Clotting Disorders

1
Clotting Disorders

• James Czarnecki, D.O.

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Classification
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Afibrinogenemia / Dysfibrinogenemia
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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

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Coagulation-promoting hemostasis

• Procoagulant afibrinogenemia / dysfibrinogenemia
• Protein C deficiency
• Protein S deficiency
• Antithrombin III deficiency
• Factor V Leiden deficiency
• Activated protein C resistance
• Disseminated intravascular coagulation

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Coagulation-impeding Conditions

• Anticoagulant afrinogenemia/dysfibrinogenemia
• Factor V deficiency
• Factor VII deficiency
• Factor X X III deficiency
• Hemophilia A
• Hemophilia B
• Hypoprothrombinemias

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Pathophysiology
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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.

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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.

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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.

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Presentation
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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.

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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.

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Presentation (continued)

• Laboratory diagnosis of dysfibrinogenemia is
  difficult
• Screen test results (PT, aPTT) may be WNL

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Presentation (continued)

• Fibrinogen levels are decreased in
• DIC
• Primary and secondary fibrinolysis
• Liver Disease
• Fibrinogen levels are increased in
• Pregnancy
• Oral contraceptive use

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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.

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Protein C, Protein S, Antithrombin III, and
Factor V Leiden Deficiencies
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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.

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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.

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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.

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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.

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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

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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.

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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.

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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

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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

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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

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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.

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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)

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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

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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.

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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.

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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.

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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.

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Disseminated Intravascular Coagulation
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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.

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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.

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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.

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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.

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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).

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DIC - Epidemiology

• Malignancies led the list of underlying disorders
  with 33.8 of subjects having solid tumors, and
  12.7 having hematologic malignancies.

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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.

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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

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DIC - Diagnosis

• Malignancy
• Trauma
• Aortic aneurysm
• Cerebral injury
• Hepatic surgery
• Burn injury
• Hypothermia
• Massive transfusion
• Prolonged surgery

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DIC - Treatment

• Treatment can be divided into these components
• Treatment of the underlying disorder
• Supportive management of bleeding complications
• Treatment aimed at the coagulation process

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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.

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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
  patients 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.

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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.

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DIC - Treatment

• Generally, the earlier treatment is initiated,
  the better the patients prognosis.

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Coagulation-impairing Deficiencies
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Factor V Deficiency
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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

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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.

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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.

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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.

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Factor VII Deficiency
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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.

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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.

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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.

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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.

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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.

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Factor X Deficiency
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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.

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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.

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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.

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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.

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Factor XI Deficiency
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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.

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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.

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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.

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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.

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Factor XII Deficiency
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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, kallikrein-kinin,
  and complement systems.
• Promotes the conversion of factor XI to its
  activated form.

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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.

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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.

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Factor XIII Deficiency
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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.

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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 cross-linkage of
  fibrin as a means of stabilizing a clot.

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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.

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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.

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Factor XIII Deficiency

• Treatment requires lifelong prophylactic therapy
  with at least monthly infusions of factor XIII
  concentrate, even during pregnancy.

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Competency Exam
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Question One

• All of the following are causes of disseminated
  intravascular coagulation. Pick the one cause
  which is the most common
• Hemorrhage
• Toxic shock syndrome
• Endotoxin release
• Sepsis
• Amniotic fluid embolism

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Question One

• All of the following are causes of disseminated
  intravascular coagulation. Pick the one cause
  which is the most common
• Hemorrhage
• Toxic shock syndrome
• Endotoxin release
• Sepsis
• Amniotic fluid embolism

85
Question Two

• True or False
• The prevalence of antiprothrombin III and protein
  C and protein S in the general population is
  greater than 20.

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Question Two

• True or False
• The prevalence of antiprothrombin III and protein
  C and protein S in the general population is
  greater than 20.

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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

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Question Three

• Which of the following deficiencies results in a
  systemic blood-clotting defect called Rosenthal
  syndrome
• Factor V
• Factor VII
• Factor XI
• Factor XII
• Factor XIII

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Question Three

• Which of the following deficiencies results in a
  systemic blood-clotting defect called Rosenthal
  syndrome
• Factor V
• Factor VII
• Factor XI
• Factor XII
• Factor XIII

90
End of Lecture

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