HEMOSTASIS, SURGICAL BLEEDING AND TRANSFUSION
The Challenge of Coagulation
Clotting & Repair Locally
Unimpaired vascular flow elsewhere
Hematologic Response to Injury
Vessel injury exposes vWF and releases tissue factor -->
Local vasoconstriction, platelet adhesion and secretion (--> formation of platelet plug), and activation of coagulation cascade -->
Stable clot
Primary Hemostasis (Formation of Platelet Plug)
- Platelet plug formed within 1-3 minutes of injury
- Prostacyclin acts as control measure, inhibiting many of these steps
Vascular injury --> exposure of endothelial vWF --> exposure/binding of Ib, IIbIIIa, Ia receptors
-->exposure of fibrinogen binding site --> secondary hemostasis
--> initial platelet adhsion
-->mobilization of intracellular Ca+--> platelet activation
-->surface Va --> secondary hemostasis
-->serotonin release --> TxA2 release -->vasoconstriction and aggregation
--> ADP release --> Aggregation
Secondary Hemostasis (Coagulation Cascade)
Classic Coagulation Cascade
Initially Described in 1960s
Serine Proteases produced in hepatocytes
In-Vitro Coagulation
Intrinsic pathway (PTT, heparin)
XII-->XIIa
XI-[XIIa]->XIa
IX-[IXa]->IXa+VIIIa
X-[IXa+VIIIa]->Xa
Extrinsic pathway (PT)
X-[VIIa + TF]->Xa+Va
Common pathway
Prothrombin (II) -[Ca+, Xa, Va]->thrombin (IIa)
Fibrinogen (I) -[thrombin IIa]-> Fibrin (Ia)
Physiologic pathway
IX-[VII+TF+Ca+]->IXa
X-[IXa+VIIIa]->Xa
Prothrombin (II)-[Xa+Va]-> thrombin (IIa)
Fibrinogen (I) -[Thrombin IIa+Ca+]->Fibrin
XI-[Thrombin]->XIa
VIII-->VIIIa and V-->Va by platelet thrombin
IXa and VIIIa only react when bound adjacent on a membrane on activated platelets
XIII (transglutaminase) - stabilizes clots
XIII-[Thrombin]->XIIa
Fibrin-[XIIa]->cross-linked fibrin
Lysine and glycine residues cross link to form a stronger fibrin clot
Hemorrhage Management Pre-OR
Control External Hemorrhage: pressure, tourniquets, hemostatics, limited resuscitation
Tourniquets
“Bad name” in past: "A tool of the Devil which sometimes saves a life"
Special Ops saw the utility 1st
18/35 (51%) reviewed casualties in GOT who died of extremity injuries 2001-4 could have been saved with tourniquet placement
400,000 tourniquets shipped to theater by 2005
US Army Surgeon General Recommends in 3/2005 that all soldiers carry tourniquets
Israeli Experience ’97-01
Effectiveness: 78% (94% UE, 71% LE), 97% c additional placements
Incidence of Neuro injury: 5.5% (all > 100 minutes)
Prehospital Tourniquet Use in Operation Iraqi Freedom: Effect on Hemorrhage Control and Outcomes
Positive effect on hemorrhage control noted with tourniquets
No documented nerve injuries (mean time = 70 min)
No difference in mortality
Survival With Emergency Tourniquet Use to Stop Bleeding in Major Limb Trauma
Prospective, non-controlled
Survival advantage noted
Average tourniquet time ~1.3 hrs
3 transient nerve pulsies, 1 long term injury, no amputations
Indications: 1) under fire scenario, 2) mass casualty, 3) Prolonged Transport, 4) Multiple severe injuries, 5) traumatic amputation
Guidelines: Tight enough to cut off arterial inflow; as far distal as possible; try to keep on < 1 hr; no IVs downstream; may need more than 1; LIFE BEFORE LIMB
1st Generation Active Hemostatics
HemCon
Chitosan based (Shrimp shells)
Mucoadhesive properties
Army’s Choice
Predeployment lab data & retrospective OIF data showed benefit
Difficulty = Application
Subsequent modifications:
Quik Clot
Lava Product (Granular zeolite)
Absorbs water --> concentrated coag factors
Exothermic reaction
Not biodegradable
Navy’s Choice
Predeployment lab data & retrospective OIF data favorable
Application:
Use:
QuikClot Use in Trauma for Hemorrhage Control: Case Series of 103 Documented Uses
92% Effective
Complications:
Moderate to severe pain in awake patients
3 cases of burns - 1 required grafting
Intracorporeal scar formation from foreign body reaction - ureteral obstruction
Z-Medica abandoned (Chambers didn't #eBay)
QuikClot Combat Gauze
Thin Gauze
Kaolin
Works but not as well
2nd Generation Topical Hemostatics
QuikClot Combat Gauze, QuikClot ACS+, Celox, Hemcon, BloodSTOP, InstaClot, X-Sponge, Woundstat, Alpha Bandage
Topical Hemostatics
Current Topical Hemostatics of Choice
Combat Gauze
Celox
My option: get old QuikClot off ebay
Coagulopathy of Trauma
Traditional Massive Transfusion Protocols are based on dilutional kinetics with FFP being recommended after 4-6 units PRBCs
Appears to underestimate the extent of coagulopathy present
Not just an issue of dilution
25% of Trauma Patients are coagulopathic on admission: 11% w/ ISS<15, 33% w/ ISS>15, 62% w/ ISS>45
Independent of IVF received in field
Correlates with Mortality
Pathophysiology
Acidosis --> Impaired clotting factor function, impaired platelet function --> coagulopathy
Hypothermia --> Impaired clotting factor function, impaired platelet function --> coagulopathy
High ISS --> CNS injuries --> increased TF release --> DIC --> coagulopathy
High ISS --> Long bone fxs --> fat embolism --> DIC --> coagulopathy
Hypotension --> Increased IVF and pRBCs --> Dilution of clotting factors and platelets --> coaguloapathy
Massive Transfusion Protocol = 1:1:1
rFactor VIIa (NovoSeven)
Adjunct to minimize transfusion requirements
With FWB
After surgical bleeding stopped
With pH > 7.1
Vials: 1 mg, 2 mg, 5 mg ($7,700.00)
rFVIIa in Combat Trauma
Retrospective review of prospectively maintained date-base from Ibn Sina CSHs
Dec. 2003 – Oct. 2005
124 Massive Transfusion cases (> 10 units/24 hr)
rFVIIa (n=49) vs. "control group" (n=75)
12 hr mortality 12% vs. 33%
24 hr mortality 14% vs. 35%
30 day mortality 31% vs 51%
No increase in thromboembolic complication rate with rFVIIa group
rFVIIa 2005 S African/European trial (32 centers)
Blunt & Penetr. Trauma pts requiring > 6 units PRBCs
N= 301 (143 blunt, 134 penetrating)
RBCs: Blunt decreased by 2.6 units, penetrating decreased by 1 unit
Massive transfusion: blunt 14 vs 33%, penetrating 7 vs. 19%
Mortality: no difference in blunt or penetrating
Adverse effects: no difference in blunt or penetrating
Problems: used too late, used without significant FFP, Plts
rFVIIa at Balt. Shock Trauma
Largest single center experience with rFVIIa in trauma
2001-2006: 285 cases
rFVIIa associated with decreased PRBC requirements
27 (9.4%) TE complications
rFVIIa .Balt. Shock Trauma Protocol
Most after 24 hour ?? causation
14-27 (52%) died with 10 deaths at least in part due to thromboembolic complications
18/27 - associated with definable high energy vascular arterial injury
Results of the CONTROL Trial: Efficacy and Safety of Recombinant Activated Factor VII in the Management of Refractory Traumatic Hemorrhage
Phase 3 multi-center Randomized clinical trial
573 pts (481 blunt, 92 penetrating)
4-8 units PRBCs within 12 hr with ongoing bleeding
Placebo VS rFVIIa (200 then 100 mcg/kg at 1&3hr)
Decrease in ARDS and MSOF and transfusion
Mortality was a wash
TE complications not significantly different
Issues:
Unexpectedly low mortality (Bundles?)
Small number of “massive” transfusion cases
rFVIIa in ICH
399 pts with HTN –related ICH
Within 4 hr of presentation
Randomized, Double Blind
73 Centers, 20 Countries
Amount of hematoma volume increase noted to be less in rFVIIa arms
Improved survival in patients with rFVIIa
Adverse thromboembolic events increased with rFVIIa:
7 MI (1 clinical, 6 asix Troponin elevations)
9 CVA (2 massive and fatal, 5 moderate with deficit, 2 asxic)
Study funded by Novo Nordisk
rVIIa in Trauma – current status
Appears to decrease the need for massive transfusions & amount of PRBCs
? effect on mortality
Benefit in ICH at expense of increased TE complications
Use caution with significant arterial vascular trauma or underlying atherosclerotic disease
rFVIIa – tips for effective use
Dose ~ 75-100 mcg/kg
Provide template with FFP & Plts
Increase pH to above 7.2 (use HCO3 if needed) otherwise it wont work
Use after surgical bleeding is controlled
Use before situation is hopeless
Prothrombin Complex Concentrate (KCentra)
Combination of II, VII, IX, X
Also contains Protein C&S
Being investigated/utilized in:
Reversal of coumadin-associated bleeds and trauma
Hemostatic & Coagulation Factors
Factor I - Fibrinogen: half life 100-150 hours
Factor II - Prothrombin: half life 50-80 hours; rarely disorders; tx: w/ FFP or PT complex
Factor III - Tissue Factor
Factor IV - Calcium Ion
Factor V - Proaccelerin: half life 24 hours, rare disorders, tx: FFP
Factor VII - Stable Factor: half life 6 hours, rare disorders, tx: FFP or rVIIa
Factor VIII - Antihemophilic factor: half life 12 hours, Hemophilia A, tx: F VIII or cryo
Factor IX - Christmas factor: half life 24 horus, Hemophilia B, tx: F IX or PT complex
Factor X - Stuart-Prower Factor: half life 25-60 hours, rare disorders, tx: FFP or PT complex
Factor XI - Thromboplastin Antecedent: half life 40-80 hours, hemophilia C, Tx: FFP
Factor XII - Hageman Factor: half life 50-70 hours, increased ptt with no clinical coagulopathy, tx: no need
Factor XIII - Fibrin-stabilizing factor: half life 150 hours, delayed post-op/post-trauma bleeding, tx: FFP, cryoprecipitate or F XIII
Coagulation Disorders
Hemophilia A & B
Vitamin K Deficiency
Liver Failure
Hypothermia
Coagulopathy of Trauma
Hemophilia A aka Classic Hemophilia
X-linked recessive deficiency of VIII
~30% are due to spontaneous mutations
Presentation: joint/deep tissue bleeds
Hemophiliacs don't usually bleed from superficial cuts, etc... due to normal primary hemostasis
Diagnosis:
Prolonged PTT with normal PT and Platelets
Decreased VIII levels
Normal bleeding time and vWF Ag levels
Severity graded on amount of VIII present
<2% - severe (PTT>65) --> often bleed spontaneously
2-5% - moderate (PTT 50-65) --> occasional spontaneous bleed
5-30% - mild --> usually undiagnosed until traumatized
Treatment:
DDAVP - Can help raise VIII levels with mild cases
Desmopressin - indirectly stimulates release of VIII and vWF from endothelial cells
0.3 mcg/kg IV --> 2-10x increase
rVIIIa - $$$
Pooled factor VIII - less expensive but infectious risk
Cryoprecipitate: 80 units/bag
- 50 U/kg pre-op or after injury then 30 U/kg Q8hr x 2 days
- then Q 12 hr infusions prn based on VIII levels
Note: Abs to VIII develop in ~20% - greatly complicates management
(rVIIa used in such cases with severe bleeding)
1u/kg VIIIa --> increase level by 2%
1 unit VIIIa = amount in 1 mL of normal plasma
Hemophilia B aka Christmas Disease
X-linked recessive deficiency in IX
Presentation = that of Classic Hemophilia
Dx:
Prolonged PTT with normal PT and Platelets
Decreased IX levels
Normal bleeding time and vWF Ag levels
Tx:
rIXa or high purity pooled IX - $$ but decreased infection and clot risk
Prothrombin complex: contains IX and all of Vit K dependent factors
Is ~50% loss of IX with administration of the complex
To offset this "double dosing" is recommended along with ~ 5 units heparin/mL (to offset the hypercoagulable effects of other factors)
Vitamin K in Coagulation
Factor---Glu --carboxilation--> Factor---Gla
K-H2 -->K
Vit K Dependent Factors: II, VII, IX, X, protein C and protein S
Causes of Vitamin K Deficiency
Poor diet
Malabsorption
Obstructive jaundice
Biliary fistula
Enteric fistula
Antibiotics
Coumadin effect
Coumadin (Warfarin)
Factor---Glu --carboxilation--> Factor---Gla
K-H2 -->K <-- inhibited by coumadin
t1/2 = 40 hr
May have transient hypercoagulable effect via Protein C&S
Initiation of Coumadin Therapy - 5-10mg standard dose (less for elderly/malnourished), check INR on day 3 and adjust dosing, continue daily monitoring and adjusting until dosing therapeutic for 3 consecutive days, then slowly space monitoring out
Treatment of Vit K Deficiency
Vitamin K po or IV
PCC or FFP
Reversal of anticoagulation effect
Less than 5 but supratherapeutic INR w/ no bleeding - lower or omit the next dose; resume Warfarin when INR approaches desired range
INR 5-9 w/ no significant bleeding - omit the next one or two doses; monitor INR daily and resume at lower dose when INR in desired range -- OR -- omit the next dose and give Vitamin K (1.25-2.5 mg tablet orally), resume at lower dose
INR>= 9 w/ no bleeding - hold warfarin, give vitamin K (2.5-5 mg orally), if INR doesn't decrease in 24-48 hours, repeat dose
Any INR w/ serious or life threatening bleeding - hold warfarin, give vitamin K 10 mg by slow IV infusion (1mg/min), supplement with FFP. Repeat Vitamin K q12 hr
Supplement with PCC 12 units/kg if INR < 4 or 25 units/kg if INR >4
Recheck INR in 30 min and repeat PRN
CHECK THE EVERNOTE APP
Preoperative Management of Warfarin Anticoagulated Patient
Low risk of thromboembolism: VTE greater than 3 months, Afib without stroke history or other risk factors, mechanical valve in aortic position
Stop 5 days prior and resume 12-24 hours postop. Consider prophylactic dosing of LMWH
Intermediate risk of thromboembilism:
Stop 5 days prio and begin bridging with LMWH or heparin 48 hours after lass dose
Stop LMWH 12-24 hours preop and start heparin 5 hours postop
High risk for thromboembolism: VTE less than 3 months ago, mechanical valve in mitral position, old model of cardiac valve (ball/cage)
Stop 5 days prior and begin bridging with LMWH or heparin 48 hours after last dose
Stop LMWH 12-24 hours preop and heparin 5 hrs preop
Procedures with low risk of bleeding:
EG: skin excision
Continue warfarin unchanged
Urgent reversal of coumadin
Vitamin K (2.5-5 mg orally) - effect takes 24 hours
Use PCC for more rapid reversal
Dental
Patients undergoing dental procedure with need to control local bleeding using aminocaproic acid solution as mouthwash without interrupting anticoagulation therapy
Pradaxa (Dabigatran etexilate)
po Direct Thrombin Inhibitor
Data supports use in place of Coumadin for DVT treatment (150 mg Q12hr), DVT prophylaxis (220 mg Q24hr), & non-valvular afib (only current FDA approval)
Potential advantages:
Affords inactivation of clot-bound thrombin (limitation of heparins)
Therapeutic effect within 2-3 hrs
t 1/2 = 12 hr (vs 40 hr for coumadin)
Predictable kinetics --> "no need for monitoring levels"
Difficulties:
No reliable reversal agent
No reliable monitoring tool (PTT current best readily available)
Avoid with renal failure
Reversal options
Med discontinuation
Activated charcoal
Dialyze off if renal failure present
PT complex or rFVIIa
FFP
Liver failure
Coagulation Factor Deficiency
All coagulation factors except VIII produced in liver
FVII has shortest t1/2 so PT is prolonged at first in liver failure
Thrombocytopenia
Splenic sequestration
Decreased production
Antiplatelet antibodies
Low Fibrinogen
1u FFP/hr necessary just to keep up with baseline needs in complete liver failure
Hypothermia
Decreased coagulation due to poor ENZ function
Decreased platelet aggregation
Increased fibrinolysis
Regulators of Coagulation
Antithrombin III
Protein C & Protein S
Fibrinolysis
Antithrombin III
Binds & neutralizes thrombin & Xa
Heparin alters configuration of AT-III to make it a more effective inhibitor (by 1000 – 4000X)
Cleared in ~ 6 hours
Monitored with Q6hr PTTs
Can reverse w/ protamine 1 mg for each 100 u Heparin
Danger = HIT
Hereditory deficiency occurs as rare AD trait assoc. with venous thromboembolic complications
Low Molecular Weight Heparin (LMWH, eg: Lovenox, Fragmin)
Selectively inhibit Factor Xa
Better safety profile than heparin
Monitoring of Xa levels now available
Now 1st line therapy for DVT, ACS, etc…
Avoid in Renal Failure
Protein C
Produced by the liver
Activated by Thrombomodulin-bound thrombin
Inhibits Factors Va & VIIIa
Homozygous deficiency: Neonatal purpura fulminans
Heterozygous deficiency: Hypercoagulable state
Also inhibits PMNs --> basis for Xigris therapy in Sepsis
Protein S = Cofactor for Protein C
Both C & S are Vit. K dependent (inhibited by Coumadin)
Fibrinolysis
Endothelial cell injury/stress/ischemia/presence of fibrin -->tPA
Alpha 2 macroglobulin, alpha 2 anti-plasmin -->plasmin
Plasminogen activator inhibitor-1 (PAI-1) inhibits Plasminogen
plasminogen--[tPA]-->plasmin
Fibrin--[Plasmin]-->fibrin degradation products (aka fibrin split products, marker of DIC - eg D-dimer)
PAI-1 low levels in plasma, high level in platelets
Plasmin inhibits ACTH and II, V, VIII
Exogenous Activators - urokinase, streptokinase
Exogenous Inhibitors - e-amino caproic acid, tranexamic acid
Tranexamic Acid
Synthetic derivative of lysine which inhibits fibrinolysis by blocking lysine binding sites on plasminogen
TA associated with decreased need for pRBC transfusion by 1/3 in 53 studies but did not decrease mortality
Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant hemorrhage (CRASH-2): a randomized, placebo-controlled trial
Randomized, multicenter trial (Europe, Asia, Africa)
20,127 trauma pts in 274 hospitals
Inclusion criteria:
Hemorrhagic shock (SBP < 90, HR > 110)
High risk of substantial bleeding
Within 8 hr of injury
TA (1gm over 10 min then another gm over 8 hr) vs. placebo
Primary Fibrinolysis
Shock, Hypoxia, Prostate Surgery, Iatrogenic --> release of excessive plasminogen activators --> depletion of fibrinogen, coagulation factors V and VIII --> bleeding
Tx: Treat underlying cause + aminocaproic acid
Tests for Coagulation Disorders
PT – measure of VII (Extrensic) & “Common” Pathway
Good measure of coumadin
More sensitive marker of non-factor specific coagulopathies (due to short t1/2 of VII)
PTT – measures the “Intrensic” Pathway
Measure of heparin effect
Increased without coagulopathy suggsts deficient XII
Note: PT, PTT measurements assume normothermia
Mixing Studies
Correction of elevated PT or PTT upon mixing pt blood with standard blood suggests Factor deficiency
Failure to correct suggests the presence of an inhibitor (eg lupus anticoagulant)
Tests for Platelet Disorders
Thrombocytopenia/ctosis – platelet level
Thrombocytopathia – Bleeding Time
Standardized cut on forearm (Ivy method) or earlobe (Duke method)
Disorders of Primary Hemostasis
Von Willebrand’s Disease
Thrombocytopathia
Thrombocytopenia
Von Willebrand’s Disease
Most common congenital bleeding disorder
~ 1% incidence
Presentation: Mucosal bleeding, epistaxis, petechia and easy bruising, menorrhagia, post-op bleeding
Subendothelial protein
Role in primary hemostasis: facilitates platelet aggregation
Role in secondary hemostasis: carrier for VIII
Type 1
Most common (80%)
AD inheritance
Decreased amount of vWF present (defect in secretion)
Type 2
15-20% of cases
Variable inheritance patterns
Defective vWF
Type 3
Very rare (occurrence = 1/1 million)
AR inheritance pattern
Near complete absence of vWF
Can present like hemophilia
Dx: bleeding time and PTT increased, PT normal; Factor VIII, vWF:Rcof, and vWF:ag decreased (changes more dramatic in type III)
Tx:
Type I moderate/severe (<30% ristocetin cofactor)
Minor - DDAVP 0.3 ug/kg daily for 1-2 doses or Humate-P 15-20 Ukg daily for 1-2 doses
Major/surgical - Humate-P, 50-75 U/kg first dose, then 40-60 U/kg every 8 hours to maintain level >50% for 3 days, then 40-50 U/kg dose for up to 7 days
Type I mild
Minor - DDAVP 0.3 ug/kg daily for 1-2 doses
Major/surgical - DDAVP 0.3 ug/kg daily for 2-3 doses or Humate-P, 40-50 U/kg first dose, then 20-30 U/kg every 12 hours for 3 days
Type IIa
Minor - Humate-P, 15-20 U/kg first dose, then 15-20 U/kg every 24 hours if needed or DDAVP 0.3 ug/kg daily or DDAVP 0.3 ug/kg daily for 1-2 doses
Major/surgical - Humate-P, 50-75 U/kg first dose, then 40-60 U/kg every 8 hours to maintain level >50% for 3 days, then 40-50 U/kg dose for up to 7 days
Type IIb
Minor - Humate-P, 15-20 U/kg first dose, then 15-20 U/kg every 24 hours if needed or DDAVP 0.3 ug/kg daily if needed
Major/surgical - Humate-P, 50-75 U/kg first dose, then 40-60 U/kg every 8 hours to maintain level >50% for 3 days, then 40-50 U/kg dose for up to 7 days
Type III
Minor - Humate-P, 40-50 U/kg for 1-2 doses
Major - Humate-P, 60-80 U/kg first dose, then 40-60 U/kg every 8-12 hours to maintain level >50% for 3 days, then 40-60 U/kg dose for up to 7 days
Thrombocytopathia
Hereditary
Glanzmann's thrombasthenia - deficiency of GIIb/IIIa
Bernard-soulier syndrome - deficiency of GIB
Storage Pool Deficiency - deficient ADP in platelet granules
Acquired
Aspirin effect - inhibits COX --> decreased platelet activation
Platelet inhibitors (Plavix, etc...)
IIb/IIIa inhibitors
Uremia
Can be partially offset with 0.3 mcg/kg DDAVP
Treatment = prn platelet transfusion
Thrombocytopenia
Normal: 250 – 400,000
< 100,000 --> Increased Bleeding Time
20-50,000 --> Increased Bleeding, Petechia/purpura
< 20,000 --> Spontaneous Bleeding
Most common abnormality resulting in surgical bleeding complications
Transfusion guidelines:
Recent (within 24 hours) platelet count < 10,000/mm3 (for prophylaxis)
Recent (within 24 hours) platelet count < 50,000/mm3 with demonstrated microvascular bleeding ("oozing") or a planned surgical/invasive procedure
Demonstrated microvascular bleeding and a precipitous fall in the platelet count
Adult patients in the operating room who have had complicated procedures or have required more than 10 units of blood and have microvascular bleeding. Giving platelets assums that adequate surgical hemostasis has been achieved
Documented platelet dysfunction (eg, prolonged bleeding time >15 min, abnormal platelet function tests), with petechiae, purpura, microvascular bleeding ("oozing"), or a surgical invasive procedure
Thrombocytopenia
Decreased Production (decreased megakaryocytes in BM)
1. Radiation effect
2. Med effect - eg. H2 blockers, thiazides, EtOH, Chemo, Quinine
3. Vit B12/Folate deficiency
4. Crowded out by leukemia, etc
Sequestration (normal or increased megokaryocytes in BM)
1. Splenic sequestration with Portal HTN
2. other causes: Sarcoid, Gaucher's disease, etc.
Increased Destruction (normal or increased megokaryocytes in BM)
1. ITP
2. TTP
3. Med effect (heparin)
4. DIC
5. Heart valve/Balloon pump
6. Post transfusion
7. Autoimmune disease (eg. SLE)
Immune Thrombocytopenic Purpora (ITP) aka “idiopathic”
Pathophysiology: Formation of anti-plt IgG antibodies
Dxic Triad:
1. Low platelet count
2. Normal or increased megakaryocytes in BM
3. Normal sized spleen
Presentation: Purpora, epistaxis, gingival bleeding, hematuria, GI bleeding, intracerebral hemorrhage (rare)
More common in women: 70% of adult cases are female
Criteria for Treatment:
Plts >50,000 and asxic - follow
Plts<50,000 or symptomatic - treat
Steroids in ITP
1st line treatment (eg prednisone 1 mg/kg daily)
Long term cure in ~50%
Splenectomy in ITP
2nd line treatment
Rationale: removes site of abnormal antibody production and the site of phagocytosis
75% long term cure rate
Most who respond do so within 1 week post op, 8% respond slower
Increased incidence of accessory spleens with ITP
Lap approach favored usually
IV Ig – helpful as a bridge to OR
2 g/kg over 2-5 days
Platelet transfusions
Try to avoid until spleen is out
Post-Op Thrombocytosis > 1 million --> ASA to prevent thrombotic complications
Thrombotic Thrombocytopenic Purpora (TTP)
Infection, meds, autoimmunity, etc --> subendothelial cell injury --> diffuse platelet trapping and microthrombus formation --> decreased platelets, hemolytic anemia, fever, neuro abnormalities, AKI
Treatment: Plasmaphoresis
Some cases demonstrate a deficiency in vWF-cleaving protease due to abnl Abs
Splenectomy may help in these cases to remove the source of the antibodies
Heparin-Induced Thrombocytopenia
Type 1 -
Frequency: 10-20%
Average onset:1-3 days
Antibody mediated?: no
Thromboembolic sequelae: None
Hemorrhage Sequelae: None
Management: Observation
Type 2 -
Frequency:1-3%
Average onset: 4-6 days
Antibody mediated?: yes
Thromboembolic sequelae: 30-80%
Hemorrhage Sequelae: Rarely
Management: Stop heparin, alternative anticoagulation
Cardiac patient with unfractionated heparin - 5 days of treatment, 20-50% frequency of HIT antibodies, 1% frequency of clinical HIT
Ortho patient with unfractionated heparin - 9 days of treatment, 9-14% frequency of HIT antibodies, 5% frequency of clinical HIT
Ortho patient with LMW heparin - 10 days of treatment, 3-8% frequency of HIT antibodies, 1% frequency of clinical HIT
Pathophysiology
Antibody formed to heparin reacts with Fc receptor on platelets causing PF4 release/platelet degranulization
Thrombocytopenia, white clot, skin necrosis, adrenal apoplexy, transient global amnesia
Moderate (average 20-60,000)
Thrombocytopenia
Moderate (average 20-60,000)
Bleeding complications rare
Platelet transfusions contraindicated
Typically occurs between day 4-10
Early Onset HIT
Typically seen with re-exposure to heparin within 3 months of prior exposure
Median time to occurance = 10 hours
Delayed Onset HIT
Occurance of HIT after heparin has been withdrawn
Median occurence within 14 days
DANGER = presentation with thrombotic complications - if treated with heparin 30% mortality
Thrombosis
“White Clot”
60% risk of venous thrombosis
DVT and PE, venous limb gangrene, central sinus thrombosis
15% risk of arterial thrombosis
CVA, MI, Limb ischemia, Mesenteric ischemia
Skin Necrosis
Similar to Warfarin Skin Necrosis preferentially involves fat rich areas of skin (eg abd wall)
Also can affect Nose & distal extremities
Erythema --> Purpura --> Necrosis
Starting Coumadin prior to Platelets increasing back toward normal (at least 150,000) poses increased risk of Warfarin Skin Necrosis
Diagnosis
Thrombocytopenia
2 = Platelets down by >50%
1 = Platelets down by 30-50%
0 = Platelets down by <30%
Timing
2 = Onset @ days 5-10 (or at onset if prior Heparin within 30 days prior)
1 = ? onset @ days 5-10, onset after day 10 or at onset with heparin within 30-100 days prior
0 = Onset at <4 days without recent exposure
Sequelae
2 = Thrombosis, skin necrosis, or acute systemic reaction
1 = Recurrent thrombosis, erythematous skin lesion or suspected thrombosis
0 = none
Other Explanations for Thrombocytopenia
2 = None apparent
1 = Possible
0 = Definite
Score 0-3--> low pretest probability
Score 4-5--> intermediate pretest probability (11% risk)
Score 6-8--> high pretest probability (11% risk)
Start treatment c high or intermediate pre-test probability.
Confirm diagnosis c HIT panel
Usually available within 24 hr if order “STAT”
Treatment
Direct Thrombin Inhibitors - monitor with PTT
Lepirudin
Renal clearance - best choice for liver failure
0.05 mg/kg/hr
High risk for antibodies - limits future use (0.16% anaphylaxis)
Argatroban
Cleared hepatically, best choice for renal failure
2 mcg/kg/min (-.5 mcg/kg if Bili > 1.5
Fondaparinux (arixtra) - evolving role
Once taking po & platelets normalized start Coumadin.
Continue Coumadin for 3 months
Avoid Heparin exposure in future
Disseminated Intravascular Coagulation (DIC)
aka Defibrination Syndrome
aka Consumptive Coagulopathy
Systemic Bleeding dominates the clinical picture (thrombi only rarely found at autopsy, but microvascular thrombosis often worsens peripheral ischemia)
Platelets, Coag Factors, Fibrinogen all consumed secondary to the introduction of thromboplastic materials into systemic circulation
Etiologies of DIC
SIRS/Sepsis
Hemolytic Transfusion Reaction
Obstetric Complications - retained dead fetus, premature placental separation, amniotic fluid embolism
Fat Embolism
Snake Venom
Treatment
Treat underlying cause
FFP/Cryoprecipitate
Platelets prn
Thromboelastography (TEG)
Described by Hartnet in ’48
Employed by Jenkins, et al at 332nd EMG in OIF
Uses vicoelastic properties of blood to eval: coagulability, platelet function, ENZ activity
Appears to be a better predictor of transfusion needs compared to PT, etc…
BLOOD TRANSFUSION
History of Blood Transfusion
1667 Denis – transfusion of 3 units of sheep’s blood
1795 Physick – 1st transfusion of human blood
1900 Landsteiner – ABO types
1915 – discovery of Na+citrate as anti-coagulant
1937 1st US Blood Bank established
2001 – 14 million units PRBCs transfused
Component therapy
Donor blood + CPDA --centrifuge w/in 6 hrs-->
pRBCs 80% HCT stored at 1-6 degrees C
Plasma and 70% of platelets --centrifuge-->
Platelet pellet and clotting factors (except factor VIII)
Plasma stored at -18 or -30 degrees C --> thaw to 4 degrees C --> cryoprecipitate/proteins
Blood “Storage Lesions”
pH alterations
Decreased 2.3 DPG
Increased K, Ph, & NH3
Changes in RBC deformability
Micro aggregate formation
Lab and retrospective data suggest worse outcomes with "old" (>14 days) pRBC transfusion (current "shelf life" = 42 days)
Leukocyte-Reduced PRBCs
“Transfusion-related immunomodulation”
Related to WBCs in Blood Products
FDA “recommends” leukoreduction of all products
Majority of US transfusions are LR’d
Leukocyte-Reduced PRBCs
Evidenced-based indications:
To decrease subsequent refractoriness to platelets in patients with need for long term platelet support
To decrease CMV transmission
To prevent recurrent febrile transfusion reactions
To decrease incidence of HLA alloimmunization in nonhepatic transplant patients
Adverse Transfusion Events
1:500,000 – HIV transmission, Fatal hemolytic reaction,
1:200,000 – Viral Hepatitis Transmission
1:33,000 – ABO Incompatibility
1:6,000 – Nonfatal hemolytic reaction
1-5:100 – Nonhemolytic Reaction
Hemolytic Transfusion Reactions
ABO incompatibility --> IgM binding --> complement activation -->
Vasoactive mediators released --> DIC and shock -->ATN
RBC lysis --> hemoglobinuria --> ATN
Presentation
Heat/Pain along IV site
Flushing, back pain, chest pain, chills
Oliguria (58%), Hypotension (50%), Jaundice (40%), diffuse bleeding (15%), Neuro changes (10%)
Management
Stop Transfusion
Recheck crossmatch
Urine for free Hg (>5mg/L = diagnostic)
Serum for direct antiglobulin test, haptoglobin, & Coombs test
Aggressive fluid resuscitation +/- Diuresis
Can see delayed hemolytic reactions - consider with unexplained anemia, fever and or indirect hyperbilirubinemia within hours to days of transfusion
Nonhemolytic Transfusion Reactions
Usually mild
Sxs: fever, urticaria
Typically develop within 60-90 minutes
Treatment: Tylenol, anti-histamines, epi, steroids
Avoid with leukocyte depletion/washed RBCs
Transfusion Related. Acute Lung Injury (TRALI)
ALI Criteria
Acute onset lung injury
P/F ratio < 300
Pulmonary Infiltrates
Lack of CHF
TRALI Criteria
New ALI post-transfusion
Onset of ALI within 6 hr
No other ALI etiology
Epidemiology
Incidence: 0.04 – 0.1%(1 case/1000-2400 transfusions)
Mortality rate = 5-8%
Leading cause of transfusion-related mortality
Pathogenesis
Underlying clinical condition and other transfused active factors --> priming -->ALI
Transfusion of blood product wtih anti-WBC Abs --> pulmonary microvasculature immune response -->ALI
TRALI – the role of anti-leukocyte Abs
70-86% of TRALI cases documented to involve anti-WBC Abs
Other mechanisms:
Preformed antibodies to donor WBCs
Inter-donor incompatibility (one donor's Abs against another donor's WBCs)
Role of anti-leukocyte Abs
Risk is greatest with FFP & Whole Blood (but can see with any blood product transfusion
Risk greatest with multiparous female donors
17% of femal donors have HLA sensitization
No pregnancies: 8% vs 15% with 1-2 and 26% with >2
Single multiparous frequent donor implicated with 15 cases
Presentation
Sudden onset of hypoxic respiratory failure
Within 6 hr of transfusion ending
Usually within 1-2 hr
Fever, Tachypnea, Tachycardia, Bilat. Crackles
Bilateral Infiltrates on CXR with normal heart size
TRALI Treatment = ARDS Treatment
Low Tidal Volume ventilation
Fluid restriction
+/- Paralysis
+/- Proning
+/- Pressure regulated ventilation
Notify blood bank
Avoid future transfusions from that donor
? Steroids ? – not routinely recommended
Prognosis
5-8% Mortality
Majority of cases resolve within 2 – 7 days
Survivors recover baseline lung function
Prevention
Produce FFP only from male donors
Screen previously pregnant or transfused donors for HLA Abs
Improve testing for detection of WBC Abs
Incidence of post-op ALI decreased in ruptured AAA pts after excluding female FFP donors
Randomized trial with pts given FFP from multiparous donors demonstrated increased hypoxia compared to control group donor FFP
Evidence – Based Transfusion Threshold
Hemoglobin <8g/dL or acute blood loss in an otherwise healthy patient with signs and symptoms of decreased oxygen delivery and two or more of the following:
Estimated or anticipated acute blood loss of >15% of total blood volume (750mL in a 70kg male)
Diastolic blood pressure < 60mmHg
Systolic blood pressure drop by >30mmHg from baseline
Tachycardia (>100 bpm)
Oliguria/anuria
Mental status changes
Hemoglobin < 10 g/dL in patients with a known increased risk for coronary artery disease or pulmonary insufficiency who have sustained or are expected to sustain significant blood loss
Symptomatic anemia with any of the following:
Tachycardia (>100 bpm)
Mental status changes
Evidence of muyocardial ischemia, including angina
Shortness of breath or dizziness with mild exertion
Orthostatic hypotension
Unfounded/questionable indications:
To increase wound healing
To improve the patient's sense of well-being
Hemoglobin between 7 and 10 g/dL (or hematocrit from 21-30%) in an otherwise stable assymptomatic patient
Mere availability of predonated autologous blood without medical indication
Multicenter (25 ICUs) Canadian Trial 1994-7
838 ICU pts c Hgb < 9 randomized to traditional (Hgb > 10) or restrictive (Hgb 7-9) transfusion protocols
Bleeding or Hypovolemic pts excluded
Blood Substitutes
Hgb-based Oxygen Carriers (HBOCs)
Initial HBOC – diaspirin x-linked Hgb
Associated with vasoconstrictive side-effects --> increased mortality
Tetrameric hemoglobin crosses endothelium -->binding of extraluminal NO
Polymerized Hgb products – current HBOCs
Appeared safe and to result indecreased pRBC requirements and decreased mortality
Less pro-inflammatory effect compared to pRBCs
Only binds intraluminal NO, not vasoconstricting
Derived from outdated human blood
pRBCs are lysed then free Hgb is polymerized with glutaraldehyde
PolyHeme Trial
Randomized, Controlled Prospective Trial
29 Level 1 Trauma Centers
Traumatic Shock pts with SBP < 90
590 evaluable pts between ’04-’08
Patients were randomized 50:50 into each treatment group. PolyHeme patients received PolyHeme in the field then PolyHeme (up to 6 U) for up to 12 hours, and blood in the hospital as needed. Control patients received crystalloid in the field, then RBC transfusion in the hospital as needed
Concluded it was a possible alternative