1. Bleeding and Thrombosis Disorders in the ICU
Division of Critical Care Medicine University of Alberta

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

3. Normal hemostatic mechanism
There are four phases to the normal coagulation cascade:
Blood vessel constriction
Platelet aggregation
Fibrin generation
Vessel repair and fibrin degradation

4. Constriction of vessels
There are 2 mechanisms for vessel constriction:
Local smooth muscle contractile response
Thromboxane A2 release from endothelium

5. 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

6. 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

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

8. 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.

9. 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.

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

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

12. 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.

13. 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.

14. The two pathways feed into …

15. … the common pathway

16. 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.

17. 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

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

19. 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.

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

21. Elevated INR, Normal aPTT
Isolated elevated INR indicate factor VII deficiency.
Causes include:
Congenital factor VII deficiency
Vitamin K deficiency
Warfarin
Sepsis
DIC (occasionally)

22. 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.

23. 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

24. 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.

25. Transfusion Therapy
Replacement therapy should be based on the lab results and the patient’s 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 < 1 g/L, transfusion of 10 units of cryoprecipitate should increase the fibrinogen level by 1.0 g/L.

26. Transfusion Therapy
In patients with an INR of >1.6 and an abnormal aPTT, FFP is given dependent on the aPTT.
aPTT >1.5 times normal – 2-4 units of FFP
aPTT >2 times normal – ml/kg of FFP
Repeat laboratory tests should be sent frequently to reassess adequacy of treatment.

27. Abnormal hemostatic mechanisms

28. Coagulopathies

29. Pathogenesis of Coagulopathies
Vascular defects
Thrombocytopenia
Platelet function defects
Coagulation defects
Excessive fibrinolysis
Often these conditions will overlap.

30. Vascular disorders Characteristics: Clinical manifestations
Easy bruising
Spontaneous bleeding
Clinical manifestations
Bleeding often not severe
Mainly bleeding into skin
Bleeding occurs immediately after trauma

31. Types of vascular disorders
Inherited
Hemorrhagic telangiectasis
Ehlers-Danlos
Osteogenesis imperfecta
Pseudoxanthoma elasticum
Acquired
Simple easy bruising
Senile purpura
Corticosteroids
Henoch-Sclonlein purpura
Cushing’s disease
Amyloidosis
Scurvy

32. 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.

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

34. 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, <1% if LMWH is used.
Suspect if platelet count drops 50% from previous level or if count < 100,000/uL.
Usually occurs in 4 days from heparin start.

35. 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 minutes but is not reversible.
Hepatic, not renally cleared.
Dose 2 ug/kg/min, adjusted to keep aPTT times normal.
Argatroban will prolong the INR.

36. 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.

37. 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.

38. Specific Causes of Thrombocytopenia - HELLP
Presents as part of the spectrum of pre-eclampsia, generally > 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.

39. 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.

40. 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.

41. 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

42. 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

43. 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.

44. 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).

45. 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.

46. 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 < 2, aPTT < 1.8 normal, and platelets >50000/uL

47. Coagulation Defects – Vitamin K Deficiency
Body stores are normally low and require 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.

48. 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 patient’s coagulation status during massive transfusion is critical.

49. Coagulation Defects – Massive Transfusion
Platelets < 50,000/uL
give 6-8 units of random donor platelets
Fibrinogen < 1 g/L
give 10 units of cryoprecipitate
Hematocrit < 30%
give red cells
INR > 1.6 and aPTT abnormal
give 2-4 units of FFP

50. 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

51. Thrombosis

52. 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.

53. 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.

54. 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.

55. Genetic Risk Factors for Thrombosis
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%
Antithrombin deficiency
0.18%

56. 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.

57. 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.

58. 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.

59. 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.

60. 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.

61. 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.

62. 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.

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