1. Hemostasis
Shaina Eckhouse
10/12/2010

2. Objectives Biology of Hemostasis Congenital Hemostasis Defects
Aquired Hemostasis Defects
Hypercoagulable States
Venous thromboembolism
Transfusion
Evaluation of the Surgical Patient at Hemostatic Risk

3. Name that Movie

4. Biology of Hemostasis
Complex process that prevents or terminates blood loss from a disrupted intravascular space
Major physiologic events
Vascular constriction
Platelet plug formation
Fibrin formation
fibrinolysis

5. Biology of Hemostasis Vascular Constriction
Initial vascular response to injury
Vasoconstriction linked to platelet plug formation
TXA2 ET
5-HT
Bradykinin & Fibrinopeptides
TXA2—derived from the release of arachadonic acid from platelet membranes during aggregation, is a powerful VC
ET (endothelin)—acts as a VC
5-HT (Serotonin)—released during platelet aggregation, is another VC
Bradykinin, Fibrinopeptides are also capable of contracting vascular smooth muscle

6. Biology of Hemostasis Platelet Function 150-400K circulating platelets
~30% sequestered in the spleen
Thrombopeptin, IL-1, IL-6 mediate platelet production

7. Biology of Hemostasis Platelets play an integral role in:
Formation of a hemostatic plug
Contributes to thrombin formation
Injury to the intimal layer in the vascular wall exposes subendothelial collagen to which platelets adhere to in ~15 seconds
vWF is a protein within the subendothelium that binds to glyoprotein I, IX, and V on the platelet membrane
Platelet adhesion also mediated by the intrxn between collagen in the subendothelium and GP IaIIa on the platelet surface. Following this, the platelets expand and develop pseudopodal processes and also initiate a release reaction that recruits other platelets from the process
Second wave of platelet aggregation—release reaction of ADP, Ca++, 5-HT, TXA, and alpha-granule proteins are discharged. Fibrinogen is a required cofactor for this process, acting as a bridge for GP IIbIIIa receptor on the activated platelets during formation of a platelet plug
Thrombospondin stabilizes fibrinogen binding to the activated platelet surface and strengthens the platelet-platelet interaction

8. Biology of Hemostasis
VC + platelet plug formation = PRIMARY HEMOSTASIS
Reversible
Not associated with secretion
Because it is not associated with secretion, heparinized patients can still form clots

9. Biology of Hemostasis

10. Biology of Hemostasis Intrinsic Pathway
All the components leading to the fibrin clot formation are intrinsic to the circulating plasma
Elevated PTT associated with an abnormality in the intrinsic clotting pathway
Begins with Factor XII and through the cascade, activates factor XI, IX, and VII in sequence

11. Biology of Hemostasis Extrinsic Pathway
Requires exposure of tissue factor on the surface of the injured vessel wall
Starts with Factor VII
Abnormality of the extrinsic pathway is associated with an elevated PT

12. Biology of Hemostasis
Both arms of the coagulation cascade merge into a common pathway at factor 10 and activation proceeds in sequence of factor II (prothrombin) and factor I (fibrinogen)
Clot formation occurs after proteolytic conversion of finbrinogen to fibrin

13. Biology of Hemostasis Fibrinolysis = lysis of the fibrin clot
Plasminogen Plasmin degrades fibrin, Factor V and VIII
Plasminogenplasmin by several activators—tPA, (kalikrein increases release of tPA), uPA, factor XII
Plasminogen levels rise due to exercise, venous occlusion, and anoxia
Breakdown of the clot permits restoration of blood flow and fibrin clot in vessel wall may be replaced with collagen
Antithrombin III
Binds and inhibits thrombin and factors IX, X, XI
Protein C
Vitamin K-dependent
Degrades fibrinogen and factors V and VIII
Protein S
Protein C cofactor

14. Biology of Hemostasis How do SCDs work?
The squeeze stimulates the release of tPA from the endothelial cells of vessels. Induction of fibrinolysis.
(tPA is selective for fibrin-bound plasminogen and converts to plasmin; therefore, fibrinolysis occurs mostly at the site of clot formation.)

15. Name that movie
Sweeny Todd

16. Congenital Hemostatic Defects
Coagulation Factor Deficiencies
Hemophilia
Factor VIII deficiency = Hemophilia A
Sex-linked recessive
Both prolonged aPTT and PT
Need level to be 100% pre-op and 30% post-op
Crosses placenta
Hemophiliac Joint
No aspiration; ice; ROM exercises, factor VIII concentrate or cryoprecipitate
Factor IX deficiency = Hemophilia B/Christmas Disease
Need level 50% pre-operatively
Prolonged aPTT and normal PT
Tx-factor IX concentrate or cryoprecipitate
Severe hemophilia—spontaneous bleeds; crippling arthropathies; develop intramuscular hematomas; retroperitoneal bleeds; GI and GU bleeding
Mild hemophilia-do not bleed spontaneously
For more detailed replacement and how to replace-refer to table 3-3 and 3-4 in schwartz

17. Congenital Hemostatic Defects
von Willibrand’s Disease
MOST COMMON congenital bleeding disorder
Low levels of vWFvariable decrease in Factor VIII due to loss of the carrier protein
vWF is necessary for normal platelet aggregation; therefore deficiency presents in a similar fashion to platelet disorders
Prolonged bleeding time, possible abnormal PTT, normal PT
Types-
I-partial quantitative deficiency (AD)
II-qualitative defect (AD)
III-total deficiency (AR)
Tx—intermediate purity factor VIII or DDAVP (Type I or II only)
vWF links Gp1b receptor on platelets to collagen
Discrepancy between types and treatments between Schwartz and ABSITE review---go with Schwartz
Sx=bruising and mucosal bleeding

18. Congenital Hemostatic Defects
Platelet disorders
Glanzmann’s thrombocytopenia—deficiency in GIIbIIIa receptor of platelets; therefore, platelets cannot bind to each other
Tx-platelets
Bernard Soulier—Gp1b receptor deficiency; therefore, platelets cannot bind collagen via vWF

19. Name that movie
Zombieland

20. Acquired Hemostatic Defects
Anticoagulation
Heparin—potentiates ATIII action
Reversed with administration of protamine (1mg protamine for every 100u heparin received)
Follow aPTTwant x upper limit of nl (60-90)
Does not cross placental barrier
Lovenox—potentiates ATIII and inhibits both thrombin and Factor Xa
“more reliable therapeutic anticoagulation can be achieved”
Drug effect can be determined by anti-Xa assay
No definitive reversal
Warfarin (Coumadin)
Inhibits Vitamin K synthesis
Reversed by FFP or Vitamin K administration
Follow INR/PT
Inhibits Vitamin K synthesis by inhibiting cyclo-oxygenase or decarboxylation step

21. Acquired Hemostatic Defects
Why do we bridge with heparin or Lovenox when initially starting Coumadin?
Protein C and S are inhibited before factors II, VII, IX and X which makes the patient relatively hypercoaguable for 5-7 days

22. Acquired Hemostatic Defects
Antiplatelet Medications
Asprin—Platelet cyclooxygenase is irreversibly inhibited ; decreases TXA2 which promotes platelet aggregation
Plavix (Clopidogrel)—ADP receptor antagonist
Pentoxifylline—inhibits platelet aggregation and decreases viscosity of blood; used in treatment of peripheral arterial disease

23. Acquired Hemostatic Defects
Heparin Induced Thrombocytopenia
2/2 antiplatelet Ab (IgG) that results in platelet destruction
Platelet count falls to <100K or by <50% in 5-7 days if first exposure or in 1-2 days if re-exposure
High incidence of platelet aggregation and thrombosis (white clot)
If suspected—
STOP heparin
Start alternate anticoagulation (lepirudin or argatroban)
Alternative anticoagulation is important to prevent thrombosis that is associated with HIT
Lepirudin—direct thrombin inhibitor; made from leech spit; don’t use in the setting of renal failure
Argatroban—direct thrombin inhibitor; metabolized by CYP450 system; don’t use in the setting of liver disease

24. Acquired Hemostatic Defects
Disseminated Intravascular Coagulation
Systemic process producing both thrombosis and hemorrhage
Exposure of blood to procoagulants
Formation of fibrin in the circulation
Fibrinolysis
Depletion of clotting factors
end-organ damage
Dx= decreased platelets, prolonged PT and aPTT, low fibrinogen, high fibrin split products, high D-dimer
Treat the underlying disease (sepsis, trauma, burns, malignancy)

25. Acquired Hemostatic Defects
Thrombocytopenia
MOST COMMON abnormality of hemostasis
Variety of etiologies (ITP, TTP, HUS, SLE, lymphoma, secondary hypersplenism, portal HTN, uremia…)
In setting of massive transfusion—exchange of 1L of blood volume (~11units) decreases platelet count from 250K to 80K. Associated impaired ADP- stimulated aggregation if >10units of blood transfused.

26. Name that movie
Snatch (parkie fight scene at the end)

27. Hypercoagulable States
Factor V Leiden Deficiency
MOST COMMON congenital hypercoagulable disorder AD
Leiden variant of Factor V cannot be inactivated by Protein C
Increased risk for DVT, spontaneous abortion
Tx = heparin or warfarin

28. Hypercoagulable States
AT-III deficiency
Spontaneous venous thrombosis
Heparin does not work on these patients unless pretreated by FFP
Tx: AT-III concentrated
Antiphospholipid Antibody Syndrome
Presence of lupus anticoagulant that bind to phospholipids and proteins on the cell membrane an interfere with clotting; HOWEVER, associated with thrombosis and habitual abortions (prolonged PTT in the face of a hypercoagulable state)
Tx: Heparin, coumadin

29. Hypercoagulable States
Amicar
Aminocaproic acid
Inhibits fibrinolysis by inhibiting plasmin
Indications: DIC, persistent bleeding following CPB, thrombolytic overdose
Aprotinin
Inhibits fibrinolysis by inhibiting activation of plasminogen to plasmin

30. Name that movie
Jaws Four

31. Venous thromboembolism
DVT and PE
Virchow’s triad = stasis, endothelial injury, hypercoagulability
Treatment for DVT
1st= warfarin x 6months
2nd= warfarin x 1year
3rd or significant PE = lifetime warfarin
Greenfield filters
For patients with contraindications to anticoagulation
Documented PE while on anticoagulation
Free-floating iliofemoral clot
IVC or femoral DVT
Patients who have undergone previous pulmonary embolectomy
PE most commonly caused by DVT in iliofemoral region

32. Name that movie
X-men prequel

33. Transfusion PRBCs 1unit=~250mL Storage life ~35days
1unit increases Hgb by 1 and Hct by 3
Fever without hemolysis is the most common transfusion reaction (1 in 6,000)
Usually recipient antibody reaction against WBCs in donor blood
Acute Hemolytic reactions occur 1 in 35,000
Caused by ABO incompatibility or Ab mediated usually from human error (Ab in recipient binding to surface Ag on donor RBC)
Sx=hypotension, fever, dyspnea, chest pain, low back pain
Tx=fluids, diuretics, HCO3, histamine blockers, pressors
Sx can develop with only 5mL of blood
Indications for transfusion in STICU: improved oxygen delivery and volume expansion
7g/dL or less with symptoms
5g/dL or less

34. Transfusion Platelets 50-100 billion in 50mL plasma
Can be stored for ~7 days (viability declines after 3 days)
Each platelet concentration should raise circulating platelets by >5,000 (4-6 pack of platelets shound increase platelets by 20-30K)
Febrile nonhemolytic reactions more common than with PRBCs (incidence is ~30%)
Antiplatelet antibodies develop in 20% of patients after transfusions
Indictions in active bleeding: plt<50K or plt<100K in setting of ICH; trauma victims who have received multiple transfusion
Contraindicated in HIT and TTP

35. Transfusion FFP ~250 mL collected from 1 unit whole blood by apheresis
Stored between -18 and -30 degree C and is good for 1 year
Dose is ~10-15mL/kg
Contains all coagulation factors, protein C, protein S, and AT-III (only blood product with factor V)
Indications-warfarin overdose, liver failure, dilutional coagulopathy associated with massive transfusion
Highest risk of TRALI—important to distinguish from volume overload. Tx=supportive

36. Name that movie
Kill Bill

37. Evaluation of the Surgical Patient at Hemostatic Risk
Preoperative Assessment
History
Bruises without apparent injury
Prolonged bleeding after injury
PMHx—liver disease, congenital or acquired bleeding disorders
Medications
Labs—CBC, Coagulation panel, T&S or T&C
Intraoperative and Postoperative
Ineffective local hemostasis
Complications of blood transfusion
Consumptive coagulopathy
Fibrinolysis

38. Questions?