Pathologic Hemorrhage and Thrombosis Flashcards
Hemorrhage vs thrombosis
Hemorrhage - porrly controlled escape of blood from circulation
Thrombosis - pathologic clot fomrmation in circulation not associated with bleeding
Result of alterations of blood composition, flow dynamis, and vessels
Composition - unbalanced procoag and anticoag factors
Dynamics - stasis, turbulence (bedridden, vascular constriction, AF), increased visocisity (sickle cell, polycythemias, waldenstrom macroglobulinemia, leukemic leukostasis)
Vessels - vascular malformations…injury exposed vWF, collagen, and TF
Pathologic hemorrhage
Composition - procoagulant def, presence of anticoagulants, excessive firbinolysis
Flow - hypertension, vascular congestion, reduced viscosity
Vessels - trauma, surgery, dz
Bleeding disorders due to
Primary/secondary hemostatic disorders and fibrinolytic disorders
NONE due to anticoagulation disorders
Primary hemostatic disorder clinical presentation
Mucosal bleeding
Easy bruising
Petechiae
Prolonged bleeding from cuts
Make sure to take a good history and ask lots of questions
Thrombocytopenia
Platelet disorder
Decreased marrow production, increased peripheral desturction, increased sequestration in an enlarged spleen
PLatelet counts low
ITP
Immune thrombocytopenia
Platelet life is very short so the platelets in circulation are younger and function better
Platelet production disorder
Normal distribution of platelet ages but might have greater risk of pbleeding
Congenital platelet dzs
Bernard Soulier Syndrome - GPIb receptor def
Glanzmann’s thrombasthemia - def of GP2b/3a
Storage pool diseases - something wrong with platelet granules, inhibits activation and recruitment of other platelets
Congenital aspirin like defect - defect in platelet intracellular signaling for activation
Acquired platelet dzs
Drug effect or uremia (granule def or vWF dysfunction)
More common than congenital
Uremic platelet dysfunction
Anemia plays rehologic role in bleeding
Increases NO synthesis of platelets
Degree of azotemia does not correlate with bleeding risk
Poorly characterized uremic toxins (not urea or creatinine) are the culprits
Txs include DDAVP and cryoprecipitate (increased vWF)…estrogens will reduce NO synthesis
Dialysis may help
Causes of acquired platelet dysfunction
Liver dz, diabetes, trauma, extracorporeal circuits, CP bypass Dysproteinemias Myeloprol disorders (essential thrombocytosis or CML)
vWD
Most common inherited
Most are type 1 (70-80)
Then type 2A (15)
Then type 2B (5)
Types 1 and 3 of vWD
1 - decreased level of normal vWF
3 - absent vWF
Acquired - anti-vWF blocking ABs, marked thrombocytosis clearing vWF from circulation, cleavage of molecule in high flow environemtns like tight aortic stenoiss or extracorporeal circuits)
Type 2s of vWD
2a - no ultra large monomers…bleeding results when needed
2b- exposes GPIb receptor permitting IV platelet binding and splenic clearance of complexes leading to thrombocytopenia
2M - platelet binding too week due to loss of function
2N - binding of F8 defective so undefended from protein C…mild hemophilia like d
Platelet type vWD
Similar to vWD type 2B…gain of function in GPIb receptor
vWF factoids
Increased by thyroxine and estrogens (but not progestins)
vWF is an acute phase reactant
Ultra large molecules (storage form) can be depleted by DDAVP or stress
How to characterize secondary bleeding disorder
Hematomas with deep tissue and joint bleeding
Delayed posttraumatic bleeding
Liver failure
Decreased factor production and dysfibrinogenemia
Cirrhotic patients at risk of bleeding AND thrombosis because both pro and anticoagulant proteins are decreased…multifactoral thrombocytopenia
Hemophilia A, B and C
A - X-linked def of F8
B - x linked def of F9
C - auto rec of def of F11
Parahemophilia and congenital F13 def
Parahemophilias - F5 def…auto rec
Congenital F13 def - delayed wound hemorrhage
F8 vs F9
F8 is a larger molecule and an actue phase reactant
F9 is smaller and not an acute phase reactant…need twice as much F9 in replacement therapy
Hemophilia A notes
Most have severe…if acquired with AI dz, will make anti-F8 ABs…severely depleted could also make anti-F8 antibodies
Heparin induced thrombocytopenia
Heparin therapy activates platelets….they are then cleared by the spleen and then it declines
PF4 is released by alpha granules of platelets…forms complex with heparin in circulation…complex activates other platelets leading to positive feedback loop…PF4-hep complex also immunogenic and IgG will attach after about 5 days….AB-hep-PF4 complex also indcues platelet activation and continue positive feedback loop…declining platelet count and further release of PF4…if it stops here, it is HIT type 1 and benign, never causes bleeding problems
HIT type 2 or HIT-T
Heparin induced thrombocytopenia with thrombosis
IgG ABs formed to heparin-PF4 may cross react with endothelial surface leading to endothelial activation and risk of thrombosis…release IL-6, vWF…venous and arterial platelet-rsi hwhite thrombis
How to diagnose HIT-T
Patient on heparin suffers 50% decline in platelet count 5-10 days into therppy…withdraw heparin permanently
TTP
Thrombotic thrombocytopenia purpura
Decreased ADAMTS activty leads to inadequate cleavage of vWF into small size
Excess multimer leads to excess vWF activity
Unwanted platelet plug formation in microvasculatiure of critical tissues and ischemia
Will see schistocytes
DIC
Disseminated IV coagulation
Secondary to other diseases
Infection - bacterial endotoxin and some viruses activate endothelium exposing TF
Trauma - endothelial injury leading to TF exposure
Obstetric catastrophe - amniotic fluid embolization
Neoplasia - high in TF expression or release cytokines that upregulate TF expression
Circulation NOT normally exposed to TF…brain and placental villi are especially likely to be involved
DIC pathology
Fibrin microthrombi formed and trapped in microvasculature…tissue ischemia
Vascular occlusion - endothelial release of tPA adding an important compoenet of fibrinolysis
Bleeding ensues when platelets and factors are consumed by intital hypercoagulability
Petechial hemorrhages, ecchymoses, oozing from surgical wounds and IV sites
Waterhouse-Friderichsen syndrome
Adrenal infarction seen in the DIC accompanying meningococemia
Lab testing for DIC
PT and aPTT are prolonger Fibrinogen decreased Antithrombin decreased D-dimer increased Microangiopathy on the periperal smear
Tx of DIC
Treat underlying cause
Pro-coag - FFP, cryo, platelets
Anticoag- antithrombin and heparin
Proteins C and S deficiencies and antithrombin def
Heterozygous prone to clotting disorders, homo die in utero
APC resistance syndromes
Mutations in F5 gene that renders F5 resistant to APC….hypercoagulable…factor 5 leiden or cambridge
Prothrombin gene mutation G20210
Excess prothrombin production
More F8 nd 9 so increased htrombosis risk
APLs
Antiphospholipid antibodies
Directed toward phospholipid-protein complexes…some are associated with thrombosis risk
Some are virally induced…repeat positive test in 8-12 weeks
Lupus anticoagulant/anticardiolipid antibodies
Lupus - Prolongation of clot based test
Lupus - Does NOT cause anticoagulatio in vivo, only by increased PTT
Both can cause catastrohpic antiphospholipid syndrome
APLs with coagulopathies are associated with loss of nromal pregnancies due to placental thrombosis
Classification of thrombi
Arterial
Mural (cardiac chambers)
Valvular (cardiac valves)
Venous
Risk for arterial thrombosis
Arterial atehroscleorosis
Areas of turbulent flow (bifurcations or aneurysms)
Endothelial damage
Abnormal stasis
Venous thrombosis risk factors
Older age, smoking history bed rest Varicose veins Conditions cause endothelial cell damage Thrombophlebitis Post op Severe burns, trauma, fracture
Mural thrombi risk
Myocardial infarction - reduced wall motion and arrythmias cause stasis
Endocardial cell injury exposes tissue factor
Valvular thrombi risk
Diseased heart valves
Rough surfaces
Abnormal blood flow
Formation of emboli
Arterial thrombosis conseuqences
Sichemia
Infarction
Embolization (generally to systemic sites)
Venous thrombosis consequences
COngestion and edema - blood flow blocked behind the clot…increased pressure…extravasation of lfuids into tissue
Infarction
Embolization - generally to the lung
Potential outcomes of thrombosis
Propogation of clot DIssolutioon ofclot Embolization Organization Recenalization
Embolization
Passage of material through circulation which lodges in a distant vessel and may produce partial or complete occlusion of the vessel
Types of emboli
Atherosclerotic Fat Air Amnitoic FB Tumor
Systemic thromboemboli
80% originate in heart
2/3 associated with LVMI
1/4 associtedwith dilated or fibrillating left atrium
Organs with most blood flow at greatest risk (brain and kidneys)
Pulmonary embolism
95% from deep veins in the leg…travels through right heart and lodges in pulmonary vasculature
Most are siletn
Types of PE
Peripheral lung field - small
Saddle - large and lodge in bifurcation
Paradoxial embolism - not pulmonary but venous in nature
DIagnosiing thromboembolic dz
Spiral CT
VQ
Doppler
Imaging of heart
D-dimer levels
Genetics
Acquired predisposition
Factors that influence infarction
Nature of supply
Rate of development
Vulnerability - neurons die quicker
Oxygen content of blood - anemia and hypoxia predispose
White vs red infarctions
White - occur in tissues with end artery circulation….dense tissue minimizes hemorrhage
Red - Profuse bleeding into tissue…venous occlusion or tissue previously congested with blood (ovarian)…in organs with dual supply (lungs)…tissues re-perfused following infarction
Morphology of infarcts
Gross - wedge shaped of white
Coagulative inheart
Liquefactive in brain
Abscess formation in sepsis
Otherwise termed bland
MI
Death of myocardial tissue due to occluded coronary artery
