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Clotting Disorders
James Czarnecki, D.O.
Classification
Afibrinogenemia /
Dysfibrinogenemia
Classification
• Disorders of nonplatelet hemostasis can be
divided into 2 groups based on whether they
increase or decrease coagulation:
– Coagulation-promoting conditions
– Coagulation-impeding conditions
Coagulation-promoting
hemostasis
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Procoagulant afibrinogenemia / dysfibrinogenemia
Protein C deficiency
Protein S deficiency
Antithrombin III deficiency
Factor V Leiden deficiency
Activated protein C resistance
Disseminated intravascular coagulation
Coagulation-impeding
Conditions
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Anticoagulant afrinogenemia/dysfibrinogenemia
Factor V deficiency
Factor VII deficiency
Factor X – X III deficiency
Hemophilia A
Hemophilia B
Hypoprothrombinemias
Pathophysiology
Pathophysiology
• Fibrinogen disorders may have both congenital
and acquired etiologies.
• Congenital afibrinogenemia is defined as a
deficiency or absence of fibrinogen (coagulation
factor I) in the blood.
• Dysfibrinogenemias are classified as qualitative
alterations in the conversion of fibrinogen to fibrin
that are caused by structural defects.
Pathophysiology
• Approximately 300 abnormal fibrinogens
have been reported, and about 83 structural
defects have been identified.
• The most common structural defect
involves the fibrinopeptides and their
cleavage sites.
• The second most common involves the
gamma-chain polymerization region.
Pathophysiology
• True prevalence of congenital fibrinogen
disorders is unknown.
• No variation by race, age, or sex is known.
• Mortality is related to the severity of
bleeding and/or to thrombotic complications
at presentation.
Presentation
Presentation
• While most patients with dysfibrinogenemia are
asymptomatic, some can present with:
– Bleeding diathesis
– Thrombophilia
– Both bleeding and thromboembolism
• Dysfibrinogenemias present particular problems
for the obstetrician because women affected by
these disorders are at risk of first-trimester
bleeding, spontaneous abortion, and/or postpartum
thrombosis.
Presentation (continued)
• Diagnosis of abrinogenemia /
dysfibrinogenemia should be considered in
a patient who has bleeding or thrombosis
unexplained by other common disorders.
• A high level of clinical suspicion should be
maintained in patients with other inherited
disorders of hemostasis, such as protein C
or S deficiency.
Presentation (continued)
• Laboratory diagnosis of dysfibrinogenemia
is difficult
• Screen test results (PT, aPTT) may be WNL
Presentation (continued)
• Fibrinogen levels are decreased in:
– DIC
– Primary and secondary fibrinolysis
– Liver Disease
• Fibrinogen levels are increased in:
– Pregnancy
– Oral contraceptive use
Treatment
• Depends on clinical setting
• Plasma fibrinogen can be replacd by the
infusion of fresh frozen plasma and
cryoprecipatate.
• Prophylactic blood product or fibrinogen
therapy has no role.
Protein C, Protein S,
Antithrombin III, and Factor V
Leiden Deficiencies
Background - General
• All are essential components of the
coagulation process.
• All are synthesized by the liver and have a
half-life in the range of 4-6 hours.
Antithrombin III
• Activated antithrombin III is a major
inhibitor of thrombin and factor Xa, with
smaller effects on factors IX, XI, and XII.
• Binds to the endothelial cell surface in the
presence of injury.
• Forms a subendothelial cell matrix that
neutralizes thrombin by complexing with it.
• Serves as a cofactor for exogenous heparin.
Protein C & S
• Are Vitamin K-dependent factors that
participate in the thrombomodulin-protein C
system.
• Thrombomodulin and thrombin form a
complex on the endothelial cell plasma
membrane in response to injury, with
activated protein S serving as a cofactor.
Protein C & S
• This complex in turn attracts and binds
protein C in the presence of calcium ion to
produce activated protein C (aPC).
• aPC then inactivates factors Va and VIIIa,
thus halting the coagulation cascade.
• Also neutralizes plasminogen-activator
inhibitor-I, thereby facilitating fibrinolysis.
Antithrombin III / Protein C & S
• Deficiencies may lead to thrombophilia.
• Clinical thrombophilia is defined as an early
thomboembolic episode (occurring before
age 50) spontaneous thrombosis, recurrent
thrombosis, unusual site of thrombosis,
family history of thrombotic episodes, or
coumarin-induced skin necrosis
complications
Antithrombin III / Protein C & S
• Such patients may have an isolated or
combined inherited deficiency in the
proteins involved in coagulation.
• Diagnosis is confirmed by the identification
of an isolated or combined inherited
coagulant deficiency.
Antithrombin III / Protein C & S
• Affected patients with inherited
thrombophilia are at risk of developing
thromboembolic disease ranging from mild,
superficial venous thrombosis to lethal
pulmonary embolism.
Antithrombin III / Protein C & S
• The most frequent venous problem was
DVT with or without pulmonary embolism:
– 90% in antithrombin III deficiency
– 88% in protein C deficiency
– 100% in protein S deficiency
Antithrombin III / Protein C &S
The frequency of these defects in the
population place:
• Antithrombin III deficiency at 0.5-9.4%
• Protein C deficiency at 1.4-8.6%
• Protein S deficiency at 1.4-7.5%
Factor V Leiden
• Factor V has both procoagulant and
anticoagulant properties
• Activated factor V stimulates the formation
of thrombin, whereas anticoagulant factor V
acts as a cofactor for aPC in the degradation
of factor VIII and factor VIIIa, thereby
reducing thrombin formation
Factor V Leiden
• High procoagulant factor V levels may
enhance prothrombinase activity and
increase the risk of thrombosis.
• Low anticoagulant factor V levels can
reduce aPC cofactor activity in the
inactivation of factor VIII, which in turn
might also promote thrombosis.
Factor V Leiden
• Factor V deficiencies can be classified as:
– Homozygous and heterozygous “true” factor V
deficiency
– Combined factor V and factor VIII deficiencies
• Type I (association type)
• Type II (common defect)
Factor V Leiden
Classification of the thrombotic factor V
defects included:
• Homozygous and heterozygous factor V
Leiden
• Combined heterozygous factor V Leiden
and hertozygous true factor V deficiency
Factor V Leiden
• Factor V Leiden mutation (R506Q) is the
most common cause of aPCR, which itself
is defined as a hemostatic disorder
characterized by a poor anticoagulant
response to aPC.
• In this state, the activated form of factor V
(factor Va) is more slowly degraded by aPC.
Factor V Leiden
• Most frequent clinical manifestations of
aPCR or factor V Leiden deficiency are
SVT or DVT and/or pulmonary embolism
and thrombosis at an unusual site.
• Risk of thrombosis associated with
pregnancy was high in the postpartum
period, especially in homozygous women.
Factor V Leiden
• Mild prolongation of PT and aPTT may provide
the first evidence of aPCR.
• Possibility should be immediately confirmed by
specific factor V activity and antigen assays.
• Laboratory screening for aPCR is performed by
functional tests measuring the effect of aPC on
aPTT in plasma containing a heparin neutralizer.
Antithrombin III / Protein C & S
/ Factor V Leiden
• Treatment of these deficiencies requires a
high index of clinical suspicion and
laboratory investigation to confirm the
diagnosis.
• Lifelong anticoagulation with oral warfarin
is recommended in patients with proven
thrombophilia.
Disseminated Intravascular
Coagulation
DIC - Definition
• Defined as a syndrome characterized by an
alteration in the elements involved in blood
coagulation due to their use / destruction in
widespread blood clotting within the
vessels.
DIC - Background
• May be caused by a wide variety of
disorders:
– Hemorrhage, trauma, sepsis, toxic shock
syndrome.
– Endotoxin release, abruptio placentae, and
amniotic fluid embolism.
• Sepsis is the most common cause of DIC.
DIC - Background
• Etiology and progression of DIC are
multifactorial and are characterized by
defects in the protein C system and in the
antithrombin and tissue-factor inhibitor
pathways.
• Release of tissue factor from endothelial
cells or other circulating cells is the most
common initiating event.
DIC - Background
• If natural inhibitors are abundant, and if the
causative agent or disease is corrected, DIC may
be halted in a compensated state.
• Persistence of the triggering agent leads to a
consumption coagulopathy, with loss of fibrinogen
and platelets and the potential for diffuse bleeding.
• Failure of the fibrinolytic system elicits deposition
of microvascular fibrin and multisystem organ
failure.
DIC - Epidemiology
• In a study of by Okajima et al examined the
incidence, clinical presentation, and
underlying disorders associated with DIC in
a series of 1882 subjects, of which 204 were
diagnosed as having DIC (overall incidence
of 10.8%).
DIC - Epidemiology
• Malignancies led the list of underlying
disorders with 33.8% of subjects having
solid tumors, and 12.7% having
hematologic malignancies.
DIC - Epidemology
• Rest of the patients had aortic aneurysm
(10.8%), infections (6.4%), unspecified
postoperative complications (4.4%), liver
disease (2.9%), obstetric disorders (2.5%),
and various miscellaneous diseases (26.5%)
completed this diverse list.
DIC - Diagnosis
• The diagnosis of DIC is based on both
clinical suspicion of DIC and a combination
of laboratory test findings.
• Patients with the following known
underlying causes should be carefully
observed for indications of the development
of DIC:
DIC - Diagnosis
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Malignancy
Trauma
Aortic aneurysm
Cerebral injury
Hepatic surgery
Burn injury
Hypothermia
Massive transfusion
Prolonged surgery
DIC - Treatment
Treatment can be divided into these
components:
1. Treatment of the underlying disorder
2. Supportive management of bleeding
complications
3. Treatment aimed at the coagulation
process
DIC - Treatment
• Triggering underlying disease must be treated
aggressively.
• This may require surgical drainage of an abscess
or necrotic tissue, antibiotic therapy, control of
temperature, volume replacement, etc.
• Early recognition and treatment of DIC is the key
to success, so a high index of clinical suspicion
must be maintained.
DIC - Treatment
• Continued DIC is characterized by a consumption
coagulopathy of platelets.
• Ongoing bleeding or rapid hemorrhage may lead
to anemia.
• Treatment should be aimed at correction of the
patient’s clinical condition, not at a measured
deficit.
• Red blood cell transfusions may increase the fibrin
deposition in DIC, so they should be used with
caution.
DIC - Treatment
• Heparin has been used as the mainstay of
treatment of DIC for more than 30 years
with little evidence of benefit.
• A trial of low molecular weight dalteparin
compared to unfractionated heparin showed
less bleeding and better organ system
scores, but it demonstrated no survival
benefit.
DIC - Treatment
• Generally, the earlier treatment is initiated,
the better the patient’s prognosis.
Coagulation-impairing Deficiencies
Factor V Deficiency
Factor V Deficiency
• Both procoagulant and anticoagulant
properties
• Activated factor V stimulates the formation
of thrombin
• Anticoagulant factor V acts as a cofactor for
aPC in the degradation of factor VIII/VIIIa,
thereby reducing thrombin formation
Factor V Deficiency
• Severity of the condition varies from
bruising to lethal hemorrhage.
• Acquired inhibitors of factor V are rare
causes of clinical bleeding, with severity
ranging from mild to life threatening.
Factor V Deficiency
• Optimal treatment of patients with factor V
inhibitors is uncertain.
• Combinations of therapies (plasma
exchange and chemotherapy) may be
needed in patients with serious hemorrhage
caused by factor V deficiency or inhibitors.
Factor V Deficiency
• Combined deficiency of coagulation factor
V and factor VIII is an autosomal recessive
disorder observed in a number of
populations around the world.
• The disease appears to be most common in
the Mediterranean basin.
Factor VII Deficiency
Factor VII Deficiency
• It is a vitamin K-dependent glycoprotein
essential to the extrinsic pathway of
coagulation.
• Deficiencies may be inherited as an
autosomal recessive characteristic or
acquired in association with vitamin K
deficiency, sepsis, autoantibodies, and
inhibitors.
Factor VII Deficiency
• The prevalence of congenital deficiency is
low, with only 238 individuals with factor
VII gene mutations described in the world
literature.
• Predisposition to bleeding is variable, and to
some extent depends on the amount of
plasma factor VII activity.
Factor VII Deficiency
• In congenital factor VII deficiency, the
clinical picture is related to the levels of
factor VII coagulant activity.
• Individuals homozygous for the mutation
who have complete absence of factor VII
activity in plasma usually die shortly after
birth because of severe hemorrhage.
Factor VII Deficiency
• Clinical symptoms and factor VII activity
levels in plasma are rather poorly related.
• Patients may have prolonged PTs, but the
final diagnosis is established by quantitative
factor VII assays.
Factor VII Deficiency
• Treatment consists of factor replacement
with fresh frozen plasma, prothrombin
complex concentrates, or factor VII
concentrates.
• Recombinant activated factor VII is a very
useful alternative.
• Because of the short half-life of factor VIIa,
repeated doses must be administered.
Factor X Deficiency
Factor X Deficiency
• Usually inherited as an autosomal recessive
trait, though it can be acquired.
• Characterized by defective activity in both
the intrinsic and extrinsic pathways,
impaired thromboplastin time, and impaired
prothrombin consumption.
Factor X Deficiency
• Factor X circulates as a serine protease that is
activated at the point of convergence of the
intrinsic and extrinsic coagulation pathways.
• Activated factor Xa is involved in macromolecular
complex formation with its cofactor factor Va, a
phospholipid surface, and calcium to convert
prothrombin into thrombin.
Factor X Deficiency
• Factor X deficiency may be acquired in patients
with light chain-related amyloidosis.
• Treatment of acquired factor X deficiency is
difficult.
• In 2001, therapy resorted to daily therapeutic
plasma exchange with concomitant administration
of intravenous immunoglobulin and steroids.
Factor X Deficiency
• The therapy produced a rapid increase in factor X
levels, which controlled bleeding, and was
followed by gradual recovery of normal factor X
levels and correction of coagulation times.
• Splenectomy eliminates the acquired factor X
deficiency in amyloidosis, but control of operative
bleeding may require recombinant factor VII.
Factor XI Deficiency
Factor XI Deficiency
• The congenital deficiency of blood
coagulation factor XI results in a systemic
blood-clotting defect called hemophilia C or
Rosenthal syndrome, which may resemble
classic hemophilia.
• It is a key component of the intrinsic
pathway of blood coagulation in vitro, but
its exact role in vivo is uncertain.
Factor XI Deficiency
• Factor XI is activated by thrombin and may
participate in clot formation once
coagulation has been initiated by other
mechanisms.
• Risk of bleeding depends on the severity of
the deficiency in certain situations and on
the location of the bleeding site in others.
Factor XI Deficiency
• Approximately 40-50% of all persons
lacking factor XI are of Ashkenazi Jewish
extraction.
• May be considered in patients evaluated for
hemorrhage or unexplained, prolonged
aPTT or through family or other genetic
studies.
Factor XI Deficiency
• Individuals with factor XI deficiency need
to be careful in planning for elective surgery
and dental extractions.
• Successful treatments have included fresh
frozen, fibrin glue, antifibrinolytic drugs,
desmopressin, and factor XI concentrates.
Factor XII Deficiency
Factor XII Deficiency
• Defined as an absence or reduced level of
blood coagulation factor XII (Hageman
factor).
• Initiates the intrinsic coagulation cascade
and is linked to the fibrinolytic, kallikreinkinin, and complement systems.
• Promotes the conversion of factor XI to its
activated form.
Factor XII Deficiency
• Typically occurs in the absence of a patient or
family history of hemorrhagic disorders and is
marked by prolonged clotting time.
• May be considered in patients with prolonged
aPTT, normal PT, normal bleeding time, and no
clinical history of bleeding.
• Confirmed by normalization of aPTT with plasma
component therapy and by factor assay.
Factor XII Deficiency
• Has clinical significance when attempts are made
to heparinize patients who have this condition.
• Routine coagulation tests used return abnormal
findings in patients with factor XII deficiency and
are useless for monitoring anticoagulation in these
patients.
• Alternative monitoring systems, such as
chromogenic heparin assay, citrated thrombin
time, and recalcified thrombin time, must instead
by used.
Factor XIII Deficiency
Factor XIII Deficiency
• Is a decrease or absence of factor XIII that
prevents blood-clot formation and results in
a clinical hemorrhagic diathesis.
• Factor XIII is an enzyme found in plasma,
platelets, and monocytes.
Factor XIII Deficiency
• In plasma, factor XIII has 2 subunits: the a
subunit, which is the active enzyme and the
b subunit, which is a carrier protein.
• Activated factor XIII stimulates crosslinkage of fibrin as a means of stabilizing a
clot.
Factor XIII Deficiency
• Congenital deficiency is a severe autosomal
recessive bleeding disorder associated with
a characteristic pattern of neonatal
hemorrhage and lifelong bleeding diathesis.
• Untreated patients have a high mortality
rate.
• Intracranial hemorrhage is a frequent
complication.
Factor XIII Deficiency
• The disorder affects both sexes, and
bleeding may occur during pregnancy.
• Acquired factor XIII deficiency has been
described in: Henoch-Scholein purpura,
various forms of colitis, erosive gastritis,
and some forms of leukemia.
• Inhibitors to factor XIII are rare.
Factor XIII Deficiency
• Treatment requires lifelong prophylactic
therapy with at least monthly infusions of
factor XIII concentrate, even during
pregnancy.
Competency Exam
Question One
All of the following are causes of disseminated
intravascular coagulation. Pick the one cause
which is the most common:
A) Hemorrhage
B) Toxic shock syndrome
C) Endotoxin release
D) Sepsis
E) Amniotic fluid embolism
Question One
All of the following are causes of disseminated
intravascular coagulation. Pick the one cause
which is the most common:
A) Hemorrhage
B) Toxic shock syndrome
C) Endotoxin release
D) Sepsis
E) Amniotic fluid embolism
Question Two
True or False:
The prevalence of antiprothrombin III and
protein C and protein S in the general
population is greater than 20%.
Question Two
True or False:
The prevalence of antiprothrombin III and
protein C and protein S in the general
population is greater than 20%.
Antithrombin III / Protein C &S
The frequency of these defects in the
population place:
• Antithrombin III deficiency at 0.5-9.4%
• Protein C deficiency at 1.4-8.6%
• Protein S deficiency at 1.4-7.5%
Question Three
Which of the following deficiencies results in
a systemic blood-clotting defect called
Rosenthal syndrome:
A) Factor V
B) Factor VII
C) Factor XI
D) Factor XII
E) Factor XIII
Question Three
Which of the following deficiencies results in
a systemic blood-clotting defect called
Rosenthal syndrome:
A) Factor V
B) Factor VII
C) Factor XI
D) Factor XII
E) Factor XIII
End of Lecture
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