Hemostasis and Related Disorders Flashcards by Michelle Bernshteyn

Hemostasis (and its two stages)

formation of a thrombus/clot in response to BV wall damage

Primary: weak platelet plug
Secondary: coagulation cascade stabilizes plug

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4 stages of Primary Hemostasis

VASOCONSTRICTION: reflex neural stimulation & endothelin
platelet ADHESION: Weibel Palade bodies & platelet a-granules–> vWF–> binds exposed collagen–> platelets bind vWF using GPIb receptor
platelet DEGRANULATION: adhesion causes release of–> ADP (released from granules; promotes GPIIb/IIIa) & TXA2 (made by platelet COX)
platelet AGGREGATION: platelet plug from aggregation via GPIIb/IIIa using fibrinogen as a linking molecule

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What are the sources of vWF?

Weibel Palade bodies of endothelial cells

2. platelet a-granules

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Secondary Hemostasis (and how its factors are activated)

coagulation cascade stabilizes platelet plug
*generation of thrombin–> converts fibrinogen to fibrin (cross-linked)

-factors are produced by liver and activated by: exposure to an activating substance, phospholipid surface of platelets & calcium

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Overview of Primary Hemostasis Disorders and Secondary Hemostasis Disorders

Primary Hemostasis Disorders (ITP, TTP and HUS causing Microthrombic Hemolytic Anemia, 4 Qualitative Platelet disorders)

Cause: usually due to abnormalities in platelets (quantitative or qualitative)
Clinical Features: mucosal (epistaxis, hemoptysis, GI bleeding, hematuria, menorrhagia, intracranial bleeding) and skin bleeding (petechiae, purpura, ecchymoses, easy bruising)

Secondary Hemostasis Disorders (Hemophila A & B, Coagulation Factor Inhibitor, von Willebrand Disease, VitK deficiency)

Cause: -factor abnormalities
Clinical Features: deep tissue bleeding into muscles and joints & rebleeding after surgical procedures

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Petechiae is a sign of:

Quantitative disorder of primary hemostasis (i.e. thrombocytopenia)

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What do blood smears & bone marrow biopsies assess?

Blood smears: #/size of platelets

Bone marrow biopsies: megakaryocytes

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Immune Thrombocytopenic Purpura (ITP)–> cause, forms, labs, treatment

-most common cause of thrombocytopenia in which there is an autoimmune production of IgG, via spleen plasma cells, against platelet antigens

Acute: self-limited after viral infection in children
Chronic: primary (unknown etiology) or secondary (underlying issue) in women of child-bearing age (can cross placenta)
low platelets, normal PT/PTT), high megakaryocytes
Treatment: corticosteroids (adults- relapse), IVIG (short-lived effect) & splenectomy (removed primary source of Ab and site of platelet destruction)

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Microangiopathic Hemolytic Anemia–> causes, labs, treatment

seen in TTP (Thrombotic Thrombocytopenic Purpura) and HUS (Hemolytic Uremic Syndrome) causing formation of platelet microthrombi that shears RBCs
TTP–> acquired autoantibody resulting in decreased ADAMTS13 which normally cleaves vWF causing renal insufficiency
HUS–> endothelial damage from drugs or infection (E coli O157:H7 verotoxin) affecting ADAMTS13 causing CNS abnormalities
thrombocytopenia, increased bleeding time, normal PT/PTT, anemia, high megakaryocytes
Treatment: plasmapheresis (removed autoantibodies) and corticosteroids (decreases autoantibody production)

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4 Qualitative Platelet Disorders

Bernard-Soulier Syndrome: no adhesion from GPIb deficiency (thrombocytopenia & enlarged/immature platelets)
Glanzmann Thrombasthenia: impaired platelet aggregation from GPIIb/IIIa deficiency
Aspirin: irreversibly inactivates COX (lack of TXA2) impairing aggregation
Uremia: disrupts function impairing adhesion & aggregation

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Extrinsic and Intrinsic Pathways to activate factors of Secondary Hemostasis

Extrinsic: factor VII (7) activated by tissue thromboplastin; measured by Prothrombin time (PT)

Intrinsic: factors XII (12), XI (11), IX (9), VIII (8) activated by subendothelial collagen; measured by Partial thromboplastin time (PTT)

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Hemophilia A–> cause, symptoms and labs

X-linked or de novo mutation causing factor VIII (8) deficiency
secondary hemostasis causing deep tissue, joint & postsurgical bleeding

-labs: high PTT, low FVIII, normal PT, platelet count and bleeding time

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Hemophilia B–> cause

-factor IX (9) deficiency

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Coagulation Factor Inhibitor–> cause and labs

acquired antibody against a coagulation factor (usually VIII)
similar labs to Hemophila A: high PTT, low FVIII, normal PT, platelet count and bleeding time

**PTT canNOT be corrected due to tremendous amount of antibody against factor VIII

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Von Willebrane Disease–> cause, symptoms, labs, treatment

vWF deficiency impairing platelet adhesion (usually autosomal dominant)
causes: mucosal and skin bleeding
labs: high bleeding time, high PTT (since vWF usually stablizes it), abnormal ristocetin test, normal PT
treatment: desmopressin–> increases vWF release from Weibel Palade bodies of endothelial cells

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RIstocetin

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used to detect for von Willebrand disease

-causes vWF to bind GPIb inducing platelet agglutination
-abnormal if there is a lack of vWF since agglutination will be impaired

Vitamin K’s role and deficiency

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Vit K enters through gut–> activation in liver by epoxide reductase–> y carboxylation of factors II, VII, IX, X (2, 7, 9, 10) which is required for factor function

-deficiency occurs in: newborns, long-term antibiotic therapy & malabsorption

other causes of abnormal Secondary Hemostasis

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liver failure: decreased production of coagulation factors and decreased activation of vitamin K by epoxide reductase
large volume transfusion: dilutes coagulation factors (relative deficiency)

Heparin-Induced Thrombocytopenia–> cause and what it potentially can lead to

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platelet destruction after Heparin forms PF4 and IgG Ab
fragments of destroyed platelets may activate remaining platelets, leading to thrombosis

Disseminated Intravascular Coagulation (DIC)–> causes, labs, treatment

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pathologic activation of the coagulation cascade causing widespread microthrombi & bleeding from consumption of platelets and factors
secondary to another disease: obstetric complications (tissue thromboplastin in amniotic fluid), sepsis (endotoxins induce endothelial cells to make tissue factor), adenocarcinoma (mucin), APL (primary granules), rattlesnake bite (venom)
labs: low platelet count & fibrinogen, high PT/PTT & D-dimer, microangiopathic hemolytic anemia
treatment: transfusing blood products and cryoprecipitate

D-dimer

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best screening test for DIC
derived from splitting of cross-linked fibrin thrombi

fibrinolysis disorders: increased fibrogen split products without D-dimer since there are no fibrin thrombi

Fibrinolysis

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-removal of thrombus

**tPA converts plasminogen to plasmin (cleaves fibrin & fibrinogen, destroys coagulation factors and blocks platelet aggregation preventing formation of new clots)

**plasmin is inactivated by a2-antiplasmin to prevent bleeding out

Disorders of Fibrinolysis–> definition, causes, labs, treatment

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-plasmin overactivity leading to increased bleeding (resembles DIC)

Radical Prostatectomy (plasmin is activated by urokinase)
Cirrhosis (reduced production of a2-antiplasmin)

labs: high PT/PTT, bleeding time & fibrinogen split products (without D-dimer), normal platelet count

-treatment: amincaproic acid (blocks plasminogen activation)

thrombosis–> characterization and risk factors

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-blood clot characterized by lines of Zahn (platelets/fibrin and RBCs), & attachment to vessel wall

risk factors:
1. blood flow disruption
2. endothelial cell damage
3. hypercoaguable state

Blood flow disruption (risk factor for thrombosis)

- continuous & laminar--> stasis & turbulence | - from immobilization, cardiac wall dysfunction, aneurysm

Endothelial cell damage (risk factor for thrombosis)

- from atherosclerosis, vasculitis, high levels of homocysteine * vitamin B and folate deficiency: mildly elevated homocysteine levels (methyl is donated from THF--> cobalamin/VB12--> homocysteine which becomes methionine * cystathionine beta synthase deficiency: CBS normally converts homocysteine to cystathionine thus a deficiency results in buildup

How do endothelial cells normally prevent formation of thrombosis?

- blocking subendothelial collagen exposure - producing PGI2 and NO (vasodilation & inhibition of platelet aggregation) - heparin-like molecule secretion (augments antithrombin III--> inactivates thrombin & coagulation factors) - tPA secretion (converts plasminogen to plasmin cleaving fibrin, destroys coagulation factors and blocks platelet aggregation) - thrombomodulin (redirects thrombin to activate protein C--> inactivates factors V and VIII)

Hypercoaguable state (risk factor for thrombosis)

- excessive procuagulant proteins or defective antiboagulant proteins (inherited or acquired) - Protein C or S deficiency decreases negative feedback since normally inactive factors V & VIII; increased risk for warfarin skin necrosis - Factor V Leiden: mutated factor V that lacks cleavage side for deactivation by proteins C & S (inherited) - Prothrombin 20210A: mutation in prothrombin--> increased expression--> more thrombin--> thrombus formation (inherited) - ATIII deficiency: decreases protective effect of heparin-like molecules produced by endothelium which normally activate ATIII; PTT does not risk with standard heparin dosing - Oral Contraceptives: estrogen increases coagulation factors

Hemostasis and Related Disorders Flashcards

(28 cards)