Pathoma Hemostasis and Related Disorders Flashcards
What mediates the transient vasoconstriction of the blood vessel upon vascular injury?
- Reflex neural stimulation
2. Endothelin - very high yield to know
Where is vWF made and what does it bind (binds two things)?
vWF - made in alpha (light) granules of platelets and Weibel Palade bodies of endothelial cells
Binds Gp1b receptor on platelets when insoluble due to binding of subendothelial collagen
What are the two types of granules in platelets and what do they release?
Delta = Dense = Dark -> release 4 things: ATP, ADP, serotonin, Ca+2 “ASC”
-> serotonin is released by activated platelets, think of the smiley face helmet in sketchy
Alpha granules - light colored, release all the rest
How does ADP improve hemostasis?
Binding of P2Y12 ADP receptor -> upregulates expression of GpIIb/IIIa receptors which improves platelet aggregation
What is meant by adhesion / aggregation of platelets? What other mediator helps with aggregation of platelets other than ADP?
Adhesion - initial attachment to von Willebrand factor via the GP1b receptor
-> stimulates platelet activation
ADP as well as TXA2 is released once the platelet is activated
-> TXA2 promotes a reduction in cAMP levels -> improvement in aggregation
Aggregation -> GpIIb/IIIa receptors start making everything stick together via fibrinogen crosslinks
What is the predominant symptom of defects of primary hemostasis and the most severe / feared consequence?
Mucosal / skin bleeding, especially epistaxis
Severe thrombocytopenia -> intracranial bleeding
What are petechiae vs purpura vs ecchymoses?
Petechiae - pinpoint bleeds 1-2mm - usually NOT seen in qualitative disorders of platelets, but rather quantitative (Thrombocytopenia)
Purpura - >3mm
Ecchymoses - bruises >1cm
What is the most common cause of thrombocytopenia in children and adults? What is the pathogenesis?
Immune thrombocytopenic purpura (ITP)
IgG antibodies are made against platelet antigens (usually GP2b/3a)
-> splenic removal of platelets results in thrombocytopenia
What typically happens in children to cause ITP? Prognosis?
Usually arises weeks after a viral infection or immunization, and is self-limiting
-> acute form of ITP
Who typically gets chronic ITP?
Usually in women of childbearing age
May be primary - idiopathic
or
Secondary - i.e. autoimmune. Commonly seen in SLE (much like you have autoimmune hemolytic anemia, you can have this auto IMMUNE reaction to platelets. NOT thrombotic!!!!!!!!!!!!!!!!!)
What is the worry for women of childbearing age who have ITP?
IgG antiplatelet antibodies can cross the placenta and can cause a transient thrombocytopenia in newborns
What is seen on bone marrow biopsy of ITP?
Megakaryocytes -> indicating reactive platelet formation (since platelet count usually falls low, i.e. <150K, even <50K)
What is the treatment for ITP?
Treatment - corticosteroids, IVIG (short-lived distraction for macrophages), or splenic removal if refractory
Splenic removal -> removes the SOURCE of the antibodies and the SITE of removal
What are the two broad causes of microangiopathic hemolytic anemia? What does this generally mean?
Process where platelet microthrombi are formed which cause intravascular hemolysis of platelets
- Thrombotic thrombocytopenic purpura (TTP) - deficiency of ADAMTS13
- Hemolytic Uremic Syndrome (HUS) - E. coli verotoxin -> platelet microthrombi
Who is TTP classically seen in and what is the pathogenesis?
Can be due to genetic deficiency in ADAMTS13 (vWF metalloprotease), but typically due to an autoantibody to ADAMTS13
-> vWF multimers lead to abnormal platelet adhesion
B/c it’s normally due to autoantibody -> usually seen in middle-aged ADULT WOMEN
What are the classic symptoms of HUS vs TTP?
HUS - increased LDH + kid + thrombocytopenia + renal insufficiency (Thrombi usually in kidney)
TTP - increased LDH + adult + thrombocytopenia + neurologic symptoms (thrombi usually involve the CNS).
There is some crossover between disorders btw (TTP can involve kidney, HUS can involve CNS)
What happens to the PT/PTT in HUS / TTP?
These are PLATELET ONLY microthrombi
- > no activation of coagulation cascade
- > PT / PTT are normal
What is the treatment for TTP?
Plasmapheresis and corticosteroids
-> decrease auto-antibody production, and plasmapheresis to remove antibodies to ADAMSTS13
What is the pathogenesis of Bernard-Soulier syndrome? What is seen in terms of platelet count and peripheral smear?
Qualitative platelet defect in Gp1b, so platelets cannot bind Gp1b. -> defective ADHESION
Mild thrombocytopenia -> defective platelets tend to not live as long
Large platelets -> these are some “big suckers” dude
Just remember “vOne Big-Sucker” for 1b Bernard Soulier.
What is wrong in Glanzmann Thrombasthenia?
Genetic Gp2b/3a deficiency - platelet AGGREGATION via fibrinogren is impaired
Glassman - 2b or not to be.
What happens to platelet function in renal failure?
Uremia disrupts platelet function -> qualitative platelet defect in adhesion and aggregation
What are the classic clinical findings in problems of secondary hemostasis?
Deep tissue bleeding into muscles / joints (hemarthrosis), and rebleeding after surgical procedures (i.e. dental extractions)
What happens at the beginning of the instrinic pathway? Steps to the common pathway?
Hageman factor (Factor 12) binds subendothelial collagen, converted from 12 to 12a
12 -> 11 to 11a
11a -> 9 to 9a
Factor 8 is the cofactor for 9a’s conversion of 10 to 10a
When endothelial cells are injured, what three compounds do they begin secreting?
- von Willebrand Factor - mediates platelet adhesion to ECM
- Tissue factor - pro-coagulant for the extrinsic pathway
- Anti-fibrinolytic - plasminogen activator inhibitors
How does the extrinsic pathway work and is this the vitamin K dependent pathway or no? Include cofactors as applicable
Tissue factor released by injured endothelium converts 7 to 7a and forms a complex
TF-7a complex activates factors IX and X to activate downstream pathways
-> note that activation of factor 9 is a bit of an overlap with the instrinsic pathway for activation of 10
YES - 2, 7, 9, and 10 are extrinsic pathway, depend on vitamin K
What is the most common clotting factor deficiency? What are the lab values? Will patients always have a family history?
Factor 8 - Hemophilia A - X-linked, may arise de novo without a family history
Prolonged aPTT Normal bleeding time (platelets not affected) Normal PT (factor 8 is cofactor for 9 in intrinsic pathway)
What is the treatment for hemophilia A?
Factor 8 replacement therapy + desmopressin (releases vWF from WP bodies which holds factor 8 / improves halflife)
What is the value of a mixing study? How do you run one?
Can assess if a prolonged PT or aPTT is due to a clotting factor deficiency or presence of an inhibitor
Mix an equal amount of normal control plasma (with known PT / aPTT) and patient’s plasma, and measure the new PT / aPTT
What are the two possible results of the mixing study and what do they mean?
- Patient’s PTT / PT value is corrected -> factor deficiency was the problem
- Patient PT/PTT value is not corrected -> an inhibitor like an antibody is binding clotting factors and rendering them useless. (Also binds clotting factors in the control plasma)
What is the most common coagulation factor inhibitor?
Anti-Factor 8 -> similar to Hemophilia AAAAAAAight.
How will platelets in Bernard-Soulier syndrome coagulate differently when given ADP/epi/collagen as agonist vs ristocetin?
ADP/epi/collagen - normal platelet aggregation -> induces aggregation via GpIIb/IIIa
Ristocetin - no response -> failure to aggregate (Gp1b receptor absent) -> induces adhesion via Gp1b
How do you tell von Willebrand Disease and Bernard Soulier apart?
Bernard-Soulier - bleeding tendency + thrombocytopenia + LARGE platelet size + no response to ristocetin
vWD - bleeding tendency + NO thrombocytopenia + NORMAL platelet size + no response to ristocetin
What is the most common inherited coagulation disorder?
von Willebrand disease
-> Hemophilia A is just the most common factor deficiency
What are the lab findings of von Willebrand disease, PT / aPTT, bleeding time? Contrast this to Bernard-Soulier.
vWD - platelet adhesion defect
Bleeding time - prolonged, always-> looks like a platelet defect
aPTT - Often elevated vWF is needed to stabilize factor 8 -> factor 8 will be low. Normal in BS.
PT - normal
What is the primary treatment of von Willebrand disease?
Desmopression -> causes release of vWF from the WP bodies of the endothelium
-> same reason why it can be used for treatment of Hemophilia A (vWF stabilizes factor 8)
Why are newborns susceiptible to hemorrhagic disease of the newborn?
Newborns lack GI colonization by bacteria that normally synthesize vitamin K
-> reason why you can have clotting defects with longterm antibiotic use as well (disruption of K-producing GI flora).
How do you follow the effect of liver failure on coagulation and why?
Follow via the PT -> vitamin K epoxide reductase occurs here, and it makes all coagulation factors. Vitamin K related clotting factors are best followed via the PT.
What is HIT and what is the mechanism? What types of heparin tend to cause it?
Heparin-induced thrombocytopenia, from forming antibodies against heparin + PF4. These antibodies bind and activate platelets, cause a hypercoagulable state and low platelet count
UFH most commonly causes it - think of dad shooting four plates
LMWH can cause it but it is rare - she throws up four plates but doesn’t shoot them
Fondaparinux never causes it
What drug is given in the management of HIT?
Direct thrombin inhibitors, i.e. espectially argatroban (gator eating thrombeaver)
What are common causes of DIC?
Sepsis - endotoxins and cytokines (IL-1/TNF) induce endothelial cells to make tissue factor
Obstetric complications - thromboplastin (tissue factor) in amniotic fluid
Malignancies - i.e. adenocarcinoma (mucin, i.e. pancreatic) and acute promyelocytic leukemia (Auer rods)
Nephrotic syndrome - loss of AT3
What can venom from a rattlesnake bite cause?
Venom can cause DIC
What is the definition of DIC and what are the laboratory findings? Include PT, PTT, and TT, fibrinogen / platelets, D-dimers, and peripheral smear.
Widespread microthrombi with consumption of coagulation factors and platelets due to procoagulant release or widespread endothelial damage
PT, PTT and TT all prolonged
Fibrinogen / platelets - decreased
D-dimers - elevated
Peripheral blood: microangiopathic hemolytic anemia leads to schistocytes
What is the best screening test for DIC?
D-dimer -> elevation indicates that their was total activation of the coagulation cascade followed by clot lysis
What activates plasmin and what does it cleave?
Activated by tPA (plasminogen to plasmin)
It cleaves fibrin (current clots), as well as fibrinogen and coagulation factors. Also inhibits platelet aggregation -> prevents formation of future clots
What is the major inhibitor of activated plasmin? What produces it?
alpha2-antiplasmin
Produced in the liver.
What condition does overactivity of plasmin cause? Give two example causes of this.
Disorders of fibrinolysis - plasmin overactivity. Leads to excessive cleavage of serum fibrinogen.
- Radical prostatectomy - release of urokinase activates plasmin
- Cirrhosis of liver - reduced production of alpha2-antiplasmin
How do you differentiate disorders of fibrinolysis from DIC based on labs?
PT/PTT will still be elevated - plasmin destroys coag factors
Bleeding time will be elevated - inhibits platelet aggregation
Platelet count will be NORMAL - clots not forming
Fibrinogen split products are increased WITHOUT D-dimers -> plasmin is cleaving fibrinogen without the full maturation of the clotting cascade
What is the treatment for disorders of fibrinolysis? When are they contraindicated?
Must inhibit the formation of plasmin by inhibiting tPA
-> aminocaproic / tranexamic acid
Contraindicated in ischemic stroke - worsening of clot
Contraindicated in DIC - will cause worsening of thrombosis although bleeding would be controlled.
What is Virchow’s triad?
The triad of interrelated factors leading to thrombosis, including
- Endothelial injury
- Abnormal blood flow
- Hypercoagulability
What direct fibrinolytic agent do healthy endothelial cells release?
Tissue-type plasminogen activator (tPA) -> keeps plasmin in proximity
What are the defenses against coagulation secreted by endothelial cells?
- Heparin-like molecules - bind antithrombin 3 to mediate its inhibition of thrombin + others
- Thrombomodulin
- Tissue factor pathway inhibitor
How do thrombomodulin and tissue factor pathway inhibitor (TFPI) work?
Thrombomodulin -> binds thrombin, activates protein C and protein S -> degrades factors 5 and 8 which are needed for coagulation pathway
TFPI - inhibits interaction between TF-7a complex and X
How does a deficiency in B9 or B12 increase risk for thrombosis?
Will lead to decreased conversion of homocysteine to methionine via methionine synthase
-> buildup of homocysteine damages endothelium
What does cystathionine synthase do and what is the cofactor?
Converts homocysteine + serine to cystathionine
-> cystathionine will be later converted to cysteine
Because it is combining two amino acids, requires B6
What does cystathione synthase deficiency cause and what is the treatment?
These are causes of homocystinuria:
Deficiency -> treat with decreased methionine (make less homocysteine), increased cysteine (since it becomes essential), increased B6 (keeps whatever residual enzyme functioning) and increased B12/folate (homocysteine -> methionine as much as possible).
What are the clinical features of homocystinuria?
Vessel thrombosis / atherosclerosis (endothelial damage by homocysteine), mental retardation, and marfanoid habitus (long, slender fingers, INFERIOR lens dislocation)
What are the general clinical features of a hypercoagulable state?
Increased venous thrombosis - recurrent DVTs or DVT’s at a young age
What is the most common inherited hypercoagulability disorder in Caucasians and what causes it?
Factor V Leiden - single base pair polymorphism switches arginine to glutamine. I’m gonna R->Q this game!!!!
- > factor V is resistant to cleavage by protein C
- > inheritance is co-dominant (worse when homozygous)
What is the second most common inherited hypercoagulability disorder in Caucasians and what causes it?
Prothrombin gene mutation
- > point mutation in 3’-UTR what causes overexpression of prothombin
- > increased prothrombin levels leads to hypercoagulability
What is the inheritance pattern of protein C / S deficiency and its claim to fame? Which factors do these inhibits?
Autosomal dominant with variable penetrance
Causes skin necrosis due to dermal vessel thrombosis when treated with warfarin (both factors are vitamin K dependent)
C/S both inhibit factors 5 and 8
What should you be thinking if you give a patient heparin and their PTT doesn’t increase? How can you anticoagulate them?
Inherited antithrombin III deficiency since heparin works thru antithrombin III
Can anticoagulate through giving extremely high dose heparin (activates remaining AT3) as bridge therapy for warfarin
What is an acquired cause of AT3 deficiency?
Nephrotic syndrome -> antithrombin III loss in urine
What are the acute and chronic manifestations of gas emboli?
Acute:
Bends - joint and muscle pain
Chokes - respiratory vessel involvement
Chronic:
Caisson disease - long bone infarction
What is the classical presentation of an amniotic fluid embolus and what will be seen in the lungs?
Shortness of breath, neurologic symptoms (like fat emboli), and DIC -> due to tissue factor in amniotic fluid
Emboli composed of squamous cells and keratin debris from fetal skin will be seen in the lungs
What is required for a pulmonary embolus to actually cause pulmonary infarction (since it has a dual blood supply)? What type of infarction?
- Obstruction of a large or medium size artery
- Pre-existing cardiopulmonary compromise -> lack of sufficient blood flow around the obstruction
Loosely organized tissue with loose blood supply -> hemorrhagic infarct
