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.
Pathoma, page 31
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”).
Pathoma, page 33
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
