Haemostasis Flashcards
Describe platelets.
- Produced in bone marrow by fragmentation of the cytoplasm of megakarocytes.
- Their main function is to form plugs during the haemostatic response to vascular injury (adhesions, aggregation and release reactions and amplification).
- non-nucleated biconvex disc
- have adhesive and contractile properties
Thrombopoietin is high in patients with thrombocytopenia cuz of marrow aplasia but low in people with raised platelet counts. T or F.
T
note: thrombopoietin is made in the liver and is used to regulate platelet formation and is removed by binding to c-MPL receptors on platelets.
Platelets aggregate with each other and adhere to the vessel endothelial wall. T or F.
T
note: both partly mediated by vWf
Adhesion to collagen is facilitated by?
Glycoprotein Ia (GPIa) & GPIb (i think)
Glycoproteins Ib, IIb/IIIa are important for?
- Attachment of platelets to von Willebrand factor (VWF), and thus to the vascular subendothelium/vessel wall.
- The binding sites for GPIIb/IIIa are also found on fibrinogen, which is important for platelet aggregation.
Primary activation of platelets leads to?
alpha granules release contents (clotting factors, VWF, platelet-derived growth factors, other proteins) leading to platelet aggregation.
What is thromboxane A2 (TXA2)?
- involved in secondary amplification of platelet activation for platelet aggregation;
- it lowers platelet cAMP (causing high Ca2+ levels) and initiates the release reactions;
- also a powerful vasoconstrictor.
what is prostacyclin (PGI2)
- inhibits platelet aggregation/primary hemostasis by increasing platelet cAMP (causing low Ca2+ levels);
- this is for when the vascular endothelium is intact/there’s no injury.
- note: other inhibitors include NO and ectonucleotidase (CD39) and aspirin; these promote vasodilation and inhibits platelet aggregation
Thrombin’s role?
- Converts fibrinogen to fibrin (enmeshes the platelet aggregates at site of injury and converts the primary plug to a firm, stable, hemostatic plug)
- note: the pathways will work to convert prothrombin to thrombin.
- the initial phase, in the extrinsic pathway, will produce small amounts of thrombin which amplifies a larger production, in the intrinsic pathway.
Coagulation is initiated after?
- Vascular injury by interaction of tissue factor (TF) with plasma factor VII.
- The TF-VIIa complex (extrinsic factor Xase) activates factors IX and X (extrinsic pathway).
- Factor X by itself, not activated will make a small amount of thrombin (that will enhance a larger production)
- The Xa-Va complex will convert prothrombin to thrombin (common pathway)
The extrinsic pathway?
- The initiation pathway which involves tissue factor;
- the formation of extrinsic Xase (TF-VIIa) initiates the coagulation cascade.
- Inhibited by tissue factor pathway inhibitor (TFPI).
- Also its predominant in-vivo.
- TF + VII –> IXa & Xa
Intrinsic pathway?
- thrombin from extrinsic pathway will initiate intrinsic factors.
- The amplification pathway/ contact activation pathway.
- Predominant in-vitro.
- intrinsic Xase is formed by IXa + VIIIa, in the presence of Ca2+ it activates enough Xa (which combines with Va) to generate thrombin.
- V and VIII are converted to Va and VIIIa (Va combines with Xa & VIIIa combines with IXa)
Factor XI deficiency causes bleeding. T or F.
T; apparently this is haemophilia C and its just mild bleeding; not major and its rare
The activity of factors II, VII, IX and X depend on what?
Vitamin K
note: coumarin is a vit K antagonist
Thrombosis?
occlusions of blood vessels (unchecked, blood coagulation could cause this)
Tissue factor pathway inhibitor (TFPI) inhibits what?
the main in vivo pathway by inhibiting factors Xa and VIIa/ the extrinsic pathway.
Protein C does what?
- destroys the activated factors V and VIII which inhibits coagulation;
- activated by thrombin-thrombomodulin complex (thrombin binds to thrombomodulin);
- it is enhanced by protein S;
- activated protein C enhances fibrinolysis; natural fibrinolytic
- note: a vit K dependent serine protease
Other inhibitors of secondary hemostasis besides TFPI?
- Antithrombin III
- heparin
theres more cant bother
Tissue plasminogen activator (TPA)?
- Converts plasminogen to plasmin, and plasmin will break down fibrin, fibrinogen, factors V and VIII into soluble fragments.
- inactivated by plasminogen activator inhibitor (PAI).
what are some fibrinolysis/tertiary hemostasis inhibitors? hint:3
- PAI (plasminogen activator inhibitor)
- alpha 2 antiplasmin
- TAFI (thrombin activated fibrinolytic inhibitor )
Ca2+ dependent reactions?
Formation of Xa
Formation of thrombin
Give egs of anticoagulants.
- EDTA, citrate- chelate Ca2+; used in vitro cuz Ca2+ needed for other reactions
- Heparin- inhibit clotting enzymes, activates antithrombin III (in secondary hemostasis); used in vivo n in vitro; monitored by PTT time
- Fluoride- inhibits glycolysis
- Coumarin- vitamin K antagonist; used in vivo; monitored by PT time
Normal platelet count?
150/250-400 x 10^9
Patients with suspected bleeding disorders like thrombocytopenia should initially have what?
a complete blood count, including a platelet count and blood film examination.
Prothrombin time (PT) measures what?
- measures EXTRINSIC and COMMON pathway factor activity 1, 2, 5, 7 & 10)
Activated partial thromboplastin time (APTT) measures what?
- Measures the intrinsic (7, 9, 11 & 12) and common pathway factors (1, 2, 5 &10)
- Measures the clotting time of plasma after the activation of contact factors but without added tissue thromboplastin.
Thrombin (clotting) time (TT) measures what?
- Measures fibrinogen function.
- TT is sensitive to fibrinogen deficiency and inhibition of thrombin
Heparin does what and is used for what?
- enhances antithrombin III by binding to it which will inactive clotting factors like Xa, IXa, XIa, XIIa, protein C and S.
- to inactivate thrombin, heparin has to bind to both antithrombin III and thrombin. LMWH isn’t long enough to bind to both.
- affects the intrinsic pathway
- used for DVT, PE, and arterial thromboembolism; may also be used in hip/knee replacement surgery
ADRS of heparin?
- Heparin induced thrombocytopenia (HIT)
- thrombosis
- can cause hyperkalemia (inhibits aldosterone)
- can cause tissue necrosis (due to protein C)
If a person overdoses on heparin, what should they take?
protamine sulphate
Low molecular weight heparin (LMWH) egs? hint: 2
Enoxaparin and dalteparin
(ED parin-enoxa & dalte)
Give some egs of direct thrombin inhibitors.
- Hirudin (IV)
- Lepuridin (IV)
- Dabigatran
- Etexilate (oral)
Harry Let Dobby Escape
note: these drugs inactivate thrombin; antithrombin III independent
Warfarin does what and is used for what?
- Reduces vitamin K (by inhibiting vit k reductase complex) which in turn reduces the synthesis of clotting factors (II, VII, IX, X & XIII)
- affects the extrinsic pathway
- given to pregnant women to avoid hemorrhage; also used for intracranial bleeding i think
- note: monitored by PT
How are the effects of wafarin reversed?
- Plasma (fast but short-lasting)
- Vit K (slow but long-lasting)
Antiplatelet drugs do what and are used for what?
- Decrease platelet aggregation
- Used for prophylaxis of arterial thrombosis and heart attacks
Antiplatelet drugs egs (inhibits platelet aggregation)?
- Aspirin: inhibit TXA2/COX1
- Dipyridamole: inhibit phosphodiesterase
- Clopidogrel, Ticlopidine: ADP/P2Y12 receptor antagonist
- Abciximab: GPIIb/GPIIIa receptor antagonist
- Vorapraxar: antagonist of the protease-activated receptor-1 (PAR-1)
Aleeyah Doesn’t Call/ Talk to Amanda Very much (not real)
Anticoagulant and antiplatelet drugs are used to prevent the formation of clots while thromobolytic drugs are used to destroy already formed clots. T or F.
T
Fibrinolytic drugs egs? hint: 4
- Streptokinase & Urokinase: increase the conversion of plasminogen to plasmin
- Tissue Plasminogen Activators: activates plasminogen that is bound to fibrin & converts it to plasmin; Tenecteplase & Reteplase
Suck Up To Rachel
The formation of platelets is controlled by what?
thrombopoietin and CSFs
note: regulates the production of platelets in the bone marrow
How long does the formation of platelets last?
10 days
How are platelets formed?
by fragmentation of the cytoplasm of megakaryocytes
Whats the lifespan of platelets?
8-10 days
What are functions of platelets?
- activation: Change in shape (pseudopodia) and secretion of granular contents like ADP, serotonin, fibrinogen, thromboxane A2
- adhesion: GPIa (collagen), GPIb and VWF
- aggregation: Stimulated by ADP and thromboxane A2
Primary haemostasis is done by the platelets while secondary haemostasis is performed by the coagulation factors. T or F.
T
Which pathway is predominant in vivo?
extrinsic pathway
which pathway is predominant in vitro?
intrinsic pathway
what are the factors of the coagulation cascade?
- factor I: fibrinogen
- factor II: prothrombin
- factor III: tissue factor/ tissue thromboplastin
- factor IV: calcium
- factor V: proaccelerin/ labile factor
- factor VII: proconvertin
- factor VIII: antihemophilic factor
- factor IX: christmas factor
- factor X: stuart factor
- factor XI: plasma thromboplastin antecedent (PTA)
- factor XII: Hageman factor/ contact factor
- factor XIII: fibrin stabilizing factor
Calcium ions are required for the activation of which coagulation factors?
- Factor IV (calcium),
- Factor IX,
- Factor X
- prothrombin (Factor II)
2,4,9,10
deficiency of factor VIII causes what?
hemophilia A
deficiency of factor IX causes what?
hemophilia B
Whats virchow’s triad?
three factors that contribute to the formation of blood clots or thrombi in blood vessels:
- endothelial injury
- hypercoagulability
- abnormal blood flow
note: can lead to deep vein thrombosis (DVT), pulmonary embolism, and stroke.
Thrombin inhibition requires heparin binding to both thrombin and ANT III. T or F.
T- LMWH bind only to ANT III and therefore increase inactivation of other factors (IXa, Xa, XIa and XIIa) and NOT
thrombin.
what are the advantages of using LMWH vs heparin?
- less inhibition of platelet function
- lower incidence of thrombocytopenia and thrombosis (HIT thrombocytopenia)
warfarin blocks activation of clotting factors and heparin speeds the inactivation of clotting factors. T or F.
T
Fibrinolytic/thrombolytic drugs do what?
- remove the fibrin formation/ lyse clots in arteries and veins and re-establish tissue perfusion
- used to manage pulmonary embolism, deep vein thrombosis and arterial thromboembolism or acute heart attack caused by a clot
- note: these drugs only useful in emergency settings
Whats an eg of an oral anti-coagulant wafarin?
coumarin
Platelet tests should evaluate?
- platelet number and function
- intrinsic, extrinsic, and common pathways
- clot formation/breakdown
- inhibitor levels
whats the normal bleeding time?
1-11 minutes
What is Glanzmann’s thromboasthenia?
- rare bleeding disorder that is caused by a deficiency or dysfunction of the glycoprotein IIb/IIIa receptor on platelet; prolonged bleeding time
- autosomal recessive
- treatment: platelet transfusions (may develop Abs), desmopressin (DDAVP), and recombinant activated factor VII (rFVIIa)
What is Bernard-Soulier syndrome?
- rare bleeding disorder that is caused by a deficiency or dysfunction of the glycoprotein Ib/IX/V complex on platelets
- autosomal recessive
- platelets are larger than normal and have an abnormal shape; prolonged bleeding time
- treatment: platelet transfusions (may develop Abs), desmopressin (DDAVP), and recombinant activated factor VII (rFVIIa)
What is Von Willebrand disease?
- most common inherited bleeding disorder that is caused by a deficiency or dysfunction of von Willebrand factor (platelet adhesion and blood clotting).
- autosomal dominant
- symptoms: frequent nosebleeds, excessive bleeding after injury or surgery, heavy menstrual bleeding, and easy bruising
- treatment: desmopressin (DDAVP) or clotting factor concentrates ( w/ VWF & factors VIII or IX). In some cases, oral contraceptives or other hormonal treatments may be used to reduce menstrual bleeding.
When measuring APTT, what is used (reagents, anticoagulant)?
- Contact Activators: Kaolin , silica or ellagic gel
- reagents used: platelet poor plasma (PPP), kaolin, phospholipid, calcium chloride
- trisodium citrate is used as the anticoagulant
What is the normal time range and control for measuring APTT?
normal time: 30-34 s
control: +/- 6 seconds
What does a prolonged APTT indicate?
- Coagulation Factor Deficiency : VIII (haemophilia A, vWD) , IX ( Haemophilia B) , XI , XII, II, X , V , I
- liver disease
- circulating anticoagulant
- Disseminated Intravascular Coagulation (DIC)
note: used to monitor wafarin therapy, heparin therapy
When measuring PT what is added?
Reagents :
- Platelet Poor Plasma (PPP)
- CaCl
- Thromboplastin
- lipids (textbook)
note: trisodium citrate is used
What is the normal time range and control for PT?
- normal time: 12-14 s
- range: +/- 4 secs
What does a prolonged PT indicate?
- Deficiency of Vit K dependent factors (II, VII , IX , X)
- Warfarin (inhibits Vit K dependent factors)
- liver disease
- factor VII deficiency
- disseminated intravascular coagulation (DIC)
- common factor pathway deficiency
note: used in warfarin therapy
When measuring TT what is added?
- Platelet poor plasma (PPP)
- diluted bovine thrombin
note: trisodium citrate is used
What is the normal time range and control for TT?
- normal time: 8-12 s
- control: +/- 2 s
What does a prolonged TT indicate?
- Hypofibrinogenaemia (DIC)
- Raised concentrations of fibrinogen degradation products (FDP); (DIC , liver disease)
- Heparin (interferes with the thrombin-fibrinogen reaction)
- Dysfibrinogenaemia
- Hypoalbuminaemia
note: used to monitor heparin therapy
What do D-dimers indicate?
- thrombus formation (DVT, PE, MI)
- DIC
- can also be elevated in conditions such as inflammation, infection, and pregnancy
- D-dimers are produced from fibrinolysis (when clots r broken down)
What is DIC?
- disseminated intravascular coagulation
- the body’s normal clotting mechanism becomes overactive, leading to the formation of small blood clots within blood vessels throughout the body.
- These clots can obstruct blood flow to organs and tissues, leading to organ damage and dysfunction.
