HEMOSTASIS 2

REVIEW- CLASSIC VS MODERN

ANTICOAGULANT THERAPY

Injectable- heparin and heparin derivatives

Unfractioned heparin

Low molecular weight heparins

Oral- antivitamin K inhibitors

Coumadins- most used= WARFARIN

HEPARIN AND HEPARAN SULFATE

Heparan sulfate- is a GAG

Similar structure to heparin

Endogenous heparin- secretory granules of

mast cells (probably being negatively charged-

retains histamine inside)

Function of heparan sulfate in coagulation-

anticoagulant- receptor for ATIII activation

thrombin inhibition

TYPES OF HEPARIN

Unfractioned- high molecular weight; injectable

iv, hospitalised patient usually, APTT monitoring

needed (administred using a heparin pump)

Low molecular weight heparin- subcutaneously,

home therapy, no APTT monitoring, less

bleeding as side effect

UNFRACTIONED HEPARIN AS A DRUG

Needs ATIII as a cofactor

Inhibits Xa and thrombin

Clinical uses

Venous thrombosis disorders

Pulmonary embolism

Prophylaxis and treatment- thrombosis in major surgeries

Extracorporeal circulation

Blood samples drowned for lab purpuses- AC

Blood transfusions- in vitro AC

LOW MOLECULAR WEIGHT HEPARIN USE

No APTT monitoring needed

Lower molecular weight

May be administrated subcutaneously- may be

used for unhospitalized patients (once/twice a

day)

Less bleeding

Tend to replace heparin in venous thrombosis,

pulm embolism, acute coronary syndomes

ORAL ANTICOAGULANT THERAPY

Vitamin K competitors- coumadin (Warfarin)

Warfarin inhibits the vitamin K-dependent

synthesis of biologically active forms of the

calcium-dependent clotting factors II, VII, IX and

X, as well as the regulatory factors protein C,

protein S.

VITAMIN K DEPENDENT FACTORS

In the liver- vitamin K helps the carboxylation of glutamic acid residues on immature coag factors; in this process it gets oxidized

Antivitamin K drugs inhibit reductase by inhibition, vitamin K stays in an inactive form

ANTI VITAMIN K

Anticoagulant effect starts in 24-36 h from

initiation – stops in 36-72 h after it is stopped

Oral treatment

At first- injectable treatment overlaps the oral

one

ANTIVITAMIN K CLINICAL USES

Venous thrombosis

Stroke

Thrombembolism

Cardiac valve replacement

Post myocardial infarction

MONITORING HEMOSTASIS

Primary

Bleeding time

Rumpel Leede

PLT count

Secondary

Clotting time

Howell Gram time

APTT

PT (Quick time)

HOWELL GRAM INTRINSIC AND COMMON

test explores the intrinsic and common pathways; for this we add CaCl2 to citrate plasma and start monitoring the time needed to clot.

Normal values= 60 -120s

High:

TR disfunction / thrombocytopenia

intrinsic pathway factor deficit (XII,XI,IX,VIII- hemophilia)

common pathway deficit- X, V, II, I (hypofibrinogenemia/ afibrinogenemia)

-anti- clotting therapy- heparin

APTT ACTIVATED PARTIAL THROMBOPLASTIN

TIME INTRINSIC AND COMMON PATHWAYS

To citrate plasma (with low amount of platelets- centrifuge for 15 min- 5000 rpm) we add Ca Cl2, kaolin, cephalin and start monitoring the time needed to clot.

Cephalin is a partial tromboplastin (only phospholipid)

Kaolin or silica is a negatively charged molecule activates factor XII

Normal values = 30- 40 s

Causes of abnormal high values- the same as Howell- except for the platelet- derived causes

It is affected by unfractioned heparin- used to monitor therapy

APTT

APTT INTERPRETATION- PROLONGATION

Deficiencies of XII,XI,IX,VIII (but in mild def is normal- the def factor needs to be <20-40% for aPTT to be low)

Antibodies against fVIII (aquired hemofilia) or lupus anticoagulant present

Liver disease

Unfractioned heparin use

PROTHROMBIN TIME (QUICK METHOD-PT/QT)

EXTRINSIC AND COMMON

To citrate plasma (with high amount of

platelets) we add Ca Cl2, thromboplastin and

start monitoring the time needed to clot.

Elevated in

Deficit of I, II, V, VII, X factors

Liver failure

K vitamin deficiency/ anti vit K anticoag therapy

Normal values = 12-15 s

PROTHROMBIN TIME

Used to monitor therapy with oral anticoagulant drugs- vitamin K blocking agents- coumarins (warfarin)!!!

By INR fraction which should be measured constantly in these patients

The therapy is used in patients with high thrombotic risk

INR

International normalized ratio

ISI- depends on the tissue factor, it is established

by the manufacturer (usually between 1- 2)

Normal range for a healthy person= 0.9- 1.3

Warfarin therapy monitoring- depends on

pathology

FIBRINOLYSIS

As the clots forms, it incorporates plasmin molecules.

Plasmin is an enzyme formed from plasminogen by tissue plasminogen activator (t-PA) and urokinase type plasminogen activator (u-PA)

Plasmin breaks down fibrin polymers into fibrin fragments = fibrinolysis

Fibrinolysis helps removing the clot as the repair processes occur.

FIBRINOLYSIS

Damage to the tissues releases TPA, which together with activated components from the coagulation pathways and protein C, activates plasminogen to plasmin.

Plasmin acts on the insoluble fibrin to form a series of soluble products: FDPs.

Fibrin that has been stabilized (crosslinked) by factor XIII gives rise to crosslinked FDPs (XDPs), as well as X Y D and E fragments.

The XDPs (D-dimer, D-dimer-E fragments), and oligomers of fragments X and Y, can be detected using antibody coated latex beads.

PLASMINOGEN

Zymogen plasmin

GP

Syntesized in liver

Lyses fbrin into fibrin degradation products (FDP) and D- dimer

PHYSIOLOGICAL ACTIVATORS OF PLASMIN

tPA- released from entoth cells responsable

for intravascular fibrinolysis- mainly activates

plasminogen bound to fibrin

uPA- high conc in urine responsible for

extravascular fibrinolysis

PHYSIOLOGICAL INHIBITORS OF PLASMIN

PAI-1 is the physiological plasminogen

activatior inhibitor 1- (tPA)- from platelets

Alpha 2 antitripsin- inhibits plasmin directly

FIBRINOLYTIC THERAPY= THROMBOLYTIC

Used to dissolve blood clots- act by

plasminogen activation

3 major classes:

tPA used in miocardial infarction therapy

uPA

sPA (streptokinase activator)

CLINICAL CASE 1

23 year old male.

Over the past week noted increasing fatigue,

sore throat, earaches, headaches, and episodic

fever and chills. Unable to run his customary 25

miles per week.

Erythematous throat and tonsils.

Swollen cervical lymph nodes.

DIAGNOSIS INFECTIOUS MONONUCLEOSIS

“kissing disease”

Viral- Ebstein Barr virus

90% asymptomatic

Pharyngitis, fatigue, malaise, fever

CASE STUDY 2

70 year old female.

Symptoms of dyspnea on exertion, easy

fatigability for past 2 to 3 months.

Physical exam- palor

DIAGNOSIS- IRON DEFICIENCY ANEMIA

CASE STUDY 3

25 year old male.

Recurrent upper respiratory infections with

fever, nausea, and submandibular swelling for

several months prior to admission.

Noted that cuts on his hands did not heal well.

Physical Exam

Submandibular adenopathy.

No other organomegaly.

DIAGNOSIS ACUTE MYELOBLASTIC LEUKEMIA

CASE STUDY 4

40 year old female.

Brought to Emergency Room with symptoms of severe frontal headache and associated confusion. Noted to have decreased energy level and a 15 pound weight loss over the previous three months.

Physical Exam

Pale appearing, but otherwise within normal limits. No organomegaly.

CASE STUDY 5

11 year old male.

Presented in emergency room with recent

onset of easy bruising, bleeding gums

Previously in excellent health. Mother stated he

was "never sick before in his entire life."

No history of recent viral infection, and no

family history of bleeding disorders.

HEMOSTASIS:

Bleeding time= 10 min

INR 0.91 (RI 0.85-1.15)

Howel Gram 2 min

PTT 24.8 sec (RI 23-34)

TT 15.8 sec (RI 13-18)

IMMUNE THROMBOCYTOPENIC PURPURA

CASE STUDY 6

History

54 year old female.

One year history of fatigue, weight loss, and

increasingly severe back pain.

Physical Exam

She appeared pale, but otherwise her physical

exam was within normal limits.

PROTEIN ELECTROPHORESIS

Total protein 11.0 g/dL (RI 5.2-8.3)

Serum protein electrophoresis:

Albumin 3.2 g/dL (RI 3.0-5.0)

Globulins:

Alpha1 0.4 (RI 0.1-0.5)

Alpha2 1.0 (RI 0.5-1.2)

Beta 0.8 (RI 0.5-1.1)

Gamma 5.6 (RI 0.6-1.7)

Immunoglobulins, quantitative:

IgA 9 mg/dL (RI 85-450)

IgG 5800 mg/dL (RI 800-1700)

IgM 25 mg/dL (RI 60-370)

Fibrinogen 650 mg/dl

ESR 70 mm/h

MULTIPLE MYELOMA

CASE STUDY 7

History

75 year old male.

Symptoms of severe headache and generalized pruritis.

Physical Exam

Spleen palpable 10 cm. below left costal margin. Liver palpable 3 cm. below right costal margin. The rest of the exam was within normal limits.

PULMONARY FUNCTION:

Oxygen saturation: 97% (RI 94-100)

POLYCYTHEMIA VERA

PRACTICE QUESTIONS

BLOOD

1. is a type of connective tissue

2. is involved in the process of homeothermy

3. bicarbonate buffer system is the most

important extracellular system

4. ADH helps at the reabsorption of Na+ in the

distal nephron

HEMATOCRIT

1. somatic hematocrit is higher than the venous

one

2. represents the % of formed elements in the

blood

3. blood viscosity is inversely proportional to the

hematocrit value

4. splenic venous blood has the highest value

PLASMA PROTEINS

1. albumin is the main contributor to oncotic

pressure

2. the normal concentration of albumin is 7 g/dl

of blood

3. ceruloplasmin is a copper carring protein

4. albumin is a positive acute phase protein

IMMUNOGLOBULINS

1. IgM is released during primary humoral

response

2. IgG may cross the placenta

3. IgA is important in local mucosal immunity

4. IgE trigger alergic reactions

ESR

1. 1. is directly proportional with blood viscosity

2. 2. low ESR can be encountered in anemia

3. 3. it’s measured after centrifuging the blood at

3000 RPM

4. 4. detects non-specific inflammation

RED BLOOD CELLS

1. 1 g of Hb can transport 1.34 mL of oxygen

2. MCV =120fL showes that there are

macrocytes present in the blood

3. 70% of the iron in the organism is found in

hemoglobin

4. when pCO2 is low, red blood cells release O2

more easely to the tissues

WHICH OF THE FOLLOWING ARE PART OF THE

SPECIFIC IMMUNE ANSWERS

1. first line of defense mechanisms

2. second line of defense

3. all three lines of defense

4. third line of defense

CHOOSE THE RIGHT MACROPHAGES FUNCTIONS

1. antigen presenting cells

2. initiation of humoral immune answer

3. initiation of celular immune answer

4. they are the first cells to respond to tissue

infection

ANTIBODIES WORK AS

1. opsonins

2. antitoxins

3. agglutinate bacteria

4. stimulate perforin- pores formation in

antigenic cell membrane

FORMS OF CO2 TRANSPORT IN THE BLOOD ARE

carbaminoHB

bound to albumin

bicarbonates

carboxyHB

CHOOSE THE RIGHT CONDITIONS WHICH SHIFT

THE OXYHB DISSOCIATION CURVE TO THE RIGHT

Hb has low affinity for oxigen

high 2,3 DPG

low pH

low temperature

WHAT WOULD BE THE ERYTHROCYTE INDICES

PROFILE FOR A PERSON WITH NORMOCHROMIC

MACROCYTIC ANEMIA

1. MCHC= 28 g/100 ml

2. MCHC= 35 g/100 ml

3. MCV= 80 fL

4. MCV= 120 fL