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Unit 3 B&L > BL 02-27-14 08-09am Hemostasis-Approach to Patient - Thienelt > Flashcards

BL 02-27-14 08-09am Hemostasis-Approach to Patient - Thienelt Flashcards

1
Q

First events in formation of clot:

A
  • Platelet Adhesion, Activation, & Aggregation
  • Forms platelet plug
  • “primary hemostasis”
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2
Q

Stabilization of Platelet plug

A
  • stabilized by formation of fibrin network generated through coagulation cascade
  • “secondary hemostasis”
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3
Q

Key to cessation of bleeding from small vascular injuries…

A

= optimal numbers & function of platelets

- Disorders of platelet number / function can lead to bleeding from skin, mucous membranes, brain, or other sites

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4
Q

Circulating platelet structure

A
  • small anuclear discoid cell ~2-3 microns in diameter
  • contain mitochondria (but no nucleus)
  • have three kinds of functional granules: dense, alpha, and lysosomal granules.
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5
Q

“Life Cycle” of platelets

A
  • arises from megakaryocytes
  • maturation time of 4-5 days
  • circulating life span of 9-10 days
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6
Q

Location of platelets (normal & pathologic states):

A
  • In pts w/normal spleen size, 80% of platelets are circulating & 20% are in the spleen
  • In some pathologic states (e.g., hypersplenism), spleen may contain up to 90% of platelets
  • Bone marrow reserve of platelets is limited & can be rapidly depleted after sudden platelet loss or destruction.
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7
Q

Newly formed platelets

A
  • larger in size

- termed megathrombocytes

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8
Q

Contents of dense granules of platelets:

A
  • contain ATP, ADP, serotonin, and calcium
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9
Q

Contents of α-granules of platelets

A

Contains several proteins essential for platelet function, including…

  • procoagulant proteins (fibrinogen, factor V, von Willebrand factor, etc)
  • platelet-specific factors for platelet activation
  • growth factors such as platelet-derived growth factor
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10
Q

Contents of Lysosomal granules of Platelets

A
  • contain acid hydrolases
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11
Q

Internal structure of Platelets

A
  • extensive system of internal membrane tunnels called surface-connected canalicular system
  • cytoplasmic framework of monomers, filaments, & tubules that constitute the cytoskeleton & allow shape change with activation
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12
Q

Surface-connected canalicular system of Platelets - PURPOSE

A
  • contents of platelet granules are extruded through this system during platelet aggregation & secretion
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13
Q

Platelet Function

A

Several important roles in hemostasis, including

  • ADHESION to vascular subendothelium at sites of injury to begin hemostatic process
  • ACTIVATION of intracellular signaling pathways leading to cytoskeletal changes & release of intracellular granules to enhance platelet plug formation
  • AGGREGATION to form platelet plug
  • SUPPORT of THROMBIN GENERATION by providing phospholipid surface for coagulation cascade to take place

A continuous & dynamic interaction of vessel, platelet, & plasma components

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14
Q

Endothelial prevention of coagulation & platelet aggregation

A

Endothelial cells of intact vessels prevent

  • blood coagulation by secretion of a heparin-like molecule & through expression of thrombomodulin (when bound to thrombin, activates protein C and S)
  • platelet aggregation by secretion of nitric oxide & prostacyclin, inhibitors of platelet activation
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15
Q

Process of Platelet Adhesion

A
  • With vessel injury, subendothelial components are exposed
  • Circulating von Willebrand factor (vWF) adheres to this exposed subendothelium
  • Under conditions of high shear flow, circulating platelets then contact exposed subendothelium in a rolling fashion & adhere via intrxns btwn glycoprotein Ib (GP1b)on platelet surface & vWF
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16
Q

Things leading to firm adherence of platelet to subendothelial surface

A
  • platelet integrin GPIIb-IIIa (αIIbβ3) increases its affinity for vWF with exposure to soluble agonist or adhesive subendothelial matrix proteins –> tighter binding
  • GPVI interacts directly w/ collagen in subendothelium
  • Numerous ligands in subendothelium (collagen, laminin, fibronectin) also interact w/ β1 integrins on the platelet surface
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17
Q

Soluble agonist that increase platelet integrin GPIIb-IIIa (αIIbβ3)‘s affinity for vWF

A
  • thrombin
  • ADP
  • Epinephrine
  • Thromboxan A2
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18
Q

Adhesive proteins in subendothelial matrix that increase platelet integrin GPIIb-IIIa (αIIbβ3)‘s affinity for vWF

A
  • Collagen

- vWF

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19
Q

Platelet Activation - Overview

A
  1. shape change & spreading
  2. granule release
  3. intracellular signaling via soluble agonist & G protein coupled platelet membrane receptors
  4. Ca mobilization
  5. Activation of phoshoplipase A2 –> release of arachidonic acid from phospholipids
  6. Arachidonic acid converted to Prostaglandin H2 by COX-1
  7. PG H2 converted to Thromboxane A2 by thromboxane synthetase
  8. Thromboxane A2 & other agonist released to further amplify platelet activation
  9. Phosphatidylserine in membrane switches from inner to outer leaflet
  10. Thrombin generation
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20
Q

Platelet Activation – Shape change

A
  • With adherence to injured vessel wall, platelets undergo shape change through cytoskeletal activation
  • Become more spherical w/ extended pseudopods
  • Spread over exposed subendothelium
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21
Q

Platelet Activation – granule release

A
  • After shape change, the contents of platelet granules are released
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22
Q

Platelet Activation – Intracellular signaling & Ca mobilization

A
  • After shape change & granule release, soluble agonists (thrombin, thromboxane A2, epinephrine, ADP) interact w/ their respective G protein coupled platelet membrane receptors
  • Leads to intracellular signaling & Ca mobilization
  • Ca activates phospholipase A2, which releases arachidonic acid from phospholipids
  • COX-1 then converts arachidonic acid to prostaglandin H2
  • PG H2 is converted to thromboxane A2 by thromboxane synthetase
  • Thromboxane A2, along with other agonists, is released, acting to further amplify platelet activation
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23
Q

Platelet Activation – Membrane affects

A
  • With platelet activation, membrane reorganization also occurs
  • Switches phospholipid phosphatidylserine from inner to outer membrane leaflet, making it available to interact w/ clotting factors
  • Leads to thrombin generation
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24
Q

Platelet Aggregation

A
  • W/ platelet adhesion & w/ binding of soluble agonists to receptors to amplify platelet activation, GPIIb-IIIa is converted to a high-affinity state where it can bind fibrinogen and vWF.
  • Binding of the membrane protein talin to GPIIb-IIIa is the last step to mediate the change from a low-affinity to a high-affinity state
  • GPIIb-IIIa can then bind fibrinogen –>bridges / laces platelets together into an aggregate
  • Thombin generated through activation of coagulation cascade then converts fibrinogen to fibrin to stabilize the platelet plug
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25
Q

Adhesion

A
  • Platelets adhere to damaged vessel wall directly via collagen or indirectly via vWF
  • Slide
  • Slide
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26
Q

Evaluation of platelet function

A

CBC w/ peripheral blood SMEAR provides platelet count & allows evaluation of platelet size / granularity
— Is this acute or chronic (review old CBCs)

Bleeding time (or platelet function analyzer, PFA-100 test) to Dx platelet dysfunction

Other possible mechanisms for low platelets (Hx, esp. drugs, Liver/Kidney function, etc.)

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27
Q

Bleeding time – how to do & normal time

A
  • Small incision in skin is made using standardized template
  • Time until cessation of bleeding is measured
  • Normal bleeding time = <9 minutes
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28
Q

Causes of Normal vs. Abnormal Bleeding times

A
  • Hemophiliac w/normal platelet count and normal platelet function will have a normal bleeding time
  • Platelet count <100,000/uL will lead to prolonged bleeding time
  • Qualitative platelet disorder will lead to prolonged bleeding time
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29
Q

Platelet aggregation studies

A
  • done to evaluate platelet aggregation in response to a set of agonists
  • agonists including thrombin, ADP, epinephrine, collagen, arachidonic acid, and ristocetin (an antibiotic which causes vWF to bind to GP1b, inducing platelet aggregation)
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30
Q

Platelet Disorders - Classified as either…

A
  • qualitative (abnormal function) or quantitative (not enough or too many platelets)
  • congenital or acquired.
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31
Q

Qualitative Platelet Disorders

A

Disorders of adhesion
Disorders of activation
Disorders of aggregation
Drug effects

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32
Q

Disorders of adhesion

A

Von Willebrand disease (vWD)

Bernard-Soulier syndrome

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33
Q

Von Willebrand disease (vWD) – inheritance/acquirement

A
  • most common congenital bleeding disorder

- can also be acquired if antibodies develop against the vWF molecule

34
Q

Von Willebrand disease (vWD) – can be due to…

A

Can be due to

  • inadequate amount of vWF
  • mutations in vWF gene leading to abnormal protein function
35
Q

vWF role/affect

A
  • vWF plays key role in adhesion of platelets to injured vascular endothelium
  • Lack of vWF leads to abnormal platelet/endothelial interaction, leading to a primary hemostatic bleeding disorder characterized by mucosal and skin bleeding
  • VWF also serves as carrier protein for factor VIII, so severe deficiencies of vWF can cause functional factor VIII deficiency and thus defects in secondary hemostasis as well
36
Q

Lab tests for diagnosis of vWD

A

Include

  • bleeding time or PFA-100 –> abnormally prolonged w/ vWD
  • factor VIII level
  • von Willebrand antigen test (measure amount of vW protein)
  • von Willebrand activity test (aka ristocetin cofactor activity; measures function of von Willebrand protein using donor platelets)
  • vWF multimer assays (occasionally obtained when evaluating for qualitative defect in vWF function)
37
Q

Treatment of vWD

A
  • Commonly DDAVP (arginine vasopressin)
  • enhances release of vWF from endothelial stores
  • effective for treatment of type 1 vWD (partial quantitative deficiency) but not type 2 (qualitative defects) or type 3 (near-complete absence of vWF)

Factor replacement used is some situations

Should avoid aspirin & other platelet inhibiting agents.

38
Q

Bernard-Soulier syndrome

A
  • rare autosomal recessive disorder
  • reduced expression of GP1b on platelet surface reduced
  • leads to defect in platelet adhesion
  • Platelet aggregation studies only show abnormal aggregation with ristocetin.
39
Q

Disorders of activation

A
  • Storage pool deficiencies

- EX: gray platelets syndrome (α-granules def.)

40
Q

Storage pool deficiency

A
  • Storage pool deficiency can occur, w/ a deficiency of either dense granules or α-granules
41
Q

Gray platelet syndrome

A

= Deficiency of α-granules is known

42
Q

Disorders from lack of dense granules

A
  • Several syndromes can be associated w/ lack of dense granules
  • These disorders can also be acquired when platelets pass across abnormal vascular surfaces (such as cardiopulmonary bypass apparatus) leading to partially degranulated platelets
  • Disorders can also be due to rare defects in signal transduction pathways within the platelets.
43
Q

Disorders of aggregation

A

Afibrogenemia

Glanzmann thrombasthenia

44
Q

Afibrogenemia

A
  • rare inherited defects in aggregation
  • leads to both primary (platelet plug formation) & secondary (formation of cross-linked fibrin) hemostatic defects
  • Pts have platelet-type mucosal & cutaneous bleeding as well as deep muscle hematomas more characteristic of coagulation defects
45
Q

Defect in primary hemostasis in afibrogenemia

A
  • due to lack of fibrinogen for binding to GPIIb-IIIa to allow platelet aggregation
46
Q

Defect in secondary hemostasis in afibrogenemia

A
  • due to lack of fibrinogen for formation of cross-linked fibrin
47
Q

Glanzmann thrombasthenia

A
  • rare autosomal recessive bleeding disorder
  • caused by absent or defective GPIIb-IIIa
  • Platelets can adhere but are unable to aggregate in response to normal agonist stimuli
  • Pts have petechiae & easy bruising
48
Q

Drug effects in platelet disorders

A

Major classes of drugs which inhibit platelet function include:

  • COX inhibitors such as Aspirin
  • NSAIDs such as Ibuprofen
  • ADP receptor inhibitors such as Ticlopidine (Ticlid) and Clopidogrel (Plavix)
  • GPIIb-IIIa receptor antagonists such as Abciximab
49
Q

Quantitative Platelet Disorders

A 
Thrombocytopenia 
Immune thrombocytopenic purpura (ITP)
Alloimmune thrombocytopenia 
Drug-induced immune thrombocytopenia 
Other non-immune-mediated causes of thrombocytopenia
50
Q

Thrombocytopenia

A
  • a low platelet count (less than 150,000/uL)
51
Q

Mechanisms of Thrombocytopenia:

A
  • decreased platelet production
  • increased platelet destruction or consumption
  • sequestration of platelets in the spleen
52
Q

PLT count & effect

A
  • Normal PLT count: 150,000-400,00 / ul
    • 20-50,000 = spontaneous bleeding (increased risk of hemorrhage w/trauma & surgery)
  • <10-20,000/uL = life-threatening spontaneous hemorrhagse, such as spontaneous intracranial hemorrhage
53
Q

Thrombocytopenia due to decreased platelet production

A
  • primary bone marrow disorders such as aplastic anemia, myelodysplasia, and leukemia
  • bone marrow invasion by metastatic cancer, myelofibrosis
  • bone marrow invasion by infections such as tuberculosis
  • toxins such as chemotherapeutic drugs, chemicals, and exposure to radiation can injure the bone marrow and lead to thrombocytopenia
  • severe nutritional disorders such as B12 or folate deficiency can affect megakaryopoiesis
  • rare congenital disorders
54
Q

Immune thrombocytopenic purpura (ITP)

A
  • most common cause of thrombocytopenia
  • formerly called idiopathic TP
  • due to increased destruction
  • two forms of ITP: acute and chronic
55
Q

Immune thrombocytopenic purpura (ITP) – Mechanism of platelet destruction

A
  • Autoantibodies develop against platelet antigens
  • Leads to their removal by macrophages of reticuloendothelial system of liver & spleen
  • similar mechanism to that seen with autoimmune hemolytic anemia
  • two forms of ITP: acute and chronic.
56
Q

Acute ITP

A
  • usually in children or young adults
  • often preceded by a viral infection
  • Onset of thrombocytopenia is sudden & can be severe
  • Present with petechiae & nosebleeds
  • Recovery is generally w/in 2-6 weeks w/out treatment or after treatment with steroids.
57
Q

Chronic ITP

A
  • more common in adults
  • often associated with concurrent autoimmune disorders (e.g., SLE or rheumatoid arthritis), lymphoma, or HIV, although most cases remain idiopathic
  • Spontaneous remissions are infrequent, and most patients require treatment
58
Q

Treatment of Chronic ITP

A
  • most commonly corticosteroids, IVIG, and splenectomy
  • rituximab (anti-CD20) to deplete B cells
  • TPO (thrombopoetin mimicker)
59
Q

Effect of steroids in Chronic ITP

A
  • work by dampening proliferation of B cell clone making the autoantibody
  • effect seen in 7-10 days of starting treatment
60
Q

Effect of IVIG in Chronic ITP

A

IVIG acts by blocking splenic Fc receptors to prevent their binding to antibody-coated platelets
- effect seen in 1-2 days

61
Q

Effect of splenectomy in Chronic ITP

A
  • Splenectomy works by removing site of autoantibody-induced platelet removal
  • leads to lasting responses in 60-70% of patients
62
Q

Alloimmune thrombocytopenia

A
  • occurs when pt develops Abs to platelet Ags not present on patient’s own platelets
  • can occur in setting of platelet transfusions
  • can occur in neonate through passive transfer of maternal IgG alloantibodies across placenta
63
Q

Drug-induced immune thrombocytopenia

A
  • can occur when Ab recognizes a neoepitope created by the binding of a drug to a platelet surface glycoprotein
  • Heparin-induced thrombocytopenia (HIT) – can be associated w/ development of thromboemboli due to platelet activation
64
Q

Other non-immune-mediated causes of thrombocytopenia include…

A

Include

  • DIC
  • Sepsis
  • thrombotic thrombocytopenic purpura (TTP)
  • hemolytic uremic syndrome (HUS)

Thrombocytopenia with these disorders is due to increased platelet consumption

65
Q

Thrombotic thrombocytopenic purpura (TTP)

A
  • characterized by fever, renal insufficiency, microangiopathic hemolytic anemia, mental status changes, and thrombocytopenia
  • occurs when endothelial damage occurs from variety of mechanisms (e.g., infection, immune complexes, HIV, pregnancy, cancer)
  • leads to abnormal release of unusually large vWF molecules from storage sites, which mediate platelet adhesion & aggregation, forming diffuse platelet plugs in small arterioles
66
Q

Large vWF multimers in TTP

A
  • present b/c of absence of metalloprotease called ADAMTS13
  • normally digests vWF into smaller multimers
  • Congenital form of disease exists, but usually acquired through development of autoantibodies to ADAMTS13
67
Q

Treatment of TTP

A
  • w/ plasmapheresis to remove large vWF multimers & replace the missing ADAMTS13
68
Q

Hemolytic uremic syndrome (HUS) vs. TTP

A
  • similar presentation to TTP
  • BUT tends to more often be associated with renal failure
  • AND tends to occur more often in children
69
Q

Hemolytic uremic syndrome (HUS) mechanism & treatment

A
  • due to damage to the endothelial lining, usually by a bacterial toxin
  • leads to platelet adhesion & activation
  • leads to microthrombi formation
  • often self-limited & generally treated w/ supportive care alone
70
Q

Why to evaluate for bleeding disorder?

A
  • Evaluate cause of acute or chronic bleeding

- Determine potential for excess bleeding prior to invasive diagnostic or surgical procedures

71
Q

Patient evaluation for bleeding disorder should include…

A
  • assessment of historical information
  • physical examination
  • performance of basic hemostatic screening tests
  • further testing depending on results of initial assessment
72
Q

Hx in Bleeding Disorder Evaluation

A
  • Detailed Hx of type, frequency, & amount of bleeding
  • Some pts may consider appropriate amount of bruising / bleeding to be excessive, making evaluation more challenging
  • Questions to address include:
  • Does pt display excessive, prolonged, recurrent, or delayed bleeding?
  • Has pt ever had opportunity to bleed excessively (physical trauma, skin lacerations, surgery)?
  • Family Hx of significant bleeding?
73
Q

Interpretation of Bleeding types – Brisk Bleeding from obvious trauma

A
  • suggests a local vascular defect
74
Q

Interpretation of Bleeding types –Prolonged / recurrent bleeding

A
  • likely a more generalized hemostatic disorder
75
Q

Interpretation of Bleeding types – Sudden resumption of bleeding from injured site

A
  • raises possibility of excessive fibrinolysis or abnormal crosslinking of fibrin
76
Q

Interpretation of Bleeding types – Multiple site bleeding

A
  • suggests more severe, generalized hemostatic disorder
77
Q

Interpretation of Bleeding types – Mucocutaneous bleeding

A
  • includes bruising, petechiae, epistaxis, menorrhagia, prolonged oozing after tooth extraction, increased bleeding after aspirin intake
  • indicative of defect in primary hemostasis (platelet disorder or von Willebrand disease)
78
Q

Interpretation of Bleeding types – Soft tissue/joint/deep bleeding

A
  • more consistent with a defect in secondary hemostasis (coagulopathy)
79
Q

Interpretation of Bleeding types—Suspicious Nosebleeds

A

Suspicious of bleeding disorder if…

  • Occur every 1-2 months
  • Last longer than 10 minutes
  • Involve both nares
  • Require medical attention or transfusion
80
Q

Findings on physical exam in bleeding disorder evaluation

A
  • may suggest an underlying disorder
  • petechiae with thrombocytopenia
  • enlarged spleen & lymph nodes with chronic infections or malignancies
  • signs of liver disease such as jaundice or edema with liver coagulopathy
  • musculoskeletal abnormalities & joint disease with hemophilias
  • Trauma (accidental or non-accidental) should be considered as a cause of multiple / unusual bruises at any age
  • Large (>2 in diameter) or indurated purpuric lesions should lead to an evaluation for a bleeding problem.
81
Q

Age differences in Bleeding disorders

A
  • Complaints / signs of easy bruising common in children & many elderly people WITHOUT an underlying bleeding disorder
  • RARE for children < 1 year of age to show bruising
  • Recurrent, brief nosebleeds are frequently seen in children
82
Q

Basic screening tests when evaluating excessive bleeding can include:

A
  • Platelet count and blood smear to evaluate for thrombocytopenia or other hematologic abnormalities
  • Bleeding time or platelet function analyzer (PFA-100) to evaluate primary hemostasis
  • APTT as a screening test for the intrinsic coagulation pathway
  • PT/INR as a screening test for the extrinsic coagulation pathway
  • Thrombin clotting time (TCT) to evaluate for fibrinogen defects, the presence of fibrin split products, or heparin effects
  • Fibrinogen level

Each of these tests may be the single abnormal test in bleeding disorders present in an outpatient.

Unit 3 B&L (18 decks)

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