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Hemostasis and Related Disorders

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HEMOSTASIS
A. Integrity of the blood vessel is necessary to carry blood to tissues.
1. Damage to the wall is repaired by hemostasis, which involves formation of a
thrombus (clot) at the site of vessel injury.
B. Hemostasis occurs in two stages: primary and secondary.
1. Primary hemostasis forms a weak platelet plug and is mediated by interaction
between platelets and the vessel wall.
2. Secondary hemostasis stabilizes the platelet plug and is mediated by the
coagulation cascade

PRIMARY HEMOSTASIS AND RELATED BLEEDING DISORDERS
I. PRIMARY HEMOSTASIS
A. Step 1- Transient vasoconstriction of damaged vessel
1. Mediated by reflex neural stimulation and endothelin release from endothelial
cells
B. Step 2- Platelet adhesion to the surface of disrupted vessel
1. Von Willebrand factor (vWF) binds exposed subendothelial collagen.
2. Platelets bind vWF using the GPib receptor.
3. vWF is derived from the Weibel-Palade bodies of endothelial cells and
a-granules of platelets.
C. Step 3-Platelet degranulation
1. Adhesion induces shape change in platelets and degranulation with release of
multiple mediators.
i. ADP is released from platelet dense granules; promotes exposure of GPIIb/
Lila receptor on platelets.
ii. TXA2 is synthesized by platelet cyclooxygenase (COX) and released;
promotes platelet aggregation
D. Step 4- Platelet aggregation
1. Platelets aggregate at the site of injury via GPIIb/IIIa using fibrinogen (from
plasma) as a linking molecule; results in formation of platelet plug
2. Platelet plug is weak; coagulation cascade (secondary hemostasis) stabilizes it.

II. DISORDERS OF PRIMARY HEMOSTASIS
A. Usually due to abnormalities in platelets; divided into quantitative or qualitative
disorders
B. Clinical features include mucosal and skin bleeding.
l. Symptoms of mucosal bleeding include epistaxis (most common overall
symptom), hemoptysis, GI bleeding, hematuria, and menorrhagia. Intracranial
bleeding occurs with severe thrombocytopenia.
2. Symptoms of skin bleeding include petechiae (1-2 mm, Fig. 4.1), ecchymoses
(> 3 mm), purpura(> 1 em), and easy bruising; petechiae are a sign of
thrombocytopenia and are not usually seen with qualitative disorders.

C. Useful laboratory studies include
l. Platelet count-normallS0-400 ~L; < 50 ~L leads to symptoms.
2. Bleeding time-norma12-7 minutes; prolonged with quantitative and qualitative
platelet disorders
3. Blood smear- used to assess number and size of platelets
4. Bone marrow biopsy-used to assess megakaryocytes, which produce platelets

III. IMMUNE THROMBOCYTOPENIC PURPURA (ITP)
A. Autoimmune production ofigG against platelet antigens (e.g., GPI!b/IIIa)
1. Most common cause of thrombocytopenia in children and adults
B. Autoantibodies are produced by plasma cells in the spleen.
C. Antibody-bound platelets are consumed by splenic macrophages, resulting in
thrombocytopenia.
D. Divided into acute and chronic forms
1. Acute form arises in children weeks after a viral infection or immunization; selflimited, usually resolving within weeks of presentation
2. Chronic form arises in adults, usually women of childbearing age. May be
primary or secondary (e.g., SLE). May cause short-lived thrombocytopenia in
offspring since antiplatelet IgG can cross the placenta.
E. Laboratory findings include
l. J.. platelet count, often < 50 ~L
2. Normal PT/PTT-Coagulation factors are not affected.
3. t megakaryocytes on bone marrow biopsy
F. Initial treatment is corticosteroids. Children respond well; adults may show early
response, but often relapse.
1. IVIG is used to raise the platelet count in symptomatic bleeding, but its effect is
short -lived.
2. Splenectomy eliminates the primary source of antibody and the site of platelet
destruction (performed in refractory cases).

IV. MICROANGIOPATHIC HEMOLYTIC ANEMIA
A. Pathologic formation of platelet microthrombi in small vessels
l. Platelets are consumed in the formation of microthrombi.
2. RBCs are “sheared” as they cross microthrombi, resulting in hemolytic anemia
with schistocytes (Fig. 4.2).
B. Seen in thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic
syndrome (HUS)
C. TTP is due to decreased ADAMTS13, an enzyme that normally cleaves vWF
multimers into smaller monomers for eventual degradation

l. Large, uncleaved multimers lead to abnormal platelet adhesion, resulting in
m icrothrombi.
2. Decreased ADAMTS13 is usually due to an acquired autoantibody; most
commonly seen in adult females
D. HUS is due to endothelial damage by drugs or infection.
l. Classically seen in children with E coli Ol57:H7 dysentery, which results from
exposure to undercooked beef
2. E coli verotoxin damages endothelial cells resulting in platelet microthrombi.
E. Clinical findings (H US and TTP) include
l. Skin and mucosal bleeding
2. M icroangiopathic hemolytic anemia
3. Fever
4. Renal insufficiency (more common in HUS)- Thrombi involve vessels of the
kidney.
5. CNS abnormalities (more common in TTP)- Thrombi involve vessels of the
CNS.
F. Laboratory findings include
l. Thrombocytopenia with t bleeding time
2. Normal PT/ PTT (coagulation cascade is not activated)
3. Anemia with schistocytes
4. t megakaryocytes on bone marrow biopsy
G. Treatment involves plasmapheresis and corticosteroids, particularly in TTP.

V. QUALITATIVE PLATELET DISORDERS
A. Bernard-Soulier syndrome is due to a genetic GPib deficiency; platelet adhesion is
impaired.
1. Blood smear shows mild thrombocytopenia with enlarged platelets.
D. Glanzmann thrombasthenia is due to a genetic GPIIb/IIIa deficiency; platelet
aggregation is impaired.
C. Aspirin irreversibly inactivates cyclooxygenase; lack ofTXA2 impairs aggregation.
D. Uremia disrupts platelet function; both adhesion and aggregation are impaired.

SECONDARY HEMOSTASIS AND RELATED DISORDERS
I. SECONDARY HEMOSTASIS
A. Stabilizes the weak platelet plug via the coagulation cascade
l. Coagulation cascade generates thrombin, which converts fibrinogen in the
platelet plug to fibrin.
2. Fibrin is then cross-linked, yielding a stable platelet-fibrin thrombus.
B. Factors of the coagulation cascade are produced by the liver in an inactive state.
Activation requires
l. Exposure to an activating substance
i. Tissue thromboplastin activates factor VII (extrinsic pathway).
ii. Subendothelial collagen activates factor XII (intrinsic pathway).
2. Phospholipid surface of platelets
3. Calcium (derived from platelet dense granules)

II. DISORDERS OF SECONDARY HEMOSTASIS
A. Usually due to factor abnormalities
B. Clinical features include deep tissue bleeding into muscles and joints (hemarthrosis)
and rebleeding after surgical procedures (e.g., circumcision and wisdom tooth
extraction).
C. Laboratory studies include
1. Prothro

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