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Med Gen Section 3 > Coagulation Disorders > Flashcards

Coagulation Disorders Flashcards

1
Q

What are the parts of primary hemostasis?

A 
vessel injury
platelet adhesion
platelet activation
platelet aggregation
platelet plug
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2
Q

What kind of disorders are associated with vessel injury?

A

vascular/connective tissue disorders

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3
Q

What kind of disorders are associated with platelet adhesion, activation, or aggregation?

A

thrombocytopenias (decreased production, increased destruction, abnormal distribution)
platelet function defects (receptor/membrane defects, storage granule defects, inhibition (eg. medications or toxins)

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4
Q

What kinds of disorders are associated with platelet plug?

A

von Willibrand disease

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5
Q

How do labs analyze platelets?

A 
electronic detection (not accurate at counts lower than 10,000/mm3 and does not detect macrothrombocytes or platelet clumping)
peripheral blood smear (can see size and morphology)
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6
Q

What are the three steps of platelet aggregation?

A
  1. adhesion to site of injury at subendothelial vWF/collagen (platelet GP1b IX-V adn GPVI)
  2. Activation (platelet shape change exposes the GPIIb/IIIa receptors and releases thrombin, ADP, TXA3, and 5HT)
  3. Aggregation (follow cross-linking of platelet activated GPIIb/IIIa by fibrinogen or vWF)
  4. propagation of coagulation (activated platelets provide an anionic aminophospholipid rich surface for the assembly of procoagulant enzyme complexes)
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7
Q

List the names and functions of alpha granules.

A

vWF: major role in blood coagulation
Fibrinogen: binds platelet GPIIb/IIIa to form bridges between platelets
PF4: binds heparin and provides neutralization heparin-like molecules (inhibits local ATIII and enhances coagulation)
Growth Factors: PDGF/TGF-beta1
Coagulation Factors: Factor V
P-selectin: cell adhesion molecule which promotes platelet aggregation through platelet-fibrin and platelet-platelet binding

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8
Q

List the names and functions of dense granules.

A

ADP/ATP: activates platelets causing recruitment of additional platelets
Serotonin: powerful vasoconstrictor
Calcium: required for binding of fibrinogen to platelet GPIIb/IIIa

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9
Q

What are halmarks of thrombocytopenias in general?

A

shortened platelet lifespan
platelet sequestration or pooling
platelet loss or dilution
diminished/impaired platelet production

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10
Q

List the immune mechanisms of thrombocytopenia.

A 
immune thrombocytopenia
Evan's syndrome/Autoimmune lymphoproliferative syndrome
Neonatal alloimmune thrombocytopenia
Neonatal autoimmune thrombocytopenia
Heparin induced thrombocytopenia
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11
Q

List the non-immune mechanisms of thrombocytopenia.

A

Disseminated intravascular coagulopathy
Bacterial infections
Thrombotic thrombocytopenia purpura/hemolytic uremic syndrome
Kasabach-Merritt syndrome

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12
Q

Describe immune thrombocytopenia.

A

most common thrombocytopenia in children
present when platelet counts <10,000
can be associated with recent bacterial infection
children present with mostly skin findings due to mucosal bleeding and are otherwise healthy
development of severe hemorrhage is rare

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13
Q

What is the mechanism of immune thrombocytopenia?

A

platelet surface looks abnormal –> autoantibody production –> increased platelet removal –> decreased platelet production

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14
Q

How can you tell which hereditary thrombocytopenia a person has by looking at the size of their platelets?

A

Small: WAS
Normal: TAR, CAMT
Large/Giant: Bernard-Soulier, MYH9

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15
Q

Describe Wiskott-Aldrich Syndrome.

A

XLR mutation of WASP gene (Xp11.23) resulting in defects in surface of glycoprotein CD43 (actin binding signalign protein)
variable thrombocytopenia with small platelets and poor function
triad of thrombocytopenia, eczema, and frequent infections
associated with defects in T and B cells and inability to form antibodies

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16
Q

What complications are associated with Wiskott-Aldrich Syndrome?

A

hemorrhage (internal and mucosal)
infection (post splenectomy sepsis, viral pneumonia)
autoimmune disorders
malignancy (ALL, lymphomas)

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17
Q

How is Wiskott-Aldrich Syndrome treated?

A

supportive management of eczema and infection
splenectomy usually beneficial
stem cell transplantation

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18
Q

Describe MYH9 related disorders.

A

AD macrothrombocytopenias
mutations involving the MYH9 gene which encodes for non-muscle myosin heavy chain 11A on chromosome 22q13.1
includes leukocytes that present as Dohle bodies
associated with renal failure, sensorineural hearing loss, and cataracts

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19
Q

Describe TAR syndrome.

A

Thrombocytopenia Absent Radii
complex inheritance of a mutation to the RBM8A gene located at 1q21.1 which provides instructions for making a protein called RNA-binding motif protein 8A
presents with radial anomalies with NORMAL thumbs
50% associated with gastritis and cow’s milk intolerance
diminished or absent megakaryocytes with elevated TPO levels

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20
Q

How is TAR syndrome treated?

A

platelet transfusions (sometimes daily) will increase platelet count to normal after about 12-14 months

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21
Q

Describe CAMT.

A

Congenital Amegakaryocyte Thrombocytopenia
AR mutation involving the gene for the TPO receptor c-MLP located at 1p34.2
neonatal platelet count is normally below 20,000/mm3 with some degree of bleeding in most children
progression to aplastic anemia within 5 years
about 50% have additional anomalies

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22
Q

How is CAMT treated?

A

supportive care with platelet transfusions

stem cell transplant is curative

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23
Q

Describe Glanzmann’s Thrombocytopenia.

A

AR defect in the alphaIIbbeta3 integrin resulting in deficiency or absence of platelet membrane fibrinogen receptor GPIIb/IIIa
severe mucocutaneous bleeding starting in infancy

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24
Q

How is Glanzmann’s Thrombocytopenia diagnosed and what is the treatment?

A

diagnosed by combination of clinical findings, platelet aggregation, and flow cytometry showing:
absent platelet aggregation in response to ADP, epinephrine, and collagen
normal risocetin induced platelet aggregation
managed with platelet infusions

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25
Describe Bernard-Soulier syndrome.
AR mutation resulting in abnormal or absent surface receptors for von Wilibran Factor mucocutaneous bleeding starting in infancy mild to moderate macrothrombocytopenia
26
How is Bernard-Soulier syndrome diagnosed?
combination of clinical findings, platelet aggregation, and flow cytometry indicating: normal response to ADP, adrenaline, and collagen abnormal response to ristocetin
27
Describe alpha granule storage pool defects.
seen on light microscopy contain fibrinogen, PDGF, vWF, PF4, Protein S, Factor V, Fibronectin, thrombospondin, beta-thromboglobulin absent in grey platelet syndrome
28
Describe dense granule storage pool defects.
seen on electron microscopy contains serotonin, calcium, ATP, and ADP absent in dense granule storage disease, Hermansky-Puldak syndrome, and Chediak-Higashi
29
What is von Wilibrand Factor?
platelet binding protein that carries Factor VIII increased by physiologic stress, DDAVP, estrogen, and pregnancy acute phase reactant
30
Why do you need to test vWF multiple times to diagnose a defect?
because it has many pathways that increase it and can give you false results, so you need to do multiple tests to see its trends over time
31
What are the disease types associated with von Wilibrand Factor?
``` Type 1 (heterozygous defect with reduced production of normal vWF) Type 2A (multimerization defect with absent large/intermediate size multimers) Type 2B (gain of function mutation in vWF resulting in platelets that are too adherent and attach to large multimers instead of letting them circle) Type 2M (loss of function where vWF doesn't bind well to platelets- opposite of 2B) Type 2N (loss of vWF binding function to FVIII- normally compound heterozygotes with Type1) Type 3 (absence of vWF production resulting in patients that bleed like hemophiliacs) ```
32
Which von Wilibrand Factor disease types are Autosomal Dominant?
all but Type 3
33
What screening tests are available to diagnose von Wilibrand Factor diseases?
no screen can rule out any of these diseases PT will always be normal PTT is only abnormal if FVIII is low bleeding time and PFA-100 are not sufficiently sensitive
34
What diagnostic testing is available for von Wilibrand Factor diseases?
``` vWF antigen (vWF:Ag)- immunologic test for presence of vWF in plasma (does not show function) Factor VIII activity- assesses FVIII activity in blood and binding to vWF Ristocetin cofactor activity (vWF:Rcof)- platelet aggregation based test assessing vWF platelet binding function vWF multimer analysis- assesses molecular structure of vWF on an agarose gel (normally present in variety of sizes- low, high, and intermediate molecular weight multimers) ```
35
How does blood type affect vWF levels?
all blood types have different vWF concentrations (Type AB>Type B>Type A> Type O) these concentrations decrease with vWF diseases so that normal Type O is about the same concentration as diseased Type AB
36
What factor defects most commonly result in the hemophelias?
FVIII and FIX
37
List they types of defects of secondary hemostasis.
inherited factor deficiencies acquired factor deficiency acquired inhibitory antibodies
38
Name the inherited factor deficiencies.
Hemophilia A and B | rare: fibrinogen, FV, FVII, FX, FXI, FXIII deficiencies
39
What are the causes of acquired factor deficiencies?
``` Vitamin K deficiency (FII, FVII, FIX, and FX plus Protein C and S) liver dysfunction (all but FVIII made here) DIC (consumption of factors) ```
40
How are disorders of the coagulation cascade screened for?
``` PTT is almost always prolonged (some mild hemophilia patients will have normal as will some genotypes due to the way FVIII/FIX interacts with phospholipids and reagents) Factor Assays (measure specific factor activity levels) Genetic Assays (genotyping to determine specific molecular defects) ```
41
What is Hemophilia A?
XL R deficiency due to mutations on Xq28 | results in spontaneous bleeding, hemarthroses, and deep tissue bleeding
42
What is Hemophilia B?
XL R deficiency due to mutations on Xq27.1 results in spontaneous bleeding, hemarthroses, and deep tissue bleeding carriers (normally female) never have bleeding issues and may not know they carry if their family have less severe versions
43
How are Hemophilias classified?
by factor activity <1%= severe (will most likely develop antibodies to platelet replacement therapy) 1-5%= moderate (trauma induced spontaneous bleeding) >5%= mild (rarely have spontaneous bleed but problems with surgery)
44
Is prenatal diagnosis possible for hemophilias?
factor levels are not reliable enough for prenatal testing because FIX levels are physiologically low in all fetuses and FVIII levels can be falsely elevated testing is easiest when genetic information is available about the family to test for mutations
45
How are carriers of hemophilias diagnosed?
heterozigous women can be symptomatic, but their factor levels fall in the mild range (so you could diagnose by factor levels but you would also need to rule out vWF disease) most reliable way is to diagnose through genotyping
46
What clinical factors are associated with Factor XIII deficiency?
delayed umbilical cord separation wounds that re-bleed unstable fibrin clots normal coagulation studies
47
How is Factor XIII deficiency treated?
FFP or cryoprecipitate | human plasma derived FXIII concentrate (Fibrogammin D) every 4-6 weeks
48
List the natural coagulation inhibitors.
antithrombin (most potent- acts at thrombin and FXa) tissue factor pathway inhibitor (acts of TF in the VII --> VIIa reaction) Protein C and S (act at FV and FVIII) other less common ones
49
What innate factors influence the production or activity of anticoagulant factors?
``` decreased at birth (results in 1st year of life need to be interpreted against age associated normal ranges; AT and PS reach adult levels by 6-12 months while PC stays low until adolescence) liver disease (liver produces coagulation proteins, so diseased livers create a deficiency and/or decrease clearance of activated factors, increasing risk for coagulopathy/thrombosis) inflammation increases FVIII activity ```
50
What is thrombophilia?
the predisposition to develop thrombosis including: venous thrombotic events (VTE) such as DVT, PE, cerebral sinovenous thrombosis (CSVT), renal vein thrombosis, potral vein thrombosis, or mesenteric OR arterial events such as arterial ischemic stroke or catheter related events
51
List the most common inherited thrombophilias.
``` Antithrombin deficiency Protein C deficiency Protein S deficiency Factor V Leiden mutation Prothrombin G20210A mutation ```
52
Describe the properties of Antithrombin.
made in the liver neutralizes thrombin (IIa), Xa, and IXa heparin potentiates activity 2 binding sites (heparin binding site and reactive center)
53
What are acquired causes of Antithrombin deficiency.
``` heparin (increases clearance) DIC hurns liver disease (decreases synthesis) sepsis trauma nephrotic syndrome (protein loss) ```
54
What is AT-III deficinecy?
Antithrombin deficiency (Type 1 or 2) autosomal dominant results in thrombotic events (PE, DVT, or mesenteric mostly) 40% of events are spontaneous with increased recurrence rate homozygotes result in fetal demise
55
Describe Protein C.
vitamin K dependent protein produced in the liver | requires activation by thrombin/thrombomodulin complex
56
What is Protein C deficiency?
AD (or rare AR form) varies with age (20-40% as neonate with normalization in adolescence) majority of events will be venous thrombotic events (illiofemoral veins, mesenteric veins, PE, CVST, superficial thrombophlebitis) possible association with arterial stroke 70% spontaneous thrombosis high risk of recurrence
57
What are acquired causes of Protein C deficiency?
liver disease (decreased production) DIC (consumption) sepsis (meningococcemia) uremia (decreased activity)
58
How can Protein C deficiency be tested?
``` antigen tests (immunologic based ELISA, Radioimmunoassays/electroimmunoassays) functional tests (snake venom activated Protein C and activity of APC measured by clotting assay or chromogenic substrate) NOTE: Factor V leiden mutants may have artificially low PC/PS activity ```
59
What is severe PC deficiency in neonates?
homozygous deficiency or double heterozygote state presents with purpura fulminans, opthalmologic or renal injury, neural treated with anticoagulation (heparin and warfarin) lifelong plus aggressive Protein C replacement case reports of liver transplant
60
Describe Protein S.
Vitamin K dependent protein produced in the liver, endothelial cells, platelets, and brain cells 40% free protein which is active, the rest is bound to C4b-binding protein and is inactive (binding is increased during inflammatory state)
61
What are the acquired causes of Protein S deficiency?
``` estrogen (OPCs and pregnancy) DIC liver disease acute thrombosis inflammatory states (decreased free PS) ```
62
What is Protein S deficiency?
Types 1-3 mostly result in venous thrombotic events (DVT, PE, superficial thrombophlebitis, mesenteric veins, CSVT, axillary vein) 50% spontaneous events high risk of recurrence
63
How is Protein S deficiency screened for?
ELISA testing for total and free PS antigens indirect functional assays based on gene ratios of APC NOTE: FV leiden mutants may have artificially low PC/PS activity
64
How do medications impact levels of natural anticoagulant proteins?
heparin decreases AT levels warfarin decreases PC and PS levels oral contraceptives decrease PS and increase activated PC resistance
65
Describe Factor V Leiden.
accounts for most of the activated protein resistance (APCR) which slows inactivation by active PC
66
What is Factor V Leiden mutation?
Arg506Gln results in primary venous disease and pregnancy complications (arterial complications debated) low risk of recurrence in heterozygous state
67
What is Prothrombin G20210A?
increases prothrombin biosynthesis increases risk of venous thrombotic event possible increase of arterial stroke in children possible increase risk of recurrence in children
68
Name the types of anticoagulants.
Vitamin K Antagonists Direct Agents Indirect Agents
69
Describe Vitamin K antagonists.
block Factors II, VII, IX, and X as well as Proteins C and S | Eg. Warfarin
70
List the direct agent anticoagulants.
Block Xa: Rivaroxaban, Apixaban | Block IIa: Argatroban, Lepirudin, Bivalrudin, Dabigatran
71
List the indirect agent anticoagulants.
Block Xa: Fondaparinax Blocks IIa: UFH Blocks both: LMWH
72
Who should be screened for thrombophilias according to the guidelines?
patients with thrombosis younger than 50 years old, unusual sites, recurrent events, 1st event, and family history

Med Gen Section 3 (13 decks)

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