Test 6: Coagulation Disorders Flashcards
Severe bleeding that require physical intervention
Hemorrhage
-Systemic-thrombocytopenia or platelet disorders
-anatomic-coagulopathies
recurrent, chronic bruising in multiple locations
Purpura
nosebleeds that are reoccurring that last more than ten minutes.
epistaxis
Is acquired or congenital coagulapathies more common?
acquired (can be acute or chronic)
Examples of acquired coagulopathies
-ACOTS
-Liver disease
-Disorders of Fibrinogen
-DIC
-Vit K deficiency
-Heparin
-Lupus Anticoagulants
-Acquired deficiency of Factor VIII
Most fatal cause of hemorrhage
Acute Coagulopathy of Trauma-Shock (ACOTS)
triggered by a combination of acute inflammation, platelet activation, tissue factor release, hyopthermia, acidosis, and hypoperfusion- all elements of systemic shock.
Acute Coagulopathy of Trauma-Shock (ACOTS)
What is the treatment for Acute Coagulopathy of Trauma-Shock (ACOTS)?
-massive RBC transfusion protocol
-FFP- 1:4, or 1:1
-Platelet concentrate
-Activated prothrombin complex concentrate (PCC)
-Cryoprecipitate or fibrinogen concentrate
ACOTS treatment of FFP is given until all coag. factors are at a min of _____%
30
What are the risks of FFP transfusion for ACOTS treatment?
TACO (transfusion-associated circulatory overload) and TRALI (transfusion-related acute lung injury)
Why can liver disease be associated with coagulation disorders?
majority of coagulation factors are synthesized in the liver, and for clearing circulating plasminogen activators and activated clotting factors.
In liver disease, which factors are the first to decrease?
Vit. K dependant factors (II, VII, IX, X), followed by Factor V*
(Factor VII is the first to show decreased activity)
Platelets can be effected by liver disease. _______ of pt show thrombocytopenia due to sequestration and shortened survival.
1/3
_____________ (acute phase reactant) elevates in early liver disease.
Fibrinogen
In moderate or sever liver disease, fibrinogen is coated with ________, interfering with its ability to perform -dysfibrinogenemia.
sialic acid
Dysfinrinogenemia ther is _________ PT and ___________ Reptilase Time Test.
prolonged, extremely prolonged
If Vit. K is decreased and factor V is decreased it means that…
the problem is not a Vit. K deficiency, rather a problem with the liver
Reptilase skips factor ____ and goes straight to ____.
VII, X?
What is seen in a blood smear with a pt that has liver disease?
Macrocytes, target cells, and acanthocytes
BUT normoblastic in bone marrow
Liver disease will have __________ plt
decreased
liver disease will cause _________ PT, PTT, and TCT tests.
prolonged
Fibrinogen will be __________ with liver disease.
decreased
FDP will be ___________ with liver disease.
Increased
D-Dimer will be ___________ with liver disease.
normal
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
Hereditary disorders of fibrinogen can be due to…
quantitative or qualitative abnormalities of either fibrinogen or fibrin stabilizing factor
Acquired disorders of fibrinogen occur ________ to other pathologic events
secondary
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)
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.
Reference range for Indirect method of Fibrinogen?
15-20 seconds
Reference range for direct method of Fibrinogen?
200-400 mg/dL
_____________ is a quantiative deficeicny of fibrinogen due to a lack of synthesisi by the liver resulting in severe hemorrhages.
Afibrinogenemia
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
_____________ is a qualitative abnormality in the structure and function of the fibrinogen molecule.
Dysfibrinogenemia
With dysfibrinogenemia, finrinogen levels are __________, and TCT is ___________.
Post-traumatic and post-operative bleeding is common.
decreased, prolonged
What are the three hereditary disorders of fibrinogen?
-Afibrinogenemia
-Dysfibrinogenemia
-Factor XIII deficiency
What is used for diagnosis of Factor XIII deficiency?
5M urea solution test (Chromogenic assay???)
__________ deficiency can be clinically severe with moderate to sever bleeding. Delayed bleeding and wound healing is often observed after trauma
Factor XIII
What test results come back normal with Factor XIII deficiency?
APTT, PT, and TCT
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)
_______ is life-threatening result of concurrent in vivo activation of both coag and fibrinolytic systems.
DIC
DIC:
Ongoing thrombosis uses up coag. factors and plts, yielding name “______________”, and then clots cause further tissue necrosis (including strokes).
Consumptive Coagulopathy
DIC is triggered by _____________ which activates platelets, catalyzes fibrin formation, and consumes control proteins.
circulating thrombin
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
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
Acute DIC develops within hours, what are the symptoms?
hemorrhage and purpura, plus gangrene from thromboses. 60-80% mortality rate.
________ 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
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.)
What is the treatment for acute hemorrhagic DIC?
give FFP or cryoprecipitate, and plt. concentrates (to replenish Fbg and plts.)
What is the new treatment for DIC?
antifibrinolytics (Amicar = aninocaproic acid, or its analong)
What are the STAT treatments for DIC?
-treat underlying disorder for both acute and chronic
-treat for shock complications
How often are acute DIC pts retested?
every 15 minutes
What test rules out DIC with 90% certainty?
negative D-Dimer
Positive FDP = some type of __________ is going on (don’t know if N. or abnormal), but suggests DIC
fibrinolysis
Pos. D-Dimer = “normal” _____________ going on, so points to some type of thrombosis (may be DIC)
fibrinolysis
Vit. K is coF that is required for final carboxylation activating factors: _____________ in the liver.
II, VII, IX, X, C, S, Z
Vit. K is fat-soluble vit. that is found in green vegetables and is also produced by normal __________.
gut flora
antagonistic drug of Vit. K?
Coumadin, et al.
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.
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)
symptoms of Vit. K deficiency?
-mucocutaneous bleeds
-epistaxis and easy bruising*
-greater deficiency = greater bleeding*
treatment for Vit. K deficiency?
-treat underlying disease
-administer vitamin K
-give FFP if severe bleeding occurs
Why is bleeding normal with Vit. K deficiency?
it is not a plt. problem
(doesn’t effect primary homeostasis)
Vit. K deficiency:
APTT is __________. Which factors are being affected?
prolonged
II, IX, and X
Vit. K deficiency:
PT is __________. Which factors are being affected?
prolonged
II, VII
__________ binds to Antithrombin, greatly enhancing its ability to bind and inactivate thrombin.
Heparin
-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
LMWH is monitored by the __________ assay.
anti-Xa
-PT and TCT also prolonged
Is the thrombin time (TCT or TT) assay affected by heparin?
yes!
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!
An alternative method to test for fibrinogen activity (snake venom instead of thrombin reagent)
Reptilase time
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
Reference range for Reptilase time?
18-22 seconds
RT (reptilase time) is insensitive to _________ and is useful for detecting hypofibrinogenemia or dysfibrinogenemia
-prolonged in the presence of FDPs
heparin
Dysfibrinogenemia or Afibrinogenemia:
TT = __________
RT = __________
Infinitely prolonged.
Infinitely prolonged
Hypofibrinogenemia:
TT = __________
RT = __________
Prolonged,
Prolonged
Heparin:
TT = __________
RT = __________
Prolonged,
normal
most well-known for the non-specific circulating inhibitors
Lupus Anticoagulants (Antiphospholipid antibodies)
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
Lupus Anticoagulants:
_______ can be affected in severe cases, but PTT is the primary test.
PT
LAs prolong clotting times in _______, but trigger thromboses in _____. (possibly via complement fixation against the Ab-phospholipid complex in vivo?)
vitro, vivo
Lupus Anticoagulants:
Prlonged dRVVT = __________
normal dRVVT =___________
probable LA
no LA
LA workup:
- mixing study with normal plasma
- 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. - Plt neutralization test (confirmatory assay)
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
Acquired disorder of Factor VII are primarily due to the presence of ____________ inhibitors of VII.
autoimmune
Most common antibody is to Factor _____.
VIII
-AutoAbs to factors V, VII, XI, and XIII have al been observed
symptoms of antibody to Factor VII?
may or may not have bleeding tendency, depending upon severity.
treatment for antibody to Factor VIII?
-treat with steroids to depress autoAb.
-give massive factor replacement or appropriate blood component if bleeding occurs.
what drug therapy can cause Acquired inhibition of Factor XIII?
tuberculosis drug, isoniazid
Acquired inhibition of Factor XIII:
PT, APTT, TCT are all _______.
normal
how is Acquired inhibition of Factor XIII confirmed?
with 5M urea solution test and chromogenic factor assay
Factor X deficiencies rarely occurs. Usually found in people with an autoimmune disease known as ___________. PT, APTT, RVVTT are all ____________.
amylodosis, prolonged
What are the top three most common hereditary coagulation disorders?
- von Willebrand disease
- Hemophilia A (factor 8)
- Hemophilia B (factor 9)
Von Willebrand Disease is a _____________ bleeding disorder caused by a quantitative or structural abnormality of vWF.
mucocutaneous
vWD dominant or recessive?
can be either depending on mutation sub-type
What is the primary function of vWF?
to mediate platelet adhesion
-also serves as the factor VII carrier molecule
How common is vWD?
1 in 1,000
What is the most common inheerited coagulopathy of all as a group?
vWD
(Group O blood type expresses least amount of vWF.
What is the most common inhibitor and deficiency?
Factor 8
(lab purchases factor 8 deficient plasma instead of single factor plasmas)
What does 1B95 bind to?
Von Willebrands factor
Currently there are ___ subs types of vWD.
A slight decease in factor _____ is secondary to decreased vWF
7, VIII
Each vWF monomer has 4 structural domains. What does each domain bind to?
-factor VIII
-Gp1b/V/IX
-Gp2b3a
-collagen
Because vWF carries factor _____, it helps concentrate it at an injury site.
VII
What cleaves vWF?
Adams 13
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
Assay that detects vWF binding to GP1b/IX, used as a screening for this vWD.
Ristocetin Induced Plt. Agglutination (RIPA test)
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
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)
RCoF assay is just RIPA (Ristocetin Induced Plt. Agglutination) with what two modifications?
- use optical aggregometry
- 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.
___________ is the definitive diagnostic test for vWD. If further detail on vWF multimer distribution defects is needed, then agarose gel elp is done.
RCoF
-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
vWD:
APTT is….
slightly prolonged. (slightly decreased factor VIII goes along with decreased vWF
vWD:
PT is …..
Normal. (slt. decreased factor VIII does not affect extrinsic pathway
vWD:
Bleeding time (PFA-100) is …
Prolonged. (vWF needed for plt. adhesion)
vWD:
Factor VIII activity assay is…
slt. decreased. (slt. deceased factor VIII goes along with decrased vWF)
vWD:
vWF:Ag EIA is…
Decreased. (Activity and mass of vWF can be decreased in this disease)
vWD:
RIPA and RCoF is…
Decreased
Note: Ristocetin aggregation absent in BSS, and VARIABLE in vWD (but usually decreased in vWD)
Why isn’t blood components used for vWD treatment?
blood components don’t have much vWF and purification removes whats there.
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)
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
Inherited bleeding disorder. Deficiency in Factor VIII:C (vWF is normal!)
Hemophilia A or Classic Hemophilia
How common is Hemophilia A?
1 in 10,000
What is VIII:C?
Factor VIII/vWF complex that circulates in plasma
What is the functional role of vWF?
to carry factor VIII around
What is the functional role of VIII:C?
cofactor in factor X activation
How is Hemophilia A inherited?
X-linked
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
Why do carriers of Hemophilia A usually have no bleeding problems?
carriers average about 50% of normal Factor 8 activity
-Normal range 50-150%
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
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
Treatment for Hemophilia A?
-Cryoprecipitate (rich in fibrinogen and VIII)
-Concentrated factor VIII:C complex
Hemophilia A:
20% of severely affected pts. develop ____________ inhibitors to factor VIII.
alloantibody
Hemophilia A Inhibitors:
Most are _____, non-complement-fixing, warm-reacting antibodies (reactive at 37 degrees C)
IgG
With Hemophilia A pts:
What is expected when plasma factor VIII activity fails to increase after therapy?
Hemophilia A Inhibitors (incidence is not predictable)
Can be used to quantify any factor inhibitor, but most often used for FVIII
Bethesda Titer Assay
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.
Bethesda Titer Assay:
Titer of inhibitor is dilution that inhibits ____% of factor VIII in assay
50
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.
Prothrombin Complex Concentrate (PCC) contains activated Factors II, VII, IX, X; thus works by?
turning on extrinsic pathway and bypassing Factor VIII
What is clinically indistinguishable from severely deficient Factor IX?
VIII
There are ______ types of Hemophilia B (or Christmas disease) and they vary tremendously in severity.
3
How is Hemophilia B inherited?
X-linked
carries usually do not have symptoms
What is the most important symptom of Hemophilia B?
hemarthroses and unexplained spontaneous bleeds
Treatment for Hemophilia B?
-Monoclonally purified Factor IX concentrates
-Prothrombin Complex Concentrate (PPP)
How does Prothrombin Complex Concentrate (PCC) work?
bypasses need for factor IX
What factors does PCC contain?
II,VII, IX, X
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)
Factor deficiencies without clinical bleeding?
-12
-Pre-K (PK) (PTT is corrected with koalin reagent and incubation)
-HMWK (HK)
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.
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.
What are the three major natural anti-coagulant mechanisms that control thrombus formation.
-antithrombin (AT-III, or AT)
-Protein C Pathway
-Fibrinolytic system
AT deficiency causes spontaneous….
thrombotic episodes
What are the two types of AT deficiency?
type-I (decrease in molecule - quantitative
type-II (decrease in activity-qualitative)
How is AT deficiency treated?
heparin, because heparin will potentiate action of whatever small amount of AT is present.
Protein C and Protein S are _____________ liver proteins.
K-dependent
Protein C and Protein S act as cofactors required for the inactivation of which coag. factors?
VIIIa and Va
Without protein C or S, pt. is permanently in a ____________ state.
hypercoagulable
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)
What testing is used for Protein C and Protein S deficiencies?
-clot-based, chromgenic, and EIA assays
What is the most common genetic mutation causing increased thrombosis in Caucasians?
Factor V Leiden (FVL)
Factor V Leiden (FVL) occurs in up to _____% of pts. with thrombotic histories.
50
Factor V Leiden (FVL) causes a condition called…
“Activated Protein C Resistance” (APCR)
Factor V Leiden (FVL):
With this unusually resistant Factor Va, pt. is permanently in a ___________ state.
hypercoagulable
Testing for Factor V Leiden?
clot-based and rocket IEP* assays, and confirmatory PCR assay
For our purposes, Factor V Leiden and APC resistance are synonymous, why?
approx. 90% APC-resistant pts. have the Factor V Leiden mutation.
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
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
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)
What pts have significantly increased complication rates with Prothrombin G20210A? same as in _____?
pregnant women, FVL
Treatment for Hypercoagulablity disorders:
For severe acute episodes?
For long-term maintenance?
Heparin
Warfarin and its derivatives
