia 1-2%
74
What is the definition of a target joint?
In the same joint: 3 bleeds in 6mths 4 bleeds in one year
75
what is primary prophylaxis?
treatment with factor before the second joint bleed, before any joint disease
76
what doses of factor rise the factor activity?
FVIII-1 IU/kg increases by 2% | FIX- 1IU/kg rises by 1%
77
what factor dosing is required in the following situations: - intracranial bleeds - joint bleeds - muscle bleed - surgery
- intracranial bleeds-correct to 100% for 14days - joint bleeds-correct to 40-60%, for 1-3 days - muscle bleed-40-60% until can move without pain - surgery- to 100% preop then keep >50% until risk of bleeding is over
78
what are the side-effects of DDAVP therapy? | which hemophilia patients can it be used in?
facial flushing hyponatremia, seizures have been reported in kids under 2yrs, contraindicated in this age thrombosis is a rare complication can be used in mild hemophilia A patients
79
what are the types of inhibitors?
low titre: <5BU low responders-if given FVIII they won't make antibodies can be treated with factor at higher than usual doses High titre: >5BU always high responders- will always make antibodies when exposed must use a bypassing agent
80
1 bethesda unit neutralizes how much factor activity?
50%
81
where is VWF stored?
in weibel-palade body in endothelial cells | in alpha granules in platelets
82
which blood type has the lowest VWF levels?
type O
83
What is type 2A VWD?
lack of large HMW multimers
84
what test results for VWD make you suspicious for type 2?
when there's a much lower level of ristocetin cofactor activity as compared to the vWF antigen (RCo:Ag ratio <0.6)
85
what is type 2B VWD?
gain of function mutation that makes VWF too adherent to platelets low dose RIPA is increased
86
what is type 2N VWD?
when VWF cannot bind to FVIII often confused with hemophilia see low FVIII level
87
what is type 2M VWD?
loss of function mutation causes VWF unable to bind well to platelets (at GP1b) this is shown by low R:Co activity
88
what oncology diagnosis causes acquired VWD?
wilms tumour
89
what clinical scenarios can occur with fibrinogen deficiency?
post trauma/surgery bleeds soft tissue bleeding splenic rupture can occur pregnancy loss
90
what clinical scenarios can occur with FX deficiency?
intracranial hemorrhages are more common
91
what clinical scenarios can occur with FXIII deficiency?
umbilical stump bleeding | ICH
92
define dysfibrinogenemia
dysfunctional fibrinogen that can either lead to bleeding or clotting bleeding due to loss of proper clot formation thromobosis due to dysfibrinogens that resist fibrinolysis See prolonged TT

SADL Haematology (13 decks)

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