Med2 - Coagulation & Hemostasis Workshop

7/16/2007

Case 3‐01‐01 • 21 year old female

Coagulation and  Hemostatic  Problems Section of Hematology‐Oncology Department of Medicine

Case 3‐01‐01 • What other questions would you ask to  provide clues as to the nature of the problem? • What laboratory examinations will you  request?

• CC:  multiple ecchymoses • (+) (+) gum bleeding bl di • Menstrual hx: ↑ flow of menses for the last 2 cycles • PE: pale (+) petechiae and ecchymoses on BLE (‐) hepatosplenomegaly

Clinical manifestations of Disorders of 1° &  2° hemostasis MANIFESTATIONS

ONSET OF BLEEDING AFTER TRAUMA

DEFECTS IN 1° 1° HEMOSTASIS (PLATELET) Immediate

DEFECTS IN 2° 2° HEMOSTASIS (COAGULATION DEFECTS) Delayed – hours to days

SITES OF BLEEDING Superficial – skin, mucous membrane, nose, GIT, GUT

Deep – joints, retroperitoneum

FAMILY Hx

+/+/Autosomal dominant

Autosomal or XX-linked recessive

RESPONSE TO Tx

Immediate, local measures effective

Requires sustained systemic therapy

Back to Questions

Laboratory Examinations • • • •

Platelet count Bleeding time Prothrombin time Activated partial thromboplastin time

Diagnostic Examinations:   Primary Hemostatic system Platelet count • Correlates with propensity to bleed • 50,000‐100,000 causes mild prolongation of bleeding  time, bleeding occurs with severe trauma or stress <50,000 is associated with easy bruising • <50,000 is associated with easy bruising • <20,000 associated with high incidence of spontaneous  bleeding

Bleeding time • Reliable & sensitive test for platelet function • Any patient with BT >10’ has an ↑ risk of bleeding but the  risk does not become great until >15‐20’

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Diagnostic Examinations:   Plasma coagulation  Patients with qualitative platelet abnormalities have a normal platelet count and a prolonged bleeding time. time.

Activated partial thromboplastin time

Intrinsic limb of coagulation system Adequacy of factors XII, HMWK, PK, XI, IX, VIII Common coagulation pathway after conversion of F X

Prothrombin time

Extrinsic or tissue factor factor-dependent pathway Common coagulation pathway after conversion of F X

Thrombin time Fibrinogen level

Conversion of fibrinogen to fibrin

Specific coagulation factors

Case 3‐01‐01 • CBC : Hgb = 9 g/dl WBC = 8500 u/L  platelet = 40,000

Hct  = 28 mg% segs =  72% lymphos = 28%

• Bleeding time = 12 minutes Bleeding time = 12 minutes • Prothrombin time = 12.3 seconds normal control = 11.2 seconds • Activated PTT = 39.8 seconds normal control = 39.1 seconds

Thrombocytopenia:  Causes • ↓ marrow production of megakaryocytes ‐ marrow infiltration (tumor, fibrosis) ‐ marrow failure ( hypoplastic, aplastic anemias, drug effects) • Splenic sequestration of circ platelets ‐ splenic enlargement due to tumor infiltration ‐ splenic congestion due to portal HPN • ↑ destruction of circ platelets ‐ non immune destruction  o u e des uc o – – – –

DIC Sepsis Vasculitis vascular prosthesis

‐ immune destruction – Antibody to platelet Antigens – Drug associated Antibodies – Circulating  immune complexes  • SLE • viral agents • bacterial sepsis

LOW PLATELET COUNT Splenomegaly N marrow Congestive splenomegaly liver disease storage diseases tumor

Abn sequestration

Abn marrow hema d/o leukemia lymphoma myeloid metaplasia p

combined d/o

N spleen N marrow

excess destruction IMMUNE drug idiopathic

Abn marrow hema d/o aplasia refractory anemia preleukemia p metastatic CA prodn defect

NON IMMUNE sepsis/DIC vasculitis prosthesis

Qualitative Platelet Dysfunction • Defects of platelet adhesion vWd uremia Bernard Soulier syndrome • Defects of platelet aggregation Glanzmann’s thrombasthenia Drugs uremia • Defects of platelet release ↓ cyclooxygenase activity drug induced (ASA, NSAIDS) congenital granule storage pool defects • Defect of platelet coagulation activity Scott’s syndrome uremia

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Evaluation  of Platelet Function

Idiopathic Thrombocytopenic Purpura

• Bleeding time • Acquired disease w/ no clinically apparent  associated conditions or other causes of  thrombocytopenia

• vWF assays • Platelet aggregometry

• Acute vs chronic ITP

• Membrane glycoproteins • Platelet granule content

Clinical Features of ITP in children & adults CHILDREN

ADULTS

Peak age

2-4 yo

15 15--40 yo

Sex (F:M) Onset

Equal Acute (<1wk) (<1 k)

2.6:1 Insidious (>2mos)

symptoms

Purpura (<10% w/severe bleeding)

Purpura (typically bleeding not severe)

Spontaneous CR

83%

2%

Chronic dse

24%

43%

Eventual CR

89%

64%

Thrombocytopenia due to  Splenic Pooling (Sequestration) • Displacement of majority of platelets from   peripheral circulation to a slowly exchangeable  splenic pool.  s/s related to the 1 related to the 1° d/o; bleeding is primarily the  d/o; bleeding is primarily the • s/s result of coagulation abnormalities caused by the 1° liver disease • Platelet transfusions rarely needed & does not  produce significant ↑ in peripheral platelet count  since as many as 90% of the transfused platelet is  sequestered into the spleen.  

Treatment for ITP • • • •

Glucocorticoids IV Ig Anti Rh(D) immune globulin Splenectomy

Chronic ITP • Cyclophosphamide • Vinca alkaloids • Danazol • Observation

Von Willebrand Disease • Most common inherited bleeding disorder  • Von Willebrand factor ‐ facilitates platelet adhesion by linking platelet  membrane receptors to vascular  endothelium d h li ‐ plasma carrier for F VIII • s/s may be mild to moderate bleeding episodes,  depending on type of vWD • Treatment: F VIII concentrates desmopressin

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Case 3‐02‐01

Case 3‐02‐01

• 52 year old male

• What other questions will ask in the history? • What laboratory examinations will you  request?

• CC:  hematemesis • PE:  BP = 90/60 PR = 112/min (+) spider angioma, chest (+) palmar erythema Traube’s space obliterated

Diagnostic Examinations in patients  with liver disease • • • •

PT, PTT Platelet count fibrinogen Whole blood or Whole blood or  euglobin clot lysis time 

• Thrombin Time • D – dimer • Fibrin degradation  products  products

Case 3‐01‐01 •

•

Results of above tests will allow one to establish whether thrombocytopenia, fibrinolysis, DIC, or deficiency of coagulation factors is present.

CBC:  Hb:  80 g/dL  Hct:  0.24 WBC count:  3.5 x 109/L, 50 % segmenters, 45%  lymphocytes, 2% eosinophils, 3% monocytes Platelets:  90 x 109/L

Prothrombin time:  patient:  24 sec Normal control:  12 secs Prothrombin activity:  50%

•

APTT:  patient 56 secs Normal control:  35 secs

Back

Interpretation? • • • •

Normochromic normocytic anemia Thrombocytopenia Prolonged prothrombin time Prolonged activated partial thromboplastin  time

XII

PK, HK

INTRINSIC Pathway

XIIa HK

XI

XIa IX

IXa

EXTRINSIC Pathway

VIIIa

X

VIIa,, TF

X Xa

X

Va prothrombin

XIII

Thrombin XIIIa

Fibrinogen

Fibrin cross linked fibrin

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Causes of Bleeding in patients with Liver Disease Anatomic factors • Portal HPN splenomegaly & 2° thrombocytopenia varices • Peptic ulceration • Gastritis Hepatic Function abnormalities • ↓ synthesis of procoagulant proteins (fibrinogen,  prothrombin, FV, VII, IX, X, XI) • ↓ synthesis of coagulation inhibitors (protein C, S, AT III) • Impaired absorption & metabolism of Vit K • Failure to clear activated coagulation proteins leading to DIC,  systemic fibrinolysis

Therapy • Treatment strategy based on careful clinical  evaluation of causes of bleeding and assessment of  the major hemostatic abnormalities involved.   • In patients who bleed spontaneously, following  trauma, or predicted to bleed following surgery, the  1° goal of treatment is correction of hemostatic  1 goal of treatment is correction of hemostatic defects. • • • • • •

FFP Prothrombin Complex concentrates Vit K Platelet transfusion Cryoppt Antifibrinolytic agents

Infection, burns Multiorgan dysfunc Autoimmune d/o Intravasc generation Of TF by monocytes, Endothelial cells

SIRS

Failure of Control mechanisms Consumption Of AT III, Prot C

Microangio Pathic HA

Trauma, burns CA Obstetric cx Hemorrhagic shock Aneurysm, vasculitis Heat stroke

Exposure Of bld to Tissues w/ / TF

Th Thrombin bi generation ti

BV obs Ischemia

Compensatory fibrinolysis BV patency

• Widespread intravascular coagulation is induced by  procoagulants introduced or produced in the blood  circulation which overcomes the natural  anticoagulant mechanisms. • Diffuse multi‐organ bleeding, hemorrhagic necrosis,  thrombus formation in blood vessels • Clinical manifestations attributable to the DIC,  underlying cause, or to both.

TRIGGERING OF TF COAG PATHWAY

DIC

Disseminated Intravascular Coagulation

Consumption of Plts, F V & VIII, fibrinogen FDP D-dimer

Clinical Manifestiations:  DIC • Bleeding • Thrombosis & thromboembolism • Shock • Renal, liver, CNS, pulmonary dysfunction

Inhibition of: thrombin plt aggreg

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Diagnostics:  DIC  • • • • •

Platelet count fibrinogen level PT, PTT, TT FDP,   D Dimer fragmented RBCs fragmented RBCs

Treatment:  DIC • Manage underlying disease • Blood component therapy

• Will reflect extent of consumption of hemostatic components

• Heparin administration 

• In most instances, changes in > 3 parameters in addition to ↓ platelet count are consistent with DIC

• Antithrombin III concentrate 

PT N, PTT ↑, PLT N Bleeding

No Bleeding ↓ F XII, HK, PK Lupus anticoag heparin

INJURY REL Severe def F XI Mild to mod Hemophilia A/B UNPROVOKED Minor vWD

Major Severe Hemophilia A/B Severe (type 3) vWD Acquired inhibitor to FVIII Acquired vWD

Hemophilia  • X‐linked hereditary d/o due to defective or  deficient Factor VIII molecule (Hemophilia A)  or IX (Hemophilia B) • A:  1:10,000 live male births B:  1:25,000‐30,000 live male births 

Clinical Classification of  Hemophilia Class Severe

Factor level

< 1%

Treatment of Hemophilia A

Clinical Features spontaneous hemorrhage from infancy Frequent spontaneous hemarthroses/hemorrhages, requiring clot factor replacement

Mod

1-5%

Hemorhage 2° 2° to trauma or surgery Occ spontaneous hemarthroses

Mild

6-30%

Hemorhage 2° 2° to trauma or surgery Rare spontaneous hemarthroses

• Factor replacement therapy  – Factor concentrate – Cryoppt (will only achieve 20% F VIII level max)

• • • •

Desmopressin A ifib i l i Antifibrinolytic agents Fibrin glue Supportive: – Avoidance of ASA, NSAIDs – Avoidance of IM injections

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Treatment of Hemophilia B • Factor replacement therapy  – Factor concentrate – Fresh Frozen Plasma

• Fibrin glue • Supportive: – Avoidance of ASA, NSAIDs – Avoidance of IM inections

PT ↑, PTT ↑, PLT N

PT ↑, aPTT N, PLT N

Bleeding Severe FVII def

No bleeding mild F VII def use of oral anticoagulants

Bleeding Afibrinogenemia Severe def F II, V, X Combined F V & VIII def Combined def of Vit K dep factors Acquired inhibitors to F II & V Acquired F X def

Case 3‐03‐01 • 72 year old male was recently admitted to the hospital  Neurology ward  – drooling of saliva from the left side of his mouth – slurring of speech  – right sided upper and lower extremity weakness • past history of hypertension, hypercholesterolemia and  di b diabetes mellitus type 2 lli 2 • medications include:  Felodipine, Simvastatin, Gliclazide and  Metformin • PE admission: drowsy, but responds to verbal stimuli • bedbound with no bathroom privileges • fifth hospital day:  swelling of his right lower extremity with  erythema • 6th hospital day: difficulty of breathing and had to be  intubated because of hypoxemia.

No Bleeding Hypofibrinogenemia Mild def F II, V, X

Case 3‐03‐01 • • • • • •

What other questions would you ask during history  taking? What other aspects of the physical examination  should you pay attention to? Wh f What factors put this patient at risk for a  hi i i kf thrombotic complication? What are the differential diagnosis? What laboratory  examinations are important to  arrive at the diagnosis? How can thrombotic complications be prevented?

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Virchow’s triad: the three risk factors

Virchow’s triad: hypercoagulability (acquired, inherited) • Advanced age

• Malignant disease

• Pregnancy and puerperium • History of DVT • Infection • Acute myocardial infarction • Stroke • Nephrotic syndrome

Inherite ed

• Myeloproliferative disorders

•

Vascular injury

Inherited

• Antiphospholipid A ti h h li id resistance i t

Venous thrombosis

Activated protein C resistance

•

Protein C deficiency

•

Protein S deficiency

•

Other congenital conditions

Acquired Rosendaal FR. Lancet 1999; 353: 1167–1173. Rosendaal FR. Lancet 1999; 353: 1167–1173.

Virchow’s triad: stasis (acquired)

Virchow’s triad: vascular injury (acquired)

A range of acquired factors is known to increase the risk of venous thrombosis by inducing stasis. • Surgery (anesthesia, immobilization)

Vascular injury

• Obesity • Paralysis

Acquired

• Congestive heart failure • Prolonged immobilization

• Infection

History of DVT • Surgical damage Trauma • Advanced age • Varicose veins • Chemotherapy

•

• Malignancy • Pregnancy

•

• Acute myocardial infarction • History of DVT • Advanced age

Rosendaal FR. Lancet 1999; 353: 1167–1173.

Diagnosis of DVT

Back to Questions

Rosendaal FR. Lancet 1999; 353: 1167–1173.

Diagnosis of DVT

Patients with suspected DVT

Ultrasonography Ultrasonography Normal

Abnormal

Abnormal

Cli i l score Clinical

Clinical Score

Low

Intermediate

High

No DVT

Repeat Ultrasonography at 1 week

Venography

No DVT

DVT

No DVT

DVT

Adapted from Lensing AWA, Prandoni P, Prins MH, Butler HR, Lancet, 1999.

Low

Intermediate

High

Venography

DVT

DVT

No DVT

DVT

Adapted from Lensing AWA, Prandoni P, Prins MH, Butler HR, Lancet, 1999.

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Normal Doppler Ultrasound Abnormal Doppler Ultrasound

Diagnosis of PE

Diagnosis of PE

Ventilation/Perfusion Scan

CUS for DVT POSITIVE

Normal o a

PE Excluded

Abnormal b o a

High/Moderate Clinical Suspicion & High probability Lung Scan

TREAT

Other combinations

Negative Low Clinical Suspicion & High Probability Scan

Low Clinical Suspicion & Low Probability Scan

Other Combinations

Pulmonary Angiogram

PE EXCLUDED

Serial CUS

TREAT

Adapted from Kearon C. ASH. 1999

Normal V/Q Scan

Adapted from Kearon C. ASH. 1999

High probability V/Q Scan

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Key Elements of Natural History of VTE

DVT and PE: two expressions of the same disease

VTE usually starts as DVT including the calf When DVT causes symptoms, over 80% involves the p popliteal or more p proximal p veins Of patients with isolated calf (‘distal”) DVT, about 20% extend into proximal veins usually within one week of presentation

The PE PE– –DVT relationship 1–2% of patients with DVT die as a result of Frequent sources of PE PE. include: „ proximal leg DVT 75% of these deaths occur during initial hospital „ isolated calf vein admission: detection of thrombosis VTE at an earlier stage „ pelvic thrombosis would allow more deaths to be prevented. „ renal/inferior vena cava thrombosis. A recent study showed that 82% of patients with acute PE had detectable DVT at the same time PE was diagnosed.

From Kearon C, ASH, 1999

Girard P et al. Chest 1999; 116: 903–908. Hirsch J et al. Circulation 1996; 93: 2212–2245. Perrier A et al. Arch Int Med 1996; 156: 531–536. Pesavento R et al. Minerva Cardioangiol 1997; 45: 369–375.

Clinical Model for Determining Clinical Suspicion of DVT

Clinical Model for Determining Clinical Suspicion of DVT

If Present, Score Active cancer (treatment ongoing or within previous 6 months or palliative

1

Paralysis, paresis or recent plaster immobilization of lower extremities

1

Recently bedridden > 3 days or major surgery within 4 weeks

1

Locali ed tenderness along distrib Localized distribution tion of deep venous eno s system

1

Entire leg swollen

1

Calf swelling 3 cm > asymptomatic side (10 cm below tibial tuberosity)

1

Pitting edema confined to symptomatic leg

1

Dilated superficial veins (non varicose)

1

Alternative diagnosis as likely or greater than that of DVT

-2

TOTAL POINTS

Total Points

Prevalence of DVT

High

>3

85%

Moderate

1 or 2

33%

Low

<0

5%

Wells PS, Hirsch J, Anderson DR et.al., J Intern Med, 1998 Wells PS, Hirsch J, Anderson DR et.al., J Intern Med, 1998

Guidelines for Anticoagulation

Risk Assessment Model (6th ACCP Consensus, 2001) RISK LEVEL

Pre--test Pre Probability

DESCRIPTION

Calf vein Throm bosis

Proximal vein throm bosis

Clinical PE

Unfractionated Heparin

Fatal PE

Suspected VTE

Low

Uncomplicated minor surgery in patients <40 yr with no clinical risk factors

2

0.4

0.2

0.002

Moderate

Any surgery in pts. 40 to 60 yr with no additional risk factors; major surgery in i pts t < 40 yr with ith no addl ddl risk factors; minor surgery in pts with risk factors

10 to 20

2 to 4

1 to 2

0.1 to 0.4

High

Major surgery in pt > 69 yr w/o addl risk factors or 40 to 60 yr with addl risk factors; pts with MI; medical pts with risk factor

20 to 40

2 to 4

1 to 2

0.1 to 0.4

Highest

Major surgery in pts > 40 yr with previous VTE, malignant disease or hypercoagulable state; pt with elective major LE orthopedic surgery, hip fracture, stroke, multiple trauma or SCI

40 to 80

10 to 20

4 to 10

1 to 5

„ „ „ „

Obtain baseline APTT, PT, CBC Check for contraindication for heparin Rx Give heparin 5000 U IV Order imaging study

Confirmed VTE „

„

„ „

„

Rebolus with heparin 80 U/kg IV, start maintenance infusion at 18 U/kg/h Check APTT at 6 hour, to maintain a range corresponding to a therapeutic level Check platelet count daily Start warfarin therapy on day 1 at 5 mg, adjust subsequent daily dose accdg to INR Stop heparin after 4 to 5 days of combined therapy, when INR is > 2.0 (range 22-3)

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Guidelines for Anticoagulation Low Molecular Weight Heparin Suspected VTE „ „ „ „

Obtain baseline APTT, PT, CBC Check for contraindication for heparin Rx Give heparin 5000 U IV Order imaging study

6th ACCP Consensus, Chest, 2001

Guidelines for Anticoagulation Low Molecular Weight Heparin Confirmed VTE „ Give LMWH Enoxaparin 1 mg/kg SC q 12 h Dalteparin 200 antianti-Xa U/kg once daily Nadroparin 90 antianti-Xa U/kg twice daily Reviparin 90 antianti-Xa U/kg twice daily Tinzaparin 175 antianti-Xa U/kg once daily „ Start warfarin therapy on day 1 at 5 mg, adjust subsequent daily dose accdg to INR „ Check platelet count on days 3 & 5. „ Stop LMWH after at least 4 to 5 days of combined therapy, when INR is > 2.0 for two consecutive days 6th ACCP Consensus, Chest, 2001 Lensing AWA, Prandoni P, Prins MH, Butler HR, Lancet, 1999.

Treatment of VTE

Vena cava filter Surgical interruption Thrombectomy Fibrinolytic therapy

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