GI: Hemostasis and Related Disorders

Question 1

• Forms a weak platelet plug and is mediated by interaction between platelets and the vessel wall

Answer 1

Primary Hemostasis

Question 2

• Stabilizes the platelet plug and is mediated by the coagulation cascade

Answer 2

Secondary Hemostasis

Question 3

1. Transient Vasoconstriction of Damaged vessel
   
   • Reflex neural stimulation
   • Endothelin release from endothelial cells
2. Platelet adhesion to the surface of disrupted vessel
   
   • Von Willebrand factor -> Subendothelial collagen
   • Platelets –> VWF w/ GPIb
   • VWF from Weibel-Palade bodies of endothelial cells and α-granules of platelets
3. Platelet degranulation
   
   • ADP –> promotes GPIIb/IIIa receptor on Platelets
   • TXA₂ –> syn. by Platelet COX –> promotes platelet aggregation
4. Platelet aggregation
   
   • Fibrinogen –> Platelet plug
   • Coag cascade stabilized plug

Answer 3

Primary Hemostasis Steps

Question 4

• Autoimmune IgG against Platelet antigens (GPIIb/IIIa)
• Most common form of Thormbocytopenia
• Splenic macrophages consume Ab-Platelets –> Thrombocytopneia and Splenomegaly
• Acute –> Children, weeks after Viral infection or immunization, self-limited, resolves w/in weeks
• Chronic –> Adults, Women of childbearing age, Primary or Secondary (SLE), Thrombocytopenia in offspring since antiplatelet IgG can cross the Placenta
• Decreased Platelet count < 50K
• Normal PT/PTT
• Increased Megakaryocytes in Bone marrow
• Tx: Corticosteroids –> Splenectomy (source + destro.)

Answer 4

Immune Thrombocytopenic Purpura (ITP)

Question 5

• Platelet Microthrombi in Small vessels
• Cosumed in the formation of microthrombi
• RBCs are “sheared” –> Hemolytic anemia –> Schistocytes
• A/w Thrombotic Thrombocytopenic Purpura (TTP) and Hemolytic Uremic Syndrome (HUS)
• TTP is due to decreased ADAMTS13 –> enzyme that normally cleaves vWF multimers into smaller monomors for degradation. –> uncleave microthrombi –> decreased ADAMTS13 due to autoantibody (adult females)
• HUS –> endothelial damage by Drugs of Infection
• A/w Children w/ E coli O157:H7 dysentery (raw beef)
• E coli Verotoxi dmgs Endothelial cells –> platelet microthrombi
• HUS –> Renal insufficiency and Kidney thrombi
• TTP –> CNS abnormalities w/ CNS vessel thrombi
• Thrombocytopenia w/ Increased Bleeding time
• Normal PT/PTT
• Anemia w/ Schistocytes
• Increased Megakaryocytes

Answer 5

Microangiopathic Hemolytic Anemia

Question 6

• Qualitative Platelet Disorder
• Genetic GPIb deficiency
• Platelet adhesion is impaired
• Blood smear shows mild Thrombocytopenia w/ enlarged platelets (immature)

Answer 6

Bernard-Soulier Syndrome

Question 7

• Qualitative Platelet Disorder
• Genetic GPIIb/IIIa deficiency
• Platelet aggregation impaired

Answer 7

Glanzmann Thrombasthenia

Question 8

• Irreversibly inactivates Cycloxygenase
• Lack of TXA₂ impairs aggregation
• PT/PTT normal

Answer 8

Aspirin

Question 9

• Disrupts Platelet function; both Adhesion and Aggregation are impaired

Answer 9

Uremia

Question 10

• Exposure to an activating substance
  
  • Tissue Thromboplastin activates Factor VII (Extrinsic)
  • Subendothelial collagen activates Factor XII (intrinsic)
  • Phospholipid surface of platelets
• Phospholipid surface of platelets
• Calcium (derived from platelt dense granules)

Answer 10

Activating Factors of the Coagulation Cascade

Question 11

• Factor VIII deficiency
• X-linked recessive
• Can arise de novo (spontaneously)
• A/w DVT, Joint, and Post-surgical bleeding
• Increased PTT
• normal PT
• decreased FVIII
• Normal platelet count and bleeding time
• Tx: Recombinant FVIII

Answer 11

Hemophilia A

Question 12

• Genetic FIX deficiency
• Resembles Hemophilia A
• FIX lvls decreased instead of FVIII

Answer 12

Hemophilia B (Christmas Disease)

Question 13

• Acquired Ab against Coagulation factor resulting in Impaired factor
• ex. anit-FVIII is the most common
• PTT or PT does not correct upon mixing normal Plasma w/ Pts. Plasma due to overabundance of Inhibitor
• Tested using a Normal Correcting Study

Answer 13

Coagulation Facotr Inhibitor

Question 14

• Most common Inherited Coagulation Disorder
• Quantitative and Qualitative defects
• Autosomal dominant decreased vWF lvls
• Mild mucosal and Skin bleeding
• Low vWF impairs Platelet adhesion
• Increased Bleeding time
• Increased PTT
• Normal PT
• Decreased FVIII half-live (vWF normally stabilizes)
• Abnormal Ristocetin Test - induces platelet agglutination by causing vWF to bind GPIb –> Impaired Agglutination
• Tx: Desmopressin (ADH analog) –> Increases vWF release from Weibel-Palade bodies

Answer 14

Von Willebrand Disease

Question 15

• Activated by Epoxide reductase in Liver
• Activated vitamin K gamma, carboxylates Factors II, VII, IX, X, and Proteins C and S
• In Newborns, due to lack of GI colonization
• Tx: Vitamin K injection prophylactically to all newborns
• Long-term ABX - disrupts Vit. K - producing bacteria in the GI tract
• Malabsorption - leads to def. of Fat-soluble Vit. ADEK

Answer 15

Vitamin K deficiency

Question 16

• Pathologic activation of Coagulation cascade
• Widespread microthrombi –> ischemia and infarction
• Bleeding from IV sites and Mucosal surfaces –> consumption of platelets and factors
• Almost always secondary to another Disease process
• Obsetetric complications - amniotic thromboplastin
• Sepsis - E. coli, N meningitidis - Endotoxins and Cytotoxins (TNF and IL-1) induce Endothelial cells to make TF
• Adenocarcinoma - Mucin activates coagulation
• Acute promyelocytic leukemia - primary granules activate
• Rattlesnake bite - venom activates coagulation
• DDx: Elevated D-Dimer best screening test

Answer 16

Disseminated Intravascular Coagulation (DIC)

Question 17

• Mildly elevated Homocysteine lvls –> Increased risk of Thrombosis
• Folic acid (Tetrahydrofolate, THF) circulates as methyl-THF in the serum
• Methyl is transferred to Cobalamin, allowing THF to participate in DNA synthesis as a precursor
• Cobalamin transfers methy to Homocystein –> Methionine
• Decreased conversion of Homocysteine –> Cystathionine Beta Synthase (CBS) deficiency –> Vessel thrombosis, Mental retardation, Lens of dislocation, and Long-slender fingers

Answer 17

Vitamin B12 and Folate Deficiency

Question 18

• Autosomal dominant
• Decreases negative feedback on the Coagulation cascade
• Proteins normally inactivate FV and FVIII
• Increased risk w/ Warfarin skin necrosis

Answer 18

Protein C or S deficiency

Question 19

• Mutated form of Factor V that lacks the cleavage site for deactivation by Protein C and S
• Most common inherited cause of Hypercoagulable state

Answer 19

Factor V Leiden

Question 20

• Inherited point mutation in Prothrombin that results in Increased gene expression
• Increased Prothrombin results in increased Thrombin
• -> promoting Thrombus formation

Answer 20

Prothrombin 20210A

Question 21

• Decreases the protective effect of Heparin-like molecules produced by the Endothelium –> Increasing the Risk of Thrombosis
• ATIII normally activated –> inactivates Thrombin and Coagulation Factors
• ATIII def., PTT does not rise w/ standard Heparin Dosing
• Pharmacologic Heparin works by binding and activating ATIII

Answer 21

ATIII deficiency