CH4.txt

Damage to the wall is repaired by hemostasis,

a thrombus (clot) at the site of vessel injury

primary and secondary.

forms a weak platelet plug

interaction between platelets and the vessel wall

stabilizes the platelet plug

the coagulation cascade.

Transient vasoconstriction of damaged vessel

by reflex neural stimulation and endothelin release from endothelial cells

Platelet adhesion to the surface of disrupted vessel

Von Willebrand factor (vWF) binds exposed subendothelial collagen,

via the GPIb receptor

the Weibel-Palade bodies of endothelial cells and a-granules of platelets.

Platelet degranulation

shape change in platelets and degranulation with release of multiple mediators

ADP and TXA

it is released from platelet dense granules; promotes exposure of GPIIb/IIIa receptor on platelets.

it is synthesized by platelet cyclooxygenase (COX) and released; promotes platelet aggregation

Step 4—Platelet aggregation

at the site of injury via GPIIb/IIIa using fibrinogen (from plasma) as a linking molecule;

formation of platelet plug

It is weak; coagulation cascade (secondary hemostasis) stabilizes it.

Usually due to abnormalities in platelets;

quantitative or qualitative disorders

mucosal and skin bleeding.

epistaxis

epistaxis, hemoptysis, GI bleeding, hematuria, and menorrhagia. Intracranial bleeding occurs with severe thrombocytopenia.

include petechiae (1-2 mm), ecchymoses (> 3 mm), purpura (> 1 cm), and easy bruising;

thrombocytopenia and are not usually seen with qualitative disorders.

platelet count, bleeding time, blood smear, bone marrow biopsy

normal 150-400 K/pL; < 50 K/pL leads to symptoms,

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

used to assess number and size of platelets

used to assess megakaryocytes, which produce platelets

(ITP) is an autoimmune production of IgG against platelet antigens (GPIIb/IIIa)

immune thrombocytopenic purpura

Antibody-bound platelets are consumed by splenic macrophages

acute and chronic forms

arises in children weeks after a viral infection or immunization;selflimited, usually resolving within weeks of presentation

arises in adults, usually women of chilbearing age. May be primary or secondary (e.g SLE).

May cause short-lived thrombocytopenia in offspring since antiplatelet IgG can cross the placenta.

decreased platelet count, often < 50 K/pL, Normal PT/FTT, Coagulation factors are not affected. increased megakaryocytes on bone marrow biopsy

corticosteroids.

Children respond well; adults may show early response, but often relapse.

IVIG is used to raise the platelet count in symptomatic bleeding, but its effect is short-lived,

Splenectomy eliminates the primary source of antibody and the site of platelet destruction (performed in refractory cases).

Pathologic formation of plateletmicrothrombin small vessels

Platelets are consumed in the formation of microthrombi sheering the RBCs as they cross microthrombi, resulting in hemolytic anemiawith schistocytes

thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS)

decreased ADAMTS13 which is an enzyme that normally cleaves vWF multimers into smaller monomers for eventual degradation.

1. Large, uncleaved multimers lead to abnormal platelet adhesion, resulting in microthrombi.

an acquired autoantibody;

adult females

Hemolytic uremic syndrome is due to endothelial damage by drugs or infection.

children with E coli G157;H7 dysentery, which results from exposure to undercooked beef

E coli verotoxin damages endothelial cells resulting in platelet microthrombi

Skin and mucosal bleeding, Microangiopathic hemolytic anemia, Fever, Renal insufficiency, CNS abnormalities

HUS — thrombi involve vessels of the kidney

TTP — Thrombi involve vessels of the CNS

Thrombocytopenia with increased bleeding time Normal PT/PTT (coagulation cascade is not activated), anemia with schistocytes, increased megakaryocytes on bone marrow biopsy

involves plasmapheresis and corticosteroids, particularly in TTP.

bernard-soulier, Glanzmann thrombasthenia, asprin, uremia

is due to a genetic GPIb deficiency; platelet adhesion is impaired.

Blood smear which shows mild thrombocytopenia with enlarged platelets.

a genetic GPIIb/IIIa deficiency; platelet aggregation is impaired.

it irreversibly inactivates cyclooxygenase; lack of TXA, impairs aggregation.

disrupts platelet function; both adhesion and aggregation are impaired.

Stabilizes the weak platelet plug via the coagulation cascade

thrombin, which converts fibrinogen in the platelet plug to fibrin.

It is cross-linked, yielding a stable platelet-fibrin thrombus.

In the liver in an inactive state.

exposure to an activating substance, Phospholipid surface of platelets, calcium

Tissue thromboplastin activates factor VII (extrinsic pathway). Subendothelial collagen activates factor XII (intrinsic pathway).

derived from platelet dense granules

factor abnormalities

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

PT (prothrombin time) and PTT (partial thromboplastin time)

measures extrinsic (factor VII) and common (factors II, V, X, and fibrinogen) pathways of the coagulation cascade

factor VII

factors II, V, X, and fibrinogen

intrinsic (factors XII, XI, IX, VIII) and common (factors II, V, X, and fibrinogen) pathways of the coagulation cascade

Genetic factor VIII (FVIII) deficiency, X-linked recessive (predominantly affects males)

Can arise from a new mutation (de novo) without any family history

deep tissue, joint, and postsurgical bleeding

the degree of deficiency

1. increased PTT; normal PT 2. decreased FVIII 3. Normal platelet count and bleeding time

recombinant FVIII.

Hemophilia B - Genetic factor IX deficiency, Resembles hemophilia A, except FIX levels are decreased instead of FVIII

Acquired antibody against a coagulation factor resulting in impaired factor function; anti-FVIII is most common,

its similar to hemophilia A, PTT does not correct upon mixing normal plasma with patient's plasma (mixing study) due to inhibitor; PTT does correct in hemophilia A.

mixing study

Genetic vWF deficiency

von Willebrand disease

Multiple subtypes exist, causing quantitative and qualitative defects;

is autosomal dominant with decreased vWF levels

mild mucosal and skin bleeding; low vWF impairs platelet adhesion.

1. increased bleeding time 2. increased PTT: normal PT — Decreased FVIII half-life (vWF normally stabilizes FVIII); 3. Abnormal ristocetin test

deep tissue, joint, and postsurgical bleeding are usually not seen.

Ristocetin induces platelet aggregation by causing vWF to bind platelet GPIb; lack ofvWF —> impaired aggregation —> abnormal test.

desmopressin (ADH analog), which increases vWF release from Weibel-Palade bodies of endothelial cells

Disrupts function of multiple coagulation factors

Vitamin K is activated by epoxide reductase in the liver

it gamma carboxvlates factors II, VII, IX, X, and proteins C and S; gamma carboxylation is necessary for factor function.

1. Newborns 2. Long-term antibiotic therapy 3. Malabsorption

its due to lack of GI colonization by bacteria that normally synthesize vitamin K; vitamin K injection is given prophylactic ally to all newborns at birth to prevent hemorrhagic disease of the newborn

disrupts vitamin K-producing bacteria in the GI tract

leads to deficiency of fat-soluble vitamins, including vitamin K

liver failure, large volume transfusion,

decreased production of coagulation factors and decreased activation of vitamin K by epoxide reductase;

followed using PT.

it dilutes coagulation factors, resulting in a relative deficiency

Platelet destruction that arises secondary to heparin therapy

Fragments of destroyed platelets may activate remaining platelets, leading to thrombosis

Pathologic activation of the coagulation cascade

1. Widespread microthrombi result in ischemia and infarction, 2. Consumption of platelets and factors results in bleeding, especially from IV sites and mucosal surfaces (bleeding from body orifices).

Almost always secondary to another disease process

Obstetric complications, sepsis, adenocarcinoma, Acute promyelocytic leukemia, Rattlesnake bite

Tissue thromboplastin in the amniotic fluid activates coagulation

(especially with E. coli or Neisseria meningitidis) — Endotoxins from the bacterial wall and cytokines (e.g TNF and IL-1) induce endothelial cells to make tissue factor.

Mucin activates coagulation.

Primary granules activate coagulation.

Venom activates coagulation

decreased platelet count, increased PT/PTT, decreased fibrinogen, Microangiopathic hemolytic anemia, Elevated fibrin split products, particularly D-dimer

Elevated D-dimer

splitting of cross-linked fibrin; D-dimer is not produced from splitting of fibrinogen.

addressing the underlying cause and transfusing blood products and cryoprecipitate (comains coagulation factors), as necessary.

Normal fibrinolysis removes thrombus after damaged vessel heals

converts plasminogen to plasmin

cleaves fibrin and serum fibrinogen, destroys coagulation factors, and blocks platelet aggregation.

inactivates plasmin.

plasmin overactivity resulting in excessive cleavage of serum fibrinogen.

radical prostatectomy, cirrohsis of the liver

Release of urokinase activates plasmin

reduced production of a2-antiplasmin

with increased bleeding (resembles DIC)

Increased PT/PTT, increased bleeding time with normal platelet count, Increased fibrinogen split products without D-dimers

Serum fibrinogen is lysed; however, D-dimers are not formed because fibrin thrombi are absent

Plasmin blocks platelet aggregation

Plasmin destroys coagulation factors.

it is aminocaproic acid, which blocks activation of plasminogen.

Pathologic formation of an intravascular blood clot (thrombus), Can occur in an artery or vein,

it is the deep veins (DVT) of the leg below the knee

lines of Zahn and attachment to vessel wall

alternating layers of platelets/fibrin and RBCs

lines of Zahn and attachment to vessel wall

disruption in blood flow, endothelial cell damage, and hypercoagulable state (Virchow triad)

blood flow is normally continuous and laminar; keeps platelets and factors dispersed and inactivated

Stasis and turbulence of blood flow increases risk for thrombosis

Immobilization—increased risk for deep venous thrombosis 2. Cardiac wall dysfunction (e.g arrhythmia or myocardial infarction) 3. Aneurysm

Endothelial damage disrupts the protective function of endothelial cells, increasing the risk for thrombosis

1. Block exposure to subendothelial collagen and underlying tissue factor 2. Produce prostacyclin (PGI2) and NO, 3. Secrete heparin-like molecules, 4. Secrete tissue plasminogen activator (tPA) 5. Secrete thrombomodulin

converts plasminogen to plasmin, which (1) cleaves fibrin and serum fibrinogen, (2) destroys coagulation factors, and (3) blocks platelet aggregation

redirects thrombin to activate protein C, which inactivates factors V and VIII

augment antithrombin III (ATIII) which inactivates thrombin and coagulation factors

vasodilation and inhibition of platelet aggregation

atherosclerosis, vasculitis, and high levels of homocysteine

mildly elevated homocysteine levels, increasing the risk for thrombosis.

methyl-THF (tetrahydrofolate, THF) in the serum,

Methyl is transferred to cobalamin (vitamin B12) which transfers methyl to homocysteine resulting in methionine

decreased conversion of homocysteine to methionine resulting in buildup of homocysteine

high homocysteine levels with homocystinuria,

CBS converts homocysteine to cystathionine

homocysteine buildup

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

excessive procoagulant proteins or defective anticoagulant proteins; may be inherited or acquired

recurrent DVTs or DVT at a young age, usually occurs in the deep veins of the leg; other sites include hepatic and cerebral veins

protein C and S deficiency, factor V Liden deficiency, prothrombin 20210A, ATIII deficiency, oral contraceptives

(autosomal dominant) decreases negative feedback on the coagulation cascade (hypercoagulable state)

inactivate factors V and VIII

warfarin skin necrosis

a temporary deficiency of proteins C and S (due to shorter half-life) relative to factors II, VII, IX, and X

a severe deficiency is seen at the onset of warfarin therapy increasing the risk for thrombosis, especially in the skin

a mutated form of factor V that lacks the cleavage site for deactivation by proteins C and S

Factor V Leiden

it is an inherited point mutation in prothrombin that results in increased gene expression,

increased thrombin, promoting thrombus formation.

decreases the protective effect of heparin-like molecules produced by the endothelium, increasing the risk for thrombus

activate ATIII, which inactivates thrombin and coagulation factors

PTT does not rise with standard heparin dosing.

binding and activating ATIII

activate limited ATIII; Coumadin is then given to maintain an anticoagulated state.

Estrogen induces increased production of coagulation factors, thereby increasing the risk for thrombosis

Intravascular mass that travels and occludes downstream vessels; symptoms depend on the vessel involved

a thrombus that dislodges;

thromboembolus (>95%)

to an atherosclerotic plaque that dislodges.

the presence of cholesterol clefts in the embolus

bone fractures, particularly long bones, and soft tissue trauma

while fracture is still present or shortly after repair

dyspnea (fat, often with bone marrow elements, is seen in pulmonary vessels and petechiae on the skin overlying the chest

decompression sickness.

Nitrogen gas precipitates out of blood due to rapid ascent by a diver (gas embolus)

joint and muscle pain (bends) and respiratory symptoms (chokes)

Chronic form of gas embolus that is characterized by multifocal ischemic necrosis of bone

may also occur during laparoscopic surgery (air is pumped into the abdomen)

enters maternal circulation during labor or delivery

with shortness of breath, neurologic symptoms, and DIC (due to the thrombogenic nature of amniotic fluid)

by squamous cells and keratin debris, from fetal skin, in the embolus

thromboembolus;

deep venous thrombus (DVT) of the lower extremity usually involving the femoral, iliac, or popliteal veins

the lung has a dual blood supply via pulmonary and bronchial arteries and the embolus is usually small (self-resolves)

if a large- or medium-sized artery is obstructed in patients with pre-existing cardiopulmonary compromise; only 10% of PEs cause infarction

with shortness of breath, hemoptysis, pleuritic chest pain, and pleural effusion

a mismatch; perfusion is abnormal.

a vascular filling defect in the lung

lower extremity Doppler ultrasound is useful to detect DVT

it is elevated

a hemorrhagic, wedge-shaped infarct

a large saddle embolus that blocks both left and right pulmonary arteries or with significant occlusion of a large pulmonary artery

electromechanical dissociation

chronic emboli that are reorganized over time.

thromboembolus

in the left heart and travels down systemic circulation to occlude flow to organs, most commonly lower extremities