Bleeding and Thrombosis Disorders in the ICU

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

2. Outline • Normal hemostasis • 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 – 15-30 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: • Easy bruising • Spontaneous bleeding • Clinical manifestations • Bleeding often not severe • Mainly bleeding into skin • Bleeding occurs immediately after trauma

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

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

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 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.

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

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 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.

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