Hemostasis and Related disorders Flashcards
Hemostatis 2 stages:
Primary: forms weak platelet pug (platelets and vessel wall)
Secondary - coagulation cascade stabilizes platelet plug
Primary hemostasis (4 steps)
- transient vasoconstriction of damaged vessel
- Platelet adhesion to surface of disrupted vessel
- Platelet degranulation
- Platelet aggregation
Vasoconstriction of damaged wall mediated by
reflex neural stimulation and endothelin release
Platelet adhesion to surface of disrupted vessel
vWF binds exposed subendothelial collagen (BM & CT underneath exposed)
Platelets bind vWF using GP1b Receptor
What is vWF derived from
Weibel-Palade bodies of endothelial cells and alpha granules of platelets
Platelet degranulation
Adhesion induces shape change in platelets and degranulation
ADP release: GP2B/3A receptor expression
TXA2: promotes platelet aggregation
Platelet aggregation
Aggregate via GP2B/3A using fibrinogen - forming weak platelet plug
Stablize platelet plug using secondary hemostasis
Disorders of primary hemostasis d/t?
abnormalities of in platelets
quantitative or qualitative
Clinical features of primary hemostasis
mucosal and skin bleeding
epistaxis, hemoptysis, GI bleeding, hematuria, mehorrhagia
intracranial bleeding w/ severe thrombocytopenia
Skin bleeding symptoms
Petechiae, purpura, ecchymoses
Petechiae sign of thrombocytopenia (NOT QUALITATIVE disorders)
normal platelet count
150-400K
normal bleeding time
2-7 minutes
Immune Thrombocytopenia Purpura
AI - IgG against platelet antigens (GP2B/3A)
most common thrombocytopenia of children and adults
Ab produced by plasma cell in spleen - ab bound platelets are consumed by splenic macrophages
Acute Immune Thrombocytopenia Purpura
children
after viral infection/immunization
Self limted
Chronic Immune Thrombocytopenia Purpura
Adults
Women of child bearing age
Primary/Secondary
Secondary associated with lupus
May cause short-lived thrombocytopenia in offspring - IgG crosses placenta
Lab findings in Immune Thrombocytopenia Purpura
Decrease platelet count
Treatment of Immune Thrombocytopenia Purpura
Corticosteroids
Adults may relapse
IVIG: when symptomatic bleeding to raise platelet count
Splenectomy (in refractory cases)
Microangiopathic hemolytic anemia cause
pathologic formation of platelet microthrombi in small vessels
RBC shear when passing thrombus - lyse and become schistocyte
Platelets are consumed
What are two disorders you seee Microangiopathic hemolytic anemia
TPP (thrombocytopenic pupura) - platelet microthrombi - skin bleeding - decrease in ADAMSTS13 which normally cleaves vWF multimers
HUS (Hemolytic uremic syndrome)
TTP d/t decrease in what enzyme?
ADAMTS13 - cleaves vWF multimer into smaller monomers for eventual degredation
Large multimers lead to abn platelet adhesion = microthrombi
Who is decreased ADAMTS13 seen in most?
adult females (acquired autonantibody)
HUS d/t?
Drugs or infection -
children: E coli O157:H7 dysentery (verotoxin damages endothelial cells resulting in platelet microthrombi)
Clinical findings of HUS/TTP
Skin/mucosal bleeding Microagniopathic hemolytic anemia Fever Renal insufficiency (HUS) CNS abnromalities (TTP)
HUS/TTP lab findings
Thrombocytopenia w/ increased bleeding time
Normal PT/PTT
Anemia w/ schistocytes
Increased megakaryocytes on bone marrow biopsy
TX: HUS/TTP
plasmapheresis
Corticosteroids
Qualitative problems of platelets
- Bernard Soullier syndrome
2. Glanzmann thrombasthenia
Bernard Soulier Syndrome
Genetic defect GP1b deficiency
Platelet adhesion impaired
Blood smear; Mild thrombocytopenia and enlarged platelets (immature)
Glanzmann Thrombasthenia
Genetic GP2b/3A deficiency
Platelet aggregation impaired
How does aspirin cause qualitative defect in platelets?
Irreversibly inhibits COX - so lack of TXA2 impairs platelet aggregation
Uremia disrupts platelet function
both adhesion and aggregation impaired
Secondary hemostasis for:
stabilizing weak platelet plug
Thrombin converts fibrinogen to fibrin in platelet plug - crosslinked stablizing platelet-fibrin thrombus
Where are coagulation cascade factors produced?
Liver in inactive form
Coagulation cascade factors activated by?
Exposure to activation factors
Phospholipid surface (of platelets)
Calcium - from platelet granules
Disorders of secondary hemostasis usually d/t
factor abnormalities
Clinical features of secondary hemostasis disorders
Deep bleeding into muscles/joints
Rebleeding after surgical procedures
PT measures:
extrinsic (VII) and common (II, V, X + fibrinogen)
Prothrombin time
PTT measures
Intrinisc factors (XII, XI, IX, VIII) and common (II, V, X + fibrinogen)
Partial thromboplasin time
Hemophilia A
VIII
males - x linked
Can be from new mutation w/o family hx
deep tissue, joint, post surgical bleeding
Lab findings in Hemophilia A
Increase PTT
Normal PT
Decrease Factor VIII
Normal platelet ct, bleeding time
Hemophilia B
IX ncrease PTT Normal PT Decrease Factor IX Normal platelet ct, bleeding time
Coagulation factor inhibitor disorder
Acquired ab against coagulation factor - impaired factor function
Anti-F VIII most common
Distinction by mixing study:
Mix with normal plasma - if hemophilia A - PTT will correct
Mix with normal study - inhibitor - PTT will not correct
vWB dz
Most common inherited coagulation disorder***
most common is AD - decreased vWF levels
Platelet adhesion can’t occur
Mild mucosal and skin bleeding
vWB dz lab findings
Increased bleeding time
Increase PTT
normal PT
abnormal ristocetin test
vWF tx
desmopressin - increases vWF release from Weibel Palade bodies
why is PTT elevated in vWF?
need to stabilze factor 8
RIstocetin test***
Introduce restocetin - normally causes platelets to aggregate - but in vWF - they don’t
VIT K deficiency
Vit K gamma carboxylates factors II, VII, IX, X and S
VIT K deficiency occurs in?
Newborns
Long term antibiotic therapy
Malabsorption
Why does liver failure cause abnormal secondary hemostasis
decreased production of coagulation factors, decreased activation of VIT K by epoxide reductase
Heparin induced thrombocytopenia (HIA
platelet destruction secondary to heparin therapy
Fragments of destroyed platelets activate remaining platelets, leading to thrombosis
Heparin forms complex with PF-4
Don’t give coumdin
DIC
Pathologic activation of coagulation cascade
Widespread microthrombi in ischemia/infarction
Consumption of platelets and factors resulting in bleeding - IV sites and mucosal surface
Common causes of DIC
obstetric complications (amniotic fluid) Sepsis - endotoxins and cytokines Adenocarcinoma Acute promyelocytic leukemia Rattlesnake bite
Lab findings of DIC
decreased platelet count Increased PT/PTT decreased fibrinogen Microangiopathic hemolytic anemia Elevated fibrin split products (D-dimer)
DIC tx
transfuse blood products and cryoprecipitate
Disorders of fibrinolysis
D/t plasmin overactivity resulting in excessive cleavage of fibrinogen
tPA cleave plasminogen to plasmin which cleaves fibrin and fibrinogen
Destroys coagulation factors
Blocks platelet aggreation
What inactivates plasmin?
alpha-2 antiplasmin
Examples of excess plamin
Radical prostatectomy - release of urokinase activates plasmin
Cirrhosis of liver - reduced alpha-2 antiplasmin production
Increased plasmin presents as & lab findings
Increased bleeding
Increased PT/PTT - destroys coagulation factors
Increased bleeding time w/ normal platelet count
Increased fibrinogen w/o D dimers (because fibrin thrombi abscent)
TX of increased plasmin
Aminocaproic acid - blocks activation of plasminogen
Thrombus characterized by
Lines of Zahn (alternating layers of platelets/fibrin & RBCs)
And
Attachemenet to vessel wall
Virchow triad:
Disruption in blood flow Endothelial cell damage Hypercoaguable state (common in cancer)
Disruption in blood flow examples
Immobilization
Cardiac wall dysfunction
Aneurysm
How to endothelial cells prevent thrombosis
- Block exposure to subendothelial collagen & underlying tissue factor
- Produce Prostacyclin & NO
- Secrete heparin like molecules
- secrete tPA
- secrete thrombomodulin
Causes of endothelial damage
Atherosclerosis
Vaculitis
High levels of homocysteine
Cystathionine beta synthase (CBS) deficiency
High homocysteine levels w/ homocysteinuria
Vessel thrombosis, mental retardation, lens dislocation, long slender fingers
Hypercoaguable state
Excessive procogaulant or defective anticoagulant proteins
Recurrent DVT as young age
Hypercoaguable state causes
- Protein C/S def
- Factor V Leiden mutation
- Prothrombin expression increased
- ATIII def
- oral contraceptives
Protein C & S inactivate which factors?
V & VIII
What can you see with warfarin when pt has protein C/S def?
Warfarin skin necrosis (coumidin skin necrosis)
Can’t produce 2, 7, 9, 10, C, S factors when given Warfarin - C& S are first to depelete
Activating 2, 7, 9, 10 so give heparin
If deficient in C & S - very increase risk of hypercoagulable state with 2, 7, 9, 10
Factor V Leiden
Mutated factor 5 - can’t be cleaved by protein C & S (can’t shut off FV)
Most common inherited cause of hypercoagulable state
Prothrombin 20210A
Inherited pt mutation in prothrombin
Increased gene expression - prothrombin to thrombrin - converts fibrinogen to fibrin - leads to thrombus
Antithrombin III def
Decreases protective effect of heparin-like molecules produced by endothelium, increasing risk for thrombus
Heparin admin - PTT in these patients doesn’t rise
Oral contraceptives
Estrogen induces increased production of coagulation factors
Atherosclerotic embolus
plaque dislodges - presense of cholesterol clefts
Fat embolus
long bone fracture, soft tissue damage
dyspnea and petechia on skin overlying chest
Gas emoblus
Decompression sickness
Nitrogen dissolves in blood - then precipitates out during ascent
Bends/Chokes
Chronic gas emoli
Caisson dz
Multifocal ishcmeic necrosis of bone
Amniotic fluid embolus
enters maternal circulation during labor or delivery - lodges in lungs
SOB, neurologic symptoms, DIC
Characterized by Squamous cells & Keratin debris from fetal skin in embolus
Pulmonary embolism
DVT - femoral, iliac, popliteal veins
disoldge and get thromboembolous
Why are most PE’s clinically silent
Lung has dual blood supply
Embolus usually small/self resolving
Pulmonary infarction clinical signs
SOB, hemoptysis, pleurtic chest pain, pleural effusion
V/Q scan shows mismatch - perfusion abn
Spiral CT shows vascular filling defect in lung (blocking blood supply)
LE doppler useful to detect DVT
D-dimer elevated
Pulm HTN is d/t what?
chronic emboli that are reorganized over time
Systemic emobli
D/t thromboembolus
Left heart
Occlude flow to organs - commonly LE
