Hematology Ch. 18

fibrinogen, thrombin, and the fibrinolytic system

What is fibrinogen?

• also known as factor I

• the principal substrate of the coagulation cascade

• has the highest molecular weight of all clotting factors

cross linked fibrin is stabilized by:

factor XIII and thrombin

What 3 polypeptide chains make up fibrinogen?

• alpha, beta, and gamma chains

• thrombin cleaves the alpha and beta chains, creating polypeptides A and B

  • A and B are then cleaved to create a fibrin monomer

• fibrin monomers are held together by peptide bonds formed by factor VIII to create a stable clot

What is the reference range for fibrinogen?

200-400 mg/dL

Which acquired disorders results in decreased fibrinogen?

• acute liver disease

• acute renal disease

• disseminated intravascular coagulation (DIC)

Which acquired conditions causes increased fibrinogen?

• inflammation

• hepatitis

• pregnancy

• atherosclerosis

afibrinogenemia

• inherited fibrinogen disorder

• less than 10 mg/dL of fibrinogen in plasma

• umbilical cord bleeding, poor wound healing, and spontaneous abortion

• lab results

  • increased PT, PTT, and thrombin time

• treatment

  • fresh frozen plasma or cryoprecipitate

hypofibrinogenemia

• inherited fibrinogen disorder

• 20-100 mg/dL of fibrinogen in plasma

• mild spontaneous bleeding and severe postoperative bleeding

• lab results depend on the amount of fibrinogen the patient has

dysfibrinogenemia

• an inherited, qualitative disorder of fibrinogen

• an amino acid substitution causes the formation of functionally abnormal fibrinogen molecules

• lab findings

  • normal fibrinogen immunologic assays

  • increased PT and PTT

  • quantitative fibrinogen assay is abnormal (because of a low amount of functioning fibrinogen)

What are the 4 roles of thrombin in hemostasis?

• participating in platelet release and aggregation

• stimulating platelets to produce the inhibitor prostacyclin

• activating factors V and VIII

  • for thrombus formation

• activating protein C

  • a naturally occurring inhibitor

  • also combines with protein S to inhibit factors V and VIII

What is the key component of fibrinolysis/clot dissolution?

• plasminogen

  • an enzyme created in the liver

• how it works

  • plasminogen is converted to plasmin by tPA (tissue plasminogen activator)

  • plasmin digests fibrin and fibrinogen

• additional plasminogen activators

  • Factor XIIa, kallikrein, high molecular weight kininogen, and urokinase

What is tPA (tissue plasminogen activator) useful for in medicine?

• useful as a medication for stroke patients

• it acts as a clot buster

Which 2 naturally occurring inhibitors prevent fibrinolysis?

• plasminogen activator inhibitor 1 (PAI 1)

  • secreted by endothilial cells during injury

  • suppresses tPA function

• alpha 2 antiplasmin

  • prevents plasmin from binding to fibrin (stops plasmin from lysing fibrin)

  • most important inhibitor in the fibrinolytic system

• secondary agents that inhibit fibrinolysis

  • substances that act on thrombin formation

  • alpha 2 macroglobulin, C1 inactivator, and alpha 1-trypsin

What are the products that are produced in the fibrinolytic system called?

fibrin split products (FSP) and fibrin degradation products (FDP)

composed of fibrin fragments

What are D dimers?

• a FSP/FDP

• presence in plasma indicates fibrin was formed and then broken down

• released when a clot is dissolved by plasmin

• used to assess DVT or pulmonary embolism (PE)

• useful for monitoring thrombolytic therapy

What is disseminated intravascular coagulation (DIC) caused by?

• an underlying pathologic event

• occurs when the hemostatic system becomes unbalanced

  • results in hyperactivation of the coagulation system, fibrinolytic system, or both

• leads to thrombus formation and excessive hemorrhage

  • clotting factors and platelets are destroyed once activated for coagulation

What conditions is DIC associated with?

• obstetrical complications

• malignancies

• massive trauma

• bacterial sepsis

• necrotic tissue

Describe the steps of the DIC cycle

• excess thromboplastin triggers production of excessive amounts of thrombin

  • this causes coagulation and fibrinolysis

• plasmin degrades fibrinogen and fibrin into FDPs

• excess FDPs degrade fibrin monomers, clotting factors are inactivated, and hemorrhage results

• formed clots are unstable, contributing to bleeding

primary fibrinolysis

• a DIC related disorder

• plasmin becomes activated in circulation by sources other than thrombin

• plasmin acts on fibrinogen and fibrin, causing hemorrhage

• platelet count is normal

  • in contrast to DIC

What are the symptoms and lab results of acute DIC?

• symptoms

  • skin and mucous membrane bleeding, epistaxis, petechiae, and ecchymoses (bruising)

• lab results

  • PT and PTT are prolonged

  • low fibrinogen and PLTs

  • FDPs are increased

  • D dimers are elevated

  • schistocytes in PBS

How is acute DIC treated?

• identifying the event that led to DIC is important for treatment

  • widespread use of antibiotics for septicemia and obstetric surgeries can cause bleeding episodes

• fresh frozen plasma

• packed RBCs

• platelet concentrates

• heparin combined with antithrombin

the process of fibrin degradation is called ____ and is controlled by the enzyme ____

fibrinolysis, plasmin