Coagulation Disorders: Secondary Hemostasis

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MLAB 1227 CoagulationKeri Brophy-Martinez

• Coagulation Disorders Secondary Hemostasis

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Disorders of the Proteins of Fibrin Formation

• Inheritance of a defective gene
• Failure of synthesis of a hemostatic protein
• Malfunction or impaired molecule
• Acquisition of a deficiency secondary to another
  condition
• Fibrin formation ineffective and slowed so
  patient presents with abnormal bleeding

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Terms

• Quantitative absence of a coagulation protein
• Qualitative Present in plasma but functionally
  defective

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Lab Diagnosis General

• PT prolonged
• aPTT prolonged
• Platelets normal

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Patient Presentation

• Coagulation Factor Disorders

• Platelet Disorders

• Bleed from ruptured arterioles
• Deep muscular joint bleeding
• Delayed bleeding
• Ecchymoses
• Hematuria
• No petechiae

• Bleed from capillaries
• Superficial bleeding
• Acute bleeding
• Ecchymoses
• Hematuria
• Petechiae

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Factor VIII Deficiency

• Hemophilia A classical hemophilia
• Sex-linked recessive (carried by female,
  manifested in the male) causing a marked decrease
  in VIIIC (VIIIvWf is normal)
• Deficiency of factor VIII portion of VIII/vWf
  complex
• Patient has normal circulating vWf
• Accounts for 80 of all hemophiliacs
• Less than 5 Factor VIII activity
• Results in symptoms of
• Bleeding occurs with NO trauma or trivial injury
• Spontaneous bleeding into joints, causes extreme
  pain and destroys cartilage of knees, elbows,
  ankles
• Deep tissue hemorrhage internally
• Hematuria
• CNS bleeding
• PTT is greatly prolonged ( normal platelet
  function tests)

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Factor VIII Deficiency

• Von Willebrand's Disease lack of or defective
  VIIIvWF
• Autosomal dominant seen in both males and
  females
• Most common inherited blood disorder
• Mild to moderately low Factor VIIIvWF (5-15).
  Factor VIII function is affected more than the
  quantity.
• Platelet abnormalities adhesiveness and
  aggregation, bleeding times

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Von Willebrand's Disease

• Clinical Features

• Lab Diagnosis

• Mild bleeding in mucosal cutaneous tissues
• Easy bruising
• Hallmark is variability of symptoms

• PTT prolonged
• PT normal
• Platelet count normal
• BT abnormal

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Factor IX Deficiency Hemophilia B, Christmas
Disease

• lt20 of all hemophiliacs
• Sex-linked recessive
• No Factor IX function
• Clinically indistinguishable from hemophilia A
  must do special coag tests to distinguish
• Can be acquired in coumadin therapy and liver
  disease

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Factor XI Deficiency Rosenthal's Disease or
Hemophilia C

• lt5 of all hemophiliacs
• Autosomal recessive
• Highest incidence in Jewish persons of Russian
  decent
• Mucosal bleeding
• Requires therapy only following childbirth or
  surgery

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Congenital Disorders of the Other Factors

• The following factors are rarely deficient or
  defective to the extent that coagulation is
  slowed I, II, V, VII, X, XII, XIII
• Very rarely seen
• Severity of bleeding dependent upon concentration
  of factor present
• PK and HMWK disorders do exist but patients do
  not have bleeding tendencies.
• Defective activation of the fibrinolytic system
  are seentherefore an increased chance of
  thrombosis
• PTT results are often markedly prolonged in
  these asymptomatic patients.

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Acquired Coagulation Disorders

• Two or more factors generally affected
• Bleeding from multiple sites
• Usually result from underlying disease
  acquired
• Produced by a variety of conditions
• Liver Disease
• Impaired or abnormal synthesis of I, II, V, VII,
  IX and X, XI, XII, XIII, PK, HMWK (also AT III,
  the antiplasmins, plasminogen)
• Enhanced destruction (primary fibrinolysis) of
  these factors
• Vitamin K Deficiency II, VII, IX and X (also
  Protein C and S)
• Absence of vitamin K renders calcium binding
  sites nonfunctional
• Sources are diet and intestinal bacterial flora
• At birth, deficiency exists due to decreased
  production of factors since the liver is immature
  and absence of normal intestinal flora
• DIC see next slides
• Pathologic Inhibitors see next slides

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DIC Disseminated Intravascular Coagulation

• Consumption Coagulopathy
• Coagulation Disorder
• Thrombo-hemorrhagic disorder
• Life threatening
• Bleeding is the most apparent characteristic
• Initiating events are thrombotic, where material
  enters circulation
• Occurs due to lack of the negative feedback
  mechanism

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DIC Disseminated Intravascular Coagulation

• Pathological syndrome
• Uncontrolled formation of fibrin clots in
  circulating blood
• Small and large vessel thrombosis with impairment
  of blood flow and possible organ damage
  (systemic)
• Activation of fibrinolytic system to break down
  the excessive clots. Large amounts of FDP formed
  due to large number of clots being broken down
• Consumption of factors and platelets resulting in
  hemorrhage
• Secondary complication of conditions which cause
  hyperactivation of the intrinsic or extrinsic
  coagulation systems

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DIC

• Causes
• Extrinsic activation
• Obstetric usually due to major tissue damage
  such as retained dead fetus, abruptio placentae,
  or placenta previa
• Acute leukemias Promyelocytic increase number
  of granules released into circulation as cells
  break down
• Intravascular hemolysis ex transfusion
  reaction
• Massive trauma (especially crushing injuries),
  burns, surgical procedures
• Heat stroke
• Snake venoms

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DIC Causes cont

• Causes
• Intrinsic activation
• Septicemias and infections viral, bacterial,
  rickettsial, fungal, protozoan (especially gram
  negative that release endotoxins)
• Tumors foreign tissues and cells
• Prosthetic devices heart valves, aortic
  balloon, peritoneal shunting
• Vascular disease damaged endothelial lining
• Snake venoms

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DIC How Does It Occur?

• Step 1 Out of control clotting
• Causes widespread fibrin deposits in vessels of
  tissues and organs
• Subsequent event Hemorrhage
• Clotting proteins consumed at a high rate
• Causes multiple factor deficiencies, especially
  fibrinogen group
• Platelets caught in thrombi and removed

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DIC How Does It Occur?

• Step 2 Triggers Fibrinolytic system to remove
  fibrin
• Results in
• Circulating degradation products that interfere
  with platelet function normal clot formation
• Degradation of Factor V VIII

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DIC How Does It Occur?

• Step 3 Uncontrolled plasmin and thrombin enter
  circulation
• Why?
• Inhibitors such as ATIII have been depleted

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DIC How Does It Occur?

• Step 4 Appearance of Symptoms
• Bleeding from multiple sites
• Petechiae
• Purpura
• Occlusions in organs
• Oozing from arterial lines, venipuncture sites

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DIC

• No one specific test for DIC, but FDP is the most
  helpful
• Lab values
• platelet count decreased
• PT increased
• PTT increased
• Fibrinogen decreased
• FDP /D-dimer positive
• RBC fragments present
• ATIII decreased

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DIC

• Treatment
• Goal is to treat the underlying condition
• Remove the triggering process treat with
  antibiotics, antineoplasms, remove dead tissue,
  treat the diseases or conditions
• Heparin to prevent or limit further coagulation
• Replace factors, platelets give FFP

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Acquired Coagulation Disorders Pathologic
Inhibitors

• Develop in patients with certain disease states
  and others with no underlying conditions
• Circulating anticoagulants which may develop
  against any clotting factor
• Classed as immunoglobulins
• Either IgG or IgM
• Can be alloantibodies or autoantibodies
• Not normally synthesized by the body, bind with
  the factors making them unavailable for use in
  the cascade

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Types of Inhibitors

• Directed against a single coagulation factor
• Seen in patients with inherited factor
  deficiencies that have had replacement therapy
  for bleeding complications
• Less commonly seen in healthy people and those
  taking certain drugs
• Rare, except Factor VIII IX
• How do we find them?
• Interfere with clotting factor activity
• PTT prolonged, other tests normal
• Mixing study test will still be prolonged

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Types of Inhibitors

• Lupus Inhibitor/Anticoagulant
• Seen in patients with autoimmune diseases, drug
  reactions, but also in normal patients
• Antibodies do not bind coag factors, but
  interfere with phospholipid-dependent reagents
  used in coag lab tests
• Patients have no in vivo bleeding problems
  (though some have an increase risk of thrombosis)
• In vitro, any coag test using a phospholipid
  reagent will be falsely prolonged (PT, PTT)
• Coag studies must be performed using reagents
  that do not contain phospholipids