Chapter 4 Flashcards
Definition of hemostasis
Process of repairing damaged blood vessel wall. Includes Primary (formation of weak platelet plug) and Secondary (coagulation cascade stabilization).
First step in Primary Hemostasis
Transient vasoconstriction of damaged vessel due to neural stimulation AND endothelin released from endothelial cells.
Von Willebrand Factor (what it binds to and what receptors)
Binds to exposed subendothelial collagen and to Platelets via the GPIb Receptor.
Von Willebrand Factor (origin)
Weibel-Palade bodies of endothelial cells as alpha-granules of platelets
Platelet aggregation receptor
GPIIb/IIIa –> links via fibrinogen
Clinical symptoms of disorders of primary hemostasis
Mucusal bleeding (epistaxis, hemoptysis, GI bleeds, hematuria, and menorrhagia. Intracranial bleeding if very severe.
Petechiae (1-2mm), Purpura (>3mm), and Eccymoses (>1cm) also seen. Petechiae specific to thrombocytopenia…
Most common cause of thrombocytopenia in children and adults
Immune Thrombocytopenic Purpura
Immune Thrombocytopenic Purpura (description of mechanism)
Autoantibodies produced by plasma cells in spleen bind to platelets, which are then phagocytosed by Macrophages in spleen.
Acute vs. Chronic Immune Thrombocytopenic Purpura
Acute- seen in kids, post viral infection/immunization, self limiting.
Chronic- adults, associated with SLE, and can cause short lived thrombocytopenia in offspring as IgG passes placenta.
Ultimate treatment for Immune Thrombocytopenic Purpura
Splenectomy- eliminates both primary source of antibodies and site of platelet destruction.
Microangiopathic Hemolytic Anemia (general definition/mechanism)
Pathologic formation of platelet microthrombi in small vessels, leading to both thrombocytopenia and shearing of RBC’s (hemolytic anemia with SCHISTOCYTES, which look like little helmets, quite cute really).
When do you see Microangiopathic Hemolytic Anemia?
With 1. Thrombotic thrombocytopenic purpura
2. Hemolytic Uremic Syndrome
Cause of Thrombotic thrombocytopenic purpura
decreased levels of enzyme ADAMTS13 (most often due to acquired autoantibody), which normally helps degrade vWF –> increased vWF, so increased abnormal platelet aggregation leading to microthrombi.
Cause of HUS
Endothelial damage due to drugs or infection. Classically due to E coli O157:H7 infection in kids, with VEROTOXIN damaging the endothelium
Laboratory findings in Thrombotic thrombocytopenic purpura OR HUS
Thrombocytopenia
NORMAL PT/PTT (clotting factors not involved)
Anemia with Schistocytes
Increase in megakaryocytes
Bernard-Soulier Syndrome
Genetic GPIb deficiency –> platelets die sooner, so see mild thrombocytopenia with enlarged platelets (more immature)
Glanzmann thromboasthenia
Genetic GPIIb/IIIa deficiency –> impaired platelet aggregation.
Basic definition of secondary hemostasis
Coagulation cascade generates thrombin, which converts fibrinogen to fibrin and forms a stable platelet-fibrin thrombus.
Extrinsic Pathway factors, start, and measurement (PT/PTT time)
VII –> TF –> X –> V –> II –> I
TIssue Thromboplastin starts cascade.
Measure using PT time
Intrinsic pathway factors, start, and measurement (PT/PTT time)
XII –> XI –> IX –> VIII –> X –> V –> II –>I
Subendothelial collagen starts cascade
Measure using PTT time
Clinical features of disorders of secondary hemostasis
Deep tissue bleeding into muscles and joints, and rebleeding after surgical procedures. Measure using PT/PTT time.
Hemophilia A cause
X-linked recessive disease of factor VIII deficiency…
Hemophilia A lab and clinical findings
Increased PTT, normal PT
Decreased factor VIII
Normal platelet count/bleeding time
Treat with recombinant FVIII
Hemophilia B cause
Genetic factor IX deficiency.
Coagulation Factor Inhibitor Syndrome
Acquired antibody against any coagulation factor. VIII most common. Presents like Hemophilia
KEY TEST: Mixing study- where the patients PTT/PT does not correct upon addition of normal plasma, unlike in Hemophilia.
Von Willebrand Disease (cause, presentation)
Genetic vWF deficiency. Presents with mild mucosal and skin bleeding.
Von Willebrand Disease lab findings
Increased bleeding time
Increased PTT, but normal PT –> as vWF stabilizes FVIII
Abnormal ristocetin test (ristocetin normally induces platelet aggregation by causing vWF to bind GPIb)
Von Willebrand Disease treatment
Desmopressin (ADH analog) which increases vWF release from Weibel-Palade bodies of endothelial cells
Vitamin K (production and use)
Activated by epoxide reductase in the liver (blocked by coumadin).
Activated vit. K gamma carboxylates factors II, VII, IX, X, and proteins C and S.
Vit. K deficiency occurs in:
- Newborns. Give shot.
- Long-term antibiotic use (bacteria killed off)
- Malabsorption (fat soluble vitamin)
Other causes of abnormal secondary hemostasis
- Liver failure (don’t make coag factors and cannot activate Vit. K. Follow using PT time)
- Large-volume transfusions (as they dilute coag factors)
Heparin Induced Thrombocytopenia
Platelet destruction following heparin therapy (autoimmune antibody linked). Must stop heparin, but give another anti-coag as thromosis a feared complication. Do NOT give coumadin.
Causes of DIC
- Obstetric (tissue thromboplastin in amniotic fluid can activate coag cascade)
- Sepsis (endotoxins or cytokines induce endothelial cells to make tissue factor)
- Adenocarcinoma
- Acute promyelocytic leukemia
- Rattlesnake bite. :)
Key lab findings in DIC
Positive D-dimer!!! Derives from splitting of cross-linked fibrin. Best screening test for DIC.
Role of Plasmin
- Cleaves fibrin and fibrinogen
- Destroys coag factors
- Blocks platelet aggregation
What inactivates plasmin ?
alpha2-antiplasmin
Causes of impaired fibrinolysis?
- Radical Prostactectomy (release of urokinase activates plasmin)
- cirrosis of liver (which normally makes a2-antiplasmin)
Symptoms of impaired fibrinolysis
Increased bleeding (looks like DIC)
Lab findings with impaired fibrinolysis
- Increased PT/PTT (plasmin destroys coag factors)
- Increased bleeding time with normal platelet count
- Increased fibrinogen split factors WITHOUT D-DIMERS!
Treatment of impaired fibrinolysis
Aminocaproic acid (blocks activation of plasminogen)
Virchow’s Triad
Stasis - Endothelial damage - hypercoagulable state
Five ways endothelial cells try to prevent damage
- Block exposure to subendothelial collagen/TF
- Produce NO and PGI2
- Secrete heparin like molecules (activate antithrombin III)
- Secrete tPA (converts plasminogen to plasmin)
- Secrete thrombomodulin (use thrombin to activate protein C, which then inactivates factor V and VIII)
Causes of endothelial cell damage
Atherosclerosis, Vasculitis, and high levels of homocystein (seen in Vit. B12/Folate deficiency as well as Cystathionine beta synthase deficiency. CBS normally converts homocystein to cystathionine…)
Protein C and S normal role
Inactivate factors V and VIII
Side effect of Protein C/S deficiency
Warfarin Skin Necrosis!
Vit. K normally helps produce FII, VII, IX, and X, as well as Proteins C and S. The proteins have shorter half lives, and when already deficient, get an increased risk for thrombus (increased relative levels of Factors II, VII, IX, and X).
Factor V Leiden
Mutated Factor V that cannot be cleaved by Proteins C/S. Most common inherited cause of hypercoagulable state.
AntiThrombin III deficiency characteristics
DO NOT SEE increase of PTT with standard Heparin therapy (which normally activates ATIII…). When high doses given, works a little, supplement with coumadin.
How are oral contraceptives linked to hypercoagulable state?
Increased estrogen increases production of coag factors.
How to tell the difference between Thromboembolus and Atherosclerotic Embolis?
Atherosclerotic emboli characterized by presence of cholesterol clefts.
Caisson DIsease
Chronic form of gas emboli (nitrogen) characterized by multifocal ischemic necrosis of bone.
