Approach to coagulopathies in icu

1. APPROACH TO COAGULOPATHY IN THE ICU
DIC AND THROMBOTIC EMERGENCIES
NEIL KUMAR, MD
UNIVERSITY OF ROCHESTER MEDICAL CENTER

2. Disclosures
u I have no financial disclosures
u I am NOT A HEMATOLOGIST

3. Outline
u Review of hemostasis and coagulopathy
u Discuss laboratory markers for coagulopathy
u Discuss an approach to a few specific coagulopathies and thrombotic
emergencies

4. Outline
u Review of hemostasis and coagulopathy
u Discuss laboratory markers for coagulopathy
u Discuss an approach to a few specific coagulopathies and thrombotic
emergencies

5. Coagulation
u Coagulation is the
process in which
blood clots
u Fibrinolysis is the
process in which clot
dissolves
u Hemostasis is the
stopping of bleeding
or hemorrhage.
u Ideally, hemostasis is
a balance between
coagulation and
fibrinolysis

6. Coagulation (classic pathways)
Michael G. Crooks
Simon P. Hart
Eur Respir Rev
2015;24:392-399

7. Coagulation (another view)
Gando, S. et al. (2016) Disseminated intravascular coagulation
Nat. Rev. Dis. Primers doi:10.1038/nrdp.2016.37

8. Coagulation (yet another view)
Gando, S. et al. (2016) Disseminated intravascular coagulation
Nat. Rev. Dis. Primers doi:10.1038/nrdp.2016.37
u Inflammation and coagulation
intersect with platelets in the
middle
u An example of this is
Disseminated Intravascular
Coagulation.

9. Outline
u Review of hemostasis and coagulopathy
u Discuss laboratory markers for coagulopathy
u Discuss an approach to a few specific coagulopathies and thrombotic
emergencies

10. PT / INR
u Prothrombin Time
u Test of Extrinsic Pathway
u Take plasma (blood without cells) and re-add calcium
u Calcium was removed with citrate in tube
u Add tissue factor
u See how long it takes to clot and normalize PT to get INR

11. Coagulation (classic pathways)
Michael G. Crooks
Simon P. Hart
Eur Respir Rev
2015;24:392-399

12. PT / INR
u Causes for elevated INR
u Warfarin or other vitamin K antagonist
u Liver disease
u Hepatocellular disease
u Cholestatic disease
u DIC

13. aPTT
u Activated Partial Thromboplastin Time
u Test of Intrinsic Pathway
u Take plasma (blood without cells) and re-add calcium
u Calcium was removed with citrate in tube
u Add “partial thromboplastin”
u Thromboplastin is a lab surrogate for tissue factor. It Is actually phospholipid
and tissue factor. Partial thromboplastin is just the phospholipid
u Add negative charged particle (usually kaolin or silica)
u Negative charged particle in the vessel is collagen exposed by vessel injury
u See how long it takes to clot

14. Coagulation (classic pathways)
Michael G. Crooks
Simon P. Hart
Eur Respir Rev
2015;24:392-399

15. aPTT
u Causes for elevated INR
u Anticoagulant use such as heparin, bivalirudin
u Mildly elevated in warfarin use
u Liver disease
u DIC

16. ACT
u Activated Clotting Time
u Test of entire coagulation cascade, except fibrinolysis
u Take whole blood and mix with glass beads or kaolin
u See how long clot will take to form
u Most commonly used in cardiac bypass due to extreme amounts of
heparin used

17. ACT
u ACT will thus be elevated in a wide range of circumstances;
a short list could resemble the following:
u Thrombocytopenia, or platelet dysfunction
u Clotting factor deficiency, or factor inhibitors
u Low fibrinogen
u Hypothermia

18. TT
u Thrombin Time
u Measures conversion of fibrinogen to fibrin.
u Take plasma and add thrombin

19. TT
u Causes of an unusually prolonged thrombin time:
u Heparin therapy
u Low fibrinogen levels
u Dysfunctional fibrinogen (eg. foetal fibrinogen)
u Direct thrombin inhibitors (eg. hirudin, argatroban, dabigatran)
u High levels of abnormal proteins, eg. paraproteins and fibrin
degradation byproducts can lead to abnormal TT by interfering with the
cleavage of fibrinogen by thrombin.
u Very high fibrinogen levels can paradoxically interfere with TT.

20. Reptilase Time
u Reptilase is secreted by vipers and catalyzes fibrinogen to fibrin
u Related to Thrombin Time
u Except, since it not mammalian, it doesn’t adhere to normal human
homeostatic feedback mechanisms

21. Reptilase Time
u Thus, reptilase time will not be affected by antithrombin III (and thus, by
heparin)
u It will not be affected by direct thrombin inhibitors such as argatroban
or hirudin
u It will only react to abnormalities of fibrinogen.
u Thus, reptilase time will be abnormally increased in the following
circumstances:
u Low fibrinogen levels
u Dysfunctional fibrinogen (eg. foetal fibrinogen)
u High levels of abnormal proteins, eg. paraproteins and fibrin degradation
byproducts
u Very high fibrinogen levels

22. Ecarin Clotting Time
u Ecarin is from venom and activates prothrombin
u Bypasses extrinsic and intrinsic pathways
u ECT will be abnormal in the presence of any direct thrombin
inhibitors.

23. TEG / ROTEM
u Both are commercial types of viscoelastic tests.
u TEG, the cup moves. ROTEM, the pin moves
u It shows interaction of platelets with the coagulation cascade

24. TEG / ROTEM
Gregory Semon, Michael Cheatham. TEG in Trauma
http://www.surgicalcriticalcare.net/Guidelines/TEG%202014.pdf

25. TEG / ROTEM

26. TEG / ROTEM
The Lancet Neurology 2017 16, 630-647DOI: (10.1016/S1474-4422(17)30197-7)

27. u No one test can adequately give a good overview of coagulopathy
u Even a battery of tests cannot always give a good overview of coagulopathy
u Why?
Tests of Coagulation

28. Outline
u Review of hemostasis and coagulopathy
u Discuss laboratory markers for coagulopathy
u Discuss an approach to a few specific coagulopathies and thrombotic
emergencies

29. u Extremely common in ICU patients – especially in the setting of surgery.
u Commonly used transfusion triggers
u 10,000 / cubic millimeter for non-bleeding patients
u If known myelodysplasia or aplastic anemia, can consider a lower trigger
u 50,000 / cubic millimeter for bleeding patients
u 100,000 / cubic millimeter for central nervous system bleeding
Thrombocytopenia

30. u Evaluation
u Pseudothrombocytopenia?
u Blood sample clotted? EDTA-dependent platelet antibodies
u Large platelets that are missed by cell counters
u Drug related?
u Heparin
u IIb/IIIa inhibitors
u ADP receptor antagonists
u Acute alcohol toxicity
u Hematinic deficiency, such as folic acid?
Thrombocytopenia

31. u Other causes
u Sepsis
u Major blood loss and hemodilution
u Mechanical fragmentation
u Cardiopulmonary bypass
u ECMO
u IABP
u Renal dialysis?
u Immune mediated disorder
u Hyperspenism
u DIC
u Microangiopathic hemolytic anemia
Thrombocytopenia

32. u Acquired syndrome
u Intravascular activation of coagulation
u Loss of localization arising from different causes.
DIC

33. u Usually presents as hemorrhage, only about 10% of cases presenting as
microthrombi alone.
u Sepsis is most common underlying cause in critical care
DIC

34. u Early animal studies showed promise in the use of activated protein c,
antithrombin, tissue factor pathway inhibitor.
u Studies in humans showed no survival benefit, but increased bleeding.
DIC

35. u Consumption of coagulation proteins and platelets produces bleeding
tendencies.
u Prolonged prothrombin time
u Prolonged activated partial-thromboplastin time
u hypofibrinogenemia
u Elevated levels of fibrinogen degradation products
u Thrombocytopenia
DIC

36. DIC

37. u Management is based upon treating underlying cause
u Expert opinion suggests replacing coagulation proteins and platelets in setting of
bleeding.
u Commonly used targets include
u Platelet level of 50,000 / cubic millimeter
u Prothrombin time less than 1.5 times normal control
u Fibrinogen level of 1.5 gram / liter
u Antifibrinolytics avoided due to widespread fibrin deposition (fibrinolytic system
necessary in recovery)
u Heparin in thrombotic phenotype is controversial.
DIC

38. u Characterized by profound thrombocytopenia and microangiopathic
hemolytic anemia (red-cell fragmentation)
u Examples include
u Thrombotic thrombocytopenia purpura
u Hemolytic uremia syndrome
u HELLP syndrome
Thrombotic Microangiopathies

39. u Acquired or hereditary
u ADAMTS13 cleaves vWF. In its absence, large multimers of vWF are present,
increasing risk for platelet thrombi in small vessels.
u Acquired TTP diagnosis is supported by ADMTS13 level less than 10% of normal
activity.
u Test not sufficiently sensitive nor specific to use in isolation.
Thrombotic thrombocytopenia purpura
ADAMTS13 deficiency-mediated TMA

40. u Initial presentation is varied. weakness, gastrointestinal symptoms, purpura,
and transient focal neurologic abnormalities are common.
u Most patients have normal or only slightly elevated creatinine levels.
u Treatment for hereditary is ADAMTS13 replacement
u Survival for acquired is increased by plasma exchange. Initiaol management
is ADAMTS13 replacement with plasma infusion.
u Glucocorticoids are standard treatment.
Thrombotic thrombocytopenia purpura
ADAMTS13 deficiency-mediated TMA

41. u Results from uncontrolled activation of alternative pathway of complement
activation.
u Acute Kidney Injury in the setting of hypertension is common presentation.
u Diagnostic criteria include
u Serum creatinine at or above upper limit of normal
u Microangiopathic hemolytic anemia
u Thrombocytopenia
u ADAMTS13 activity of 5% or more.
u Negative stool sample for Shiga-toxin producing infection.
u Treatment is with anti-complement agents. Eculizumab
Complement mediated
Thrombotic Microangiopathy

42. Conclusion
u Hemostasis is the interplay between coagulation and fibrinolysis
u Laboratory evaluation is not perfect
u Management of coagulopathy and thrombotic emergencies requires a
high degree of suspicion and vigilance.
u References
u Amish N. Raval et al. Circulation. 2017;135:e604-e633
u Rachel Rosovsky et al. Techniques in Vascular and Interventional Radiology.
2017; 20,3:141-151
u James N. George et al. New England Journal of Medicine. 2014;371:654-666
u Beverly J. Hunt et al. New England Journal of Medicine. 2014;370:847-859