Friday, 17 January 2020

HEMOSTASIS, SURGICAL BLEEDING AND TRANSFUSION

BIOLOGY OF HEMOSTASIS

- Vascular constriction

• initial response

• dependent on local
contraction of smooth
muscle

• platelet membranes —>

release of arachidonic
acid —> Thromboxane
A2 (TXA2) = potent
constrictor of smooth
muscle

• endothelin from injured

endothelium and
serotonin (5-hydroxy-
tryptamine [5-HT]) from platelet aggregation = potent vasoconstrictors

• bradykinin and fibrinopeptides = contracting vascular smooth muscle

- Platelet function

• are anucleate fragments of megakaryocytes

• normal value is 150,000 and 400,000/μL.

• average life span of 7 to 10 days

• by forming a hemostatic plug and by contributing to thrombin formation

• Injury to the intimal layer —> exposes subendothelial collagen —> needs von

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Willebrand factor (vWF) + glycoprotein (GP) I/IX/V on the platelet membrane —>
platelet adhesion = primary hemostasis.

• not affected by heparin

• Adenosine diphosphate (ADP) and serotonin are the principal mediators

• platelet membranes —>

Arachidonic acid —> prostaglandin
G2 (PGG2) by cyclooxygenase —>
prostaglandin H2 (PGH2) —> TXA2
(potent vasoconstriction and
platelet aggregation effects)

• Arachidonic acid —> prostacyclin

(PGI2) a vasodilator —> inhibit
platelet aggregation

• Platelet cyclooxygenase is
irreversibly inhibited by aspirin and reversibly blocked by nonsteroidal
anti-inflammatory agents but is not affected by cyclooxygenase-2 (COX-2)
inhibitors.

• 2nd wave of platelet aggregation: fibrinogen as a bridge for the GP IIb/IIIa receptor
—> compaction of the platelets into a plug —> no longer reversible

- inhibited by aspirin and nonsteroidal anti-inflammatory drugs, by cyclic

adenosine monophosphate (cAMP), and by nitric oxide.

• Thrombospondin stabilizes fibrinogen —> strengthens the platelet-platelet

interactions

• Platelet factor 4 (PF4) is a potent heparin antagonist.

- Coagulation

• An elevated activated partial thromboplastin time (aPTT) = abnormal function of

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the intrinsic arm (II, IX, X, XI, XII)

• Prothrombin time (PT) = extrinsic arm (II, VII, X)

• Vitamin K deficiency or warfarin = factors II, VII, IX, and X.

- Fibrinolysis

• Fibrin clot is degraded by

plasmin from plasminogen

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which is activated by tPA

• Bradykinin (potent endothelial- dependent vasodilator) from kininogen by kallikrein

—> enhances the release of tPA

COAGULATION FACTOR DEFICIENCIES

- Factor VIII deficiency (hemophilia A or von Willebrand’s disease)

- Factor IX deficiency (hemophilia B or Christmas disease)

- Factor XI deficiency

• autosomal recessive

• hemophilia C

• more prevalent in the Ashkenazi Jewish

• Factor VIIa is recommended for patients with anti-factor XI antibodies

- Hemophilia A and hemophilia B: inherited as sex-linked recessive disorders with

males exclusively affected

- von Willebrand’s disease (vWD)

• most common congenital bleeding disorder

• quantitative or qualitative defect in vWF (carrying factor VIII and platelet adhesion)

• Type I: partial quantitative deficiency; respond well to desmopressin (DDAVP)

• Type II: qualitative defect; may respond

• Type III: total deficiency; usually unresponsive.

- Factor II (prothrombin), V and X

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• autosomal recessive

• treated with FFP

- Factor VII

• autosomal recessive

• treatment is with FFP or recombinant factor VIIa.

- Factor XIII

• autosomal recessive

• severe bleeding diathesis.

PLATELET FUNCTIONAL DISORDERS

- Thrombasthenia, or Glanzmann thrombasthenia

• autosomal recessive pattern

• platelet glycoprotein IIb/IIIa (GP IIb/IIIa) complex is either lacking or present but
dysfunctional —> faulty platelet aggregation —> subsequent bleeding

• treated with platelet transfusions

- Bernard-Soulier syndrome

• defect in the GP Ib/IX/V receptor for vWF —> for platelet adhesion to the
subendothelium

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• treatment is platelet transfusion

ACQUIRED HEMOSTATIC
DEFECTS

- Secondary immune thrombocytopenia

• with a very low platelet count

• seen as petechiae and purpura, and epistaxis

• large platelets are seen on peripheral smear

• Initial treatment: corticosteroids, intravenous gamma globulin, or anti-D

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immunoglobulin for Rh positive

- Primary immune thrombocytopenia

• also known as idiopathic

thrombocytopenic purpura (ITP)

• In children

- acute in onset, short lived, and

typically follows a viral illness

• In adults

- gradual in onset, chronic in nature,

and has no identifiable cause

• platelets are young and functional —>

bleeding is less

• impaired platelet production and T cell–mediated platelet destruction

- Thrombotic thrombocytopenic purpura (TTP)

• large vWF molecules interact with platelets —> activation

• present as thrombocytopenia, microangiopathic hemolytic anemia, fever, and renal

and neurologic signs or symptoms

• schistocytes on a peripheral blood smear

- Hemolytic uremic syndrome (HUS)

• secondary to infection by Escherichia coli 0157:H7 or other Shiga toxin-producing

bacteria

- One unit of platelet concentrate = 5.5 × 1010 platelets —> increase platelet count by
about 10,000/μL

- Impairment of ADP-stimulated aggregation with massive transfusion of blood

products

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• Clopidogrel —> selective irreversible inhibition of ADP-induced platelet aggregation

• Aspirin —> irreversible acetylation of platelet prostaglandin synthase

- DIC

• excessive thrombin generation and diffuse formation of microthrombi —>

consumption and depletion of platelets and coagulation factors —> diffuse bleeding

- Polycythemia

• excess of red blood cells —> spontaneous thrombosis = increased blood viscosity,
increased platelet count, and increased tendency toward stasis

• reduced by low-dose aspirin, phlebotomy, and hydroxyurea

COAGULOPATHY OF LIVER DISEASE

- prolongation of the prothrombin

time and international
normalized ratio (INR).

- related to hypersplenism,
reduced production of
thrombopoietin, and
immune-mediated destruction of
platelets, defective interactions between platelets and the endothelium

- platelet transfusions are the mainstay of therapy

- may be at risk for vitamin K deficiency

COAGULOPATHY OF TRAUMA

- trauma-induced coagulopathy

- activated protein C-mediated clotting factor deactivation, endothelial injury and

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“auto-heparinization” due to shedding of endothelial heparin sulfate and chondroitin

sulfate into the circulation, platelet dysfunction, and hyperfibrinolysis.

ACQUIRED COAGULATION INHIBITORS

- Antiphospholipid syndrome (APLS)

• lupus anticoagulant and anticardiolipin antibodies

• with systemic lupus, rheumatoid arthritis and Sjögren’s syndrome

• hallmark: prolonged aPTT but an increased risk of thrombosis

ANTICOAGULANTS

- Heparin

• bleeding is reduced with a continuous infusion technique or with a low molecular

weight heparin

• more rapid reversal = protamine sulfate

• for high-risk (mechanical heart valves, recent (within 30 days) myocardial infarction,

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stroke, or pulmonary embolism) patients: heparin infusion should be held for 4 to 6
hours before the procedure and restarted within 12 to 24 hours of the end of its
completion

- Warfarin

• for long-term anticoagulation

• reversal options: vitamin K, plasma, cryoprecipitate, recombinant factor VIIa, and

factor (II, VII, IX, X) concentrates

TRANSFUSION

- RBCs

• shelf life of 42 days

• reduction of intracellular ADP and 2,3-diphosphoglycerate (2,3-DPG) —> alters

oxygen dissociation curve of hemoglobin = decrease in oxygen transport

• storage results to acidotic with elevated levels of lactate, potassium, and ammonia.

• Frozen (cryopreserved) red blood cells have a shelf life of ten years at -80∞C

• thawing and preparation period of about 90 minutes

- Platelet

• shelf life of 5 days

• volume of 50ml

• therapeutic level of 50,000 to 100,000/μL

- Plasma

• usual source of the vitamin K–dependent factors

• the only source of factor V

• stored for up to two years at -18∞C

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• requires 20 to 30 minutes to thaw

• thawed plasma can be stored for up to 5 days at 2∞ to 4∞C.

• freeze-dried plasma: shelf-stable for up to 2 years at room temperature

- Tranexamic acid

• antifibrinolytic = inhibits both plasminogen activation and plasmin activity —>

preventing clot breakdown

• 10 times more potent in vitro than aminocaproic acid

• binds on lysine end of plasminogen

• half life of 2 hrs

- Indications for transfusion

• hemoglobin of <7 g/dL for

hemodynamically stable patients

• 8 g/dL for patients undergoing

cardiac surgery, orthopedic
surgery, and with pre- existing
cardiovascular disease.

• with symptomatic anemia

• in damage control surgery

- balanced resuscitation with

early delivery of plasma and
platelets

- limiting crystalloid and artificial colloid, permissive hypotension

- 4 Basic components:

• permissive hypotension

• minimizing crystalloid-based resuscitation

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• immediate release and administration of red blood cells, plasma, and platelets

• use of hemostatic adjuncts

• 1:1:1 vs. 1:1:2 plasma to platelets to RBCs

• Massive bleeding

- ≥3 units of red blood cells within any hour

- ≥10 units of red blood cells in 24 hours

- Whole blood resuscitation

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• has higher hematocrit, clotting factor activity

• can be stored for 14 days

- Complications of transfusion

• transfusion-related acute lung injury (TRALI), ABO hemolytic transfusion reactions,

and bacterial contamination of platelets (Gram-negative organisms)

• Febrile, nonhemolytic reactions = an increase in temperature (>1°C)

- due to preformed cytokines in donated blood and recipient antibodies reacting

with donated antibodies

- reduced by leukocyte-reduced blood products

- pretreatment with acetaminophen

• transfusion-associated circulatory overload (TACO)

- rapid infusion of blood, plasma expanders, and crystalloids

• TRALI

- noncardiogenic pulmonary edema related to transfusion

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- with the administration of any plasma-containing blood product

- fever, rigors, and bilateral pulmonary infiltrates on chest X-ray

- within 1 to 2 hours after the onset of transfusion but virtually always before 6
hours.

- Hemolytic reactions

• Acute

- intravascular destruction of red blood cells —> hemoglobinemia and

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hemoglobinuria

- acute renal insufficiency —> tubular necrosis and precipitation of hub in tubules

• Delayed

- 2-10 days after transfusion

- extravascular hemolysis, mild anemia, and indirect (unconjugated)

hyperbilirubinemia

• In anesthetized patients: diffuse bleeding and hypotension

• positive Coombs’ test = transfused cells coated with patient antibody

- Coagulation Tests

• platelet greater than 1,000,000/μL —> bleeding or thrombotic complications

• below 50,000/μL —> increased bleeding with major surgical procedures

• below 30,000/μL —> minor surgical procedures

• below 20,000/μL —> spontaneous hemorrhage

• platelet transfusions are still recommended in ophthalmologic and neurosurgical

procedures if less than 100,000/μL.

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