Test 6: Coagulation Disorders Flashcards
1
Q
Severe bleeding that require physical intervention
A
Hemorrhage
-Systemic-thrombocytopenia or platelet disorders
-anatomic-coagulopathies
2
Q
recurrent, chronic bruising in multiple locations
A
Purpura
3
Q
nosebleeds that are reoccurring that last more than ten minutes.
A
epistaxis
4
Q
Is acquired or congenital coagulapathies more common?
A
acquired (can be acute or chronic)
5
Q
Examples of acquired coagulopathies
A
-ACOTS
-Liver disease
-Disorders of Fibrinogen
-DIC
-Vit K deficiency
-Heparin
-Lupus Anticoagulants
-Acquired deficiency of Factor VIII
6
Q
Most fatal cause of hemorrhage
A
Acute Coagulopathy of Trauma-Shock (ACOTS)
7
Q
triggered by a combination of acute inflammation, platelet activation, tissue factor release, hyopthermia, acidosis, and hypoperfusion- all elements of systemic shock.
A
Acute Coagulopathy of Trauma-Shock (ACOTS)
8
Q
What is the treatment for Acute Coagulopathy of Trauma-Shock (ACOTS)?
A
-massive RBC transfusion protocol
-FFP- 1:4, or 1:1
-Platelet concentrate
-Activated prothrombin complex concentrate (PCC)
-Cryoprecipitate or fibrinogen concentrate
9
Q
ACOTS treatment of FFP is given until all coag. factors are at a min of _____%
A
30
10
Q
What are the risks of FFP transfusion for ACOTS treatment?
A
TACO (transfusion-associated circulatory overload) and TRALI (transfusion-related acute lung injury)
11
Q
Why can liver disease be associated with coagulation disorders?
A
majority of coagulation factors are synthesized in the liver, and for clearing circulating plasminogen activators and activated clotting factors.
12
Q
In liver disease, which factors are the first to decrease?
A
Vit. K dependant factors (II, VII, IX, X), followed by Factor V*
(Factor VII is the first to show decreased activity)
13
Q
Platelets can be effected by liver disease. _______ of pt show thrombocytopenia due to sequestration and shortened survival.
A
1/3
14
Q
_____________ (acute phase reactant) elevates in early liver disease.
A
Fibrinogen
15
Q
In moderate or sever liver disease, fibrinogen is coated with ________, interfering with its ability to perform -dysfibrinogenemia.
A
sialic acid
16
Q
Dysfinrinogenemia ther is _________ PT and ___________ Reptilase Time Test.
A
prolonged, extremely prolonged
17
Q
If Vit. K is decreased and factor V is decreased it means that…
A
the problem is not a Vit. K deficiency, rather a problem with the liver
18
Q
Reptilase skips factor ____ and goes straight to ____.
A
VII, X?
19
Q
What is seen in a blood smear with a pt that has liver disease?
A
Macrocytes, target cells, and acanthocytes
BUT normoblastic in bone marrow
20
Q
Liver disease will have __________ plt
A
decreased
21
Q
liver disease will cause _________ PT, PTT, and TCT tests.
A
prolonged
22
Q
Fibrinogen will be __________ with liver disease.
A
decreased
23
Q
FDP will be ___________ with liver disease.
A
Increased
24
Q
D-Dimer will be ___________ with liver disease.
A
normal
25
liver disease treatment?
-treat underlying disease
-give FFP for bleeding episodes
-Vit. K therapy
-therapeutic plt
-antithrombin concentrate
-recombinate activated factor VII
-provide generalized supportive care
26
Hereditary disorders of fibrinogen can be due to...
quantitative or qualitative abnormalities of either fibrinogen or fibrin stabilizing factor
27
Acquired disorders of fibrinogen occur ________ to other pathologic events
secondary
28
What is the indirect method of fibrinogen assay?
Use Thrombin Time (TT); add thrombin to pt's PPP. The longer it takes to clot, the less fbg it has (semi-quantitative)
29
What is the direct method of fibrinogen assay?
use "Fbg assay" with standard curve (utilizes highly diluted samples and excessive amount of thrombin reagent) so pt's clotting time can be extrapolated.
30
Reference range for Indirect method of Fibrinogen?
15-20 seconds
31
Reference range for direct method of Fibrinogen?
200-400 mg/dL
32
_____________ is a quantiative deficeicny of fibrinogen due to a lack of synthesisi by the liver resulting in severe hemorrhages.
Afibrinogenemia
33
What is the treatment for Afibrinogenemia?
replacement therapy with cryoprecipitate (rich in factor I and VIII) or fresh frozen plasma (FFP) to raise blood fibringoen levels above 60 mg/dL
34
_____________ is a qualitative abnormality in the structure and function of the fibrinogen molecule.
Dysfibrinogenemia
35
With dysfibrinogenemia, finrinogen levels are __________, and TCT is ___________.
Post-traumatic and post-operative bleeding is common.
decreased, prolonged
36
What are the three hereditary disorders of fibrinogen?
-Afibrinogenemia
-Dysfibrinogenemia
-Factor XIII deficiency
37
What is used for diagnosis of Factor XIII deficiency?
5M urea solution test (Chromogenic assay???)
38
__________ deficiency can be clinically severe with moderate to sever bleeding. Delayed bleeding and wound healing is often observed after trauma
Factor XIII
39
What test results come back normal with Factor XIII deficiency?
APTT, PT, and TCT
40
Refers to a deposition of large amounts of fibrin throughout the microcirculation which results in a pathological activation of coagulation pathways.
Disseminated Intravascular Coagulation (DIC)
41
_______ is life-threatening result of concurrent in vivo activation of both coag and fibrinolytic systems.
DIC
42
DIC:
Ongoing thrombosis uses up coag. factors and plts, yielding name "______________", and then clots cause further tissue necrosis (including strokes).
Consumptive Coagulopathy
43
DIC is triggered by _____________ which activates platelets, catalyzes fibrin formation, and consumes control proteins.
circulating thrombin
44
What are the coagulation tests for DIC?
(everything is abnormal)
-decreased platelet count
-PT, APTT, and TCT are prolonged
-FDP and D-Dimer are elevated
-Dcreased fibrinogen level
-shistocytes and incrased RDW
45
causes of DIC...
snake bite, spetic shock, major tissue necrosis, cytotoxic drugs, crush injuries, heat stroke with hypovolemia and retained dead fetus syndrome. (last two are usally chronic DIC triggers.)
*all these conditions release massive amounts of tissue thromboplastin
46
Acute DIC develops within hours, what are the symptoms?
hemorrhage and purpura, plus gangrene from thromboses. 60-80% mortality rate.
47
________ DIC occurs in pt. with pre-existing thrombotic tendency or event, and hemorrhage less frequent problem (because chronic nature allows liver and b.m. some time to try and compensate for "over-consumption")
Chronic
48
what is the treatment for chronic thrombotic DIC?
Give low-dose heparin IV drip to stop intavascular clotting, unless contradicted by certain conditions (head injury, surgery, etc.)
49
What is the treatment for acute hemorrhagic DIC?
give FFP or cryoprecipitate, and plt. concentrates (to replenish Fbg and plts.)
50
What is the new treatment for DIC?
antifibrinolytics (Amicar = aninocaproic acid, or its analong)
51
What are the STAT treatments for DIC?
-treat underlying disorder for both acute and chronic
-treat for shock complications
52
How often are acute DIC pts retested?
every 15 minutes
53
What test rules out DIC with 90% certainty?
negative D-Dimer
54
Positive FDP = some type of __________ is going on (don't know if N. or abnormal), but suggests DIC
fibrinolysis
55
Pos. D-Dimer = "normal" _____________ going on, so points to some type of thrombosis (may be DIC)
fibrinolysis
56
Vit. K is coF that is required for final carboxylation activating factors: _____________ in the liver.
II, VII, IX, X, C, S, Z
57
Vit. K is fat-soluble vit. that is found in green vegetables and is also produced by normal __________.
gut flora
58
antagonistic drug of Vit. K?
Coumadin, et al.
59
who is at risk for Vit. K deficiency?
sterile guts with antibiotic use, newborns (lack of E. coli and Bacteroides), absorption syndromes like obstructive jaundice or Crohn's disease.
60
Vit. K deficiency can be caused by hemorrhagic (not hemolytic) disease of the newborn that can occur in the first few days of life due to what confluence factors?
-sterile gut
-reduced Vit. k stores
-functional immaturity of liver
(In the U.S. it is standard practice to inject baby with H2O-soluble analog of Vit. K shortly after birth)
61
symptoms of Vit. K deficiency?
-mucocutaneous bleeds
-epistaxis and easy bruising*
-greater deficiency = greater bleeding*
62
treatment for Vit. K deficiency?
-treat underlying disease
-administer vitamin K
-give FFP if severe bleeding occurs
63
Why is bleeding normal with Vit. K deficiency?
it is not a plt. problem
(doesn't effect primary homeostasis)
64
Vit. K deficiency:
APTT is __________. Which factors are being affected?
prolonged
II, IX, and X
65
Vit. K deficiency:
PT is __________. Which factors are being affected?
prolonged
II, VII
66
__________ binds to Antithrombin, greatly enhancing its ability to bind and inactivate thrombin.
Heparin
67
-Used in the treatment of thrombosis and following a major surgery to prevent emboli
-A fast and potent form of anticoagulation
-APTT is the most commonly used test to monitor UFH
Heparin
68
LMWH is monitored by the __________ assay.
anti-Xa
-PT and TCT also prolonged
69
Is the thrombin time (TCT or TT) assay affected by heparin?
yes!
70
What can be done if heparin is suspected of interfering in a TCT result?
-treat the sample with Hepzyme or
-prepare a dilution made with protamine sulfate and saline
*the repeated TCT corrects (at least somewhat) if haparin was in the sample
***This is NOT a way of monitoring heparin therapy!
71
An alternative method to test for fibrinogen activity (snake venom instead of thrombin reagent)
Reptilase time
72
Reptilase time is similar to TT (TCT) except reptilase reagent is added to plasma instead of thrombin to activate proteolytic conversion of ________ to _________.
fibrinogen, fibrin
73
Reference range for Reptilase time?
18-22 seconds
74
RT (reptilase time) is insensitive to _________ and is useful for detecting hypofibrinogenemia or dysfibrinogenemia
-prolonged in the presence of FDPs
heparin
75
Dysfibrinogenemia or Afibrinogenemia:
TT = __________
RT = __________
Infinitely prolonged.
Infinitely prolonged
76
Hypofibrinogenemia:
TT = __________
RT = __________
Prolonged,
Prolonged
77
Heparin:
TT = __________
RT = __________
Prolonged,
normal
78
most well-known for the non-specific circulating inhibitors
Lupus Anticoagulants (Antiphospholipid antibodies)
79
Lupus Anticoagulants:
___________ are directed against the phospholipid portion of phospholipoprotien components found in APTT reagent (prevents them from being used as a stable surface to build the clot upon)
autoantibodies
80
Lupus Anticoagulants:
_______ can be affected in severe cases, but PTT is the primary test.
PT
81
LAs prolong clotting times in _______, but trigger thromboses in _____. (possibly via complement fixation against the Ab-phospholipid complex in vivo?)
vitro, vivo
82
Lupus Anticoagulants:
Prlonged dRVVT = __________
normal dRVVT =___________
probable LA
no LA
83
LA workup:
1. mixing study with normal plasma
2. If no correction... do dRVVT (dilute Russell Viper Venom Time) screening clotting time test.
Use low [phospholipid], so if LA present, it will NOT be overwhelmed by autoantibodies, and clotting time will be prolonged due to its effects.
3. Plt neutralization test (confirmatory assay)
84
this test quantitates the LA by determining how much thromboplastin (or reagent-grade plts.) it takes to overwhelm the LA antibody
Platelet neutralization test
-follow with specialty immunoassays for specific inhibitors
85
Acquired disorder of Factor VII are primarily due to the presence of ____________ inhibitors of VII.
autoimmune
86
Most common antibody is to Factor _____.
VIII
-AutoAbs to factors V, VII, XI, and XIII have al been observed
87
symptoms of antibody to Factor VII?
may or may not have bleeding tendency, depending upon severity.
88
treatment for antibody to Factor VIII?
-treat with steroids to depress autoAb.
-give massive factor replacement or appropriate blood component if bleeding occurs.
89
what drug therapy can cause Acquired inhibition of Factor XIII?
tuberculosis drug, isoniazid
90
Acquired inhibition of Factor XIII:
PT, APTT, TCT are all _______.
normal
91
how is Acquired inhibition of Factor XIII confirmed?
with 5M urea solution test and chromogenic factor assay
92
Factor X deficiencies rarely occurs. Usually found in people with an autoimmune disease known as ___________. PT, APTT, RVVTT are all ____________.
amylodosis, prolonged
93
What are the top three most common hereditary coagulation disorders?
1. von Willebrand disease
2. Hemophilia A (factor 8)
3. Hemophilia B (factor 9)
94
Von Willebrand Disease is a _____________ bleeding disorder caused by a quantitative or structural abnormality of vWF.
mucocutaneous
95
vWD dominant or recessive?
can be either depending on mutation sub-type
96
What is the primary function of vWF?
to mediate platelet adhesion
-also serves as the factor VII carrier molecule
97
How common is vWD?
1 in 1,000
98
What is the most common inheerited coagulopathy of all as a group?
vWD
(Group O blood type expresses least amount of vWF.
99
What is the most common inhibitor and deficiency?
Factor 8
(lab purchases factor 8 deficient plasma instead of single factor plasmas)
100
What does 1B95 bind to?
Von Willebrands factor
101
Currently there are ___ subs types of vWD.
A slight decease in factor _____ is secondary to decreased vWF
7, VIII
102
Each vWF monomer has 4 structural domains. What does each domain bind to?
-factor VIII
-Gp1b/V/IX
-Gp2b3a
-collagen
103
Because vWF carries factor _____, it helps concentrate it at an injury site.
VII
104
What cleaves vWF?
Adams 13
105
What are the symptoms of Von Willebrand Disease (vWD)?
-Epitaxis (nose bleeds)
-Easy bruising
-Excessively lengthy post -op. bleeding
-Bleeding after tooth extraction
-Bleeding from mucous membranes
-GI bleeds
106
Assay that detects vWF binding to GP1b/IX, used as a screening for this vWD.
Ristocetin Induced Plt. Agglutination (RIPA test)
107
What results are seen in Ristocetin Induced Plt. Agglutination (RIPA test) with a pt that has vWD?
decreased (or sometime absent) response with ristocetin in classic plt. aggregation
108
After screening for vWD by RIPA test, what further testing should be performed?
-VWF Activity Immunoassay and VWF Collagen Binding Assay and/or Ristocetin CoFactor Assay (RCoF)
109
RCoF assay is just RIPA (Ristocetin Induced Plt. Agglutination) with what two modifications?
1. use optical aggregometry
2. Use standard dilutions of N., fixed, reagent-grade plts. to derive a reference curve of ristocetin-induced agglutination times. Since the vWF activity of these dilutions is known, the pt's sample can be plotted on the curve and their vWF functional activity then extrapolated.
110
___________ is the definitive diagnostic test for vWD. If further detail on vWF multimer distribution defects is needed, then agarose gel elp is done.
RCoF
111
-Two assays used together to gain more information about VWF
-Offers more precision that RCoF Assay
-Involves a monoclonal antibody specific for VWF epitope, and analyzes the collagen adhesion ability
-both reflect VWF activity rather than concentration
VWF Activity Immunoassy and VWF Collagen Binding Assay
112
vWD:
APTT is....
slightly prolonged. (slightly decreased factor VIII goes along with decreased vWF
113
vWD:
PT is .....
Normal. (slt. decreased factor VIII does not affect extrinsic pathway
114
vWD:
Bleeding time (PFA-100) is ...
Prolonged. (vWF needed for plt. adhesion)
115
vWD:
Factor VIII activity assay is...
slt. decreased. (slt. deceased factor VIII goes along with decrased vWF)
116
vWD:
vWF:Ag EIA is...
Decreased. (Activity and mass of vWF can be decreased in this disease)
117
vWD:
RIPA and RCoF is...
Decreased
Note: Ristocetin aggregation absent in BSS, and VARIABLE in vWD (but usually decreased in vWD)
118
Why isn't blood components used for vWD treatment?
blood components don't have much vWF and purification removes whats there.
119
What is the treatment for vWD?
-Pressure and ice packs for localized hemorrhages
-DDAVP (induces vWF release from endogenous stores)
-Estrogen- along with DDAVP
-Commercial factor VII (used with severe vWD)
120
The goal for drug therapy with vWD is to reach ______% activity. How is drug therapy managed?
75
using serial runs of RCoF assay and vWF Ag EIA
121
Inherited bleeding disorder. Deficiency in Factor VIII:C (vWF is normal!)
Hemophilia A or Classic Hemophilia
122
How common is Hemophilia A?
1 in 10,000
123
What is VIII:C?
Factor VIII/vWF complex that circulates in plasma
124
What is the functional role of vWF?
to carry factor VIII around
125
What is the functional role of VIII:C?
cofactor in factor X activation
126
How is Hemophilia A inherited?
X-linked
127
What are the three categories for Hemophilia A?
-severe = <1% Factor 8 activity
-Moderate = 1-5% factor 8 activity
-mild = 5-20% factor 8 activity
128
Why do carriers of Hemophilia A usually have no bleeding problems?
carriers average about 50% of normal Factor 8 activity
-Normal range 50-150%
129
What are the symptoms of Hemophilia A?
-Hemarthroses*** (bleeding into joints)
-easy bruising
-mucous membrane hemorrhages
-sever postoperative bleeding
-unexplained severe spontaneous hemorrhages***(post-circumcision or umbilical stump)
-hematuria
-GI bleeds
130
Hemophilia A coagulation profile:
-Normal bleeding time
-Normal PT and APTT if case is mild
-Prolonged APTT if VIII:C level is <20% normal level
131
Treatment for Hemophilia A?
-Cryoprecipitate (rich in fibrinogen and VIII)
-Concentrated factor VIII:C complex
132
Hemophilia A:
20% of severely affected pts. develop ____________ inhibitors to factor VIII.
alloantibody
133
Hemophilia A Inhibitors:
Most are _____, non-complement-fixing, warm-reacting antibodies (reactive at 37 degrees C)
IgG
134
With Hemophilia A pts:
What is expected when plasma factor VIII activity fails to increase after therapy?
Hemophilia A Inhibitors (incidence is not predictable)
135
Can be used to quantify any factor inhibitor, but most often used for FVIII
Bethesda Titer Assay
136
How is Bethesda Titer Assay done?
Pts PPP is mixed with known amount of factor VIII, serially diluted, and incubated for 2 hours. The residual amount is tested and compared with results from control mixture.
137
Bethesda Titer Assay:
Titer of inhibitor is dilution that inhibits ____% of factor VIII in assay
50
138
What is the treatment for Hemophilia A Inhibitors?
-Massive doses Factor VIII concentrate-
-Porcine Factor VIII (in life-threatening situations)
-Recombinate Factor VIIa (bypasses factor VIII)
-Prothrombin Complex Concentrate (PCC)
-Plasmapheresis and immunosuppresive drugs- done in conjuction with factor concentrates.
139
Prothrombin Complex Concentrate (PCC) contains activated Factors II, VII, IX, X; thus works by?
turning on extrinsic pathway and bypassing Factor VIII
140
What is clinically indistinguishable from severely deficient Factor IX?
VIII
141
There are ______ types of Hemophilia B (or Christmas disease) and they vary tremendously in severity.
3
142
How is Hemophilia B inherited?
X-linked
carries usually do not have symptoms
143
What is the most important symptom of Hemophilia B?
hemarthroses and unexplained spontaneous bleeds
144
Treatment for Hemophilia B?
-Monoclonally purified Factor IX concentrates
-Prothrombin Complex Concentrate (PPP)
145
How does Prothrombin Complex Concentrate (PCC) work?
bypasses need for factor IX
146
What factors does PCC contain?
II,VII, IX, X
147
What are the lab results for Hemophilia B?
APTT: prolonged
PT: Normal
Bleeding time: usually normal
Factor IX activity assay: variable decrease (definition of the disease)
148
Factor deficiencies without clinical bleeding?
-12
-Pre-K (PK) (PTT is corrected with koalin reagent and incubation)
-HMWK (HK)
149
Factor 12 is unique in that it dose NOT cause bleeding problems. What does it cause instead?
Thrombotic events because lack of factor XIIa means major mechanism for triggering fibrinolysis is lost.
150
Why cant a deficiency in Factor XIII be detected by a normal screening method?
Because it is outside the intrinsic and extrinsic pathways tested by the usual PTT and PT screening tests.
151
What are the three major natural anti-coagulant mechanisms that control thrombus formation.
-antithrombin (AT-III, or AT)
-Protein C Pathway
-Fibrinolytic system
152
AT deficiency causes spontaneous....
thrombotic episodes
153
What are the two types of AT deficiency?
type-I (decrease in molecule - quantitative
type-II (decrease in activity-qualitative)
154
How is AT deficiency treated?
heparin, because heparin will potentiate action of whatever small amount of AT is present.
155
Protein C and Protein S are _____________ liver proteins.
K-dependent
156
Protein C and Protein S act as cofactors required for the inactivation of which coag. factors?
VIIIa and Va
157
Without protein C or S, pt. is permanently in a ____________ state.
hypercoagulable
158
How is protein C and protein S deficiency treated?
-protein C administration and OACs (OACs do decrease endogenous protein C, bu that effect is outweighed by the fact that they combat the overall hypercoagulablity tendency)
159
What testing is used for Protein C and Protein S deficiencies?
-clot-based, chromgenic, and EIA assays
160
What is the most common genetic mutation causing increased thrombosis in Caucasians?
Factor V Leiden (FVL)
161
Factor V Leiden (FVL) occurs in up to _____% of pts. with thrombotic histories.
50
162
Factor V Leiden (FVL) causes a condition called...
"Activated Protein C Resistance" (APCR)
163
Factor V Leiden (FVL):
With this unusually resistant Factor Va, pt. is permanently in a ___________ state.
hypercoagulable
164
Testing for Factor V Leiden?
clot-based and rocket IEP* assays, and confirmatory PCR assay
165
For our purposes, Factor V Leiden and APC resistance are synonymous, why?
approx. 90% APC-resistant pts. have the Factor V Leiden mutation.
166
What pts. have significantly increased complications with FVL?
pregnant women. Ex: pre-eclampsia, stillbirth, and recurrent spontaneous abortion
"double-hit"
pregnant women are hypercoagulable to begin with due to increased Fbg
167
a translocation mutation causing elevated levels of prothrombin
2nd most common genetic mutation causing increased thrombosis in Caucasians.
Prothrombin G20210A mutation
-PRC assay now available
168
What does Prothrombin G20210A cause?
slightly increased factor II levels (at around 115-130%) but for some reason this puts pt. permanently in a hypercoagulable state (for venous thromboses)
169
What pts have significantly increased complication rates with Prothrombin G20210A? same as in _____?
pregnant women, FVL
170
Treatment for Hypercoagulablity disorders:
For severe acute episodes?
For long-term maintenance?
Heparin
Warfarin and its derivatives
