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STEP 1 Pathoma > Chapter 4 > Flashcards

Chapter 4 Flashcards

1
Q

Primary vs Secondary Hemostasis

A

Primary- formation of a weak platelet plug mediated by interaction between platelets and the vessel wall

Secondary- hemostasis stabilizes the platelet plug and is mediated by the coagulation cascade

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2
Q

Primary Hemostasis Steps 1 and 2

A

1) Transient vasoconstriction of a damaged vessel mediated by reflex neural stimulation and endothelin release from endothelial cells
2) Platelet adhesion to the vessels- vMF from Weibel Palade bodies of endothelial cells and a-granules of platelets bind to the exposed subendothelial collagen and platelets bind to vMF via GP1b

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3
Q

Primary Hemostasis Step 3

A

Platelet degranulation- adhesion induces shape change in platelets and degranulation with release of multiple mediators including:
ADP from dense granules to promote exposure of GPIIb/IIIa receptor on platelets

TXA2 is synthesized by COX and released to promote platelet aggregation

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4
Q

Primary Hemostasis Step 4

A

Platelet aggregation- platelets aggregate at the site of injry via GPIIb/IIIA using fibrinogen from plasma as a linking molecule, resulting in a WEAK platelet plug that is stabilized by the coag cascade

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5
Q

What are the clinical features of defects in primary hemostasis (typically in platelets)?

A

Mucosal bleeding including epistaxis, hemoptysis, GI bleeding, heamturia, and menorrhagia. Intracranial bleeds can occur

Skin bleeding including petechiae (1-2mm), purpura (3+ mm), and ecchymoses (1+cm) and easy brusing

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6
Q

Petechiae are a sign of __________

A

thrombocytopenia and are not usually seen with qualitative defects

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7
Q

Normal platelet count: 150-400 K/ul (less than 50 leads to symptoms)

Bleeding time- normal 2-7 minutes; prolonged with quantitative and qualitative platelet disorders

A
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8
Q

What causes Immune thrombocytopneic purpura (ITP)?

A

Autoimmune production of IgG against platelet antigens like GPIIb/IIIa (most common cause of thrombocytopenia in children and adults)- These auto-Abs are produced by plasma cells in the spleen and Ab-bound platelets are consumed by splenic macrophages resulting in thrombcytopenia

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9
Q

What are the forms of ITP?

A

Acute- arises in children weeks after a viral infection or immunization; self-limited

Chronic forms arises in adults, usually childbearing aged women

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10
Q

What are the lab findings of ITP?

A
  • low platelets
  • normal PT/PTT (coag factors not affected)
  • Increased megakaryocytes on bone marrow biopsy
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11
Q

How is ITP tx?

A

Initially with steroids. Children respond well and adults may show early response but often relapse

IVIG to raise the platelet count in symptomatic bleeding but its effects are shoft lived

Splenectomy

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12
Q

What is microangiopathic hemolytic anemia?

A

Pathologic formation of platelet microthrombi in small vessels resulting in consumption of platelets and ‘shearing” of RBCs as they pass, resulting in hemolytic anemia with schistocytes

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13
Q

Microangiopathic hemolytic anemia is seen in what diseases?

A

Thrombotic thrombocytopenic purpura (TTP) and HUS

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14
Q

What causes TTP?

A

decreased ADAMST13, an enzyme that normally cleaves vMF multimers into smaller monomers for eventual degradation. Large multimers lead to abnormal platelet adhesion

Common in adult females

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15
Q

What causes HUS?

A

Endothelial dmaage by drugs or infection classically seen in children with E. ColI 0157:H7 dysentery

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16
Q

What are the clinical findings of HUS and TTP?

A

skin and mucosal bleeding

microangiopathic hemolytic anemia

fever

renal insufficiency (more common in HUS)

CNS abnormalities (more common in TTP)

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17
Q

What are the lab findings of HUS and TTP?

A

Thrombocytopenia with icnreased bleeding time

Normal PT/PTT

Anemia with schistocytes

Elevated megakaryoctes on bone marrow biopsy

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18
Q

What is the tx of Microangiopathic hemolytic anemia in TTP and HUS?

A

Plasmapheresis and steroids, esepcially in TTP

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19
Q

What is Bernard Soulier disease?

A

GPIb deficiency

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20
Q

What is Glanzmann thrombasthenia?

A

GPIIb/IIIa deficiency

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21
Q

Note that ______ disrupts platelet functioning; both adhesion and aggregation are impaired

A

uremia

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22
Q

Describe secondayr hemostasis

A

Designed to stabilize the weak platelet plug via the coag cascade in which thrombin is generated and that covnerts fibrinogen in the plug to fibrin

NOTE: Factors of the coag cascade are made in the liver in an inactive state and activation requires:

1) Exposure to an activating source such as tissue thromboplastin activating factor VII or subendothelial collagen activating factor XII
2) Phospholipid surface of platelets
3) Calcium (from platelet dense granules)

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23
Q

What are the clinical features of coag factor defects?

A

deep tissue bleeding into muscle and joints (hemarthrosis) and rebleeding after surgical procedures (e.g. circumcision and wisdom tooth extraction)

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24
Q

What are the main lab marked of the efficiency of the coag cascade?

A

1) PT time measures extrinsic (VII) and common (II, V, X, and fibrinogen) pathways
2) PTT time measures intrinsic (XII, XI, IX, and VIII) and common (II, V, X, and fibrinogen) pathways

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25
Q

What causes Hemophilia A?

A

genetic factor VIII deficiency (X-linked recessive; affects males; can arise de novo)

26
Q

How does Hemophilia A present?

A

deep tissue, joint, and postsurgical bleeding

27
Q

What are the lab findings of Hemophilia A (tx with recombinant factor VIII)?

A

elevated PTT

normal PT

decreased factor VIII

Normal platelet count and bleeding time

28
Q

What causes Christmas Disease?

A

aka Hemophilia B, factor IX deficiency

same labs as Hemophilia A except factor IX is low

29
Q

What is Von Willebrand Disease?

A

A genetic VMF deficiency (most common inherited coag disorder)- multiple subtypes exist causing quantitative and qualitative defects (the most common type is AD with decreased vMF levels)

30
Q

How does Von Willebrand Disease present?

A

with mild mucosal and skin bleeding; low vMF impairs platelet adhesion

31
Q

What are the lab findings of Von Willebrand Disease?

A

increased bleeding ime

elevated PTT; normal PT- Due to decreased FVIII half-life (vMF normally stabilizes FVIII); however, deep tissue, joints, and postersurgical bleeding are usually not seen

Abnormal ristocetin test-Ristocetin induces platelet agglutination by causing vMF to bind platelet GPIb; lack of vMF= impaired agglutination- abnormal test

32
Q

How is Von Willebrand Disease tx?

A

desompression (ADH analog) which increased vMF release from Weibel-Palade bodies of endothelial cells

33
Q

How does vitK deficiency present?

A

It disrupts the function of multiple coag factors (vitK is activated by epoxide reductase in the liver and activated vitK gamma carboxylates factors II, VII, IX, X, and proteins C and S)

34
Q

VitK deficiency is common:

A

1) In newborns de to lack of GI colonization by bacteria that normally synhtesize vitK; vitK injections are given prophyalically to all newborns at birth
2) Long term ABX therapy
3) Malabsorption

35
Q

What are some other causs of abnormal 2ndary hemostasis?

A

1) Liver failure- decreased production of coag factors and decreased activaiton of vitK by epoxide reductase
2) Large-volume transfusion dilutes coag factors

36
Q

What is Heparin-Induced Thrombocytopenia?

A

Platelet destruction secondary to heparin therapy (may lead to thrombosis)

37
Q

What causes Disseminated Intravascular Coagulation (DIC)?

A

This is the pathologic activation of the coag cascade resulting in widespread microthrombi that cause ischemia and infarct as well as bleeding.

38
Q

DIC occurs almost always secondary to another disease. Name some:

A
  1. Obstetric complications-tissue thromboplastin in the amniotic fluid activates coag
    2) Sepsis (especially with E. Coli or N. meningitis)= endotoxins form the bacterial wall and cytokines (e.g. TNF and IL1) induce endothelial cells to make tissue factor
    3) Adenocarcinoma-mucin activates coag
    4) Acute promyelocytic leukemia- primary grnaules activate coag
    5) Rattlesnake bite
39
Q

What are the lab findings of DIC?

A

decreased platelets and fibrinogen

elevated PT and PTT

microangiopathic hemolytic anemia

Elevated fibrin split products, particularly D-Dimer (Best screen for DIC; derived from splitting of cross-linked fibrin)

40
Q

How is DIC tx?

A

Address underlying cause and tranfuse blood porducts and cryoprecipitate

41
Q

Describe fibrinolysis

A

Normal fibrinolysis removes thrombi after the damage vessel healds and is dependent on tPA to covnert plasminogen to plasmin, which clevaes fibrin, destroys caog factors, and blocks platelet aggregation.

42
Q

__________ inactivates plasmin

A

a2-antiplasmin

43
Q

Disorders of fibrinolysis are due to plasmin overactivity resulting in excessive cleavage of serum fibrinogen. Ex:

A

1) Radical prostatectomy-release of urokinase activates plasmin
2) Liver cirrhosis- reduced production of a2-antiplasmin

These present with increased bleeding resembling DIC

44
Q

How might disorders of overactive plasmin appear in labs?

A

1) elavted PT and PTT-plasmin destroys coag factors
2) Elevated bleeding time with normal platelet count- plasmin blocks platelet aggregation
3) Increased fibrinogen split products without D-dimers- serum fibrinogen is lysed; however, D-dimers are not formed because fibrin thrombi are absent

45
Q

How would disorders of overactive plasmin be tx?

A

aminocaproic acid, which blocks activation of pasminogen to plasmin

46
Q

What are thrombi marked by?

A

Lines of Zahn

47
Q

What is the Virchow Triad of hypercoagulability?

A

Disruption of Blood Flow

Endothelial Cell Damage

Hypercoaguable State

48
Q

How do disturbances in blood flow lead to thrombi?

A

Normal laminar blood flow keeps platelets and factors dispersed and inactivated. Ex include immobiliaztion, cardiac wall dsyfunction, and aneurysm

49
Q

How do endothelial cells prevent thrombosis normally?

A

1) Block exposure to subendothelial collagen and underlying tissue factor
2) Produce PGI2 and NO
3) Secrete heparin like molecules, which augment antihtrombin III, which inactivated thrombin ad coag factors
4) Secrete tPA which converts plasminogen to plasmin
5) Secrete thrombomodulin which redirects thrombin to activate protein C, which inactivates factors V and VIII

50
Q

Causes of endothelial damage include:

A

1) atherosclerosis
2) Vasculitis
3) Elevated homocysteine

51
Q

What things elevate homocysteine levels?

A

VitB12 and folate deficiency

Folic acid (THF) circulates as methyl-THF in serum. The methyl is transferred to cobalamin (VitB12), allowing THF to participate in the synthesis of DNA precursors. Cobalamin tranfers the methyl to homcysteiene resulting in methionine.

Lack of B12 or folate = buildup of homocysteine

52
Q

What else can raise homocsysteine levels?

A

Cystathionine beta synthase (BCS) deficiency = eleavted homocysteine levels with homocystinuria

CBS converts homocysteine to cystathionine

53
Q

How does CBS deficiency present?

A

vessel thrombosis, mental retardation, lens dislocation, and long slender fingers

54
Q

What are the main genetic causes of a hypercoagulable state (as classically marked by reucrrent DVTs at a young age)?

A

1) Protein C/S deficiency (AD)- lack of inactivation of factors V and VIII
2) Factor V Leiden- mutated form of FV that is resistant to cleavage by proteins C/S (most common)
3) Prothrombin 20210A- inherited point utation in prothrombin that results in increased gene expression= more thrombin
4) ATIII deficiency

55
Q

Protein C/S deficiency (AD) increases the risk of what?

A

Warfarin skin necrosis- the intitial stage of warfarin therapy results in a temporary deficiency of proteins C and S due to their shorter half-life relative to factors II, VII, IX, and X. In preexisting C or S deficiency, a severe deficiency is seen at the osnet of warfarin therpay increasing the risk for thrombi, especially in the skin

56
Q

Describe ATIII deficiency

A

ATIII deficiency decreases the protective effect of heparin-like molecules produced by the endothelium, increasing the risk of thrombus. (heparin like molcules usually activate ATIII, which inactivates thrombin and coag factors)

In ATIII deficiency, PTT does not rise with standard heparin dosing.

57
Q

What else classically causes a hypercoaguable state?

A

Oral contraceptives- estrogen induces increased production of coag factors

58
Q

What are the main types of emboli?

A

Thromboemoblus (95%)

Atherosclerotic emboli

Fat emboli

Gas emboli

Amniotic fluid emboli

59
Q

Atherosclerotic emboli- marked by cholesterol clefts

A

Fat emboli- associated with bone fracturs, particularly long bones and soft tissue trauma. Develops while fracture is still present or shortly after repair

Marked by dyspnea and petechiae on the overlying skin

60
Q

Gas Emboli- classically seen in decompression sickness

-Nitrogen gas precipitates out of blood due to rapid ascent: present with muscle and joint pain and respiratory symptoms

A
61
Q

Pulmonary emboli most commonly arise from where?

A

femoral, iliac, or popliteal veins

STEP 1 Pathoma (18 decks)

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