Hemostasis and Related Disorders Flashcards
What is hemostasis? Primary vs. secondary hemostasis?
Hemostasis, or formation of a thrombus/clot, occurs when a blood vessel is damaged. Primary hemostasis involves the aggregation of platelets, resulting in formation of a weak “platelet plug.” Secondary hemostasis involves stabilization of the platelet plug with the coagulation cascade.
Pathoma, page 31
What is the initial response to a damaged vessel and what factors mediate this response?
Transient vasoconstriction of the damaged vessel before primary hemostasis.
Mediated by reflex neural stimulation (“knee jerk reaction”) and release of endothelin by endothelial cells.
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Factors/process of platelet adhesion to surface of disrupted vessel?
vWF binds to exposed subendothelial collagen and acts as a linker molecule to bind platelets via GPIb receptor.
vWF derived from Weibel-Palade bodies (which also release P-selectins during process of inflammation) of endothelial cells and alpha-granules of platelets (minimal contribution).
Pathoma, page 31
Platelet degranulation and aggregation?
Platelet adhesion to the endothelium results in degranulation of platelets to release factors that promote/mediate aggregation.
Dense granules of platelets release ADP that promotes exposure of GPIIb/IIIa that mediates platelet aggregation to one another via fibrinogen (from plasma) to form platelet plug–still weak at this point and needs stabilization from secondary hemostasis.
TXA2 synthesized by platelet cyclooxygenase (COX) to promote aggregation.
Pathoma, page 31
Common presenting symtoms of a patient with primary hemostasis?
Mucosal bleeding - epistaxis (most common), hemoptysis, GI bleeding, hematuria, menorrhagia, intracranial bleeding from SEVERE thrombocytopenia.
Skin bleeding - skin petechiae (often due to thrombocytopenias and usually not seen with qualitative disorders), purpura, ecchymoses, easy brusing
Pathoma, page 31
How do blood smear and bone marrow biopsy differ in terms of what they are assessing for regarding hemostasis?
Blood smear - used to assess number and size of platelets
Bone marrow biopsy - used to assess megakaryocytes (which produce platelets)
Pathoma, page 32
Pathophysiology for thrombocytopenia in ITP? What are the anticipated laboratory findings (platelet count, PT/PTT, BM bx)? Treatment?
Splenic macrophages produce IgG autoantibodies against platelet antigens (e.g. GPIIb/IIIa). Antibody-bound platelets are then consumed by splenic macrophages, resulting in thrombocytopenia.
Decreased platelet count
Normal PT/PTT - coagulation factors unaffected
Increased number of megakaryocytes on bx –> response of bone marrow to thrombocytopenia is hyperplasia to compensate for loss
Initial treatment is corticosteroids, which children respond well to but may show relapse in adults later in course of treatment. IVIG can be used to raise the platelet count in symptomatic bleeding (splenic macrophages consume IVIG instead of IgG-bound platelets), especially to avoid intracranial bleeding but effect is short-lived.
Splenectomy, which eliminates source of IgG and destruction, may be performed in refractory cases.
Pathoma, page 32
Acute vs. chronic forms of ITP?
Acute form - arises in children weeks after viral infection/immunization; self-limited
Chronic form - arises in adults, usually women of childbearing age; primary or secondary (SLE important secondary association!); may cause short-lived thrombocytopenia in offspring since antiplatelet IgG can cross placenta
Pathoma, page 32
Classic finding on smear for microangiopathic hemolytic anemia? Clinical findings? Lab findings? Etiologies?
Microangiopathic hemolytic anemia is a condition in which platelet microthrombi are formed in small vessels, thereby consuming platelets. These microthrombi then “shear” RBCs as they pass through, resulting in hemolysis and formation of “schistocytes” or “helmet cells.”
Clinical findings include skin/mucosal bleeding, microangiopathic hemolytic anemia, fever. Renal insufficiency more common in HUS and CNS abnormalities more common in TTP.
Causes include TTP and HUS.
Pathoma, page 32
Pathophysiology for TTP (thrombocytopenic purpura)?
Due to decreased ADAMTS13, an enzyme that normally cleaves vWF multimers, which need to be degraded over time into smaller monomers for eventual degradation.
If the multimers are not “chopped up” into smaller monomers, they can pile up over time and cause abnormal platelet adhesion and eventual formation of microthrombi.
Decreased ADAMTS13 is most commonly due to acquired autoantibody seen classically in ADULT FEMALES.
Pathoma, page 32-33
Pathophysiology of HUS (hemolytic uremic syndrome)?
Due to endothelial damage by drugs or infection.
“Uremic” indicates damage to kidneys.
Classically seen in children with E. coli O157:H7 dysentery (i.e. due to exposure from undercooked beef). E. coli verotoxin damages endothelial cells, resulting in formation of platelet microthrombi.
Pathoma, page 33
Treatment for microangiopathic hemolytic anemia?
Plasmapheresis and corticosteroids, ESPECIALLY for TTP.
Plasmapheresis can remove proteins (e.g. auto-antibodies against ADAMTS13) from blood.
Corticosteroids can decrease immune response/antibody production.
Pathoma, page 33
Bernard-Soulier syndrome - pathophysiology and lab findings?
Loss of platelet ADHESION - due to genetic deficiency in GPIb, resulting in inability of platelets to bind to vWF for adhesion to subendothelium.
Blood smear would reveal mild thrombocytopenia with enlarged platelets (immature “big suckers”).
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Glanzmann thrombasthenia - pathophysiology?
Loss of platelet AGGREGATION - due to genetic deficiency in GPIIb/IIIa –> loss of aggregation via receptor and fibrinogen
Pathoma, page 33
How does aspirin and uremia result in platelet dysfunction?
Aspirin IRREVERSIBLY inactivates cyclooxygenase, resulting in decrease in TXA2 generation to impair aggregation.
Uremia is kidney dysfunction, resulting in buildup of nitrogenous products and thereby disrupting both platelet adhesion and aggregation.
Pathoma, page 33
How is the platelet plug stabilized during secondary hemostasis?
Coagulation cascade generated through thrombin (activation of prothrombin Factor II), which converts fibrinogen to fibrin. Fibrin is then cross-linked to form a stable platelet-platelet thrombus.
Pathoma, page 33
Activation of the inactive coagulation factors from the liver require…?
1) Exposure to an activating substance. For the extrinsic pathway, tissue thromboplastin (aka Tissue Factor) activates Factor VII. For intrinsic pathway, subendothelial collagen activates factor XII.
2) Phospholipid surface of platelets
3) Calcium
Pathoma, page 33
Clinical features of secondary hemostasis disorders?
Deep tissue bleeding into muscles and joints (hemarthrosis) and rebleeding after surgical procedures (e.g. circumcision, wisdom tooth extraction).
Pathoma, page 33
Which lab study is best to used to measure effect of Coumadin/Warfarin? Heparin?
PT - Coumadin/Warfarin
PTT - Heparin
Pathoma, page 34
Hemophilia A pathophysiology? Lab findings? Treatment?
Factor VIII deficiency that can either be X-linked recessive or can also commonly arise de novo without family history.
Lab findings: increased PTT, normal PT, decreased FVIII, normal platelet count and bleeding time
Treatment: recombinant FVIII
Pathoma, page 34
Hemophilia B?
aka “Christmas Disease”
Genetic FIX deficiency. Similar to Hemophilia A.
Pathoma, page 34
How do results of mixing studies differ in Hemophilia A vs. condition involving coagulation factor inhibitor?
In coagulation factor inhibitor, most common inhibitor is anti-FVIII. The decreased FVIII activity is therefore due to an inhibitor rather than deficiency, so studies involving mixing normal plasma with patient’s plasma would not correct PTT. On the contrary, PTT would be corrected in a mixing study for Hemophilia A.
Mixing studies help differentiate between coagulation factor inhibitor vs. hemophilia A.
Pathoma, page 34
vWF disease pathophysiology? Symptoms? Lab findings? Treatment?
Can be quantitative or qualitative defect but most common is autosomal dominant mutation leadings to decreased vWF levels–most COMMON inherited coagulation disorder! vWF also acts to stabilize FVIII so decreased levels leads to destabilized FVIII.
Symptoms include those of primary hemostasis disorders with mild mucosal/skin bleeds due to impaired platelet adhesion. Destabilization of FVIII not sufficient to cause symptoms of secondary hemostasis disorders.
Lab findings: increased bleeding time, increased PTT, normal PT, abnormal ristocetin test (induces platelet agglutination by causing vWF to bind platelet GPIb).
Treatment is with desmopressin (ADH/anti-diuretic hormone analog), which INCREASES release of vWF from Weibel-Palade bodies.
Pathoma, page 34
How is Vitamin K activated? How does Vitamin K deficiency lead to coagulation disorder? What are some causes of Vitamin K deficiency?
Vitamin K is first needs to be activated by epoxide reductase in the liver.
Vitamin K is required from gamma carboxylation of factors II, VII, IX, and X, as well as proteins C and S (anti-coagulants).
Vitamin K normally produced by the bacteria that colonizes the GI tract. Causes include:
1) Lack of GI colonization in newborns –> Vitamin K given prophylactically to ALL newborns at birth to prevent hemorrhagic disease.
2) Long-term antibiotic therapy
3) Malabsorption of fat-soluble vitamins
.Pathoma, page 34-35
Mechanism of action for coumadin/wafarin?
Acts as anticoagulant by inhibiting epoxide reductase in liver, which normally activates Vitamin K.
Pathoma, page 34
How is the effect of liver failure on coagulation followed?
PT
Pathoma, page 35
Heparin-induced thrombocytopenia?
Platelet destruction arises secondary to heparin therapy. IgG to heparin-platelet factor 4 (on surface of platelet) complex.
Fragments of destroyed platelets may activate remaining platelets to led to thrombosis –> rx with another anti-coagulant and NOT coumadin (risk for skin necrosis).
Pathoma, page 35
What is the best way to test for DIC/disseminated intravascular coagulation? Treatment for DIC?
Test for D-dimers, which are elevated FIBRIN split products (cross-linked fibrin). D-dimers are NOT produced from splitting of fibrinogen. Presence of D-dimers is an indication of activation of entire coagulation cascade until the process of fibrinolysis to proceed with healing.
Treatment involves addressing underlying/primary cause and transfusion of cryoprecipitate (contains coagulation factors).
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Describe the process of fibrinolysis and the factors involved.
Normal fibrinolysis removes thrombus after damaged vessel heals.
Tissue plasminogen activator (tPA) converts plasminogen to plasmin. Plasmin then cleaves fibrin and serum fibrinogen, destroys coagulation factors, and block platelet aggregation. Plasmin is then inactvated by alpha2-antiplasmin.
Pathoma, page 35
How would you differentiate between DIC and disorders of fibrinolysis? Treatment for fibrinolysis disorders?
Presents similarly to DIC with increased bleeding.
Increased bleeding time due to plasmin with NORMAL PLATELET COUNT for fibrinolysis disorders, whereas platelet count DECREASED in DIC.
Increased fibrinogen split products WITHOUT D-DIMERS due to overactivation of plasmin without activation of coagulation cascade–no clot formed in the first place due to plasmin!
Treat with aminocaproic acid to block activation of plasminogen.
Pathoma, page 36
What findings would differentiate a thrombus from postmortem clot?
1) Lines of Zahn, which consist of alternating layers of platelets, fibrins, and RBCs
2) Attachment to vessel wall
Pathoma, page 36
What is Virchow’s triad?
Virchow’s triad describes the three major risk factors for thrombus:
1) Disruption in (laminar) blood flow - stasis/turbulence
2) Endothelial cell damage - disrupts protective function of endothelial cells that include blocking exposure to subendothelial collagen and underlying tissue factor; prostacyclin (PGI2) and NO production that promotes vasodilation and inhibition of platelet aggregation; etc.
3) Hypercoagulable state - classically present with recurrent DVTs or DVTs in a young age
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Role of thrombomodulin?
Redirects thrombin, which usually cross-links fibrin to form stable clot, to activate Protein C, which inactivates Factors V and VIII. This is a protective mechanism of the endothelium.
Pathoma, page 36
High levels of homocysteine can cause endothelial cell damage. Describe how Vitamin B12/folate deficiency, as well as cystathionine beta synthase (CBS) deficiency, can lead to buildup of homocysteine.
Folic acid (THF) circulates as methyl-THF in the serum, and the methyl is transferred to Vitamin B12 (cobalamin) so that THF can participate in DNA precursor synthesis. Cobalamin transfers methyl to homocysteine to result in methionine.
CBS converts homocysteine to cystathionine. Deficiency characterized by thrombosis, mental retardation, and long slender fingers.
Pathoma, page 37
Association of Protein C/S deficiency and warfarin skin necrosis?
Protein C and S, which normally inactivate factors V and VIII, deficiency is normally autosomal dominant and results in decreased negative feedback to coagulation cascade.
In initial stages of warfarin therapy (which blocks epoxide reductase and therefore blocks activation of Vitamin K), there is temporary deficiency of proteins C and S (due to shorter half-life) relative to factors II, VII, IX, and X –> increased risk for thrombosis. This is the reason for when patients are on coumadin, we make sure to put them on heparin as well to ensure that the factors eventually get degraded.
In preexisting deficiencies, a severe deficiency seen with onset of warfarin therapy. This increases the risk for thrombosis, especially on the skin which can lead to skin necrosis.
Pathoma, page 37
Factor V Leiden
A mutated form of Factor V that is resistant to deactivation by Protein C and S due to lack of cleavage site.
It is the most common cause of hypercoagulable state.
Pathoma, page 37
Prothrombin 20210A
An inherited point mutation in prothrombin that increases gene expression, resulting in increased thrombin and thrombus formation.
Pathoma, page 37
Why does PTT does not rise with standard heparin dosing in patient with ATIII (anti-thrombin III/heparin-like molecule) deficiency? Remember that PTT is used to monitor effect of heparin.
Pharmacologic heparin works by binding and activating ATIII. HIGH doses of heparin can activate limited ATIII and coumadin is then given to maintain anticoagulated state.
Pathoma, page 37
Describe the pathophysiology of decompression sickness and its association with gas embolus. What are the classic presenting symptoms? What is Caisson’s disease?
Decompression sickness occurs with rapid ascent from a dive. As someone dives, the increase in pressure causes nitrogen to dissolve in the blood. With rapid ascent, the gas precipitates as bubbles that can lodge itself into tissues.
Classic presentations include the “bends” or muscle/joint pains and “chokes” or respiratory symptoms.
Caisson’s disease is the chronic form that is characterized by multifocal ischemic necrosis of bones.
Pathoma, page 38
What are the classic presentations of amniotic fluid embolism? What are the components of the embolus?
Classic presentations include:
1) Shortness of breath due to embolus in lung
2) Neurologic symptoms due to embolus in brain
3) DIC due to thrombogenic nature of amniotic fluid–contains thromboplastin that converts prothrombin to thrombin!
Embolus composed of fetal skin components: squamous cells and keratin debris. Remember baby floats around in amniotic fluid and skin sloughs off!
Pathoma, page 38
Why is it that cases of pulmonary embolism often clinically silent?
1) Lung has dual blood supply: pulmonary and bronchial arteries
2) Embolus usually small and self-resolves
Pathoma, page 38
What would gross examination reveal for pulmonary infarct?
Hemorrhagic, wedge-shaped infarct in tissue.
Pathoma, page 39
How would someone experience sudden death with pulmonary embolism?
Can occur with large saddle embolus blocking both left and right pulmonary arteries or with significant occlusion of large pulmonary artery.
Death is due to electromechanical dissociation.
Pathoma, page 39
