Hemostasis Flashcards
What is the first step of hemostasis? What are the two mediators of this?
Transient vasoconstriction mediated by a neural reflex arc and endothelin release
What is the molecule that is on endothelium and causes vasoconstriction?
Endothelin
What is the molecule on platelets that binds vWF?
GPIb
Where does vWF come from (which cells)? (2)
- Weibel-Palade bodies within Endothelium
- Platelets
What is step II of hemostasis?
vWF binding to GPIb
What is in Weibel-Palade bodies?
vWF
P-selectin
What is released from platelets when the bind vWF?
ADP
TXA2
What is the enzyme that makes TXA2?
COX
platelet cyclooxygenase
What is the receptor on platelets that ADP induces? What does this do?
GpIIb/IIIa
Causes platelet-platelet binding
What does TXA2 do in platelets?
Causes platelet linking
What is the linker molecule between platelets that is used in aggregation?
fibrinogen + GPIIb/IIIa
What are the two, broad types of disorders of primary hemostasis?
Qualitative
Quantitative
What is the most common symptom of hemostasis disorders?
Mucosal and skin bleeding (epistaxis, hemoptysis etc)
What is the most feared complication of platelet defects?
Intracranial bleeding
Are petechia usually seen in qualitative or quantitative disorders?
Quantitative (thrombocytopenia)
Petechiae are characteristic of what hematological defect?
Quantitative Platelet issues
What is the drug that binds to and inhibits GpIIa/IIIb?
Abciximab
Define primary and secondary hemostasis
Primary = platelet plug Secondary = Fibrinogen cross linking
What are the four useful lab studies for hemostasis disorders?
- Platelet count
- Bleeding time
- Blood smear
- Bone marrow biopsy
What are the cells that produce platelets?
Megakaryocytes
What is immune thrombocytopenic purpura (ITP)?
Autoimmune production of IgG against platelet antigens (e.g. GPIIb/IIIa)
What is the most common cause of thrombocytopenia in adults?
ITP
What organ makes the IgG in ITP?
Spleen
What is the acute form of ITP? What is the treatment?
Develops weeks after viral infection/immunization
Usually self-limited, thus supportive treatment
What is the chronic form of ITP? Who is this usually seen in (disease/age group)?
Usually women of childbearing age, associated with SLE.
What is the problem with ITP in pregnant women?
IgG that is produced can cross the placenta, and resulting in thrombocytopenia in fetus
What is the platelet count in ITP (up, down, or normal)?
Down
What is the PT/PTT in ITP (up, down, or normal)?
Normal
What is the megakaryocyte count in ITP (up, down, or normal)?
Up
What is the treatment for the fetus in ITP?
Corticosteroids
What is the treatment for symptomatic ITP? Why does this work?
IVIG–causes macrophages to eat IG, not bound to platelets (effect is short lived)
What is the treatment of refractory ITP? Why?
Splenectomy–eliminates the site of antibody production, and the site of destruction
What is microangiopathic hemolytic anemia?
Pathologic formation of platelet microthrombi in small vessels, causing RBCs to rupture d/t platelet microthrombi
What is the characteristic finding of a blood smear in microangiopathic hemolytic anemia?
Sheared RBCs (schistocytes)
Helmet cell = ?
Schistocyte (seen in microangiopathic anemia)
What are the two diseases that cause microangiopathic anemia?
Thrombocytopenic purpura (TTP)
Hemolytic uremic syndrome (HUS)
What is the deficient enzyme in TTP? What does this do?
Decrease in ADAMTS13 enzyme, which normally cleaves vWF for degradation, causing abnormal platelet adhesion on uncleaved monomers
What causes the decrease in ADAMS-13 in TTP?
Acquired antibody; most commonly seen in females
What causes HUS?
E.coli OH157:H7 verotoxin damages endothelial cells, resulting in platelet microthrombi
What is the bacteria that causes HUS? Who is affected, and where does this bacteria come from?
E.coli OH157:H7
Children affected when eating undercooked beef
What are the clinical findings of HUS? (4)
- Dysentery
- Skin and mucosal bleeding
- Renal damage
- CNS dysfunction
What is the predominant problem in TTP and HUS respectively?
TTP = CNS dysfunction HUS = Renal insufficiency
Why is the PT/PTT normal in HUS/TTP?
No activation of the coagulation cascade
What are the findings of a blood smear with TTP/HUS?
Schistocytes
What are the findings of a bone biopsy with TTP/HUS?
Increased megakaryocytes
What happens to bleeding time with TTP/HUS?
Increased
What is the treatment for TTP?
Plasmapheresis and corticosteroids
What is the cause of Bernard-Soulier syndrome?
Genetic GP1b deficiency; platelet adhesion is impaired
What are the findings of a blood smear with Bernard-Soulier syndrome?
Mild thrombocytopenia with enlarged platelets
(Big Suckers with Bernard-Soulier)
What is the cause of Glanzmann thrombasthenia?
Genetic GIIb/IIIa causing platelet aggregation impairment
What is the MOA of ASA in preventing platelet aggregation?
Lack of TXA2 d/t irreversible inhibition of COX
What is the coagulation problem with uremia?
Uremia disrupts platelet function; both adhesion and aggregation is impaired
What is the goal of secondary hemostasis?
Stabilize the platelet plug
What is the end product of coagulation?
Thrombin/fibrin
What protein connects the GPIIb/IIIa proteins on platelets together? What forms this, and what enzyme activates it?
Fibrin, which is formed from fibrinogen by thrombin
What produces fibrinogen, and where does it go (before activation?
Liver, floats around in the blood stream until activated
What are the three things that are needed to activate the coagulation cascade?
- Activating substance
- Ca
- Phospholipid surface of platelets
What are the two activating substances of the coagulation cascade?
- Tissue thrombin activator (VII)
2. Subendothelial collagen activates factor XII
What causes disorders of secondary hemostasis?
Usually d/t factor abnormalities
What are the clinical features of secondary hemostasis disorders?
- Deep tissue bleeding into muscles/joints
- Rebleeding after procedures
What does PT measure (intrinsic or extrinsic pathway)?
The extrinsic pathway
What does PTT measure (intrinsic or extrinsic pathway)?
The intrinsic pathway (“has more factors, so has an extra T”)
What are the factor steps of the intrinsic pathway?
12, 11, 9, 8, 10
What are the factor steps of the extrinsic pathway? Common pathway?
3, 7, 10
Common = 5, 2, 1
What activates factor 12?
Subendothelial collagen
What activates the extrinsic pathway?
Tissue thromboplastin (factor 3)
Which lab value measures the effect of heparin (PT or PTT)?
PTT (HEP and PTT both have three letters)
Which lab value measures the effect of warfarin (PT or PTT)?
PT
What is the factor that has a genetic defect in hemophilia A?
Factor VIII (“Hemophilia aaa–eeeight”)
What is the inheritance pattern of hemophilia A?
X-linked recessive or new mutation
What are the PT and PTT findings of hemophilia A?
Increased PTT
Normal PT
What is the platelet count and bleeding time in hemophilia A? (up, down, normal)
Normal
What is the treatment for hemophilia A?
Recombinant factor 8
What is the factor deficiency for hemophilia B (“Christmas disease”)?
Factor IX
What is the cause of coagulation factor inhibitor? Which factor is affected most commonly?
Acquired antibody against coagulation factor, resulting in impaired factor function
Factor VIII most commonly affected
How do you distinguish between hemophilia A caused by a coagulation factor inhibitor vs a factor deficiency (since both have increased PTT)?
PTT does not correct upon mixing normal plasma with pts plasma (mixing study) if caused by a coagulation factor inhibitor (since antibodies are in serum)
What is von Willebrand disease? Symptoms?
Deficiency of vWF
Mucosal and skin bleeding
What is the most common inherited coagulation factor disorder?
Genetic vWF deficiency
What is the most common type of vWF disease? Inheritance pattern?
AD decrease in vWF levels (quantitative, not qualitative defect)
What happens to bleeding time, PTT, and PT in vWF disease?
- Increased bleeding time
- Increased PTT
- Normal PT
Why does the PTT increase in vWF disease?
vWF is needed to stabilize factor 8
What is the ristocetin test, and what is the result in vWF disease?
Ristocetin induces platelet agglutination by causing vWF to bind to platelet GPIb; thus abnormal test
What is the treatment for vWF disease? MOA?
desmopressin
Increases the release of vWF from WP bodies
What are the factors that need vitamin K for gamma carboxylation?
10, 9, 7, 2 (vitamin K was born in 1972)
protein C and S
Why are newborns susceptible to vitamin K deficiency, as well as pts on long term abx?
Lack of bacterial colonization in the gut that make vit K
How does liver failure lead to coagulation disorders? How about abx therapy? Malabsorption?
- Decreased production of coagulation factors
- Decreased vit K from bacteria
- Decrease in fat soluble vitamin (K) absorption
What is the enzyme the liver produces that activates vitamin K?
Epoxide reductase
What lab value is followed in liver damage-caused coagulation disorders?
PT (same as warfarin)
Why does large volume transfusion cause secondary coagulation defects?
Dilution of coag factors
What is the cause of heparin induced thrombocytopenia (HIT)?
Antibodies to Hep-PF4 complex
Fragments of destroyed platelets may activated remaining platelets, leading to thrombosis
What, generally, is DIC caused by?
Pathologic activation of the coagulation cascade, leading to the consumption of factors and platelets
What are the two major problems with DIC?
- Widespread microthrombi
2. Thrombocytopenia
What causes DIC in sepsis?
Cytokines and induction of coag by bacteria
What happens to platelet count in DIC (up, down, nl)?
Goes down
What happens to PT/PTT in DIC (up, down, nl)?
Up
What happens to fibrinogen in DIC (up, down, nl)?
Goes down
What is the screening lab test for DIC?
D-Dimer (elevated fibrin split products)
Microangiopathic hemolytic anemia is found in DIC. What is the blood smear finding to confirm this?
Schistocytes
What is the treatment for DIC?
Transfuse blood products or cryoprecipitate
What is the function of fibrinolysis normally?
Remove thrombus after damaged vessel heals
What is the function of plasmin? (3)
- Degrades fibrin/fibrinogen
- Shuts down clotting factors
- Blocks platelet aggregation
What do endothelial cells release to activate plasmin from plasminogen?
tPA
What is the endogenous molecule that inactivates plasmin?
alpha-2-antiplasmin
What are disorders of fibrinolysis caused by, generally?
Plasmin overactivity, resulting in excessive cleavage of fibrinogen
What is the chemical released during a radical prostatectomy that activates plasmin?
Urokinase
Why does liver cirrhosis lead to fibrinolysis disorder?
Loss of alpha-2 antiplasmin
Disorders of fibrinolysis present similar to what other process?
DIC
What are happens to PT/PTT with disorders of fibrinolysis? Why?
increase–cleavage of coaulation factors
What happens to bleeding time and platelet count with disorders of fibrinolysis? Why?
Increased bleeding time
Normal platelet count–inhibition of platelet aggregation
What is the difference between DIC and fibrinolysis disorders in terms of platelet count? D-dimer?
DIC has reduced platelets with increased d-dimer
Both normal with fibrinolysis
Why is the d-dimer not elevated with disorders of fibrinolysis?
No clot formed, just overactivation of plasmin
What is the treatment for disorders of fibrinolysis? MOA?
Aminocaproic acid–blocks activation of plasminogen
What are the two characteristics that distinguish a thrombus from a post mortem clot?
- Lines of Zahn
- Attachment to the blood vessel walls
What are the three major risk factors for thrombosis?
- Disruption of blood flow
- Endothelial cell damage
- Hypercoagulable state
What protects blood vessels from thrombosis? (4)
- Barrier via endothelial cells does not allow attachment
- PGI2
- NO
- Heparin-like molecules
What is the function of PGI2 that endothelial cells release?
Prevents coagulation and dilates vessels
What is the function of antithrombin III?
Inactivates thrombin and coagulation factors
What are lines of Zahn?
Alternating layers of RBCs, platelets, and fibrin in a thrombus
What is the function of tPA that endothelial cells secrete?
Activates plasminogen to plasmin, which will cleaves fibrin and fibrinogen to prevent clot formation
What is the function of plasmin? (3)
- Cleaves fibrin & fibrinogen
- Destroys coag factors
- Blocks platelet aggregation
What is the function of thrombomodulin?
Redirect thrombin to activate protein C
What is the action of protein C once activated by thrombomodulin/thrombin?
Inactivates factors V and VIII
What are the ways that we can develop elevated levels of homocysteine? (recall that this damages endothelial cells)
- Vitamin B12/folate deficiency
2. Cystathionine beta synthase (CBS) deficiency (homocysteine)
Why does a Vit B12/folate deficiency lead to increased levels of homocysteine?
THF needs to hand off a methyl group to vit B12, which hands off to homocysteine, which produces methionine
What is the enzymatic deficiency that leads to high levels of homocysteine, and is the cause of homocystinuria?
Cystathionine beta synthase (CBS)
What are the symptoms of homocystinuria?
- Vessel thrombosis
- MR
- Long, slender fingers
- Lens dislocation
What are the two ways that can result in a hypercoagulable state?
- Excessive procoagulant factors
2. Lack of anticoagulant factors
What is the classic presentation for patients with a hypercoagulable state?
Recurrent DVTs, or DVTs at a young age
Deficiencies in protein C or S leads to what? Why? How is this inherited?
Hypercoagulable state, since protein C will not block factors 5 and 8.
AD
Patients with deficiencies in protein C or S are more likely to have a complication with what drug? Why?
Warfarin (coumadin) since protein C and S are lost first, and these are already defective or deficient
What is the treatment that we start patients with when starting coumadin?
Heparin first
What is factor V leiden? Does this lead to a hypercoagulable state or a bleeding disorder?
Mutated form of factor V that prevents deactivation by protein C
Leads to a hypercoagulable state
What is the most common cause of a hypercoagulable state?
Factor V leiden
What is the prothrombin 20210A defect?
Inherited point mutation in prothrombin, leading to increased gene expression, and thus a hypercoagulable state
What does an antithrombin III deficiency lead to?
Decreases the protective effect of heparin-like molecules produced by the endothelium, increasing the risk for thrombus
What normally activates antithrombin III? What does activation of antithrombin III lead to?
Heparin like molecules activates it
inactivates thrombin and coagulation factors
Why doesn’t the PTT rise when patients with antithrombin III deficiency are given heparin? What is given to these patients instead?
Limited number of ATIII
Warfarin
Why are oral contraceptives associated with a hypercoagulable state?
Estrogen induces an increased production of coagulation factors
What is an atheroscleotic embolus? How can you differentiate this from a normal embolus?
One that results from an arthresclerotic plaque
Will see cholesterol crystals in the embolus
Fat emboli are associated with what?
Bone fractures
What are the signs/symptoms of a fat embolus?
-Dyspnea and petechiae on the skin overlying the chest
Gas emboli are classically seen in what condition?
Decompression sickness
What causes decompression sickness?
N gas precipitates out of the blood due to rapid ascent by a diver
What are the two symptoms that decompression sickness can present with?
Bends or the chokes
What is Caisson’s disease?
Chronic form of gas emboli that is characterized by multifocal ischemic necrosis of bone
Why can gas emboli result from laparoscopic surgery?
Air is pumped into the abdomen
What are the symptoms that occur when amniotic fluid enters maternal circulation?
- Dyspnea
- DIC
- Neuro symptoms
What is found within amniotic fluid that causes an embolism?
-Tissue thromboplastin
-Squamous cells
Keratin debris
What are the three veins usually associated with DVTs?
Iliac
Popliteal
Femoral
Why are PEs usually silent? (2)
- Dual blood supply to the lung
2. Usually small embolus
When do pulmonary infarction usually occur with PEs?
Obstruction of medium to large vein
Pre-existing cardiopulmonary compromise
Why is the D-dimer elevated with DVTs or a PE?
Clot is actively being lysed, resulting in fibrin breakdown products
Why is the characteristic shape of infarcts caused by PEs? Why is it hemorrhagic?
Wedge
Hemorrhagic d/t other blood supply and loose CT d/t infarct
What is a saddle embolus?
Blockage of both pulmonary arteries by a clot
What is the major complication of chronic pulmonary emboli?
Pulmonary HTN (type IV)
What is the most common cause of a systemic thromboembolism?
Thrombus that arose from the left heart
What drug should never be given to patients with HIT?
Coumadin
What causes DIC in the obstetric setting?
Amniotic fluid contains tissue thromboplastin, which can activate the coag cascade if exposed in maternal blood
How can adenocarcinoma cause DIC?
Mucin production causes activation of coagulation cascade
How can acute promyelocytic leukemia cause DIC?
Auer rods in cells leak out of cells and activate the coagulation cascade
How can rattle snake bite cause DIC?
Toxin causes activation of coag
What is the MOA of heparin?
Binds to and activates ATIII
What is the MOA of vincristine and vinblastine? Use? Side effects?
bind to beta-tubulin, and inhibit polymerization into microtubules
Solid tumors, leukemias/lymphomas
Neurotoxic and myelosuppression
What is the MOA, use, and side effects of: paclitaxel and other taxols?
- Hyper Stabilize polymerized tubules
- Ovarian and breast cancer
- Myelosuppression and alopecia
What is the MOA, use, and side effects of: cisplatin and carboplatin?
- Cross link DNA
- Testicular, bladder, and ovarian cancer
- Nephrotoxic and acoustic nerve damage
What is the MOA, use, and side effects of: Irinotecan and topotecan?
- Topoisomerase II inhibitors
- Solid tumors
- Myelosuppression, alopecia
What is the MOA, use, and side effects of: hydroxyurea
Inhibits ribonucleotide reductase (S phase specific)
- Melanoma, CML
- Myelosuppression
What is the MOA, use, and side effects of: cyclophosphamide
- Covalently linking DNA
- Solid tumors
- Myelosuppression, hemorrhagic cystitis
What is the MOA, use, and side effects of: Nitrosoureas (carmustine, lomustine)
- Cross BBB and covalently links DNA
- Brain tumors
- CNS toxicity
What is the MOA, use, and side effects of: busulfan
- Cross links DNA
- CML, and bone marrow ablation
- Pulmonary fibrosis
What is the MOA, use, and side effects of: bleomycin
- Induces free radical damage to cause breaks in DNA
- Testicular cancer
- Pulmonary fibrosis
What is the MOA, use, and side effects of: doxorubicin
- Generates free radicals and intercalates DNA
- Solid tumors, leukemia
- Cardiotoxic
What is dexrazoxane used for?
Prevent cardiotoxicity from doxorubicin
What is the MOA, use, and side effects of: 5-FU
- Pyrimidine analog, inhibits thymidylate synthase
- Colon cancer
- Photosensitivity and myelosuppression
What is the MOA, use, and side effects of: ritixumab
- Anti CD20
- RA, non-hodgkin’s lymphoma
- PML
What is the MOA, use, and side effects of: Vemurafeib
- BRAF kinase inhibitor
- Metastatic melanoma
What is the MOA, use, and side effects of: bevacizumab
- Monoclonal ab against VEGF
- Solid tumors
- Hemorrhage