• You need the integrity of the blood vessel to carry blood to tissue
• Damage to the wall is repaired by hemostasis, which involves formation of a thrombus (clot) at the site of vessel injury
• -Hemostasis occurs in 2 stages: primary and secondary
• Primary hemostasis forms a weak platelet plug and is mediated by interaction between platelets and the vessel wall
• Secondary hemostasis stabilizes the platelet plug and is mediated by the coagulation cascade

• step 1- transient vasoconstriction of damaged vessel
• mediated by reflex neural stimulation and endothelin release from endothelial cells
• Step 2
• Platelet adhesion to the surface of disrupted vessel
• vWF binds exposed subendothelial collagen
• platelets bind vWF using the GPIb receptor
• vWF is derived from the Weibel-Palade bodies of endothelial cells and alpha granules of platelets
• Step 3
• Platelet degranulation
• Adhesion induces shape change in platelets and degranulation with release of multiple mediators
• ADP is released from platelet dense granules; promotes exposure of GPIIb/IIIa receptor on platelets
• TXA2 is synthesized by platelet cyclooxygenase (COX) and released; promotes platelet aggregation
• Step 4-platelet aggregation
• Platelets aggregate at the site of injury via GPIIb/IIIa using fibrinogen (from plasma) as a linking molecule; results in formation of platelet plug
• Platelet plug is weak; coagulation cascade (secondary hemostasis) stabilizes it.

[image]

• step 1- transient vasoconstriction of damaged vessel
• mediated by reflex neural stimulation and endothelin release from endothelial cells
• Step 2
• Platelet adhesion to the surface of disrupted vessel
• vWF binds exposed subendothelial collagen
• platelets bind vWF using the GPIb receptor
• vWF is derived from the Weibel-Palade bodies of endothelial cells and alpha granules of platelets
• Step 3
• Platelet degranulation
• Adhesion induces shape change in platelets and degranulation with release of multiple mediators
• ADP is released from platelet dense granules; promotes exposure of GPIIb/IIIa receptor on platelets
• TXA2 is synthesized by platelet cyclooxygenase (COX) and released; promotes platelet aggregation
• Step 4-platelet aggregation
• Platelets aggregate at the site of injury via GPIIb/IIIa using fibrinogen (from plasma) as a linking molecule; results in formation of platelet plug
• Platelet plug is weak; coagulation cascade (secondary hemostasis) stabilizes it.

[image]

• B/c of platelet abn; divided into quantitative or qualitative disorders
• Clin features=mucosal and skin bleeding
• Epistaxis, hemopytsis, GI bleeding, hematuria, and menorrhagia, intracranial bleeding occurs with severe thrombocytopenia
• Symptoms of skin bleeding include petechia, ecchymoses, purpura, and easy bruising; petechiae are a sign of thrombocytopenia and are not usually seen with qualitative disorders
• Platelet count normal 150-400, <50-->symptoms
• Bleeding time normal 2-7 min; prolonged w/ quantitative and qualitative platelet disorders
• blood smear--used to assess number and size of platelets
• bone marrow biopsy--used to assess megakaryocytes which should be producing the platelets

• Autoimmune production of IgG against platelet antigens (ex GPIIb/IIIa)
• most common cause of thrombocytopenia in children and adults
• autoantibodies are produced by plasma cell in the spleen
• antibody-bound platelets are consumed by splenic macrophages, resulting in thrombocytopenia
• Divided into acute and chronic forms
• Acute=in children weeks aafter a viral infection or immunization; self-limited, usually resolves w/i weeks of presentation
• Chronic form=in adults, usually in women of childbearing age.  May be primary or secondary ex SLE, may cause short-lived thrombocytopenia in offspring since antiplatelet IgG can cross the placenta
• Laboratory findings include
• Decreased platelet count, often <50 K/uL
• Normal PT/PTT b/c coagulation factors are not affected
• Increased megakaryocytes on bone marrow biopsy
• Initial treatment is corticosteroids.  Children respond well; adults may show earl response, but will often relaps
• IVIG is used to raise the platelet count in symptomatic bleeing, but its effect is short-lived
• Splenectomy eliminates the primary source of antibody and the site of platelet destruction (performed in refractory cases)
• [image]
• [image]

• Pathologic formation of platelet microthrombi in small vessels
• platelets are consumed in the formation of microthrombi
• RBCs are sheared as the cross microthrombi-->hemolytic anemia w/ shistocytes
• [image]
• Seen in Thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS)

• TTP is due to decreased ADAMTS13, an enzyme that normally cleaves vWF multimers into smaller monomers for eventual degradation
• Large uncleaved multimers lead to abnormal platelet adhesion, resulting in microthrombi.
• Decreased ADAMTS13 is usually due to an acquired autoantibody; most commonly seen in adult females
• [image]

• due to endothelial damage by drugs or infection
• classically seen in children w/ E. coli O157:H7 dysentery, which results from exposure to undercooked beef
• E. coli verotoxin damages endothelial cells resulting in platlet microthrombi
• These platelet microthrombi cause reduced blood flow through the narrowed blood vessels of the microvasculature leads to reduced blood flow to vital organs, and ischemia may develop
• http://www.netterimages.com/images/vpv/000/000/032/32934-0550x0475.jpg
• If you can't see the image go to the site above, it was really good, but wouldn't let me blow it up bigger
• [image]

Clinical Findings (HUS and TTP)

Lab findings

treatment

1. Skin and mucosal bleeding
2. Microangiopathic 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

• Laboratory findings include:
• Thrombocytopenia with increased bleeding time
• Normal PT/PTT (coagulation cascade is not activated)
• anemia with schistocytes
• increased megakaryocytes on bone marrow biopsy
• treatment involves plasmapheresis and corticosteroids, particularly in TTP

• due to a genetic GPIb deficiency; platelet adhesion is impaired
• Blood smear shows mild thrombocytopenia with enlarged platelets

• aspirin irreversibly inactivates cyclooxygenase
• lack of TXA2 impairs aggregation

• disrupts platelet function
• both addhsion and aggregation are impaired

• Stabilizes the weak platelet plug via the coagulation cascade
• coagulation cascade generated thrombin, which converts finbrinogen in the platelet plug to fibrin
• fibrin is then cross-linked, yielding a stable platelet-fibrin thrombus
• Factors of the coagulation cascade are produced by the liver in an inactive state
• Activation requires:
• 1)exposure to an activating substance
• tissue thromboplastin activates factor VII (extrinsic pathway)
• subendothelial collagen activates factor XII (intrinsic pathwa)
• 2)Phospholipid surface of platelets
• calcium (derived from platelet dense granules)
• [image]
• The fibrin strands strengthen the hemostatic platelet plug.

• Usually due to factor abnormalities
• Clinical features include deep tissue bleeding into muscles and joints (hemarthrosis) and rebleeding after surgical procedures (ex circumcision and wisdom tooth extraction)
• Lab studies: Prothrombin (PT)- measures extrinsic (factor VII) and common (factors II, V, X, and fibrinogen) pathways of the coagulation cascade
• Partial thromboplastin time (PTT)- measures 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 so mostly affects males
• can be de novo
• presents with deep tissue, joint, and postsurgical bleeding
• clinical severity depends on the degree of deficiency
• Laboratory findings include
• increased PTT; normal PT
• decreased FVIII
• normal platelet count and bleeding time
• treatment involves recombinant FVIII

• Christmas Disease
• 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
• clinical and lab findings are similar to hemophilia A
• PTT does not correct upon mixing normal plasma w/ platient's plasma (mixing study) b/c inhibitor
• PTT does correct in hemophilia A

• Genetic vWF deficiency
• Most common inherited coagulation disorder
• multiple subtypes exist, causing quantitative and qualitative defects; the most common type is AD w/ decreased vWF levels
• presents with mild mucosal and skin bleeding; low vWF impairs platelet adhesion
• Laboratory findings include
• increased bleeding time
• increased PTT; normal PT-- Decreased FVIII 1/2 life (vWF normally stabilizes FVIII) however, deep tissue, joint, and post surgical bleeding ar usually not seen
• abnormal ristocetin test--Ristocetin induces platelet aggregation by causing vWF to bind platelet GPIb; lack of vWF-->impaired aggregation-->abnormal test.
• Treatment is desmopressin (ADH analog), which increases vWF realease from Weibel-Palade bodies of endothelial cells

• Disrupts function of multiple coagulation factors
• vitamin K is activated by epoxide reductase in the liver
• activated vitamin K gamma carboxylates factors II, VII, IX, X, and protein C and S; gamma carboxylates factors II, VII, IX, X, and protein C and S; gamma carboxylation is necessary for factor function
• deficiency occurs in:
• Newborns due to lack of GI colonization by bacteria that normally synthesize vitamin K; vitamin K injection is given Prophylactically to all newborns at birth to prevent hemorrhagic disease of the newborn
• Long-term antibiotic therapy- disrupts vitamin K- producing bacteria in the GI tract
• malabsorption leads to deficiency of fat soluble vitamins, including vitamin K

weird cause of abnormal secondary hemostasis

• Liver failure-decreased production of coagulation factos and decreased activiation of vitamin K by epoxide reductase; effect of liver failure on coagulation is followed using PT
• large volume transfusion- 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
• [image]

• Pathologic activation of the coagulation cascade
• widespread microthrombi result in ischemia and infarction
• 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

1. Obstetric complications-Tissue thromboplastin in the amniotic fluid activates coagulation
2. sepsis-esp. w/ E. coli or N. meningitidis- endotoxins from the bacterial wall and cytokines (eg TNF and IL-1) induce endothelial cells to make tissue factor
3. adenocarcinoma- mucin activates coagulation
4. acute promyelocytic leukemia- primary granules activate coagulation
5. rattlesnake bite-venom activates coagulation

• Lab findings

1. decreased platelet count
2. increased PT/PTT
3. decreased fibrinogen
4. microangiopathic hemolytic anemia
5. elevated fibrin split products, particularly D-dimer
6. elevated d-dimer is the best screening test for DIC
7. derived from splitting of cross-linke fibrin; D-dimer is not produced from splitting of fibrinogen
8. Treatment involves addressing the underlying cause and transfusing blood products and cryoprecipitate (contains coagulation factors), as necessary
9. http://img.medscape.com/fullsize/migrated/583/101/cjon583101.fig1.gif
10. [image]

• Normal fibrinolysis removes thrombus after damaged vessel heals
• TPA converts plasminogen to plasmin
• plasmin cleaves fibrin and serum fibrinogen, destroys coagulation factors, and blocks platelet aggregation
• alpha2 antiplasmin inactivates plasmin
• [image]

• due to plasmin overactivity resulting in excessive cleavage of serum fibrinogen.

1. Radical prostactomy-release of urokinase activates plasmin
2. Cirrhosis of liver-reduced production of alpha2-antiplasmin
3. presents with increased bleeding (resembles DIC)
4. Lab findings include: increased PT/PTT- plasmin destroys coagulation factors.
5. Increased bleeding time with normal platelet count- plasmin blocks platelet aggregation
6. increased fibrinogen split products without D-dimers- serum fibrinogen is lysed; however, D-dimers are not formbed b/c fibrin thrombi are absent
7. Treatment is aminocaproic acid, which blocks activation of plasminogen

• Pathologic formation of an intravascular blood clot (thrombus)
• can occur in artery or vein
• most common location is DVT of the leg below the knee
• characterized by lines of Zahn (alternating layers of platelets/fibrin and RBCS and attachment to vessel wall
• both features distinguish thrombus from postmortem clot
• major risk factors are disrupiton in blood flow, endothelial cell damage, and hypercoagulable state (virchow triad)

should normally be continuous and laminar which keeps platelets and factors dispersed and inactivated

-examples include:immobilization-increased risk for DVT

-cardiac wall dysfunction (ex arrhythmia or MI)

-aneursym

• disrupts the protective function of endothelial cells, increasing the risk for thrombosis
• causes:arthrosclerosis, vasculitis and homocysteine
• Vitamin B12 and folate deficiency-->mildly increased homocysteine levels-->increasing the risk for thrombosis
• folic acid (tetrahydrofolate, THF) circulates as methyl-THF in the serum
• methyl is transferred to cobalamin (vitamin B12), allowing THF to participate in the synthesis of DNA precursors
• cobalamin transfers methyl to homocysteine resulting in methyionine
• lack of vitamin B12 or folate leads to decreased coversion of homocysteine to methionine resulting in buildup of homocysteine

1. Cystathionine beta cynthase (CBS) deficiency results in high homocysteine levels with homocystinuria

• CBC converts homocysteine to cystathionine; enzyme deficiency leads to homocysteine buildup
• characterized by vessel thrombosis, mental retardation, lens dislocation, and long slender fingers

• block exposure to subendothelial collagen and underlying tissue factor
• produce prostacyclin (PGI2) and NO-vasodilation and inhibition of platelet aggregation
• secrete heparin-like molecules- augment antithrombin III (ATIII), which inactivates thrombin and coagulation factors
• secrete tPA-- converts plasminogen to plasmin, which 1) cleaves fibrin and serum fibrinogen
• 2)destroys coagulation factors and
• 3)blocks platelet aggregation
• secrete thrombomodulin-redirects thrombin to activate protein C, which inactivates factors V and VIII

• due to excessive procoagulant proteins or defective anticoagulant proteins; may be inherited or acquired
• classic presentation is 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 or S deficiency (AD) decreases negative feedback on the coagulation cascade. (protein C and S normally inactivate factors V and VIII, increased risk for warfarin skin necrosis, initial stage of warfarin therapy results in a temporary deficiency of proteins C and S due to shorter 1/2 life relative to factors II, VII, IX, and X
• In preexisting C or S def, a sever deficincy is seen at the onset of warfarin therapy increasing risk for thrombosis, especially in the skin
• Factor V leiden is a mutated form of factor V that lacks the cleavage site for deactivation by proteins C and S-most common inherited cause of hypercoagulable state
• prothrombin 20210 A is an inherited point mutation in prothrombin that results in increased gene expression.  Increased prothrombin results in increased thrombin, promoting thrombus formation
• ATIII def. decreases the protective effect of heparin-like molecules produced by the endothelium, increasing the risk for thrombus
• Heparin-like molecules normally activate ATIII, which inactivates thrombin and coagulation factors
• in ATIII def. PTT does not rise w/ standard heparin dosing
• pharmacologic heparin works by binding and activating ATIII
• High doses of heparin activate limited ATIII; coumadin is then given to maintain an anticoagulated state

• Oral contraceptives are associated with a hypercoagulable state b/c estrogen induces increased production of coagulation factors-->increasing the risk for thrombosis

• Oral contraceptives

• intravascular mass that travels and occludes downstream vessel; symptoms depend on the vessel involved.
• thromboembolues is due to a thrombus that dislodges; most common type of embolus >95%
• Atherosclerotic embolus is due to an atherosclerotic plaque that dislodges- char. by the presence of cholesterol clefts in the embolus
• Fat embolus-->bone fractures, usually long bones and soft tissue traum, dev. while fracture is still present or shortly after repair, char. by dyspnea (fat, often with bone marrow elements, is seen in pulmonary vessels) and petechiae on the skin overlying the chest
• gas embolus-->classically seen in decompression sickness

1. Nitrogen gas precipitates out of blood due to rapid ascent by a diver
2. presents with join and muscle pain (bends) and respiratory symptoms (chokes)
3. Chronic form (Caisson disease) char. by multifocal ischemic necrosis of bone
4. gas embolus may also occur during laproscopic surgery b/c air is pumped into the abdomen

• Amniotic fluid embolus enters maternal circulation during labor or delivery

1. Presents with shortness of breath, neurological symptoms, and DIC (b/c of thrombogenic nature of amniotic fluid)
2. char. by squamous cells and keratin debris, from fetal skin, in embolus

• Usually due to thromboembolus; the most common source is DVT of LE, usually involving the femoral, iliac, or popliteal veins
• most ofetn clinically silent b/c 1)lung a a dual blood supply (via pulmonary and bronchial arteries) 2)the embolus is usualy small (self-resolves)
• pulmonary infarction occurs if a large or medium sized artery is obstructed in patients with pre-existing cardiopulmonary compromise; only 10% of PEs cause infarction
• Presents w/ SOB, hemoptysis, pleuritic chest pain, and pleural effusion
• V/Q lung scan shows mismatch; perfusion is abnormal
• spiral CT shows a vascular filling defect in the lung
• lower extremity Doppler ultrasound is useful to detect DVT
• D-dimer is elevated
• gross examination reveals a hemorrhagic, wedge-shaped infarct
• sudden death occurs w/ a large saddle embolus that blocks both left and right pulmonary aa or w/ sig. occlusion of a large pulmonary artery death is due to electromechanical dissociation
• Pulmonary htn may arise w/ chronic emboli that are reorganized over time

• usually due to thromboembolus
• most commonly arise in the left heart
• travel down systemic circulation to occlude flow to organs, most commonly the lower extremeties