4.2 Haemostasis and its abnormalities

Question 1

FORMATION OF HAEMOSTATIC PLUGS
The formation of haemostatic plugs is central to the haemostatic process, which is a response to injury to the endothelial cell lining (through vasoconstriction)
• Primary haemostasis: formation of _____________ (by platelet adhesion and aggregation)
• Secondary haemostasis: stabilisation of plug with _______ (via blood coagulation)
• Fibrinolysis: __________ and physiological dissolution of clot (resolution of injury)

Answer 1

Unstable platelet plug;

fibrin;

vessel repair

Question 2

INITIAL RESPONSE TO VESSEL INJURY
When injury to the endothelial cell lining is detected, vasoconstriction occurs as vascular smooth muscle cells contract locally, decreasing vessel radius and limiting blood flow to injured vessel
• Local contractile response to injury mainly important in the _______________ (sufficient to prevent blood loss)
• Smooth muscle cells underlie the single layer of endothelial cells in the ________________________
o Endothelial cell monolayer has anticoagulant properties via ___________ (on endothelial cell surface) and _______________ (secreted by endothelial cells)  prevent coagulation process
▪ Important barrier preventing contact with subendothelium, which has procoagulant properties
o Subendothelial layers (includes basement membrane) include collagen (platelet response), tissue factors (on smooth muscle cells and fibroblast surfaces)

Answer 2

small blood vessels;

subendothelial space (tunica media);

thrombomodulin;

tissue factor pathway inhibitor

Question 3

PRIMARY HAEMOSTASIS
The formation of an unstable platelet plug involves platelet adhesion and platelet aggregation to limit blood loss and provide surface for coagulation
• Platelets (thrombocytes) are derived from _______________ in the bone marrow (from haematopoietic stem cells)
o Megakaryocytes have multi-lobular nuclei, and ____________ cytoplasm (development during differentiation and maturation)
o Fragmentation of cytoplasm occurs, from which platelets are formed (no nucleus)

Answer 3

megakaryocytes;

granulated

Question 4

What is the function of the phospholipid membrane?

Answer 4

Defines the boundaries of the platelet and separates contents from external environment (maintaining constant internal environment

Question 5

What is the open canalicular system for?

Answer 5

Invaginations in phospholipid membrane (sponge-like structure)
• Pathway for transport of substances into the cells
• Conduit for discharge of α granule products secreted during platelet release section

Question 6

What is cell surface receptors for?

Answer 6

Binds to thrombin, ADP and prostaglandins (activation of platelets)

Question 7

What are surface glycoproteins for?

Answer 7

Important in platelet adhesive and aggregation reactions (GpIa, GpIb, GpIIb, GpIIIa)

Question 8

What are dense granules for?

Answer 8

Storage granules for ADP (important for activation of platelets), ATP, serotonin and calcium

Question 9

What are a granules for?

Answer 9

Storage granules for proteins (growth factors, fibrinogen, factor V, von Willebrand factor)

Question 10

Platelet adhesion: recruitment of platelets from circulating blood to the site of injury
• Platelets and important proteins (e.g. VWF produced by endothelial cells and stored in platelets) circulate in plasma in a globular concentration
o Circulates as __________ without interaction with platelets (binding sites hidden from platelet GpIb)
• When vascular injury occurs, endothelium is damaged, exposing the ____________, which results in VWF binding
• Tethered VWF unravelled by rheological shear forces of flowing blood, exposing platelet binding sites (GpIb)  tethering of platelets
o Binding of VWF to platelet GpIb recruits platelets to the site of vessel damage
o Platelets also bind directly to subendothelial collagen via __________ (under low shear forces  insufficient to unravel VWF), recruiting platelets to site of vessel damage

Platelet activation: conversion of platelets from passive to active, interactive cells:
• Change in shape, membrane composition (phospholipid changes nature to attract activated coagulation factors), and presentation of new/activated surface proteins (____________ normally quiescent on surface, but responds in aggregation)
• When platelets bind to VWF or directly to collagen, they become activated, releasing stored ADP from α granules, and synthesising thromboxane (platelet activation)
o ____________________ can also directly activate platelets
• Membrane phospholipid composition changes to attract activated coagulation factors (more active GpIIb and GpIIIa)

Platelet aggregation: formation of an unstable platelet plug
• GpIIb and GpIIIa are activated, binding more tightly to collagen and VWF
o Also binds to ___________ which circulates in high concentrations in the blood to form the unstable haemostatic plug
o Helps to slow bleeding and provides surface for coagulation

Answer 10

globular protein;

subendothelial collagen;

GpIa;

GpIIb and GpIIIa;

Collagen and thrombin;

fibrinogen

Question 11

SECONDARY HAEMOSTASIS
The stabilisation of the plug with fibrin results in blood coagulation to stop blood loss
• Coagulation involves many haemostatic proteins, mainly synthesised in the liver
o Some proteins are synthesised by the endothelial cells (________________________), and megakaryocytes (____________-) for local use
• Clotting factors circulate as inactive precursors (serine protease zymogens or procofactors), activated by specific proteolysis

Coagulation system is a cascade (amplification) system, converting zymogens (inactive) to proteinases (active)
• Cofactors like TF initiate coagulation, while others like FVa and FVIIIa localise and accelerate (10000-fold) reactions on phospholipid surfaces
• Surface may be platelets formed during primary haemostasis
• Trigger for coagulation in vivo is tissue factor
• Activation of FXII to FXIIa is mainly an _______________ used in some important diagnostic tests

Answer 11

VWF, thrombomodulin, tissue factor pathway inhibitor;

VWF, factor V;

in vitro reaction

Question 12

Which factors contain vitamin K dependent carboxylation domains?

Answer 12

Prothrombin, factor 7+9+10

Question 13

Intrinsic pathway: blood coagulation is initiated by the activation of factor XII to factor XIIa, which in turn activates factor XI to XIa, then IX to IXa, and finally X to Xa
• Cofactor VIIIa is involved in activation by factor IXa (requiring phospholipids provided by platelet membrane) –> phospholipids change to provide _________ when platelet is activated
o Activated coagulation factors bind to ________________, and factor VIIIa accelerates conversion of factor X to Xa
• Factor VIIIa is activated by factor VIII by trace amounts of ___________

Extrinsic pathway: tissue factor released from cells of the _______________ exposed by vessel damage binds to factor VIIa to fully activate it
• Factor VIIa results in activation of factor X to Xa OR activation of intrinsic pathway by activating _______________
• Factor VII circulates in a partially activated form (VIIa) which complexes with TF to become fully active

Common pathway: factor Xa activates prothrombin to thrombin (IIa), requiring cofactor Va acting on phospholipid surface of platelets
• Cofactor Va is activated from factor V by trace amounts of thrombin  positive feedback loop resulting in activation of more cofactors and thus more thrombin
• Soluble fibrinogen (structural) is converted to insoluble fibrin by thrombin via proteolysis, which spontaneously assembles to form a clot (traps __________________)
o Stabilised mechanically by covalent crosslinking by action of the enzyme factor XIIIa
o Factor XIIIa is activated from factor XIII by ________________

Answer 13

surface;

activated platelets (surface);

thrombin;

subendothelial matrix;

factor IX to IXa;

RBC and leukocytes;

trace amounts of thrombin

Question 14

INHIBITORY MECHANISMS TO COAGULATION
A large amount of thrombin can be produced from a small amount of factor VIIa (amplification), but blood does not clot completely/excessively whenever it is initiated by vessel injury  inhibitory mechanisms

TISSUE FACTOR PATHWAY INHIBITOR (TFPI)
TFPI is synthesised by endothelial cells, and recognises ___________________
• Complex inhibits factor Xa and binds with ______________________, thus inactivating the TF/FVIIa complex
• Important physiological reaction, though circulating concentrations of TFPI are low
o Extensive vessel damage resulting in extensive exposure of TF may result in overwhelming of TFPI mechanism

PROTEIN C
Thrombin can bind to ____________________ anticoagulant protein thrombomodulin, redirecting its activity towards activating protein C to APC
• Activated protein C can act with cofactor protein S to target and inactivate ____________________
• Negative feedback loop preventing over-acceleration of thrombin production and amount of thrombin generated

ANTITHROMBIN
Antithrombin is an inhibitor protein circulating in high concentrations, and directly inhibits thrombin (irreversible reaction)
• Antithrombin-thrombin complexes are quickly cleared from the circulation
• Broad spectrum inhibitor able to inhibit ______________– along with thrombin

Answer 14

factor Xa (forms complex Xa/TFPI);

tissue factor and factor VIIa;

endothelial cell surface

factor VIIIa and factor Va;

factors Xa and IXa

Question 15

FAILURE OF MECHANISMS
Coagulation inhibitory mechanisms are essential in regulating the cascade amplification from occurring and clotting blood completely:
• May fail due to deficiencies in ___________________(congenital deficiencies) or presence of _________(mutated factor V causing hypercoagulability)
o Congenital deficiencies of anticoagulant proteins lead to 50% reduction in concentration and increased risk of venous thrombosis
o FV Leiden avoids normal binding from __________, resulting in increased tendency for patient to form abnormal and potentially dangerous blood clots (present particularly in _____________________)
• These are all risk factors for thrombosis

Answer 15

antithrombin, protein C, protein S;

factor V Leiden ;

APC;

5% of white skinned population

Question 16

DISSOLUTION OF CLOT
Dissolution of the blood clot is caused by fibrinolysis and cell proliferation, and initiates vessel repair to restore the vessel integrity
• Tissue plasminogen activator (tPA) is synthesised by endothelial cells and circulates in partially activated form in the blood
o Activates the zymogen plasminogen to plasmin
• Under normal circumstances, tPA is unable to convert plasminogen to plasmin; when a fibrin clot forms, binding of ________________ to surface of clot occurs
o Brings plasminogen near partially active tPA
o Conformational change occurs in tPA, to activate plasminogen to plasmin via cleavage
• Plasmin breaks down the fibrin clot to generate _________________ –> diagnostic test for widespread clot formation breakdown in disseminated intravascular coagulation (DIC)
o tPA and streptokinase (bacterial activator) are used in therapeutic thrombolysis for myocardial infarction, ischaemic stroke etc. (clot busters)

Answer 16

plasminogen and tPA;

fibrin degradation products (FDP)

Question 17

ALTERATION OF HAEMOSTATIC BALANCE
Normal haemostasis occurs in a state of equilibrium between anticoagulation (fibrinolytic factors and anticoagulant proteins) and coagulation (coagulation factors and platelets)
• Bleeding occurs with decreased coagulation factor concentration or circulating platelet number, or increased fibrinolytic factor and anticoagulant protein concentration
o von Willebrand disease (platelets and adhesion reactions), thrombocytopenia (decrease in _____________ ), or haemophilia ( __________ deficiency)
• Thrombosis occurs with decreased fibrinolytic factor and anticoagulant protein concentration, or increased coagulation factor concentration or circulating platelet number
The type of bleeding experienced in different conditions are very different:

Answer 17

platelet count;

FIX or FVIII

Question 18

ABNORMAL BLEEDING
Bleeding that is ____________ (without any obvious precipitant, like in haemophilia), out of proportion to the trauma/injury, unduly prolonged, and restarts after appearing to stop (delayed bleeding)
• Bleeding no longer proceeds according to expectation as the haemostatic mechanisms are out of equilibrium
• However, about 12% of the population experiences “easy bruising” even though they would not be considered as having any major haemostatic disorder
o System by which bleeding history is taken must be refined

ABNORMAL BLEEDING HISTORY
• Epistaxis (bleeding from the nostril or nasal cavity/“nosebleeds”) not stopped by _______________, requiring medical attention or blood transfusion.
• Cutaneous haemorrhage or bruising without apparent trauma, especially if large (>5cm) or on multiple parts of the body.
• Prolonged (>15 min) bleeding from trivial wounds, or in oral cavity, or recurring spontaneously in 7 days after the wound. Spontaneous gastrointestinal bleeding leading to ___________ (indicating severity).
• ____________ (menstrual periods with abnormally heavy or prolonged bleeding) requiring treatment or leading to anaemia, and not due to structural lesions of the uterus.
• Heavy, prolonged or recurrent bleeding after surgery or dental procedures (if patient has been through major surgery without any significant problems in bleeding, it is unlikely to be a coagulation system problem at the time of the surgery).

Answer 18

spontaneous;

10 minutes of compression;

anaemia;

Menorrhagia;

Question 19

Primary haemostasis requires platelets, von Willebrand factor (VWF) (bind to collagen) and collagen (in subendothelial matrix)
• Deficiency or defects in collagen or the vessel walls may result from ____________ or age (acquired disorders of collagen), or _____________ (rare, inherited disorders of collagen)
• Deficiency of VWF or presence of abnormal VWF molecules may lead to von Willebrand disease (more common genetic disorder)
• Deficiency of platelets could result from _____________ (low platelet count), while impaired platelet function could result from drugs like _________________

With vessel damage, the two key proteins (____________________) triggering blood coagulation are exposed
• Globular VWF binds to collagen and unravels due to high shear forces, exposing binding sites for platelets  activation and degranulation of platelets
• More VWF released from platelets results in another layer of the clot forming (primary platelet plug)
o Primary haemostasis is sufficient for ______________, but the coagulation system needs to be activated (secondary haemostasis for larger vessels or injuries)

In patients with von Willebrand disease (VWF deficiency), no VWF is present to bind to collagen, so only a few platelets will bind to collagen directly (most will flow past)
• Primary haemostasis is not achieved, and the patient continues to bleed

Answer 19

steroid therapy ;

Ehlers-Danlos syndrome;

thrombocytopenia;

aspirin or clopidogrel;

collagen and tissue factor;

small blood vessels and small injuries

Question 20

PATTERN OF BLEEDING FOR PRIMARY HAEMOSTATIC DEFECTS
Defects of primary haemostasis tend to give rise to a characteristic pattern of bleeding:
• Immediate (no period of stopping because primary haemostatic mechanisms do not start)
• Easy bruising/cutaneous bleeding (bleeding from smaller, peripheral or mucosal blood vessels  high shear stress)
• ________/nosebleeds (prolonged >20 min)
• Gum bleeding (prolonged)
• Menorrhagia (abnormal bleeding during menstrual periods)
• Bleeding after trauma or surgery
• ______________ (specific for thrombocytopenia): appear like small blood spots
o Platelets are constantly plugging small vessel breaks in the circulation (primary haemostasis), so they are very essential; without them, small vessel breaks are left to occur, resulting in petechiae

Answer 20

Epistaxis;

Petechiae

Question 21

SECONDARY HAEMOSTATIC DEFECTS
The process of coagulation (secondary haemostasis) can be measured via _____________ (net product of coagulation) generation over time (thrombogram):
• Coagulation system is designed to produce a large
amount of thrombin to convert fibrinogen to
fibrin (mesh of clot) later crosslinked by factor
XIIIa
• After coagulation system is triggered by ______________ (extrinsic pathway) exposed by endothelial damage, there is a time lag (taken for pathways to be activated and initial generation of thrombin)
o Rapid, high level production of thrombin, which is then gradually suppressed by regulatory proteins (antithrombin, protein C)
• In patients with factor VIII deficiency (_____________) <1%, the burst of thrombin does not occur
o Time lag for thrombin production still occurs, and when thrombin is produced, there is only a weak and feeble amount (inadequate for clotting)
o Fibrin is required for binding and stabilisation of the platelet plug and other cells (RBC, leukocytes)

Answer 21

thrombin;

tissue factor;

haemophilia

Question 22

Patients with defects of secondary haemostasis (fibrin mesh formation) may have deficiencies or defects of coagulation factors (I – XIII):
• Haemophilia (hereditary): factor VIII or IX deficiency due to genetic defect
• Liver disease (acquired disease): most coagulation factors are made in liver  lack one or more factors (most people with advanced liver disease have bleeding disorders)
• Drugs like warfarin (anticoagulant drug) inhibits the synthesis of coagulation factors (II, VII, IX, X) –> ___________ is involved in these reactions
• Dilution of blood: patients with major haemorrhage are often resuscitated using factors (e.g. RBC, crystalloid solutions/volume expanders like Ringer’s lactate/Hartmann’s solution) –> at risk of dilution effect reducing serum concentration of coagulation factors (____________________)
• ______________________ is an acquired disease and a consumptive process which uses up or depletes coagulation factors in the blood, increasing tendency for bleeding
o Generalised activation of coagulation around the body by tissue factor (cells in the blood like monocytes can express TF in response to inflammation)  exposed throughout the circulation
o Associated with ________________ (sepsis, major tissue damage, incompatible blood transfusion)
o Consumes and depletes coagulation factors and platelets
o Activation of fibrinolysis depletes fibrinogen in the body
o Leads to widespread bleeding from __________, internal bleeding, widespread bruising, organ failure (deposition of fibrin in vessels of major organs like _______________)

Answer 22

calcium;

dilutional coagulopathy;

Disseminated intravascular coagulation (DIC);

major inflammatory stimuli;

IV lines;

kidneys and lungs

Question 23

In patients with haemophilia, the primary haemostatic mechanism is normal, but their deficiency in factor VIII or IX results in failure to generate thrombin and thus fibrin to stabilise the platelet plug
• Platelets are only held loosely together by VWF  _____________ tends to fall apart, causing delayed bleeding

Answer 23

primary haemostatic plug

Question 24

PATTERN OF BLEEDING FOR SECONDARY HAEMOSTATIC DEFECTS
• Bleeding is often delayed, occurring only after _____________ (normal) has occurred  secondary haemostasis fails to stabilise the primary plug
• Occurs deeper in the body (in joints and muscles) because it is dependent on tissue factor (particularly in areas with low TF concentration)  ____________ (bleeding into joints) causes extreme pain (held in flex position), and is spontaneous, causing severe damage to the joint (requiring joint replacement)
• Does not occur from small cuts (primary haemostasis still sufficient)
• _____________ are rare (primary haemostasis still sufficient)
• Bleeding after trauma or surgery
• Bleeding after intramuscular injections (tend to produce very __________)

Answer 24

primary haemostasis;

haemarthrosis ;

Nosebleeds/epistaxis;

large haematomas

Question 25

DEFECTS OF CLOT STABILITY
An increase in anticoagulant proteins or fibrinolytic factors may also lead to the same tendency to bleeding (excess fibrinolysis):
• Defects of excess fibrinolytic activity tend to be fairly rare, but may include excessive plasmin or tissue plasminogen activator
o Due to therapeutic administration of __________ (clot lysis) or some tumours
o Hereditary defects of antifibrinolytic system (antiplasmin) due to antiplasmin deficiency  excessive fibrinolytic activity
↓ Easy bruising (ecchymosis) occurs in virtually all bleeding disorders
 _____________ is the hallmark of haemophilia
• Excess anticoagulant proteins only occur due to therapeutic administration of _________________ (never congenital)

Answer 25

plasmin or tPA;

Haemarthrosis;

heparin or direct anti-Xa or anti-II (prothrombin) drugs

Question 26

DEEP VEIN (VENOUS) THROMBOSIS
DVT is the formation of a thrombus (blood clot) within a deep vein, most commonly in the legs, which may become dislodged from the vessel wall, and travels within the circulation back to the right heart and into the pulmonary circulation
• Thrombus may become lodged in pulmonary vessels, causing pulmonary embolism (venous thromboembolism)  may cut off perfusion to the lungs
• Results in \_\_\_\_\_\_\_\_\_\_\_\_\_ and insufficient oxygen delivery to the rest of the body  \_\_\_\_\_\_\_\_\_\_ (shortness of breath), \_\_\_\_\_\_\_\_\_\_ (rapid breathing), chest pain, cough, \_\_\_\_\_\_\_\_ (coughing up blood), \_\_\_\_\_\_\_\_ (blue discolouration of lips and fingers), circulatory instability, sudden death (if clot is large enough to block pulmonary circulation completely)

Answer 26

V/Q mismatch;

dyspnoea;

tachypnoea;

haemoptysis;

cyanosis

Question 27

DEE
Venous thromboembolism is very prevalent (overall 1 in 1000 – 10000 per annum)
• Incidence (number of new cases) doubles every decade, and is the cause of 10% of hospital deaths (estimated 25,000 preventable deaths per annum in UK)
• Prevalence of DVT and PE increases with age
• Mortality is 5% (for VT) and 1 in 1000 for pregnant women
• 20% recurrence (in first 2 years) and 4% recurrence (thereafter)
Venous thromboembolism may result in ______________ and pulmonary hypertension
• Thrombophlebitic syndrome/post-thrombotic syndrome occurs in 23% of cases at 2 years (11% in those with stockings)
o Damage to vein valves results in pain, heaviness and swelling (oedema) of the lower limbs, venous ulceration after DVT
o Lower incidence in those wearing stockings as it compresses leg muscles and veins, increasing the power of skeletal muscle pump and prevents stasis and pooling (thus reducing DVT and TPS)  compression therapy
• _________________ occurs in 4% of cases at 2 years
o High blood pressure due to remodelling of pulmonary circulation affecting arteries in lungs and right side of the heart, reducing the _______________ along veins  reduced venous return and perfusion of blood
o Right ventricle needs to work harder to pump blood through the lungs, causing it to weaken and fail (could be fatal)

Answer 27

thrombophlebitic syndrome;

Pulmonary hypertension;

pressure gradient

Question 28

CAUSES OF THROMBOSIS
Some people get thrombosis due to genetic constitution (hereditary), effects of age and previous events/illnesses/medications, or acute stimuli (acquired)
• Thrombosis is multi-causal arising from interactions between genetic and acquired risk factors  contributory factors (Virchow’s triad: blood, vessel wall, flow)

Blood (dominant in venous thrombosis)
• Deficiency of anticoagulant proteins (antithrombin, protein C, protein S) –> decreased regulation of coagulation activity in blood
• Increased coagulant protein concentration or activity (factor VIII, factor II/IX/XI, factor V Leiden, thrombocytosis/increased platelet count)
o Factor V Leiden leads to increased factor V activity due to ____________ in European populations particularly
• Absolute risks for thrombosis include age (20 years: 1/10000 pa; 60 years: 1/1000 pa), while relative risks include thrombophilic traits (anticoagulant deficiency, procoagulant excess)

Vessel wall (dominant in arterial thrombosis)
• Many proteins active in coagulation (e.g. thrombomodulin, tissue factor, TFPI) are expressed on the surface of endothelial cells -->  mostly by atherosclerotic mechanisms altering the vessel wall
o Expression of these proteins are altered in \_\_\_\_\_\_\_\_\_\_ (caused by malignancy, sepsis, immune disorders)  downregulation

Flow of blood (complex; contributes to arterial and venous thrombosis)
• Reduced blood flow (stasis) increases the risk of venous thrombosis (due to surgery, fractures, long haul flights, bed rest)  accumulation of factors at one site
An increased risk of thrombosis (thrombophilia) can be identified clinically or in the laboratory:
• Clinical syndromes: thrombosis at young age, idiopathic thrombosis (without apparent external trigger), multiple thromboses, ______________ (indicated severe hypercoagulability)
• Laboratory signs: identifiable causes of increased risk (antithrombin deficiency, factor V Leiden, global measures of coagulation activity like thrombin generation assays)

Acquired risks for thrombosis may include conditions which alter blood coagulation, vessel wall and flow (e.g. oral contraceptive pills, pregnancy, malignancy, surgery, inflammatory responses)
• Oral contraceptive pills produce changes in ______________________; pregnancy causes coagulation factor, vessel wall changes and venous obstruction
• The risk of postoperative VTE spikes within the first 4 weeks (120-fold) after inpatient surgery  part of the preventable deaths

Answer 28

increased protein C resistance (does not bind);

inflammation;

thrombosis while anticoagulated;;

coagulation factor concentrations and vessel wall

Question 29

THERAPY FOR THROMBOSIS
Treatment to lyse clot: increasing fibrinolytic activity via increasing tPA (side effect of generalised high bleeding risk)  in acute phase of peripheral arterial occlusions, strokes
• For VTE, tPA may sometimes be used, but only in emergency and last-resort situations (e.g. pulmonary embolism and hypertension)  requires immediate lysis of clot
• Hardly ever used on DVT, unless _________________ is a significant risk

Treatment to limit recurrence/extension: increasing anticoagulant activity or lowering procoagulant factors (to prevent embolism by restoring equilibrium)
• Increasing anticoagulant activity via heparin (immediate-acting, indirect and parenteral) or direct acting anticoagulants (e.g. _________________)  short-term therapy
o Augments the effects of antithrombin  inhibit effects of factors IIa and Xa (primarily) and IXa and XIa  affects clotting cascade
o Venous thromboembolism is primarily contributed by formation of fibrin (clotting cascade), so to treat VTE, agents affecting the cascade should be chosen
o To treat/prevent arterial thrombosis, choose antiplatelet drugs (e.g. aspirin)

• Lowering procoagulant factor via warfarin (oral, slow-acting for long-term therapy) to inhibit procoagulant synthesis
o Paradoxical procoagulant effect in early treatment as it also inactivates the anticoagulants protein C and protein S  promoting coagulation
Thrombosis prevention (NICE Guidelines 2010): assess individual risk and circumstantial risk (all patients admitted to hospitals should have VTE risk assessment done)
• Prophylactic (preventive) antithrombotic therapy should be given for those at high risk (e.g.\_\_\_\_\_\_\_\_\_ for inpatients, T.E.D. compression stockings)  altering balance of equilibrium to accommodate possible changes

Answer 29

venous gangrene;

rivaroxaban, dabigatran, apixaban;

heparin