Unit 4 Hemostasis as a perfusion problem Jeff Acsell “” Rick Kunz “” Chad Smith “*”...

Unit 4Hemostasis as a perfusion

problemJeff Acsell “*”

Rick Kunz “*”

Chad Smith “*”

Juan Tucker “*”

Mindy Valleley

Tammy Murray

Grant Catlett

Eric Rauch

Mark Brown

University of Nebraska Medical Center

Clinical Perfusion Education

CLPR 775 – Fall 2004

Hemostasis as a perfusion problem

Is there a problem more central to the practice of perfusion? Perhaps gas exchange. Yet extracorporeal gas exchange cannot occur without some understanding and control over the process of hemostasis.

It is a problem we all struggle with each day we practice our craft. A problem that we often only understand minimally, yet treat cavalierly. It is easy as a Perfusionist to get into the automaticity of giving every patient 400 iu/kg because, “that’s what we’ve always done”.


It is a big problem

Chapter 22 of Gravelee: Cardiopulmonary bypass. Principles and Practices is titled, Anticoagulation for Cardiopulmonary Bypass, is one of five chapters that try to address various issues involved in hemostasis. This one chapter alone contains over 350 references to the scientific literature, in an effort to address this complex topic.


• A search on Google for Hemostasis yielded about 145,000 “results”

• A further search for the British version Haemostasis revealed another 95,800 “results”

• Clicking on definition brought up 5 American definitions and 3 British, all of which were various forms of “stoppage of the flow of blood” or “arrest of bleeding”.


• It is obvious to every Perfusionist that the definition of the word, doesn’t fairly express what it is that makes hemostasis so important for extracorporeal circulation.

• Surely there isn’t another profession that is more concerned with the arrest of, control of, preservation of, and restoration of hemostasis.


• The first problem with hemostasis, in this forum, is its size and scope. There are many sub-topics within this broad subject that should spawn examinations as perfusion problems.

• In an effort to “whittle a little off the tree” we narrowed the scope a bit in choosing a topic worthy of inspection.

• My fear is that we only saw the root, and may be trying to cut down a sequoia with a butter knife.

Heparinization (and Protamine Neutralization)

As a Perfusion Problem

There are hundreds of thousands surgeries performed each year in the US requiring cardio-pulmonary bypass. In the vast majority of these cases the patient is anticoagulated with heparin and later the heparin is neutralized with protamine

–Source: STS Adult CV Surgery national database, Spring 2004

The heparin-protamine regimen has been the method of choice for extracorporeal circulation since 1939 when John Gibbon used this combination approach on laboratory animals, and then humans in 1953

In the intervening 51 years, much research has been conducted on how to safely use heparin and protamine.

Research continues today.

Heparin / protamine administration has become an automatic process in the daily routine of cardiac surgery.

Often, little thought goes into this aspect of the surgery

– Protocols are written

– The reasons are forgotten

This is what prompted this project

Through experience and observation, these authors hypothesize that:

Many surgeons, anesthesiologists and Perfusionists administer these drugs with such regularity, that the reasons behind their protocols have become clouded by the passing of time.

Through experience and observation, these authors hypothesize that:

Only when confronted by deviations from the normal case Such as:

• Heparin resistance• Heparin allergy (HIT, HITT)• Protamine reaction

do clinicians question the processes with which they have become so comfortable.

“Familiarity with its use has led to the assumption on the part of many that the control of heparin during, and the neutralization of heparin after, extracorporeal circulation are straightforward matters which can be adequately handled by means of set protocols.”

– Brian S. Bull, M.D. 1974 Heparin therapy during extracorporeal circulation I. Problems inherent in existing heparin protocols. The Journal of Thoracic and Cardiovascular Surgery:1975;69(5)674-684

The intent of this project is to:

• review the literature in an effort to elucidate the reasons behind the protocols in use today,

• to re-acquaint ourselves with these reasons so that we can evaluate our own protocols,

• informally poll the perfusion “World” to discover the range of, similarities of, and differences in hemostasis management in use,

• and, let’s not kid ourselves; get a good grade in CLPR775.

Heparin

• Glucosaminoglycan (polysaccharide)

• Found most commonly in mast cells

• Strongest macromolecular acid in the body

Heparin Acts as a catalyst for ATIII to accelerate the neutralization of :

– Thrombin

– Xa

– IXa

– XIa

– XIIa

– VIIa/TF complex

Jack Hirsh, et al. Heparin and Low-Molecular-Weight Heparin Mechanisms of Action, Pharmacokinetics, Dosing, Monitoring, Efficacy, and Safety. Chest. 2001;119:64S-94S

Heparin

Yep, that’s about all we’re going to go into the specifics of it’s chemical interaction and

function with respect to the clotting cascade.

This and related problems would provide another excellent topic for inspection.

Heparin

• Normally Unfractionated

– heterogeneous mixture of molecules from 3,000 to 40,000 daltons (mean ~ 15,0000)

– batch to batch heparin preparations may have different activity levels per milligram

– standardized activity levels reported in units• 100 units = 1 mg

– 1 unit will maintain anticoagulation of 1 ml of recalcified sheep serum for 1 hour

Sources of Heparin

• First isolated from liver extract (hepatic)

• Porcine intestinal mucosa

• Bovine lung

Problem: What heparin should we use?

• Porcine– Lower molecular weight

– More cross linked structure

– Higher content of binding sites for ATIII

• Bovine– Higher molecular weight

– Less cross linking

– Lower content of ATIII binding sites


• Porcine– Higher incidence

of delayed hemorrhage?

• Bovine– Lower incidence

of heparin rebound?

Abbott WM, Warnock DF, Austen WG. The relationship of heparin source to the incidence of delayed hemorrhage. Surg Res 1977:22:593-597.


• Porcine

– Higher doses needed for CPB?

• Bovine

– Perhaps lower doses needed?

Stewart SR, Gaich PA. Clinical comparison of two brands of heparin for use in cardiopulmonary bypass. J Extracorporeal Technology 1980:12:29-33.


• Porcine

– 25-30% less protamine needed compared to bovine?

• Bovine

– May need more protamine to neutralize?

Novak E, Sekhar NC, Dunham NW, et al. A comparative study of the effect of lung and gut heparins on platelet aggregation and protamine neutralization in man. Clin Med 1972:79:22—27.

Lowary LR, Smith FA, Coyne E, et al. Comparative neutraliza tion of lung- and mucosal-derived heparin by protamine sulfate using in vitro and in vivo methods. / Pharm Sci 1971;60: 638-640.


• Porcine– Inhibits factor Xa more

effectively than Bovine

– (only partially neutralized by protamine)

• Bovine– Inhibits factor IIa more

effectively than Porcine

– (totally neutralized by protamine)

Barrowcliffe TW, Johnson EA, Eggleton CA, et al. Anticoagulant activities of lung and mucosal heparins. Thromb Res 1977; 12:27-36.


• Porcine– Lower incidence of

HIT with porcine• Rao AK, White GC,

Sherman L, et al; Arch Intern Med 1989:149:1285-1290

• Bovine– Cannot rule out

bovine spongiform encephalopathy transmission

• Bolt J, Zickmann B, Ballesteros m, Scholz D, Dapper F, Hempelmann G, J of Cardiothorac and Vasc Anest 1991:5:449-453


• Porcine– Longer lasting

• Bovine– Shorter lasting

– Renal elimination of bovine and porcine does not differ

Bolt J, Zickmann B, Ballesteros m, Scholz D, Dapper F, Hempelmann G, Does the Preparation of Heparin Influence Anticoagulation During Cardiopulmonary Bypass, J of Cardiothorac and Vasc Anest 1991:5:449-453


The answer to this problem may have already been made for us, as there have been several reports from Perfusionists around the United States being unable to obtain bovine lung heparin.

With the increased awareness of “mad cow” disease, certain countries (Canada) have imposed restrictions on its use.

Additional information to help answer this problem will follow later in this presentation.

Heparin

• Half life of heparin is dose dependent.

– Olsson P, Lagergren H, Ek S. The elimination from plasma of intravenous heparin. An experimental study on dogs and hu mans. Acta Med Scand 1963:173:619-630.

• And Highly variable between patients

Dose Half life

Minutes

400 u/kg 126 +- 24

200 u/kg 93 +-6

100 u/kg 61 +-9

Problem: How should we monitor heparin therapy?

Problem: How should we monitor heparin therapy? Historical Monitoring of Heparin Effect

• 1953 Extension of the bleeding time

• Lee-White clotting time

• 1958 Kaolin clotting time - plasma

• 1964 Celite clotting time – plasma

• 1966 ACT of whole blood

• 1977 Automated ACT

Problem: How should we monitor heparin therapy? Activated Clotting Time

• Hattersley 1966:

– Introduced ACT for whole blood

“probably technique of choice in the control of therapeutic heparin”, “quick and more reliable than the Lee-White.”

• Hattersley PG, Activated Coagulation Time of Whole Blood. JAMA 1966:196(5)150-154

Problem: How should we monitor heparin therapy? The ACT

• Hattersly found that

– room temp values were 60 sec longer than 37o.

– variables that showed no appreciable variation in ACT:

• quantity of celite, tube diameter, volume of blood between 1 and 3 ml, number of inversions of the tube

– 0.1 u of heparin increased ACT in 1ml of blood by ~45 seconds


• Hattersly

“simple, reliable, and reasonably sensitive bedside test of the coagulation mechanism.”

– He did not use it for extracorporeal circulation monitoring

– His test has lasted as the standard of care for 51+ years

Problem: How should we monitor heparin therapy? Heparin Management

Empiric management – Primary method for the first 30 years of bypass

– Based on knowledge of effect of heparin

– Applied to general population

– No individualization

– No assessment needed

– Example• Bolus 300 mg/kg heparin and follow with 1.5 mg/kg/hr until end

of bypass• Reverse with 3.6 mg/kg protamine

Problem: What is an adequate dosage?

The method was as simple as that. Administer the heparin, do the surgery and reverse with a set quantity of protamine. If there was still bleeding they would give more protamine.

For many years the determination of safe anticoagulation was the lack of observed clot in the extracorporeal circuit.

Problem: How should we monitor heparin therapy? Empiric management - Problems

There is a wide range of variability between patients in

– Patient Response to heparin

– Half life of heparin

Bolt J, Zickmann B, Ballesteros m, Scholz D, Dapper F, Hempelmann G, Does the Preparation of Heparin Influence Anticoagulation During Cardiopulmonary Bypass, J of Cardiothorac and Vasc Anest 1991:5:449-453

Culliford AT, Gitel SN, Starr N, et al. Lack of Correlation Between Activated Clotting Time and Plasma Heparin during Cardiopulmonary Bypass. Ann. Surg. 1981: 105-111

Problem: How should we monitor heparin therapy? Empiric management - Advocates

Metz S, Keats AS. Low activated coagulation time during cardiopulmonary bypass does not increase postoperative bleeding. Annals of Thoracic Surgery. 1990:49(3):440-444

– 300 U/kg heparin to 193 patients

– No additional heparin given

– 51 patients had ACTs less than 400

– 4 patients had ACTs less than 300

– No postoperative bleeding

– No clots in the circuits


Landmark paper by Bull, et al in 1975

– Analyzed 30 different protocols of anticoagulation from around the country

– Using bovine heparin, he defined ranges• < 180 seconds – unsafe

– as determined by observations from long term bypass

• < 300 seconds – insufficient heparin• 300 – 600 seconds “Safe Zone”

– As determined by observations of lack of clot in circuit

• Above 600 seconds – Excess heparin

Bull BS, Korpman RA, Huse WM, et al. Heparin therapy during extracorporeal circulation. I. Problems inherent in existing heparin protocols. J Thoracic Cardiovascular Surg 1975:69:674-684.

Problem: How should we monitor heparin therapy? Bull, Brian MD

• Recommended the ACT as the standard for monitoring anticoagulation on CPB

• Recommended that sufficient heparin be administered to raise the ACT to 8 minutes (480 seconds)

– easily remembered arbitrary number, approximately between 300 and 600 seconds, which falls in the “safe zone”.

• 480 seconds is still the most common target ACT today


Introduced the concept of heparin dose response to individualize heparin and protamine dosages (HDR) CPB

Bull BS,. Huse W M, Brauer FS, Korpman RA, Heparin therapy during extracorporeal circulation II. The use of a dose-response curve to individualize heparin and protamine dosage. The Journal of Thoracic and Cardiovascular Surgery. 1975:69(5)685-689


HDR protocol

– Perform ACT prior to surgery

– Administer 2 mg/kg dose and perform ACT

– Construct a dose response curve

– Calculate dose needed to reach 480 seconds

– Calculate dose of protamine needed from last ACT on CPB

Problem: How should we monitor heparin therapy? ACT-HDR method

Comparing the empiric approach to the ACT

– Group I – 3mg/kg plus 1.5 mg/kg/45 minutes

– Group II – 2.0 mg/kg and maintain at ACT of 400 seconds

Group II results

1. Decrease in postoperative blood loss

2. Decrease in heparin administered

3. Lower dose of protamine required

With the ACT-HDR method

Babka R. Colby C. El-Etr A. Pifarre R. Monitoring of intraoperative heparinization and blood loss following cardiopulmonary bypass surgery. Journal of Thoracic & Cardiovascular Surgery. 1977;73(5):780-782

Problem: How should we monitor heparin therapy? ACT-HDR method

Comparing 58 historic cases using empiric method to 56 cases monitored by automated ACT

• In the automated ACT cases.

– Protamine to heparin ratio was 25%less

– Postoperative blood loss was 48% less

Verska JJ. Control of heparinization by activated clotting time during bypass with improved postoperative hemostasis. Annals of Thoracic Surgery. 1977:24(2);170-173

Problem: How should we monitor heparin therapy? ACT monitoring and change in

clinical practice

• The introduction of the ACT in the 1960s and 1970s brought about a significant change in the practice of perfusion.

• The test is easy to perform, especially when automated

• Studies comparing dosage based on patient weight or BSA verses ACT demonstrated a reduction in post-operative bleeding when ACTs were used or no difference.

• This was compelling evidence that the ACT should become the standard of care.

• By the late 1970s and continuing until today the ACT became the most common method of determining heparin dosage and effect

Problem: What is a safe ACT?

1978 Young, et al, using an animal model, bovine heparin, experimented to determine the minimum safe ACT

• Used the appearance of fibrin monomer as indicator of coagulation

– “The lower limit as measured by the ACT...is at least 400 seconds”

Young JA, Kisker TC, M.D., Doty DB Adequate Anticoagulation During Cardiopulmonary Bypass Determined by Activated Clotting Time and the Appearance of Fibrin Monomer. The Annals of Thoracic Surgery 1978:26(3)231-237

Problem: What is a safe ACT?

• The study by Young, is often reported as the first controlled study that used a biological marker to determine a safe level of anticoagulation. It was another step in solving this problem

• The appearance of fibrin monomer in blood indicated that coagulation had been initiated and that there was a consumption of fibrin occurring, which meant that there was not enough heparin circulating to totally inhibit thrombin.

• This reinforced the work of Bull, and more Perfusionists began to adopt the protocol of maintaining ACTs greater than 400 seconds.

Problem: What is a safe ACT? Problems with ACT-HDR?

Heparin administration by ACT can be problematic

– ACT values are altered by temperature

– ACT values are altered by hemodilution

– ACT does not measure units of heparin

– ACT does not accurately reflect the protamine needed

1. Culliford AT, et al. 1981;191(1):105-1112. G. J. Despotis, et al. J Thoracic Cardiovascular Surg 1994;108:1076-

10823. Tian L, et al. JECT 1995:27(4)192-1964. Fox DJ, Gaines J, Reed G. JECT;11(4):137-142

Problem: What is a safe ACT? Problem: with ACT-HDR

These inherent inconsistencies in ACT driven HDR could lead to;

– Overestimation of the actual heparin level

– Under heparinization

– Consumption of coagulation factors

– Increased transfusion requirements

Problem: What is a safe ACT? What is needed?

Hypothesis: The inherent inconsistencies with the ACT based heparin management might be overcome with a method to monitor the concentration of heparin circulating in the plasma.

• Protamine titration

– Automatic heparin-protamine titration device (AHPT) Hepcon A-10

Hill AG, Lefrak EA. Monitoring heparin and protamine therapy during cardiopulmonary bypass procedures. Proceedings, American Society of Extra-Corporeal Technology. 1978;6:10-13

Problem: How should we monitor heparin therapy? Hepcon

In 1979 two studies, Hill and Lefrak, Fox et al, compared anticoagulation monitoring by the Hemochron device (AACT), and the Hepcon device (AHPT).

– The ACTs by the manual method correlated with the AACT

– The ACTs did not correlate with AHPT

– The AHPT “…more precise in determination of heparin levels and the doses required to facilitate reversal.”

Fox DJ, Gaines J, Reed G. Vehicles of heparin management: A comparison. JECT;11(4):137-142

Problem: Does heparin concentration make a clinical difference?

• Investigators began to wonder if there would be a clinical difference in maintaining anticoagulation by heparin concentration or by ACT or by the empiric method

• Several studies were published showing variable results


Patient assigned to one of 3 groups using bovine heparin

1. 300 iu/kg and ACT >400 sec

2. 250 iu/kg and ACT >400 sec

3. 350 iu/kg and heparin concentration of 4.1 iu/ml

Results

– Sub clinical coagulation occurred in all 3

– Post-op drainage correlated with increased heparin levels

– ACT > 350 seconds results in acceptable hemostasis

Gravlee GP. Haddon WS. Rothberger HK. Mills SA. Rogers AT. Bean VE. Buss DH. Prough DS. Cordell AR. Heparin dosing and monitoring for cardiopulmonary bypass. A comparison of techniques with measurement of sub clinical plasma coagulation. Journal of Thoracic & Cardiovascular Surgery. 1990;99(3):518-527.


1. Used porcine heparin

2. Control group, 250U/kg + heparin to ACT of 480sec, protamine 0.8:1

3. Intervention group, HDR to 480sec, protamine by HDR

– Higher heparin concentrations are maintained by anticoagulation by heparin concentration

– Higher heparin concentrations result in more effective suppression of coagulation

Despotis GJ. Joist JH. Hogue CW Jr. Alsoufiev A. Joiner-Maier D. Santoro SA. Spitznagel E. Weitz JI. Goodnough LT. More effective suppression of hemostatic system activation in patients undergoing cardiac surgery by heparin dosing based on heparin blood concentrations rather than ACT. Thrombosis & Haemostasis. 1996:76(6):902-908.



2. Control group, “conventional” to ACT of 400sec, protamine “conventional”

3. Intervention group, HDR to 400sec, protamine by HDR

– Intervention group received slightly larger heparin doses and significantly lower protamine dosages

– Chest tube drainage was less in the intervention group

– Donor exposures less in the intervention group

Jobes DR. Aitken GL. Shaffer GW. Increased accuracy and precision of heparin and protamine dosing reduces blood loss and transfusion in patients undergoing primary cardiac operations.Journal of Thoracic & Cardiovascular Surgery. 1995;110(1):36-45



2. Control group, celite ACT

3. Intervention group, kaolin ACT and heparin concentration measurement

– Intervention group had higher heparin concentrations than the control group

– Intervention group had lower fibrinopeptide A and D-dimer levels after bypass

– Intervention group had higher levels of factors V, and VIII, fibrinogen and ATIII after bypass

Despotis GJ. Joist JH. Hogue CW Jr. Alsoufiev A. Joiner-Maier D. Santoro SA. Spitznagel E. Weitz JI. Goodnough LT. More effective suppression of hemostatic system activation in patients undergoing cardiac surgery by heparin dosing based on heparin blood concentrations rather than ACT. Thrombosis & Haemostasis. 1996:76(6):902-908.


1. 94 patients undergoing DHCA for aortic surgery, aprotinin and 3 mg/kg heparin given to all

2. During CPB

– Group A. 49 patients were given additional 1 mg/kg heparin

– Group B. 45 patients were given 1 mg/kg heparin if ACT fell below 500 seconds

• Heparin dose was higher in Group A

• Levels of TAT, fibrinogen, DD,PF-4, beta-TG were lower in Group A

• Intra and post-operative platelet count was higher in Group A

Okita Y. Takamoto S. Ando M. Morota T. Yamaki F. Matsukawa R. Kawashima Y. Coagulation and fibrinolysis system in aortic surgery under deep hypothermic circulatory arrest with aprotinin: the importance of adequate heparinization. Circulation. 1997 ;96(9 Suppl):II-376-381


Comparing the porcine heparin concentration (HC) with ACT, during hypothermia and DHCA

1. Maintained ACT >400seconds• Or

2. Maintained heparin concentration at 3 mg/kg• Resulted in

– Higher blood concentrations were maintained by the HC method• and

– Better suppression of the coagulation system

Shirota K. Watanabe T. Takagi Y. Ohara Y. Usui A. Yasuura K. Maintenance of blood heparin concentration rather than activated clotting time better preserves the coagulation system in hypothermic cardiopulmonary bypass. Artificial Organs. 2000; 24(1):49-56


Results of surgery on 487 patients using multiple logistic and linear regression on variables that may have an association on blood loss and/or transfusion.

• Female gender, lower heparin dose, pre-op ASA use, and number of transfusions were associated with increased chest tube drainage.

Despotis, George J. MD; Filos, Kriton S. MD; Zoys, Timothy N. MD; Hogue, Charles W. Jr., MD; Spitznagel, Edward PhD; Lappas, Demetrios G. MD. Factors Associated with Excessive Postoperative Blood Loss and Hemostatic Transfusion Requirements: A Multivariate Analysis in Cardiac Surgical Patients. Anesthesia & Analgesia 1996:92(1)12-21


In a Anesthesiology 1999 review of the available literature published, the following statements were made

• “Because generation of FPA and inhibition of clot-bound thrombin have been shown to relate inversely to heparin concentration, maintenance of heparin concentrations that more effectively inactivate thrombin may preserve hemostasis during prolonged CPB”

and

• “..maintenance of higher patient-specific heparin concentrations should be considered to reduce thrombin –mediated activation and consumption of platelets in patients requiring longer CPB intervals.”

Despotis GJ, Gravlee G, Filos K, Levy J. Anticoagulation Monitoring during Cardiac surgery; A Review of Current and Emerging Techniques. Anesthesiology 1999:(91)1122-1151

Problem: When should the baseline sample be taken?

Though Bull, et al. suggested that the baseline ACT should be determined prior to the start of surgery, there is evidence to the contrary.

• Baseline ACTs decrease with anesthesia and surgery.

• Therefore an ACT baseline found prior to surgery, could lead to the mistaken diagnosis that all heparin had been neutralized after protamine administration.

Gravlee GP. Whitaker CL. Mark LJ. Rogers AT. Royster RL. Harrison GA. Baseline activated coagulation time should be measured after surgical incision. Anesthesia & Analgesia. 1990;71(5):549-553

Problem: How much time should elapse between heparin administration and ACT to

confirm anticoagulation?

The answer to this question requires us to know:

• how fast is the onset of action for heparin?

• what is the circulation time of heparin?

• how heparin is distributed in the body?


confirm anticoagulation?

The onset of action is very fast

– In one study Using bovine heparin

– Peak arterial ACT occurred within 30 seconds

– Peak venous ACT occurred within 60 seconds

Heres EK. Speight K. Benckart D. Marquez J. Gravlee GP.The clinical onset of heparin is rapid. Anesthesia & Analgesia. 2001;92(6):1391-1395


confirm anticoagulation? The onset of action is very fast

– In a second study Using bovine heparin

– ACT of 400 seconds was obtained within one minute

– There was a progressive increase for 4 minutes followed by a slow decline where the one minute ACT is essentially equivalent to the 10 minute ACT

– An ACT taken at one minute will save time and approximate a long term ACT which is a better indicator of heparinization.

E.T. Coleman, M. Hargrove, H.P. Singh, T. Aherne, Estimation of Minimum Heparin Circulation Time for Activated Clotting Time Determination. Journal of Extra-Corporeal Technology. 1994;26(2):61-63


confirm anticoagulation?How is heparin distributed in the body?

• Heparin is a highly polarized molecule

• This pre-disposes it to stay within the plasma and not cross into any lipid bearing tissues

• Some portion of administered heparin moves into an attaches to vascular endothelial cells.

• There is also some degree of sequestration in reteculoedothelial cells and vascular smooth muscle.

• This may account for the relatively quick fall in the ACT seen within the first few minutes after administration.

Hiebert LM. McDuffie NM. The internalization and release of heparins by cultured endothelial cells: the process is cell source, heparin source, time and concentration dependent Artery. 1990;17(2):107-118

Have we found solutions to any of our identified problems?

With respect to: What heparin should we use?

• On slide #27 we suggested that the decision may have already been made for us in favor of porcine heparin.

• In our exploration of the monitoring of heparin, several papers were discovered, hinting that porcine heparin administered and maintained at high concentrations resulted in less post-operative blood loss, better preserved coagulation factors, and better platelet function.

• Porcine heparin has a higher anti Xa activity that is not completely reversed by protamine administration, which may be a potential cause of heparin rebound. Another problem to be investigated.

• With respect to HIT porcine heparin may be a better choice. For this reason alone, The Medical University of SC switched the entire hospital formulary to porcine heparin three years ago.

• For now – porcine heparin has an edge


With respect to: How should we monitor heparin therapy?

• It is obvious to most, that strict empiric therapy should not be utilized these days. The advent of the automated ACT, with its proven benefits of reducing post-operative bleeding, and catastrophic coagulation, reduction of transfusion requirements, and reduced protamine dosages, has hopefully put an end to that practice.

• The ACT is known to fall short of being the perfect monitoring regimen. It fails to correlate well with circulating heparin concentrations, mainly due to the effects of hemodilution and hypothermia.


With respect to: How should we monitor heparin therapy?, What is a safe ACT?, and Does heparin concentration make a clinical difference?

• Most of the studies that compared heparin management by the ACT or heparin concentration, favor maintaining heparin concentration or show no difference.

• At the time of most of these studies (late 1970s – 1990s) most CPB involved diluting patients to lower hematocrit levels, and utilizing deeper hypothermia than is practiced today. (We don’t have a printed reference for this)

• With the current trends toward smaller circuits, retrograde autologous prime, and the resulting higher hematocrits, along with tepid or normothermic bypass, there seems to be an opportunity to investigate whether the ACT better correlates with heparin concentration, under these seemingly more favorable conditions.



• In the book, Cardiopulmonary bypass : principles and practice, the authors conclude that “in most situations” they see no clinical advantage to heparin concentration monitoring. They advocate using the ACT maintained at 400 – 480 seconds. This also seems to be the level accepted by the perfusion community as reflected by our informal survey. (see Chart)

• That having been said, one of the editors and co-author of the chapter that this was written in, has conducted research, mainly using bovine heparin, that showed few of the benefits found in other investigations. Dr Gravlee is an expert in the field, but could be considered to be biased in his opinion.

“World” Target ACT for Bypass

68%

16%

5%

11%

480 sec

400 sec

350 sec

500 sec

N=19


With respect to: How should we monitor heparin therapy?, What is a safe ACT?, Does heparin concentration make a clinical difference?

• It is difficult to deny that monitoring the concentration of circulating heparin has distinct advantages over the ACT method. From our informal poll of “World” Perfusionists, extrapolated to the perfusion community at large, the technology to perform protamine titration and monitor heparin concentration, has been embraced by a significant percentage of practitioners

• The following chart indicates that 69.6% of the Perfusionists responding to our survey, that indicated what instrument they use for heparin monitoring, have the technology to perform protamine titration for heparin concentration, by using the Hepcon system or the RXDX system.

“World” Anticoagulation Monitoring Instruments Reported

N=23Hepcon 60.9%

Hemochron 21.7%

ACT II 8.7%

RXDX 8.7%



• The previous slide provides evidence that the standard of care in perfusion today is, maintaining the technology for heparin concentration determination, and utilization of the ACT.

• This seems to be an appropriate choice. For many procedures that are relatively quick and performed at normothermia or tepid temperatures, the ACT is probably adequate.

• It also seems reasonable that if the procedure is long and/or requires deep hypothermia, heparin concentrations should be checked and/or additional heparin should be administered.

• However, the protocol best supported by the literature reviewed is to maintain both adequate heparin concentration and a corresponding ACT.

• From the survey data collected, it isn’t possible to tell how many Perfusionists are actually using protamine titration for heparin management.


With respect to: What is an adequate dosage?, and Does heparin concentration make a clinical difference?

• Again the answer not crystal clear, though there seems to be an advantage to the patients maintained with heparin concentrations between 3iu/ml and 5iu/ml, and achieving ACTs between 400 and 480 seconds.

• This seems to be achievable with loading doses of 300 to 400 iu/kg, which is the range of loading dosages that the majority of Perfusionists in our survey use. (see the chart)

• Most importantly though, Perfusionists must be aware that the circulating concentration of heparin poorly correlates with the ACT, because of hemodilution, hypothermia, and individual patient differences.

• For these reasons, an ACT that seems adequate may not be enough to stop the coagulation cascade, and prevent the consumption of factors.

“World” heparin loading doses

49%

5%5%

9%

27%

5%

N=22

150/kg 1

200/kg 1

300/kg 11

350/kg 2

400/kg 6

600/kg 1


With respect to, Problem: When should the baseline sample be taken?

• The evidence that was elucidated by Gravlee provides the best answer that we could find.

• The baseline should be taken after anesthesia and surgery has been initiated.


With respect to, Problem: How much time should elapse between heparin administration and ACT to confirm anticoagulation?

• Considering onset of action, circulation time, and redistribution the most common recommendation is to take a sample 3 to 5 minutes after administration of the initial dose.

• However in emergency situations, where speed is of utmost importance, a sample taken one minute after the loading dose should provide a reasonable ACT value.

• At the very least it will confirm whether the heparin dose was delivered into the patients circulatory system, which could be missed at any time but especially in the confusion that sometimes accompanies an emergent case.

Have we found solutions our original problem: Heparinization (and Protamine neutralization)

• As it is so many times when looking for the solutions of problems, we soon discovered many related problems.

• First: it was quickly revealed that “Heparinization” alone is a complex problem of a scale much larger than was first imagined.

• Therefore we have addressed the problem of protamine neutralization, only peripherally.

• The topic of “protamine administration as a perfusion problem” would make another excellent topic for inclusion in subsequent classes of CLPR 775.

• We all should be cognizant that the potential answers hinted at in this forum should not be considered the final word. By inspection of the other branches of the hemostasis tree, we may well need to alter our present conclusions.

Have we found solutions our original problem: Heparinization (and Protamine neutralization)

• There are many sub-topics and side branches to the original problem that we would have liked to include in this project. They were excluded, not by desire, but by time and space constraints. (“beam me up Scotty”)

• Some of the identified topics are:

– Heparin rebound

– Heparin resistance

– Heparin bonded circuits (as well as non-heparin coatings)

– Pharmacology (aprotinin, amicar, LMWH, alternative anticoagulants, etc.)

– Hemoconcentration

– Review of available instruments for monitoring coagulation

– HIT, HITT

Have we found solutions our original problem: Heparinization (and Protamine neutralization)?

• There are very few true solutions to most complex problems. What is important is a close inspection of the problems, to try to get a handle on as many pieces of potential solutions that we can.

• This is especially true of any profession where decisions made, on seemingly mundane issues, can have life and death consequences.

• We hope we have made a reasonable attempt to inspect the problem of heparinization, but realize that the work is not done. This is just one small area of the ‘jigsaw puzzle”, and the pattern is only beginning to be fully revealed.

Have we found solutions our original problem: Heparinization (and Protamine neutralization)?

The truth is that the original problem posed was,


We have placed the first piece of that puzzle in the corner.

BibliographyAuthor,Primary Authors, RemainingTitle Journal Vol Iss Year Pages Keyword1Keyword1Keyword1Keyword1

Boldt Zickmann, Ballesteros, Scholz, Dapper, HempelmannDoes the Preparation of Heparin Influence Anticoagulation During Cardiopulmonary Bypass?Journal of Cardiothroacic and Vascular Anesthesia5 5 1991 449-453 HeparinBovinePorcineBull Korpman, Huse, BriggsHeparin therapy during extracorporeal circulation The Journal of Thorac and Cardiovascular Surgery69 5 1975 674-84 HeparinkineticsprotocolsBull Huse, Brauer, KorpmanHeparin therapy during extracorporeal circulation II. The use of a dose-response curve to individualize heparin and protamine dosageThe Journal of Thorac and Cardiovascular Surgery69 5 1975 685-9 Dose response curveheparinACTClark Ecklund, McCall, Wolk, RileyComparison of Three Methods to Estimate Heparin Loading Dose for Cardiopulmonary BypassJECT 32 2 1996 67-70 HeparinDoseEstimateRX/DXColleman Hargrove, Singh, AherneEstimation of Minimum Heparin Circulation Timefor ActivatedClotting Time DeterminationJECT 26 2 1994 61-63 ACTMinimumDespotis Gravlee, Filos, Levy, Anticoagulation Monitoring during Cardiac Surgery Anesthesiology 91 1999 1122-51 AnticoagulationMonitoringHeparinProtamineDespotis Summerfield, Joist, Goodnough, Santoro, Spitznagel, Cox, LappasComparision of activated coagulation time and whole blood heparin measurements with laboratory plasma anti-Xa heparin concentration in patients having cardiac operationsJ Thorac Cardiovasc Surg 1994108 1994 1076-82 XaHeparin concentrationGravlee Haddon, RothbergerHeparin dosing and monitoring for cardiopulmonary bypass: A comparison of techniques with measurement of subclinical plasmaq coagulation.J Thorac Cardiovasc Surg 99 1990 518-27 ACTheparinfibrinogenfibrinTian Coffin, Sutton, Murray, Olson, PloesslThe Effect of Hypothermia on Heparin anticoagulation as Measured by Activated Clotting Time and Factor Xa InhibitionJECT 27 4 1995 192-6 ACTXaHypothermiaSearles Nasrallah, Darling, YarcuskoHow Does the Age of Blood Sample Affect It's Activated Clotting Time?JECT 34 2002 175-77 ACTAge of blood

Hirsh Warkentin, Shaughnessy, Anand, Halpern, Raschke, Granger, Ohman, DalenHeparin and Low-Molecular-Weight Heparin Mechanisms of Action, Pharmacokinetics, Dosing, Monitoring, Efficacy, and SafetyChest 2001 64S-94S ACTHeparinLMWH

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Novak Sckhar, DunhamA comparative study of the effect of lung and gut heparins on platelet aggregation and protamine neutralization in manClin Med 79 1972 22-27 HeparinPorcineBovineplatelet

Lowary Smith, CoyneComparative neutraliza tion of lung- and mucosal-derived heparin by protamine sulfate using in vitro and in vivo methodsJ Pharm Sci 60 1971 638-640 HeparinPorcineBovineProtamine

Barrowcliffe Johnson, EggletonAnticoagulant activities of lung and mucosal heparinsThromb Res 12 1977 27-36 HeparinPorcineBovine

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Olsson Langergren, EkThe elimination from plasma of intravenous heparin. An experimental study on dogs and hu mansActa Med Scand 173 1963 619-630 Heparinelimination

Hattersley Activated Coagulation Time of Whole Blood JAMA 196 5 1966 150-154 HeparinACT

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Metz KeatsLow activated coagulation time during cardiopulmonary bypass does not increase postoperative bleedingAnnals of Thoracic Surgery49 3 1990 440-444 ACTbleedingdose

Babka Colby, El-EtrMonitoring of intraoperative heparinization and blood loss following cardiopulmonary bypass surgery. Journal of Thoracic & Cardiovascular Surgery73 5 1975 780-782 HDRheparin

Verska Control of heparinization by activated clotting time during bypass with improved postoperative hemostasisAnnals of Thoracic Surgery24 2 1977 170-173 ACTCPBhemostasis

Young Kisker, DotyAdequate Anticoagulation During Cardiopulmonary Bypass Determined by Activated Clotting Time and the Appearance of Fibrin MonomerThe Annals of Thoracic Surgery 26 3 1978 231-237 ACTfibrinbypass

Fox Gaines, ReedVehicles of heparin management: A comparison JECT 11 4 1979 137-142 hemochronhepconheparin

Hill LefrakMonitoring heparin and protamine therapy during cardiopulmonary bypass proceduresProceedings, American Society of Extra-Corporeal Technology6 1978 10-13 HepconheparinACT

Despotis Joist, Hogue, Alsoufiev, Joiner-Maier, Santoro, Spitznagel, Weitz, GoodnoughMore effective suppression of hemostatic system activation in patients undergoing cardiac surgery by heparin dosing based on heparin blood concentrations rather than ACTThrombosis & Haemostasis76 6 1996 902-908 HepconACTcoagulation

Jobes Aitken, ShafferIncreased accuracy and precision of heparin and protamine dosing reduces blood loss and transfusion in patients undergoing primary cardiac operationsJournal of Thoracic & Cardiovascular Surgery110 1 1995 36-45 ACTprotamineheparin

Okita Takamoto, Ando, Morota, Yamaki, Matsukawa, KawashimaCoagulation and fibrinolysis system in aortic surgery under deep hypothermic circulatory arrest with aprotinin: the importance of adequate heparinizationCirculation 96 9 1997 376-381 HeparinCDHCAHeparin Concentration

Shirota Watanabe, Takagi, Ohara, Usui, YasuuraMaintenance of blood heparin concentration rather than activated clotting time better preserves the coagulation system in hypothermic cardiopulmonary bypassArtificial Organs 24 1 2000 49-56 heparin concentrationACTDHCA

Despotis Filos, Kriton, Zoys, TimothyFactors Associated with Excessive Postoperative Blood Loss and Hemostatic Transfusion Requirements: A Multivariate Analysis in Cardiac Surgical PatientsAnesthesia & Analgesia 92 1 1996 12-21 heparin concentrationACTtransfusion

Heres Speight, Benckart, Marquez, GravleeThe clinical onset of heparin is rapid Anesthesia & Analgesia92 6 2001 1391-1395 heparinonset

Hiebert McDuffieThe internalization and release of heparins by cultured endothelial cells: the process is cell source, heparin source, time and concentration dependent Artery 17 2 1990 107-118 heparindistributionrebound

Gravlee Cardiopulmonary bypass. Principles and Practices2001

ai STS Adult CV Surgery national databaseSpring 2004

Additional ReferencesAkpek Erol, Sekerci, ArsianHeparin and Protamine Requirements of Patients in Chronic Renal FailureTransplantation Proceedings30 1998 805-6 coagulopathyplateletrenal failureAldea Doursournian, O'Gara, Treanor, Shapira, Lazar, SheminHeparin -Bonded Circuits With a Reduced Anticoagulation Protocol in Primary CABG: A Prospective, Randiomized StudyThe Society of Throacic Surgeons62 1996 410-8 Heparin-BondedLow-anticoagulationACTButterworth Yonggu, Prielipp, Bennett, Hammon, MstatRapid Disappearance of Protamine in Adults Unergoing Cardiac Operation With Cardiopulmonary BypassAnn Thorac Surg 74 2002 1589-95 HeparinProtaminehalf-lifeCodispoti Ludlam, Simpson, MankadIndividualized Heparin and Protamine Management in Infants and Children Undergoing Cardiac OperationsAnn Thorac Surg 71 2001 922-8 ACTpediatricdose-responseblood lossGruenwald Souza, Chan, AndrewWhole blood heparin concentrations do not correlate with plasma antifactor Xa heparin concentrations in pediatric patients undergoing cardiopulmonary bypassPerfusion 15 2000 203-9 XaHMSACTHartstein JanssensTreatment of Excessive Mediastinal Bleeding After Cardiopulmonary BypassAnn Thorac Surg 62 1996 1951-4 MediastinalProtamineHeparinJong High dose Thrombin Time versus the Activated Clotting Time during Cardiopulmonary BypassJECT 31 2 1999 76-79 HiTTACTNewsome Stipanovich, FlahertyComparison of Heparin Administration Using the Rapidpoint coag and Hepcon HMSJECT 36 2004 139-44 HeparinHMSRapidpointOlshove TallmanHeparin Use in Pediatric Bypass-Empirical Regimen (ACT) vs. Heparin Concentration: A Multicenter TrialJECT 32 2 2000 84-88 HeparinAdministrationEmpiricalOvrum Holen, Tangen, Brosstad, Abdelnoor, Ringdal, Oystese, IstadCompletely Heparinized Cardiopulmonary Bypass and Reduced Systemic Heparin: Clinical and Hemostatic EffectsAnn Thorac Surg 60 1995 365-71 Heparin coatedlow dose hparinblood lossOvrum Tangen, Tollofsrud, RingdalHeparin-Coated Circuits and Reduced Systemic Anticoagulation Applied to 2500 Consecutive First-Time Coronary Artery Bypass Grafting ProceduresAnn Thorac Surg 76 2003 1144-8 Heparin coatedreduced anticoagulationACTblood transfusionsSegesser Mueller, Marty, Horisberger, CornoAlternatives to unfractioned heparin for anticoagulation in cardiopulmonary bypassPerfusion 16 2001 411-416 HeparinUnfractionedHITCPBPTurner-Gomes Nitschmann, Norman, Andrew, WilliamsEffect of Heparin Loading During Congenital Heart Operation on Thrombin Generation and Blood LossAnn Thorac Surg 63 1997 482-8 Congenital heparin protocolthrombinATIIICodispoti MankadManagement of anticoagulation and its reversal during paediatric cardiopulmonary bypass: a review of current UK practicePerfusion 15 2000 191-201 pediatricheparin protocolACTFernandes Mayer, MacDonald, Cleland, Hay-McDayUse of danaparoid sodium (Orgaran) as an alternative to heparin sodium during cardiopulmonary bypass: a clinical evaluation of six casesPerfusion 15 2000 531-9 OrgaranHITheparinJenkins Morris, SimpsonAustralasian perfusion incident survey Perfusion 12 1997 279-88 accidentperfusionclottingLevy Platelet Inhibitors and Bleeding in Cardiac Surgical PatientsAnn Thorac Surg 70 2000 S9-11 abciximabbleedingheparinplateletPugsley Kalra, Froebel-WilsonProtamine is a low molecular weight polycationic amine that produces actions on cardiac muscleM.K Pugsley/Life Sciences72 2002 293-305 protaminecardiacheparincontractilityBaufreton Brux, Binuani, Corbeau, Subayi, Daniel, TreanorA combined approach for imporvingcardiopulmonary bypass in coronary artery surgery: a pilot studyBennett Perfusion Strategies for Low-Dose and Heparin-Free BypassJECT 27 1 1995 44-48 HeparinLow DoseHeparin-BondedBiocompatibleO'Gara Natarajan, Husain, Shaira, SheminClinical outcomes of on-pump coronary bypass using heparin-bonded circuits and reduced anti-coatgulation compare favorably with off-pump approachPefusion 17 2002 91-94 heparin bondedACToff-pumpPouard Review of Efficacy Parameters Ann Thorac Surg 65 1998 S40-4 pediatricheparinaprotininKimmel Sekeres, Berlin, Ellison, DrSesa, StromRisk Factors for Clinically Important Adverse Events After Protamine Administration Following Cardiopulmonary BypassJ Am Coll Cadiol 32 1998 1916-22 riskprotamineACTKoster Huebler, Merkle, Hentschel, Grundel, Krabatsch, Tambeur, Praus, Habazettl, Wolfgang, Kuebler, KuppeHeparin-Level-Based Anticoagulation Management During Cardiopulmonary Bypass: A Pilot Investigation on the Effects of a Half-lDose Aprotinin Protocol on Postoperative Blood Loss and Hemostatic Activation and Inflammatory ResponseAnesth Analg 98 2004 285-90 Aprotininheparininflammatory responseWallock Jeske, Bakhos, WalengaEvaluation of a new point of care heparin test for cardiopulmonary bypass: the TAS heparin management testPerfusion 16 2001 147-153 ACTHMTdose-responseKuitunen Heikkila, SalmenperaCardiopulmonary Bypass with Heparin-Coated Circuits and Reduced Systemic AnticoagulationAnn Thorac Surg 63 1997 438-44 HeparinBiocompatibilityCoatedlow doseRay O'BrianComparisonof Epsilon Aminocaproic Acid and Low-Dose Aprotinin in Cardiopulmonary Bypass: Efficiency, Safety and CostAnn Thorac Surg 71 2001 838-43 EACAaprotininbleedingWeerwind Verkroost, Novakrova, BrouwerFamilial antithrombin-III deficiency during cardiopulmonary bypass: a case reportPerfusion 15 2000 553-6 AT-IIIHeparinizationACTSvensson How To Obtain Hemostasis After Aortic Surgery Ann Thorac Surg 67 1999 1981-2 hemostasistransfusionKumano Shigefumi, Hattori, Shibata, Sasaki, Horsono, KinoshitaCoagulofibrinolysis During Heparin-Coated Cardiopulmonary Bypass With Reduced HeparinizationAnn Thorac Surg 68 1999 1252-6 Reduced heparinizationcoated circuitpost operative bleedingLaDuca Zucker, WalkerAssessing heparin neutralization following cardiac surgery: sensitivity of thrombin time-based assays versus protamine titration methodsPerfusion 14 1999 181-187 heparin neutralizationACTPRTthrombin time

Additional References

Landis Haskard, TaylorNew Antiinflammatory and Platelet-Preserving Effects of AprotininAnn Thorac Surg 72 2001 S1808-13 aprotininplateletpreservationRaymond MarshAlterations to haemostasis following cardiopulmonary bypass and the relationship of these changes to neurocognitive morbidityBlood Coagulation and Fibrinolysis 12 2001 601-618 HaemostasisACTFibrinolyticFibrin emboliRaymond Ray, Callen, MarshHeparin monitoring during cardiac sugery. Part 2: calculating the overestimation of heparin by the activated clotting timePerfusion 18 2003 277-281 HeparinoverestimationACTEdwards Hamby, WorrallSuccessful Use of Argatroban as a Heparin Substitute During Caridopulmonary Bypass: Heparin-Induced Thrombocytopenia in a High-Risk Cardiac Surgical PatientAnn Thorac Surg 75 2003 1622-4 HITargatro anthrombin inhibitorRaymond Ray, Callen, MarshHeparin monitoring during cardiac sugery. Part 1: validation of whole-blood heparin concentration and activated clotting timePerfusion 18 2003 269-276 ACTHemoTecanti-factor XaHeparinLubenow Selleng, Wollert, Eichler, Mullejans, GreinachedrHeparin-Induced Thrombocytopenia and Cardiopulmonary Bypass: Periperative Argatroban UseAnn Thorac Surg 75 2003 577-9 HITanticoagulantantibodiesFrancis Palmer, Moroose, DrexlerComparison of Bovine and Porcine Heparin in Heparin Antibody Formation After Cardiac SurgeryAnn Thorac Surg 75 2003 17-22 HITheparinPF4porcineGabriel O'Gara, Shapira, Treanor, Osman, talis, Arkin, Diamond, Babikian, Lazar, SheminEffect of Anticoagulation Protocol on Outcome in Patients Undergoing CABG with Heparin-Bonded Cardiopulmonary Bypass CircuitsAnn Thorac Surg 65 1998 425-33 Heparin-BondedHeparinblood conservationWilliams D'Ambra, Beck, Spanier, Morales, Helman, MehmetA Randomised Trial of Antithrombin Concentrate for Treatment of Heparin ResistanceAnn Thorac Surg 70 2000 873-7 ACTHeparin resistanceJackson Danby, AlvingHeparinoid Anticoagulation and Topical Fibrin Sealant in Heparin-Induced ThrombocytopeniaAnn Thorac Surg 64 1997 1815-7 XaHITheparinoidChristiansen Jahn, Meyer, Scheld, Aken, Kehrel, Hammelwhole blood heparin concentrations do not correlate with plasma antifactor Xa heparin concentrations in pediatric patients undergoing cardiopulmonary bypassAnn Thorac Surg 69 2000 774-7 HITTLVADHeparinXaJacobsen Brauer, SmithHeparin Activity Monitoring during Vascular Surgery The American Journal of Surgery136 1978 141-4 heparinvariabilityvascular surgeryAouifi Blanc, Piriou, Bastien, Ffrench, Hanss, LehotCardiac Surgery With Cardiopulmonary Bypass in Patients With Type II Heparin-Induced ThrombocytopeniaAnn Thorac Surg 71 2001 678-83 HITTplateletanticoagulationheparinJaryno Bennett, Loder, Zucker, Pan, LaDucaValidation of a new Whole Blood Coagulation Monitoring SystemJECT 34 2002 271-5 HemochronOCACTJegger Tevaearai, Horisberger, Mueller, Seigneuil, Pierrel, Bood, SegesserAssembly of the Heparin Removal Device for patients with suspecdted adverse reaction to protamine sulphatePerfusion 15 2000 453-456 heparinProtamineremoval

Unit 4 Hemostasis as a perfusion problem Jeff Acsell “” Rick Kunz “” Chad Smith “*”...

Documents

Transcript of Unit 4 Hemostasis as a perfusion problem Jeff Acsell “” Rick Kunz “” Chad Smith “*”...

Unit 4 Hemostasis as a perfusion problem Jeff Acsell “*” Rick Kunz “*” Chad Smith “*”...

Documents

Transcript of Unit 4 Hemostasis as a perfusion problem Jeff Acsell “*” Rick Kunz “*” Chad Smith “*”...

Unit 4 Hemostasis as a perfusion problem Jeff Acsell “” Rick Kunz “” Chad Smith “*”...

Transcript of Unit 4 Hemostasis as a perfusion problem Jeff Acsell “” Rick Kunz “” Chad Smith “*”...