thrombosis and bleeding - se Áok i. sz. belgyógyászati ... · thrombosis and bleeding,...

Thrombosis and bleeding, Semmelweis University, september, 2011

THROMBOSIS

AND

BLEEDING

Klara Gadó MD. PhD.

Senior Professor of Internal Medicine

Semmelweis University,

Budapest


• formation of a blood clot in a blood vessel

• Blood can not flow

• Organ supply is

not appropriate,

• Organ damage, necrosis

What is thrombosis?

Blood clot.

Coloured scanning electron micrograph (SEM)

The red blood cells (erythrocytes, red) are trapped in filaments of fibrin protein (grey).


• Clot forms when

• circulation to a particular part of the body is abnormally sluggish

• damage has been done to a blood vessel,

• there is an imbalance between clotting and bleeding factors.

bleeding thrombosis

Conditinons promoting clot formation


How common is DVT?

• every year about 1 in 5,000 people are diagnosed

with DVT.

• The risk is even greater among older people.

• affects approximately 200,000 Americans

per year

•

•Source:Fowkes FJI, Price JF, Fowkes FGR, et al.European Journal of Vascular and Endovascular Surgery. 2003; 25: 1-5.


What are the consequences of DVT?

• Leg ulcer

• is an extremely common problem affecting

about 1-2% of the general population in the UK.

• Postthrombotic syndrome


What are the consequences of DVT?

• if the clot breaks free and travels

through the veins where it can

reach the lungs,

obstructing the pulmonary artery

or its branches, which supply the

lungs with blood

• This is pulmonary embolism


Clinical assessment

of VTE(venous thromboembolism)


Symptoms of

deep vein thrombosis

in the lower leg

• swelling

• erythemia (redness)

• warmth in the area

caused by capillary

congestion.

• Pain

• stiff and shiny skin


Signs of deep vein thrombosis

in the lower leg

• Physical examination: Homans’ sign:

development of pain in the calf or popliteal region

on forceful dorsiflexion of the ankle

with the knee in flexed position.

• sensitivity 13 to 48%

• specificity from 39 to 84%


Examination of Homans’ sign

• How to perform?

• Flex knee slightly; Dorsiflex foot


But !

• In the 50 % of cases

people with DVT

do not get any symptoms!!!!!


Diagnosis of DVT

• ultrasound

Cross sectionLongitudinal section


Diagnostics

• DVT in the lower limb, color Doppler,


Pulmonary embolism

• about 30,000 people die each year in the United

States

• Often post-mortem diagnosis


Pulmonary embolism

• incidence of the disease:

50-150/100 000 inhabitant/year

• 10 % of cases leading to

immediate death

• mortality among survivors: 30 %

• with proper treatment this can be

lowered to 10 %

• Dg: spiral CT, echocardiography


Symptoms of pulmonary embolism

• sudden, severe CHEST PAIN

• DYSPNEA (difficulty BREATHING)

• diaphoresis (breaking into a cold sweat)

• HYPOTENSION (low BLOOD PRESSURE)

• TACHYCARDIA (rapid heart rate)

• TACHYPNEA (rapid BREATHING)

http://www.beltina.org/health-dictionary/chest-pain-causes-symptoms-information.html

http://www.beltina.org/health-dictionary/dyspnea-definition-grades-symptoms-treatment-causes.html

http://www.beltina.org/health-dictionary/hypotension-definition-symptoms-treatment-causes.html

http://www.beltina.org/health-dictionary/blood-pressure-high-low-normal-systolic-diastolic.html

http://www.beltina.org/health-dictionary/tachypnea-definition.html

http://www.beltina.org/health-dictionary/breathing.html


ECG signs of PE• The most common ECG finding is sinus tachycardia,

• the "S1Q3" pattern of acute cor pulmonale is classic (only occurs in about 10%) A large S wave in lead I, a Q wave in lead III,

• indicates acute right heart strain.


Pulmonary embolism

• COMPUTED TOMOGRAPHY (CT) SCAN,

• MAGNETIC RESONANCE IMAGING

(MRI),

• pulmonary angiography,

• ventilation/perfusion scan

• echocardiography.


CT image of pulmonary embolism


Ventillation/perfusion scan image of

pulmonary embolism• Lung scintigraphy is an

indirect imaging method which non-invasively visualizes the perfusion defect caused by an embolus

• the procedure is highly sensitive and easily detects even small embolisms on a subsegmental level.

• coupled with a ventilation scan specificity improves

• a typical mismatch defect caused by pulmonary embolism.


Laboratory findings

• D-dimer test

• Bedside test


D-dimer test

• D-dimers are specific cross-linked fibrin derivatives

product of plasmin-mediated fibrinolytic degradation.

marker of fibrinolytic activity.

• The D-dimer assay can be used as a “rule out” test


Non-pathological conditions associated

with elevated D-dimer titres include:

• Age (healthy elderly people)

• Cigarette smoking

• Functional impairment

• Post-operatively

• Pregnancy

• Race (e.g. African Americans)


Pathological conditions associated

with elevated D-dimer titres include• Acute coronary syndromes

• Acute upper gastrointestinal haemorrhage

• Aortic dissection

• Arterial or venous thromboembolism

• Atrial fibrillation

• Consumptive coagulopathy – DIC

• Infection

• Malignancy

• Pre-eclampsia

• Stroke

• Superficial thrombophlebitis

• Trauma


D-dimer & VTE

• The D-dimer test is a marker of blood

clotting activity and is not diagnostic of

VTE.

• When used appropriately the D-dimer test

helps “rule out” VTE if the test is negative

and the chance of the patient having a VTE

is relatively low.


Risk factors of thrombosis


Risk factors

• Thrombophilia

a group of abnormalities where there is a

tendency for the occurrence of thrombosis,

• may be classified as

inherited or

acquired


Aquired risk factors

• Persistant

• Advancing age

• Malignancy

• Antiphosphilipid antibodies

• Prior history of VTE/PE


Aquired risk factors

• Transient• Recent surgery

• Recent trauma

• Pregnancy, labour

• Prolonged immobilization(bedrest, travelling, leg fracture)

• Comorbities(heart failure, nephrotic syndrome)

• Drugs(oral contraceptives, chemotherapyhormon replacement therapy)


Inherited risk factors

• Antithrombin deficiency

• Protein C and S deficiency

• Factor V Leiden mutation

• Factor II G20201A gene mutation

POSSIBLE INDICATORS

OF THROMBOPHILIA

• Thrombosis at early age (under 50)

• Thrombosis at unusual sites

• Thrombosis recurrence

• Thrombosis developed by mild provoking

factor

• Habitual abortion, miscarriage, still-birth


MODERN TREATMENT

OF VTE


Post-surgical

TROMBOPROFILAXIS

• No thrombocyte aggregation inhibitor

1 week before surgery

• Changing vitamin K antagonist to LMWH

• Na-heparin 12 hours before operation

• EDA10-12 hours after LMWH

LMWH can be given 4 hours after intervention


IN CASE OF

RENAL INSUFFICIENCY

• need for decreasing heparine dose

• practical to give UFH


Monitoring of the treatment

• Vitamin K antagonist:

• Measuring INR

• Monitoring heparin therapy:

• Measuring aPTT

• Monitoring LMWH efficiency:

• anti-Xa activity

• Obes patients

• on pregnant women

• Renal impairment


THE SIDE-EFFECTS OF HEPARIN I.

• HEPARIN-INDUCED

THROMBOCYTOPENIA (HIT)

• OSTEOPOROSIS

• ALOPECIA


THE SIDE-EFFECTS OF HEPARIN

II.

•HIT

• 5 days after the beginning of the therapy

• thrombocytopenia + thrombosis

• Therapy:

• thrombocyte prohibited

give direct thrombin inhibitors (lepirudin)

• Monitoring the number of thrombocytes

during the therapy


•self-injection

•neat therapy skilling of patients

LMWH


Coumarin (warfarin, Syncumar)

• Some aspects:•narrow therapy range

•Strong plasma protein binding

• Appropriate dose• Starting with a small dose• Starting: always overlapping with heparin• Frequent control measuring INR• Education (diet, medicines)


•In the beginning of the therapy

•More frequent with Protein C absence

•Histology:

fibrinoid thrombus in small veins

•Profilaxis:

low starting dose, heparin protection

COUMARIN NECROSIS


Bleeding disorders


Classification of bleeding disorders

• Congenital

• Coagulation factor deficiency

• Aquired

• Consumption– DIC

• Abnormal synthesis of coagulation factors– Liver diseases

• Iatrogenic

• Overdosing anticoagulants

• Antibodies against coagulation factors

• toxic


Congenital Bleeding disorders

Coagulation factor deficiency

• Hemophilia A (fVIII)

• Hemophilia B (fIX)

• Von Willebrand’s disease


Hemophilia A

• Incidence: 1:10.000

• Factor VIII is synthesized by the liver.

• It circulates in plasma in a form bound to a

transport protein known as

Von Willebrand factor (VWF).


Genetic aspects

• The gene for factor VIII is located

on the long arm of chromosome X.


„King’s disease”

Queen Victoria

The Tsarevich Alexis had suffered from hemophilia,


Clinical aspects

• Severe hemophilia A : in 30 to 40% of cases.

• The most common hemorrhagic episodes consist of:

• hemarthrosis: 70%, (joint deformity)

• subcutaneous or intramuscular hematomas: 10 to 20%,

• bleeding in the urinary tract, nasal and gastrointestinal

mucosa, and intra-abdominal organs: 10 to 20%.

• Gastrointestinal and central nervous system hemorrhagic

accidents are potentially life-threatening,


Screening for mutations

• Numerous mutations responsible for

hemophilia A have been described

• screening techniques to characterize patients,

carriers

make prenatal diagnosis

• 1/3 of patients de novo mutation

in a family hitherto unaffected by the disease.


Amniocentesis

• Usually performed 14-20 weeks

• Risk of fetal death estimated as 1:200


Laboratory findings

• Prolonged PTT

• Normal PT

• Normal bleeding time

• Normal platelet count


Factor levels

• Factor activity

– Mild 5-25%

– Moderate 2-5%

– Severe 1%

• PTT prolonged only if activity 25%

• Spontaneous bleeding: 5%


Treatment

• “replacement therapy” — giving or replacing the clotting factor that is too low or missing.

• Concentrates of the clotting factor are infused, or injected, directly into the bloodstream.

• The specific factors used to treat hemophilia are: Factor VIII for hemophilia A – Factor IX for hemophilia B

• The activity level for factor VIII needed to ensure clotting is around 30%.


Treatment

• Replacement therapy can be used:

– To prevent bleeding (prophylactic or preventive

therapy)

– To stop bleeding when it occurs, on an as-

needed basis (demand therapy)

• The type of treatment you receive depends

on several things, including whether you

have mild, moderate or severe hemophilia.


• Subcutaneous hematoma

Epidural hematoma

gingival bleeding


• Joint deformity


Inhibitors• Antibodies develop against clotting factors

• Examining the presence of inhibitors

– Mixing studies

– Patient : normal plasma mix: 1:1

– If:

– aPTT has normalized means: factor deficiency

– aPTI does not normalized means: inhibitor is present


HEMOPHILIA B• FIX deficiency, Christmas-disease

• More scarce, incidence 1:50000

• difference:

only with special laboratroy tests

• Coding gene on chromosome X,

near to gene of fVIII,

much smaller gene than gene fVIII

• Treatment:

• IXf concentrate

• Needed scarcer (IXf T1/2 longer)

• Dose calculation

• (wanted % - actual %) x bwkg = Unit


Therapy of the future: gene therapy

• Genes of clotting factors are taking into liver cells


Von Willebrand disease

• vWf is a large multimeric molecule

• Role:

– protecting fVIII

– Platelet binding to endothel


Classification

1. vWf protein

2. Inappropriate vWf function

3. No vWf : severe bleeding


Clinical signs

• Bleeding during surgery

• Postoperative re-bleeding


Diagnosis

• Platelet count may be decreased

• Abnormal bleeding time

• fVIII activity decreased

• Ristocetin-induced platelet aggregation decreased

• vWf ag

• vWf activity decreased

• Normal aPTT, PT

• Special tests


therapy

• Desmopressin (DDAVP),

• VIIIf concentrate

• cryoprecipitate

• antifibrinolytics

• platelet


Aquired

coagulopathies


Aquired coagulopathies

• More frequent

• Vitamin K dependent coagulation factor

deficiency

– Liver disease

– malabsorption

• Disseminated intravascular coagulation


Liver disease

• Vitamin K dependent coagulation factor deficiency

• AT III , vWf

• aPTT, PT

• Liver biopsy is dangerous

• Platelet count


THANK YOUFOR

YOUR ATTENTION

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