Hematologic/Coagulation Cases in Critical Care

Hematologic/Coagulation Hematologic/Coagulation Cases in Critical CareCases in Critical Care

Alice Ma, M.D.Alice Ma, M.D.University of North Carolina-Chapel HillUniversity of North Carolina-Chapel Hill

Division of HematologyDivision of Hematology

Case 1Case 1

• A 21 y.o. UNC student presented to the coagulation A 21 y.o. UNC student presented to the coagulation clinic from the plastic surgery clinic. He had clinic from the plastic surgery clinic. He had undergone nipple piercing 11 days prior and had undergone nipple piercing 11 days prior and had prolonged bleeding, requiring 2 trips to the prolonged bleeding, requiring 2 trips to the emergency room, gelfoam application, pressure emergency room, gelfoam application, pressure dressing, stitching, re-stitching. He was still actively dressing, stitching, re-stitching. He was still actively bleeding.bleeding.

• PMHx was notable for tongue laceration at age 7 PMHx was notable for tongue laceration at age 7 following a fall, with persistent bleeding. Thumb following a fall, with persistent bleeding. Thumb injury with persistent bleeding, ganglion cyst removal injury with persistent bleeding, ganglion cyst removal without abnormal bleeding.without abnormal bleeding.

Case 1Case 1

• Family History - mother is on iron for Family History - mother is on iron for unknown reasons. Maternal grandmother unknown reasons. Maternal grandmother may have abnormal bleeding (pt unsure) may have abnormal bleeding (pt unsure) Sister alive and well without abnormal Sister alive and well without abnormal bleeding.bleeding.

• Meds - noneMeds - none

• SHx - senior at UNC, occasional alcohol, no SHx - senior at UNC, occasional alcohol, no tobacco or drugstobacco or drugs

• PEx - actively bleeding left nipple. No bruises PEx - actively bleeding left nipple. No bruises or petechiae.or petechiae.

Case 1- Initial Laboratory StudiesCase 1- Initial Laboratory Studies

• PT 13.9 sec (11-14)PT 13.9 sec (11-14)

• aPTT 52.2 sec (22-32)aPTT 52.2 sec (22-32)

Case 1 - questionsCase 1 - questions

• Question 1: How do we evaluate Question 1: How do we evaluate patients with an abnormal aPTT?patients with an abnormal aPTT?

• Question 2: What does the patient Question 2: What does the patient have?have?

• Question 3: How should the patient Question 3: How should the patient be treated?be treated?

Obligatory Confusing Coag CascadeObligatory Confusing Coag Cascade

Coagulation made easyCoagulation made easy

The PTT Pathway The PT Pathway


X



VX



V

X

Prothrombin Thrombin



VX


Fibrinogen Fibrin


Coagulation made easy - the PTCoagulation made easy - the PT


Fibrinogen Fibrin

7

VX

Coagulation made easy - the aPTTCoagulation made easy - the aPTT


Fibrinogen Fibrin

VX

XIIXI

IXVIII



Fibrinogen Fibrin

T

NE

TVX

E



Fibrinogen Fibrin

Twelve

NineEight

TenVX

Eleven

• Deficiencies of factor XI, Deficiencies of factor XI, IX, VIII, VII. X, V, IX, VIII, VII. X, V, prothrombin and prothrombin and fibrinogen are clinically fibrinogen are clinically significant. significant.

• Inhibitors of these factors Inhibitors of these factors are clinically significant.are clinically significant.

• Deficiency of Factor XII, Deficiency of Factor XII, and the presence of the and the presence of the lupus anticoagulant are lupus anticoagulant are not clinically significant.not clinically significant.

XII

XI

IX

X

VIII VII

Thrombin

V

Fibrinogen Fibrin

What matters clinicallyWhat matters clinically

Coagulation Made Easy- The Mixing StudyCoagulation Made Easy- The Mixing Study

• Useful to differentiate etiologies of prolonged Useful to differentiate etiologies of prolonged clotting in a coagulation assay.clotting in a coagulation assay.

• Patient’s plasma is mixed 50:50 with normal Patient’s plasma is mixed 50:50 with normal plasma. Coagulation assay is repeated.plasma. Coagulation assay is repeated.

• If “substantial” correction is noted after mix, If “substantial” correction is noted after mix, suspect suspect clotting factor deficiencyclotting factor deficiency..

• If no or minimal correction seen, suspect If no or minimal correction seen, suspect inhibitorinhibitor..

Case 1 - More Laboratory DataCase 1 - More Laboratory Data

• aPTT - 52.2 sec (22-32)aPTT - 52.2 sec (22-32)

• aPTT mix - 31.5 secaPTT mix - 31.5 sec


• aPTT - 52.2 sec (22-32)aPTT - 52.2 sec (22-32)

• aPTT mix - 31.5 secaPTT mix - 31.5 sec

• Interpretation: Interpretation: Factor DeficiencyFactor Deficiency

Case 1 - Which Factor(s) are deficient?Case 1 - Which Factor(s) are deficient?


Fibrinogen Fibrin

Twelve

NineEight

TenVX

Eleven


Factor IIFactor II 104%104%

Factor VFactor V 111%111%

Factor VIIIFactor VIII 128%128%

Factor IXFactor IX 2%2%

Factor XFactor X 129%129%

Factor XIFactor XI 78%78%

Question 2: What does the patient have?Question 2: What does the patient have?

HemophiliaHemophilia

• X-linked recessive disorderX-linked recessive disorder

• Hemophilia A - deficiency of Factor VIIIHemophilia A - deficiency of Factor VIII

• Hemophilia BHemophilia B - deficiency of Factor IX - deficiency of Factor IX

• Incidence 1/5000 live male birthsIncidence 1/5000 live male births

• Estimated 20,000 cases in US; 1,000 in NCEstimated 20,000 cases in US; 1,000 in NC

• Racial groups affected with similar frequencyRacial groups affected with similar frequency

Clinical Classification of HemophiliaClinical Classification of Hemophilia

Severe < 1%

Moderate 1% - 5%

Mild 5% - 25%

Severe hemarthrosisSevere hemarthrosisSpontaneous bleedingSpontaneous bleeding

Serious bleeding afterSerious bleeding afterminor traumaminor trauma

Bleeding after surgeryBleeding after surgeryor traumaor trauma

Moderate bleeding afterModerate bleeding aftertrauma or surgerytrauma or surgery

TypeType FVIII/IX activityFVIII/IX activity Clinical pictureClinical picture

Subclinical 25% - 50%

Hemophilia TreatmentHemophilia Treatment

• Replace Deficient FactorReplace Deficient Factor• Many Products: Two general categories:Many Products: Two general categories:

– Plasma derivedPlasma derived• Virally inactivatedVirally inactivated• Generally reserved for individuals who are HIV/HepC Generally reserved for individuals who are HIV/HepC

positivepositive

– RecombinantRecombinant• More expensiveMore expensive• Should be product of choice for all children and Should be product of choice for all children and

previously untreated patientspreviously untreated patients

• Inhibit Fibrinolysis - in mucosal bleedingInhibit Fibrinolysis - in mucosal bleeding

Hemophilia TreatmentHemophilia Treatment

• Clotting factor is dosed in UNITSClotting factor is dosed in UNITS• One Unit = amount of factor present in 1 ml of One Unit = amount of factor present in 1 ml of

normal plasmanormal plasma

• Replacement Factor Dosing is based on 3 Replacement Factor Dosing is based on 3 variablesvariables– Volume of distribution Volume of distribution

(extravascula/intravascular)(extravascula/intravascular)– Half-lifeHalf-life– Level of factor required for hemostasisLevel of factor required for hemostasis

Hemophilia Treatment

Site of Bleeding Optimal Factor Level

Duration in days

Joint or muscle 30-50 1-2

GI tract 40-60 7-10

Oral, nasal, GU mucosa

30-50 Until healing

CNS 80-100 10-21

Retroperitoneal 80-100 7-14

Surgery/Trauma 80-100 7-21

Case 1 - Followup

• The patient was given a bolus dose of 4,000 units of BeneFIX (recombinant Factor IX) calculated to raise his Factor IX level to 50%. Pressure was re-applied, and the bleeding stopped. This dose of factor cost approximately $6,000. The patient is uninsured.

• The patient was instructed to seek care at the regional comprehensive hemophilia center after graduation.

Teaching PointsTeaching Points

• A prolonged PTT should be evaluated first by A prolonged PTT should be evaluated first by mixing study, then with factor levels, if mixing study, then with factor levels, if appropriate.appropriate.

• Hemophilia can be undiagnosed until Hemophilia can be undiagnosed until adulthood, especially if mild or moderate.adulthood, especially if mild or moderate.

• Treating hemophilia is expensive and Treating hemophilia is expensive and complicated, and patients should be followed complicated, and patients should be followed in a comprehensive hemophilia center.in a comprehensive hemophilia center.

Case 2Case 2

• A 33 y.o. man presented with post-operative A 33 y.o. man presented with post-operative bleeding after a tonsillectomy.bleeding after a tonsillectomy.

• 10/15/01 – Hb/Hct = 15.3/42.7. 10/15/01 – Hb/Hct = 15.3/42.7. – PT/aPTT = 13/35.6 (22-33.4)PT/aPTT = 13/35.6 (22-33.4)

• 10/17/01 – Tonsillectomy.10/17/01 – Tonsillectomy.

• 10/17-10/24, pt took ibuprofen for pain10/17-10/24, pt took ibuprofen for pain

• 10/24 early am – Pt awoke with severe bleeding10/24 early am – Pt awoke with severe bleeding– Hb/Hct in ER 14.1/38Hb/Hct in ER 14.1/38

Case 2Case 2

• Bleeding did not stop with ER cauterization.Bleeding did not stop with ER cauterization.

• Pt given platelets, FFP, then taken to ORPt given platelets, FFP, then taken to OR

• Notice made of persistent venous oozing and Notice made of persistent venous oozing and bleeding. DDAVP givenbleeding. DDAVP given

• 10/25 – Pt had persistent post-op bleeding10/25 – Pt had persistent post-op bleeding

• H/H eventually reached 9.1/25H/H eventually reached 9.1/25

Case 2 Case 2

• Bleeding History:Bleeding History:– Lifelong nosebleedsLifelong nosebleeds

– Gum bleeding with brushing teethGum bleeding with brushing teeth

– Prolonged bleeding with nicksProlonged bleeding with nicks

– Bleeding with multiple tooth extractions (characterized as Bleeding with multiple tooth extractions (characterized as delayed)delayed)

– appy at age 19, wound dehisced and bled appy at age 19, wound dehisced and bled

• FHx - sister with easy bruising and abnormal FHx - sister with easy bruising and abnormal menstrual bleeding. Mother had hysterectomy in menstrual bleeding. Mother had hysterectomy in early 30’s.early 30’s.

Case 2 - QuestionsCase 2 - Questions

• Question #1 - What is a reasonable screening Question #1 - What is a reasonable screening evaluation for patients pre-operatively?evaluation for patients pre-operatively?

• Question #2 - What is a reasonable screening Question #2 - What is a reasonable screening evaluation for patients with a positive bleeding evaluation for patients with a positive bleeding history?history?

• Question #3 - What does the patient have?Question #3 - What does the patient have?

• Question #4 - How should the patient be Question #4 - How should the patient be treated prior to future surgical interventions?treated prior to future surgical interventions?

Case 2

• PT - 12.9 seconds. (11-14)PT - 12.9 seconds. (11-14)

• aPTT - 33.9 seconds (22-33.4). aPTT - 33.9 seconds (22-33.4).

• Platelet function screen.Platelet function screen.

– col/epi closure time col/epi closure time >300 sec>300 sec (84-178) (84-178)

– col/ADP closure time col/ADP closure time 136 sec136 sec (60-107) (60-107)

The platelet function screen

• An in vitro method to test primary hemostasis

• Measures the length of time for whole citrated blood taken up by microcapillary membranes permeated with either collagen + epinephrine or collagen + ADP to close off the microcapillaries.

• Designed to replace the bleeding time



• Prolonged in cases of platelet dysfunction (acquired or congenital) or von Willebrand’s disease.

• If hematocrit is <30 or if platelet count is <100, this test will be abnormal.

• Assay must be run within 4 hours of sample draw.

• Sample is run on Whole Blood--NOT PLASMA!!

Case 2 - More laboratory data

• vWF antigen - 58%

• vWF activity - 50%

• Platelet aggregation studies: abnormal aggregation in response to epinephrine, ADP, arachidonic acid.

Case 2Case 2

Pre-DDAVPPre-DDAVP Post-DDAVPPost-DDAVP

Col/epiCol/epi >300 sec>300 sec 133 sec133 sec

Col/ADPCol/ADP 98 sec98 sec 56 sec56 sec

vWF antigenvWF antigen 67%67% 151%151%

vWF activityvWF activity 78%78% 219%219%

Question #3: How should the patient be treated prior to Question #3: How should the patient be treated prior to future invasive procedures?future invasive procedures?

Case 2

• The patient was told he had mild Type I von Willebrand’s disease, coupled with a mild platelet dysfunction. He subsequently suffered a left ACL rupture and underwent surgical repair under coverage with DDAVP.

• He did well and had no abnormal bleeding.

Teaching PointsTeaching Points

• Take a bleeding history. Then, write it down.Take a bleeding history. Then, write it down.

• Not all bleeding diatheses show up with a Not all bleeding diatheses show up with a PT/PTT.PT/PTT.

• Defects in primary hemostasis cause Defects in primary hemostasis cause mucocutaneous bleeding (“Oozing and mucocutaneous bleeding (“Oozing and Bruising”) and are best screened for by using Bruising”) and are best screened for by using the platelet function screen (PFA-100).the platelet function screen (PFA-100).

• DDAVP can improve primary hemostasis.DDAVP can improve primary hemostasis.

Bleeding History

• Nosebleeds

• Gum bleeding

• Bleeding with (wisdom) tooth extraction

• Easy bruisability

• Bleeding with surgeries (including circumcision)– Include timing of bleeding

• Menstrual bleeding

• Transfusion requirements

• Family history of bleeding– Hysterectomies at an early age

– Bleeding with surgeries

Case 3

• A 72 y.o. man suffered complications of an MVA with multiple fractures and splenic rupture 7 days prior. He is now thought to be septic and all wounds are bleeding.

• Labs show H/H 7/21, Plts 14, PT 33, PTT 60 Fibrinogen 81

• After transfusion of 4 units PRBC, H/H only 8/23

Case 3 - Questions

• Q1. What blood products should be given to the patient?

• Q2. What are the indications for use of Novo-Seven in the bleeding surgical patient?

What blood products to give?

• H/H 7/21, Plts 14, PT 33, PTT 60 Fibrinogen 81

• Platelets - With active hemorrhage, try to keep platelets > 50. If no bleeding, keep platelets >10

• Cryoprecipitate - With active bleeding, keep fibrinogen >100. Cryo also contains FVIII, VWF, FXIII

• RBCs - With active bleeding and thrombocytopenia, plts will work better if Hgb >10

Review Cascade model of hemostasis

Intrinsic pathwayIntrinsic pathway

XI, IX, VIIIXI, IX, VIII

Extrinsic pathwayExtrinsic pathway

TF, VIITF, VII

Xa generationXa generation

Thrombin GenerationThrombin Generation

A Cell-Based Model of Hemostasis

• Initiation

• Amplification

• Propagation

Initiation

Amplification

Propagation

Hemostasis

Hemophilia is a Defect in Plateetl Surface Thrombin Generation

NovoSeven can Ameliorate the Defect in Hemophilia

NovoSeven Augments Thrombin Generation on the Platelet Surface in Non-Hemophilics

NovoSeven in Surgery/Trauma

• This is an Off-Label Use

• Pts are at significant risk for thrombosis, especially if they have activated platelets in circulation (ie vasculopaths, DIC)

• Remember that rVIIa requires platelets, Factor X, prothrombin, and fibrinogen to work, so

• Fix the Plts, PT, PTT, Fibrinogen.

• If pt still bleeding, can then give rVIIa

Case 4

• A patient presents with a perforated diverticular abscess. He has alcoholic cirrhosis and poor nutrition.

• His PT and PTT are prolonged at baseline to 18 and 48 sec, respectively. DIC screen shows fibrinogen of 300, Ddimers of 800

• How can we use factor levels to determine the cause of his coagulopathy?

Case 4

Vitamin K Deficiency

Liver Disease DIC

Factor V

Factor VII

Factor VIII /

Case 5

• A 65 y.o. female smoker with a h/o peripheral vascular disease presented to the ER with unstable angina. She was admitted to the hospital and placed on heparin. Platelet count on admission was 450. Cardiac catheterization showed severe 3-vessel coronary disease, and the patient was scheduled for CABG which occurred on hospital day #7. Pre-op platelet count was 200. Post-op platelet count was 90.

Case 5

• On hospital day #12, the patient developed acute left leg swelling and a DVT was diagnosed by ultrasound. Platelet count was 150. The patient was started on IV heparin. The next day, she developed a pulseless left leg and had a platelet count of 30. While in vascular radiology, he developed acute chest pain and suffered a cardiac arrest and subsequently died. Autopsy showed occlusion of all of her bypass grafts

HIT

• Seen in 1-3% of patients treated with heparin• Usually, 7-10 d after heparin started, platelets fall by at

least 1/3 to 1/2. – Patients do not have to be thrombocytopenic.

– Can occur earlier in patients who have been previously exposed to heparin, even as SQ injections.

• Caused by antibodies against the complex of heparin and PF4. These antibodies activate platelets.

• Can lead, paradoxically, to THROMBOSIS, in up to half of patients.

• More common in patients with vascular disease

Alternate Presentations of HIT/T

• Small drop in platelet count (especially with

skin necrosis)

• Earlier onset thrombocytopenia with heparin re-

exposure

• Delayed-onset thrombocytopenia/ thrombosis

after stopping heparin

• Thrombosis after heparin exposure

HIT/T treatment

1. IF PLATELETS FALL ON HEPARIN, STOP HEPARIN IMMEDIATELY.

2. Stop heparin

3. Stop heparin

4. Use a different anticoagulant1. Lepirudin

2. Argatroban

3. Bivalirudin (off label)

4. Fondaparinux (off-label)

HIT Testing

Test Advantages Disadvantages

HIPA HIPA Specificity: high Specificity: high Sensitivity: low Sensitivity: low Rapid turn around timeRapid turn around time Technique-dependentTechnique-dependent

ELISAELISA Sensitivity: high Sensitivity: high Specificity: low (false-positives Specificity: low (false-positives Technically easy Technically easy high for some populations) high for some populations) Poor concordance with SRA Poor concordance with SRA

There is no Gold Standard in diagnostic testing;

HIT is a clinical diagnosis

Pts Must Be off heparin for 16 hours prior to testing

LepirudinLepirudin

• Recombinant protein, irreversibly binds to and Recombinant protein, irreversibly binds to and inactivates thrombininactivates thrombin

• Associated with increased bleeding, compared to Associated with increased bleeding, compared to heparin.heparin.

• Short t Short t 1/21/2..• Renally excreted.Renally excreted.• Antibody formation is commonAntibody formation is common

– decrease clearance and potentiate anticoagulation decrease clearance and potentiate anticoagulation effect.effect.

– Allergic reactions may occurAllergic reactions may occur• Monitor by using aPTT (aim for 50-70 sec)Monitor by using aPTT (aim for 50-70 sec)

ArgatrobanArgatroban

• Synthetic direct thrombin inhibitorSynthetic direct thrombin inhibitor• Reversibly binds to thrombin’s catalytic siteReversibly binds to thrombin’s catalytic site• Associated with increased bleeding compared to heparinAssociated with increased bleeding compared to heparin• Short t Short t 1/21/2 - must give as continuous infusion - no loading - must give as continuous infusion - no loading

dosedose• Dose is 0.2 mcg/kg/min (maximum dose is 10 mcg/kg/min)Dose is 0.2 mcg/kg/min (maximum dose is 10 mcg/kg/min)• Monitor using the aPTT (aim for aPTT 50-80) Monitor using the aPTT (aim for aPTT 50-80) • Hepatically cleared - reduce dose by 75% in liver failure.Hepatically cleared - reduce dose by 75% in liver failure.• Prolongs the PT.Prolongs the PT.

FondaparinuxFondaparinux

• Derived from AT-binding moiety of heparin.Derived from AT-binding moiety of heparin.

• Leads to indirect inhibition of Xa.Leads to indirect inhibition of Xa.

• Once daily SQ therapyOnce daily SQ therapy

• Renally clearedRenally cleared

• Approved for treatment of VTE and prophylaxis of Approved for treatment of VTE and prophylaxis of

patients at high risk for VTE (hip, knee surgery, patients at high risk for VTE (hip, knee surgery,

abdominal surgery)abdominal surgery)

• Not approved for use in HIT

Case 6

• A 72 y.o. woman requires red cell transfusion for symptomatic anemia. Red cells are delivered to the bedside. The patient verbally confirms her name and date of birth, which correlate with the label on the red cell bag. Which of the following is the most appropriate course of action to take at this time?

Case 6

A. Proceed with the transfusion.

B. Have another health care professional witness the patient’s confirmation of her ID, then proceed with the transfusion.

C. Check the patient’s wrist ID band against the red cell bag tag, along with another health care professional witness, then proceed with the transfusion.

D. Check the patient’s wrist ID band against the red cell bag tag, along with another health care professional witness, confirm that the consent for transfusion form has been signed, then proceed with the transfusion.

Case 7

• A patient in the SICU is in the process of receiving a transfusion of platelets for a platelet count of 8. Midway through the transfusion, the patient’s temperature rises from a baseline of 36.8 to 38. The blood pressure is stable, and the pulse has risen from 88 to 102. There are no hives, stridor, back pain, or rash. The patient is already on broad spectrum antibiotics. What is the most apropriate course of action to take at this time?

Case 7

A. Draw blood cultures, administer acetominophen, then proceed with the transfusion before the unit of platelets expire.

B. Draw blood cultures, administer acetominophen, then proceed with the transfusion when the temperature reaches baseline.

C. Draw blood cultures, change antibiotics, administer acetominophen, then proceed with the transfusion when the temperature reaches baseline.

D. Stop transfusion, draw workup for possible transfusion reaction, send workup and remainder of platelets to blood bank, and do not give further blood products until workup is negative.

Case 8

• A patient with aplastic anemia is scheduled to undergo breast biopsy in the morning. Her platelet count is 4. What is the most appropriate course of action at this point?

Case 8

A. Order 2 doses of platelets for transfusion.

B. Order 2 doses of platelets for transfusion, then check platelet count in the morning before procedure.

C. Order 1 dose of platelets for transfusion , then check platelet count in the morning before procedure.

D. Order 1 dose of platelets for transfusion , then check platelet count before ordering another dose of platelets.

Documents

Hematologic/Coagulation Cases in Critical Care