Hemostasis and Related Disorders

• "lucky pathway"
• -only have to remember one factor

• -factor VII ("lucky number 7")
• -PT Pathway

-Activated by TT: Tissue thromboplastin

• -"less numbers, less letters: PT, TT"

"unlucky pathway"

• Need to remember multiple numbers
• XII, XI, IX, VIII

• -PTT Pathway
• -activated by SEC (subendothelial collagen)
• -"more numbers, more letters: PTT, SEC"

• "Small Bills:
• FI (Fibrinogen)
• FII (Prothrombin)
• FV (interacts with FX: FII --> FIIa)
• FX

• Deficiency: increase in PT and PTT
• "V x II x I = X"

-Reduced in the LV by epoxide reductase

-Needed to activated factors: II, VII, IX, X and Protein C and S

*** Warfarin inhibits epoxide reductase

-Protein C: inactivates V and VIII

-Protein S: helps protein C inactivate V and VIII

• -ATIII (antithrombin III): inhibitis activation of II, VII, IX, X, XI, XII
• -ATIII is activated by heparin

-tPA: used to activate plasminogen to plasmin --> cleavage of fibrin mesh

• 1. Injury:
• -(endothelial damage): vWF binds exposed collagen

• 2. Adhesion:
• -platelet GP11b binds vWF
• -platelets release ADP and Ca (necessary for coagulation cascade)

• 3. Activation:
• -ADP induces GPIIb/IIIa

• 4. Aggregation:
• -Fibrinogen binds GpIIb/IIIa --> links platelets

Temporary Platelet plug

• PRO-AGGREGATION
• -TXA2 (platelets)
• -decreased blood flow

• ANTI-AGGREGATION
• -PGI2 and NO (endothelial cells)
• -increased blood flow

-acute phase reactants in plasma (eg: fibrinogen) cause RBC aggregation --> increased ESR

Increased ESR: infections, autoimmunity, malignancy, GI disease, pregnancy

Decreased ESR: polycythemia, SCA, CHF, microcytosis, hypofibrinogenemia

• 1. Primary
• -weak platelet plug
• -platelets interacting with vessel wall

• 2. Secondary
• -stabilized platelet plug
• -coagulation cascade

1. Transient vasoconstriction (neural stim, endothelin release)

• 2. Platelet adhesion (vWF binds GPIb)
•      ***wVW from Weibel-Palade bodies of endothelium and aplha granules of plt

• 3. Platelet degranulation (change in shape and degranulation)
•      -ADP (promotes GPIIb/IIIa)
•      -TXA2 (plt aggregation)

4. Platelet aggregation (fibrinogen links plts by GpIIb/IIIa)

• 1. Immune Thrombocytopenia Purpura (ITP)
• 2. Microangiopathic Hemolytic Anemia (TTP, HUS)
• 3. Bernard-Soulier Syndrome
• 4. Glanzmann thrombasthenia
• 5. Aspirin
• 6. Uremia

-quantitative and qualitative abnormalities of platelets

-mucosal and skin bleeding: epistaxis, hemoptysis, GI bleeding, hematuria, menorrhage

-intracranial hemorrhage with severe thrombocytopenia

• Labs:
• -increased bleeding time
• -possible decreased platelet count

• Symptoms:
• -petechiae, ecchymoses, purpura, easy bruising

***petechiae not usually seen with qualitative disorders

FA: "Idiopathic Thrombocytopenia Purpura

Anti-GpIIb/IIIa antibodes produced by plasma cells in spleen --> splenic macrophage consumption of platelets

• Acute: children
• -after viral infection or vaccination
• -self limiting

• Chronic: adults
• -women of child-bearing age
• -primary
• -secondary (ie: SLE)
• ***IgG can cross the placenta

• Labs:
• -decreased platelet count
• -NORMAL PT/PTT
• -increased megakaryocytes on BM bx

• Treatment:
• -corticosteroids: children respond well, adults relapse
• -IVIg
• -Splenetctomy

Form of extrinsic hemolytic normocytic anemia

• Causes:
• -TTP
• -HUS
• -DIC
• -SLE
• -Malignant HTN

• Pathogenesis:
• -formation of platelet microthrombi in small vessels
• -platelets are consumed
• -RBCs are sheared --> schistocytes (helmet cells)

• Presentation:
• 1. neurologic sx (more common in TTP)
• 2. renal sx (more common in HUS)
• 3. fever
• 4. thrombocytopenia (skin and mucosal bleeding)
• 5. microangiopathic hemolytic anemia

• Pathophysiology:
• -most commonly autoantibody to to ADAMTS13
• -ADAMTS13 cleaves vWF multimers into monomers for degradation
• -commonly seen in adult females

• Labs:
• -thrombocytopenia
• -increased bleeding time
• -increased megakaryocytes on BM bx
• -schistocytes on blood smear
• -increased LDH
• **PT/PTT NORMAL!
• Treatment:
• -plasmapheresis
• -corticosteroids

Damage to endothelial cells due to drugs or infection

• Pathophysiology:
• -commonly in children with E. coli O157:H7 (EHEC) dysentery (undercooked beef)
• -verotoxing damages endothelial cells
• -damages --> platelet microthrombi

• Presentation:
• 1. Anemia
• 2. Acute renal failure
• 3. Thrombocytopenia

• Labs:
• -thrombocytopenia
• -increased bleeding time
• -increased megakaryocytes on BM bx
• -schistocytes on blood smear

**PT/PTT normal!

• Pathophysiology:
• -genetic deficiency in GPIb (defect in plt adherence to vWF)
• -impaired platelet adhesion and platelet plug formation
• -platelets don't live as long without GPIb

• Labs:
• -thrombocytopenia
• -increased bleeding time

• Pathophysiology:
• -defect in GPIIb/IIIa (defect in plt-plt aggregation)

• Labs:
• -normal Plt count
• -increased bleeding time
• -blood smear shows no platelet clumping

-Aspirin: irreversibly inactivates COX --> lack of TXA2 --> impaired aggregation

-Uremia: due to poor kidney function, disrupts platelet function --> impaired aggregation and adhesion

• -stabilizes weak platelet plug via the coagulation cascade
• -coag cascade generate thrombin
• -thrombin converts fibrinogen to fibrin
• -fibrin crosslinks and stabilizes platelet plug

• Coagulation Factors:
• -produced in liver in inactive form
• -activation:
•      -exposure to activating substance  
•      -phospholipid surface of platelets
•      -Ca from platelet dense granules

• 1. Hemophilia A
• 2. Hemophilia B
• 3. Coagulation Factor Inhibitor
• 4. von Willebrand Disease
• 5. Vitamin K therapy
• 6. Liver Failure
• 7. Large Volume Transfusion

-usually due to factor abnormalities

• Labs:
• -Prothrombin Time (PT): extrinsic and common pathways
• -Partial Thromboplastin Time (PTT): measures intrinsic and common pathways

• **PTT better for measuring effects of heparin
• **PT better for measuring effects of coumadin

• Symptoms:
• -deep tissue bleeding into muscles and joints
• -rebleeding after surgical procedures

• FVIII deficiency (defect in intrinsic pathway)
• 1. X linked recessive
• 2. de novo mutation

• Presentation:
• -deep tissue, joint and postsurgical bleeding
• -easy bruising

• Labs:
• -increased PTT
• -Normal PT
• -platelet count and bleeding time normal

• Treatment:
• -recombinant FVIII

• "Christmas disease"
• FIX deficiency (defect in intrinsic pathway)

Same presentation and labs as Hemophilia A except FIX is decreased

• Acquired antibody against coagulation factor
• -most commonly FVIII

Presents like hemophilia A

*PTT does NOT correct upon mixing patient's plasma with normal plasma (antibodies inactivate normal FVIII) vs Hemophilia

• Epidemiology:
• -mild
• -most common inherited bleeding disorder

• Pathophysiology:
• -defect in vWF (autosomal dominant)
• -leads to a defect in the intrinsic pathway and in platelet plug formation
• -vWF acts to carry/protect FVIII from degradation

• Presentation:
• -varies depending on severity
• -mild mucosal skin bleeding

• Labs:
• -normal platelet count
• -increased bleeding time
• -normal PT
• -increased or normal PTT
• -risotcetin test

• Treatment:
• -desmopressin (DDAVP) (releases vWF stored in endothelium)

• -disrupts multiple coagulation factors
• -vitamin K is activated by epoxide reductase in liver
• -activated vitamin K gamma carboxylates factors II, VII, IX, X, prot C and S

• Causes:
• 1. Newborns (lack GI colonization that generates vitamin K)
• 2. Long term antibiotic therapy
• 3. Malabsorption (deficiency in fat soluble vitamins)

• Labs:
• -elevated PT and PTT

• -decreased production of coagulation factors
• -decreased activation of vitamin K

-dilutes coagulation factors

• 1. Heparin-Induced Thrombocytopenia (HIT)
• 2. Disseminated Intravascular Coagulation (DIC)
• 3. Disorders of Fibrinolysis

• -platelet destruction secondary to heparin therapy
• -heparin forms a complex with platelet factor 4 (PF4)
• -Antibodies target heparin-PF4 complex

-fragments of destroyed platelets may activate remaining platelets --> thrombosis

*these patients are at high risk for coumadin skin necrosis

• Pathophysiology:
• -widespread activation of clotting
• -leads to a deficiency in clotting factors --> creates a bleeding state

• -widespread microthrombi (ischemia and infarction)
• -bleeding from IV sites and mucosal surfaces

• Causes:
• "STOP Making New Thrombi"
• Sepsis (G-)
• Trauma
• Obstetric complications
• Pancreatitis, acute
• Malignancy
• Nephrotic syndrome
• Transfusion

• Labs:
• -schistocytes
• -thrombocytopenia
• -increased bleeding time
• -increased PT
• -increased PTT
• -increased fibrin split products (D-dimers)
• Treatment:
• -tx underlying cause
• -transfuse blood products and cryoprecipitate

Normally removes thrombus after damaged vessel heals

tPA converts plasminogen to plasmin

• Plasmin
• 1. cleaves fibrin and fibrinogen
• 2. destroys coagulation factors
• 3. blocks platelet aggregation
• --> breaks down clot and prevents new clot formation

a2-antiplasmin: inactivates plasmin

• Causes:
• 1. Radical Prostatectomy
• -release of urokinase activates plasmin
• 2. Cirrhosis
• -decreased production of a2-antiplasmin

• Presentation:
• -increased bleeding
• **resembles DIC!!

• Labs:
• -increased PT
• -increased PTT
• -increased bleeding time
• -normal platelet count
• -no D-dimers!

-lines of Zahn (alternating RBCs and fibrin/platelets)

• Virchow's Triad
• 1. Stasis
• 2. Endothelial damage
• 3. Hypercoagulable state

• -immobilization
• -cardiac wall dysfunction (MI, arrhythmia)
• -aneurysm

• Endothelial cells are protective:
• 1. block exposure to collagen and TF
• 2. produce PGI2 and NO (vasodilation and inhibit platelet aggregation)
• 3. heparin like molecules (activate ATIII)
• 4. secrete tPA
• 5. secrete TM

• Causes:
• -atherosclerosis
• -vasculitis
• -high levels of homocysteine (B12/Folate deficiency, CBS deficiency)

• Classic Presentation:
• -recurrent DVTs
• -DVTs at young age

• 1. Protein C or S deficiency
• 2. Factor V Leiden
• 3. Prothrombin 20210A
• 3. ATIII deficiency
• 4. OCPs

• -autosomal dominant
• -Prot C and S normally inactivate FV and VIII

• **increased risk of warfarin skin necrosis
• -prot C and S (anticoagulation) have a shorter half life and are depleted first compared to II, VII, IX and X (procoagulation)
• -this increases risk for thrombosis esp in skin in patients who already have a deficiency

*why you bridge warfarin therapy with heparin

-mutated FV that is resistant to degradation by Prot C

-most common cause of hypercoagulable state in whites

-activating mutation that increases gene expression

-results in increased thrombin

-increased venous clots

-inherited

• -Normally heparin like molecules produced by endothelium normally inactivate ATIII
• -ATIII inactivates thrombin and coagulation factors

PTT does NOT rise with standard heparin dosing

• -hypercoagulable state
• -estrogen induces production of coagulation factors

-intravascular mass that travels and occludes downstream vessels

1. Thromboembolism (>95%)

2. Atherosclerotic embolus (XOL clefts)

3. Fat embolus (bone fractures: --> pulmonary vessels, dyspnea, petechiae)

4. Gas embolus (the bends, caisson disease, laparoscopic surgery)

5. Amniotic fluid embolus (SOB, neuro sx, DIC, squamous cells)

-usually thromboembolus from DVT

-usually clinically silent: dual blood supply, small embolus

Pulmonary infarction if large vessel is obstructed and the patient has pre-existing cardiopulmonary compromise (only 10%)

• Presentation:
• -SOB
• -hemoptysis
• -pleuritic chest pain
• -pleural effusion

• Labs:
• -V/Q lung scan (abnormal perfusion)
• -Spiral CT (lung filling defect)
• -lower ext doppler ultrasound
• -D-dimer elevated (DVT)

• Complications:
• -Sudden death with large saddle embolism (blocks L and R PAs)
• -Pulmonary HTN with chronic emboli

• -usually due to thromboembolus
• -most commonly arise in L heart
• -occlude flow to organs (usually lower extremities)