Bleeding and Thrombosis Disorders in the ICU

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Bleeding and Thrombosis Disorders in the ICU

• Division of Critical Care Medicine University of
  Alberta

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Outline

• Normal hemostasis
• Coagulation pathways
• Initial investigations
• Coagulopathies
• Pathogenesis of coagulopathies
• Specific causes
• Thrombosis
• Pathogenesis
• Diagnosis
• Treatment
• Prevention

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Normal hemostatic mechanism

• There are four phases to the normal coagulation
  cascade
• Blood vessel constriction
• Platelet aggregation
• Fibrin generation
• Vessel repair and fibrin degradation

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Constriction of vessels

• There are 2 mechanisms for vessel constriction
• Local smooth muscle contractile response
• Thromboxane A2 release from endothelium

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Formation of the unstable platelet plug

• Exposure of the subendothelial layers cause
  platelets to adhere.
• They release ADP and TxA2, inducing further
  platelet aggregation and activation

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Binding and activation of platelets

• Adhesion requires von Willebrand factor (vWf)
  from the subendothelial layers.

Binding of vWf to platelet receptor induces the
release of ADP and thromboxane
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Generation of fibrin

• Aggregated platelets provide a surface on which
  blood coagulation occurs through the generation
  of thrombin and cleavage of fibrinogen.

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Stabilization of platelet plug with fibrin

• A platelet plug is inherently unstable and needs
  to be buttressed with support beams.
• This function is supplied by fibrin strands.

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Blood coagulation

• Fibrin generation can be activated by two
  pathways that lead into a common pathway.
• The central feature is the sequential activation
  of a series of pro-enzymes in a stepwise manner
  that causes amplification at each step.

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Intrinsic clotting system

• The intrinsic clotting pathway requires at least
  four coagulation proteins and two co-factors.
• Tested using the aPTT.

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Activation of intrinsic pathway

• The intrinsic pathway is initiated by the
  exposure of blood to a negatively charged surface.

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Extrinsic clotting system

• The extrinsic system, in contrast, requires only
  one coagulation protein and two co-factors which
  allows for rapid activation.
• Tested using the INR.

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Activation of extrinsic pathway

• Tissue thromboplastin (also known as tissue
  factor) is present in the endothelial but is only
  exposed to blood flow during injury.
• Thromboplastin, in the presence of calcium, binds
  to Factor VII to cause the activation of Factor X.

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The two pathways feed into
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the common pathway
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The Common Pathway

• Both the extrinsic and intrinsic pathway converge
  on the activation of Factor X (this also
  facilitates amplification).
• Factor Xa converts prothrombin to thrombin, the
  final enzyme in the clotting cascade.
• Thrombin converts fibrinogen from a soluble
  plasma protein into an insoluble fibrin clot.
• Thrombin also is an important feedback protein on
  the rest of the clotting cascade and platelets.

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Role of thrombin

• Thrombin induces platelets to release ADP and
  endothelial cells to release PGI2
• Only small amounts of thrombin are generated by
  the extrinsic pathway, but amplification occurs
  through intrinsic pathway feedback loop stabilizes

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Fibrinolysis

• The restore vessel patency, the clot must be
  organized and removed by plasmin while wound
  healing and tissue remodeling occur.

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Fibrinolysis and repair

• Plasminogen binds fibrin and tissue plasminogen
  activator (tPA).
• This complex then converts the plasminogen to
  plasmin.
• Plasmin cleaves fibrin in addition to fibrinogen
  and a variety of plasma proteins and clotting
  factors.
• tPA is an endothelial cell enzyme that is
  released in response to thrombin, serotonin,
  bradykinin, cytokines and epinephrine.
• When fibrin is degraded by plasmin it exposes new
  lysine terminals on the clot that act as further
  binding sites for plasminogen creating a positive
  feedback loop.

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Investigations

• The basic investigations into any coagulation
  problem are
• INR
• aPTT
• Platelet count
• Fibrinogen
• Three patterns of defects can be seen.

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Elevated INR, Normal aPTT

• Isolated elevated INR indicate factor VII
  deficiency.
• Causes include
• Congenital factor VII deficiency
• Vitamin K deficiency
• Warfarin
• Sepsis
• DIC (occasionally)

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Normal INR, Elevated aPTT

• Causes include
• Isolated factor deficiency (VIII, IX, XI, XII)
• Specific factor inhibitor
• Heparin
• Lupus inhibitor
• Mixing study can help narrow the differential
  diagnosis.

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Elevated aPTT, Elevated INR

• Usually due to multiple factors.
• Multiple coagulation factor deficiencies
• Dilutional effect
• Liver disease
• DIC
• Isolated factor X, V, II deficiency
• Factor V inhibitors
• High hematocrit
• High heparin levels
• Severe vitamin K deficiency
• Low fibrinogen
• Dysfibrinogemia

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Investigations

• When a low platelet count, a blood smear should
  be sent to rule out clumping and microangiopathic
  process.
• Low fibrinogen levels reflect either severe liver
  disease, consumptive coagulopathy, or massive
  transfusion (dilution effect).
• Other bleeding defects are harder to diagnosis on
  routine testing and are usually platelet function
  defects or increases in fibrinolysis.

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Transfusion Therapy

• Replacement therapy should be based on the lab
  results and the patients clinical situation.
• The transfusion trigger for platelets can be less
  than 10,000/uL if the patient is not bleeding, is
  not on platelet inhibitors, has preserved renal
  function, and does not have DIC.
• The usual dose of platelets is one
  plateletpheresis unit.
• For a fibrinogen level lt 1 g/L, transfusion of 10
  units of cryoprecipitate should increase the
  fibrinogen level by 1.0 g/L.

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Transfusion Therapy

• In patients with an INR of gt1.6 and an abnormal
  aPTT, FFP is given dependent on the aPTT.
• aPTT gt1.5 times normal 2-4 units of FFP
• aPTT gt2 times normal 15-30 ml/kg of FFP
• Repeat laboratory tests should be sent frequently
  to reassess adequacy of treatment.

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Abnormal hemostatic mechanisms
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Coagulopathies
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Pathogenesis of Coagulopathies

• Vascular defects
• Thrombocytopenia
• Platelet function defects
• Coagulation defects
• Excessive fibrinolysis
• Often these conditions will overlap.

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Vascular disorders

• Characteristics
• Easy bruising
• Spontaneous bleeding
• Clinical manifestations
• Bleeding often not severe
• Mainly bleeding into skin
• Bleeding occurs immediately after trauma

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Types of vascular disorders

• Inherited
• Hemorrhagic telangiectasis
• Ehlers-Danlos
• Osteogenesis imperfecta
• Pseudoxanthoma elasticum

• Acquired
• Simple easy bruising
• Senile purpura
• Corticosteroids
• Henoch-Sclonlein purpura
• Cushings disease
• Amyloidosis
• Scurvy

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Thrombocytopenia

• Three general mechanisms
• Decreased production
• Causes include thrombopoietin underproduction in
  liver disease, bone marrow suppression by viral,
  drugs, toxins, nutritional deficiency, congenital
  or acquired disorders of hematopoiesis.
• Increased destruction
• Caused by immune or nonimmune processes.
• Dilution or distribution
• Caused by massive transfusion or splenic
  sequestration in splenomegaly.

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Causes of Increased Platelet Destruction
Disorder Mechanism
Idiopathic ITP Immune
Alloimmune (posttransfusion, neonatal) Immune
Drug induced (especially heparin) Either
Infection associated Either
HELLP syndrome Either
DIC Nonimmune
TTP-HUS Nonimmune
Antiphospholipid antibody syndrome Nonimmune
Physical destruction (bypass,hemangiomas) Nonimmune
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Specific Causes of Thrombocytopenia - HIT

• Antibodies form against the heparin/platelet
  factor IV (PF4) complex.
• Despite the low platelets, thrombosis is the
  major clinical problem.
• Occurs 1-5 when unfractionated heparin is used,
  lt1 if LMWH is used.
• Suspect if platelet count drops 50 from previous
  level or if count lt 100,000/uL.
• Usually occurs in 4 days from heparin start.

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Specific Causes of Thrombocytopenia - HIT

• First step in treatment is to stop all heparin.
• Do not use warfarin alone because of the
  hypercoagulable period and only after the
  platelet count has recovered.
• Argatroban is a thrombin inhibitor with a half
  life of 40-50 minutes but is not reversible.
• Hepatic, not renally cleared.
• Dose 2 ug/kg/min, adjusted to keep aPTT 1.5-3
  times normal.
• Argatroban will prolong the INR.

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Specific Causes of Thrombocytopenia - HIT

• Danaparoid is a heparinoid which can be used as
  an alternative to heparin in HIT.
• There is a 10 cross reactivity with the antibody
  responsible for HIT but clinical significance is
  unknown.
• It has a long half life of 25 hours and is not
  reversible.
• Monitor using anti-factor Xa levels.

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Specific Causes of Thrombocytopenia - TTP

• Caused by an inhibitor against an enzyme
  responsible for cleaving vWF causing spontaneous
  platelet aggregation.
• Often spontaneous but can be induced by drugs
  such as cyclosporin, tacrolimus, and ticlopidine.
• Suspect in patients presenting with fever,
  thrombocytopenia, hemolysis, neurological
  symptoms, and renal dysfunction.
• Plasma exchange is gold standard followed by
  steroids.
• Exchanges should be 1.5 plasma volume/day until
  LDH normalizes and platelets rebound.

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Specific Causes of Thrombocytopenia - HELLP

• Presents as part of the spectrum of
  pre-eclampsia, generally gt 28 weeks.
• Pre-eclampsia need not be severe.
• First sign is a fall in platelets, then abnormal
  liver function tests, and hemolysis.
• Can progress to liver failure and death from
  hepatic rupture.
• Delivery usually resolves the condition.
• May require steroids or plasma exchange if
  condition worsens.

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Specific Causes of Thrombocytopenia CAPS

• Catastrophic antiphospholipid antibody syndrome
  (CAPS) is caused by widespread microthrombi in
  multiple vascular fields.
• Patients generally have a known autoimmune
  condition with anticardiolipin antibodies.
• Treatment is with plasmaphreresis and
  immunosuppression.

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Platelet Dysfunction Uremia and Drugs

• Renal failure can cause bleeding from platelet
  dysfunction.
• Best treatment is aggressive dialysis to control
  the uremia and DDAVP (20 ug IV) for acute
  bleeding or pre-procedure.
• ASA irreversibly inhibits platelet function and
  so platelets must be replaced if bleeding occurs.
• Other drugs such as ketorolac and hydroxyethyl
  starch reversible inhibit and platelet function
  will recover as the drug clears.

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Coagulation Defects - DIC

• Syndrome of inappropriate thrombin activation
  leading to
• Fibrinogen conversion to fibrin
• Platelet activation and consumption
• Activation of factors V and VIII
• Protein C activation (and degradation of factors
  Va and VIIIa)
• Endothelial cell activation
• Fibrinolysis

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Coagulation Defects DIC Causes
Sepsis Crush injury Severe head injury Cancer AML (M3)
Amniotic fluid emboli Abruptio placentae HELLP Pre-eclampsia Dead fetus
Septic abortion Amphetamine overdose Giant hemangioma AAA Peritoneovenous shunt
Acute transfusion reaction Paroxysmal nocturnal hemoglobinuria Snake and viper venoms Fulminant hepatic failure Reperfusion after liver transplant
Heat stroke Burns Severe meningococcemia
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Coagulation Defects - DIC

• Patients can present in one of four ways
• Asymptomatic - Laboratory evidence only but no
  bleeding or thrombosis.
• Bleeding Caused by factor and platelet
  depletion, platelet dysfunction and fibrinolysis.
  Present with diffuse bleeding from multiple
  sites.
• Thrombosis Despite the microthrombi,
  macrothrombi are unusual but can occur in cancer
  patients.
• Purpura fulminans Described in more detail
  later.

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Coagulation Defects DIC Diagnosis

• Diagnosis established by the history and presence
  of thrombocytopenia, microangiopathic changes on
  the smear.
• FDP or D-dimers are always elevated due to the
  marked fibrinolysis.
• Both the INR and aPTT are elevated.
• Fibrinogen is low.
• Liver failure can mimic DIC but factor VIII
  levels are low in DIC (consumed) and normal in
  liver failure (produced by the endothelium not
  the liver).

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Coagulation defects DIC Treatment

• First, treat the underlying condition.
• Initiate other supportive measures as necessary
  (i.e. intubation, vasopressors).
• Low levels of evidence suggest that low doses of
  heparin in non-bleeding patients may be helpful.
• Both factor and platelet replacement in bleeding
  patients and those at risk for major bleeding can
  be life-saving but only supportive until the
  underlying condition can be treated.

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Coagulation Defects Purpura fulminans

• DIC in association with limb ecchymosis and skin
  necrosis.
• Often associated with meningococcemia and
  post-splenectomy sepsis.
• Optimum therapy has not been established but
  includes
• rhAPC infusion
• Blood products to keep INR lt 2, aPTT lt 1.8
  normal, and platelets gt50000/uL

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Coagulation Defects Vitamin K Deficiency

• Body stores are normally low and require 40-80
  ug/day.
• Once depleted, production of factors II, VII, IX,
  and X fall and INR rapidly rises.
• The diagnosis should be suspected when there is a
  history of prolonged antibiotic use, biliary
  obstruction, and pre-existing malnutrition.

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Coagulation Defects Massive Transfusion

• Defined as requiring more than one blood volume
  in 24 hours or less.
• Coagulation defects occur from dilution of the
  plasma volume by fluid resuscitation or red cell
  transfusions and consumption from the underlying
  disorder.
• It is difficult to predict the degree of
  coagulopathy from the amount of blood transfused.
  Therefore, monitoring the patients coagulation
  status during massive transfusion is critical.

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Coagulation Defects Massive Transfusion

• Platelets lt 50,000/uL
• give 6-8 units of random donor platelets
• Fibrinogen lt 1 g/L
• give 10 units of cryoprecipitate
• Hematocrit lt 30
• give red cells
• INR gt 1.6 and aPTT abnormal
• give 2-4 units of FFP

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Coagulation Defects Use of Factor VIIa

• Recently released, recombinant factor VIIa is a
  very effective hemostatic agent.
• Has been used for the treatment of congenital
  FVII, XI, or V deficiency, liver failure
  coagulopathy, reversal of warfarin overdose,
  thrombocytopenia due to antiplatelet glycoprotein
  antibodies, and intracerebral hemorrhage.
• rFVIIa enhances platelet-surface thrombin
  generation independent of tissue factor.
• A platelet dependant mechanism explains why
  rFVIIa localizes to sites of endothelial injury.
• Dosing varies based on the indication
• 40 ug/kg for ICH

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Thrombosis
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Thrombosis - Incidence

• Most ICU patients have one or more risk factors
  for thrombosis.
• The true incidence is unknown but estimates run
  up to 33.
• 15 of DVT are in the upper limbs and are
  associated with central lines.

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Thrombosis - Pathophysiology

• Virchow triad endothelial damage, abnormal
  blood flow, altered blood composition.
• Trauma and surgical patients inevidently have
  endothelial damage triggering coagulation.
• Inflammation and stress response causes
  thrombocytosis, hyperfibrinogenemia, altered
  coagulation factors, and elevated levels of PAI-1
  which tips the balance toward thrombosis.
• Patients are immobilized, ventilated and sedated
  which alters blood flow causing stasis.

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Thrombosis - Pathophysiology

• There are many inherited hypercoagable states.
• These increase the relative risk by 10 fold on
  top of the acquired risks.
• The most important risk factors for DVT are a
  previous episode of thrombosis and a family
  history of DVT.

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Genetic Risk Factors for Thrombosis
Risk Factor Prevalence in the General Population Prevalence in Patients with DVT
Elevated factor VIII level 11 25
Factor V Leiden 5 20
Hyperhomocysteinemia 5-10 10
Prothrombin gene variant 2 6
Protein S deficiency 1 3
Protein C deficiency 0.2 3
Antithrombin deficiency 0.18 1
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Thrombosis PE Pathophysiology

• Pulmonary artery obstruction causes a rise in
  pulmonary artery pressure that leads to right
  ventricular failure.
• RV failure leads to a rise in central venous
  pressures and fall in cardiac output.
• RV oxygen demands is higher in the presence of
  hypoxia, hypotension, and reduced coronary
  perfusion causing infarction.
• Infarction leads to worsening RV function and
  output perpetuating the vicious cycle.
• Patients with a PFO can also develop paradoxical
  embolism.
• A PE with PFO can lead to greater hypoxia due to
  an intracardiac right-to-left shunt.

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Thrombosis - Diagnosis

• Clinical symptoms and signs are fraught with poor
  sensitivity and specificity.
• Acute onset dyspnea
• Pleuritic chest pain
• Cough
• Hemoptysis
• Tachypnea
• Sinus tachycardia
• Syncope
• Although the gold standard test is pulmonary
  angiogram, the most practical in the critically
  ill patient is CT chest angiogram.
• V/Q scan is likewise impractical because of the
  long image acquisition time.

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Thrombosis Use of echo in PE

• Sensitivity and specificity of TEE in the
  diagnosis of proximal PE is 84.
• RV volume and pressure overload following massive
  PE is readily identified.
• Echo findings includes dilated right atrium and
  ventricle, increased ratio of RV to LV chamber
  size, paradoxical septal bulging and a reduction
  in RV function.
• In severe cases of RV volume and pressure
  overload, an under filled and hyperdynamic left
  ventricle will be evident.

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Thrombosis DVT/PE Treatment

• Once detected, both DVT and PE require full
  anticoagulation with heparin.
• LMWH is a therapeutic option but can be
  contraindication by it long half life and renal
  clearance.
• Coumadin is best avoided in the critical care
  phase because of the number of interactions with
  other medications and difficult reversibility.

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Thrombosis PE and tPA

• While most of the treatment for PE is supportive
  (oxygen, vasopressors etc.), intravenous tPA for
  clot lysis is indicated for the following
  conditions
• Persistent hypotension
• Severe hypoxemia
• Large perfusion defect
• RV dysfunction
• Free floating RV thrombus
• PFO
• Maybe RV dilation and/or hypokinesis without
  systemic hypotension.

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Thrombosis DVT Prevention

• Preventative strategies fall into two groups
  pharmacological (UFH and LMWH) and mechanical
  (stockings and compression devices).
• Heparin either UFH or LMWH in the mainstay of
  prophylaxis. Reduces incidence by over 50.
• LMWH is as effective as UFH but is superior in
  trauma and spinal cord injury.

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Thrombosis DVT Prevention

• The incidence of hemorrhagic complications is no
  different in treated and control patients.
• Only contraindications to prophylaxis heparin is
• Intracranial bleeding
• Spinal cord injury associated with hematoma
• Uncontrolled ongoing bleeding
• Uncorrected coagulopathy
• Warning Liver failure patients may be thrombotic
  despite an elevated INR.
• Those at high risk for bleeding should receive a
  pneumatic compression devices until able to be
  converted to heparin.

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Summary

• Normal hemostasis
• Coagulation pathways
• Initial investigations
• Coagulopathies
• Pathogenesis of coagulopathies
• Specific causes
• Thrombosis
• Pathogenesis
• Diagnosis
• Treatment
• Prevention