Thrombotic complications in pediatric patients

Thrombotic complications in pediatric patients

15בן •

עקב דלקת ריאות.5.96אושפז במחלקת ילדים ב-•

באשפוז התקבלה אנמנזה של מאורע פתאומי של הפרעה •, מלווה ברעד כשנתיים לפניכן. בדיבור

מאז המאורע התרשמו ההורים מירידה בתפקוד עם קשיים •והילד, שהיה עד אז תלמיד טוב, הפסיק ללמוד. בריכוז

עקב כאבי ראש פרונטלים, סחרחורות 9.96אשפוז שני ב-•ובחילות.

במשפחה: הורים, שני אחים ואחות ללא מחלות ידועות.•

אוטם באזור הגלובוס פלידוס MRI:ב-•

בבירור של קרישיות-יתר: •

Factor V Liedenהטרוזיגוטי ל-•

בדראן איבטיסם

חליל15

אמג'ד13

רוזין8

מג'ד3

לאחרונה:

עם קונטרקטורות שלילודבמחלקת תינוקות: • )בעיקר השמאלית( שורשי כפות ידיים, הידיים

צמודות לגוף.

מח: ממצאים בעד:USב-•

Rt. Periventricular infarction

במחלקת ילדים:

9ילד בן •

CNS עם מעורבות ALLרלפס של •

סימנים נוירולוגים•

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17ילדה בת •חצי שנה על גלולות למניעת הריון• סיגריות ליום3עישון •כחודשיים לפני האשפוז ביד שמאלית•אירוע פתאומי של חולשה-נימול ביד אושפזה עקב •

שמאלית והפרעה בדיבור,בטריטוריה של אוטם פרונטו-פריאטלי מימין: MRIב-•

middle cerebral arteryענף של ה-• Young stroke

16בן •

•Acute otitis media

•Mastoiditis

•Viral meningitis

•Inflammatory bowel disease

•Common variable immunodeficiency

•sigmoid sinus thrombosis :CT

Thrombotic events in children

• Age-related features

• Adults guidelines not optimal for children

• Presentation may be more extensive

• Over 50% of events: in upper venous system, secondary to central venous lines )CVLs(

• More unusual locations

• Essentially in all children: severe underlying disorders.

5. Different underlying pathology )for example, Congenital Heart Disease(

6. Patients with homozygous Protein S or Protein C deficiency present at birth with purpura fulminans, entity essentially unknown in adult population.

7. Hemostatic system of the young differs from the adult.

Incidence of thrombotic complications in children appear to be increasing:

• Unlike venous thromboembolism in adults, VTE in children is usually a complication of a primary illness or therapy.

• As survival rates for major childhood illnesses such as CHD and cancer improve, the incidence of VTE is increasing dramatically.

Risk factors:

Multiple in the majority of patients.

Age distribution:

Two age groups together account for approximately 70% of thrombosis:

Early infancy:

• Risk approximately 40 times greater than in any other age during childhood:

• Small vesell diameter, high hematocrit, immature hemostatic system with decrease reserve capacity to insults.

Around puberty, late teenage years:

• Hormonal changes

• Oral contraceptives

• Pregnancy

Venous thromboembolism

From the data in the literature:

• 4% idiopathic

• 12% only one risk factor

• 84% two or more risk factors

• Upper limb DVT more frequently associated with CVLs.

• Long term parenteral nutrition using CVL: high risk situation

• Gold standard for diagnosis: venography• CVL’s predispose to thrombosis by

introducing foreign surface, damaging the endothelium, disturbing blood flow, content of fluid infusions(

Central Venous lines )cont.(

• Leading cause of thromboembolic disease in children.

• Incidence underestimated, perhaps because of different diagnostic modalities.

• Symptoms: Catheter malfunction, requirement of local

thrombolytic therapy to restore patency, recurrent sepsis, multiple CVL replacements, development of superficial collaterals, swelling, pain.

Consecuences:

NOT TRIVIAL

• Can lead to repeat anesthesia for CVL replacement

• Lethal Pulmonary embolism

• Superior Vena Cava Syndrome

• Chylothorax

Long term problems:

• Postphlebitic syndrome• Recurrent thrombosis• Side effects of long-term anticoagulants

Canadian registry of 525 children:Death from untreated thrombosis: 2.9%Recurrent thromboembolic disease: 3.3%Postphlebitic syndrome: 12.8%Urgent need to develop safe strategies for

preventing CVL-related thrombosis

Right atrial thrombosis

• Children tend to be young

• CVL’s present in over 80% of cases

• Most common underlying disease: CHD

• Patients may be asymptomatic

• Diagnosis: on routine echocardiography or present with CVL malfunction, sepsis, CHF

Paradoxical emboli

VTE can also present as stroke with

paradoxical emboli )in children with right-to-left shunt(

Cerebral vein thrombosis

Largest group of affected children:• Newborns within 1st month of life

• Most common symptoms: headache, seizures, lethargy, intermittent hyper-excitability.

• Most common underlying disorders: Cardiac disease, thrombophilia

• Diagnostic test of choice: MRI / MRV

Thrombotic complications in ALL:

• Disease process itself

• L-Asparaginase

• Effect of other chemotherapeutic agents

Congenital / acquired Cardiac disease

Cardiac catheterizationrisk of at least 40% in small children if heparin is

not used.

Mechanical prosthetic valves• Considerable risk.• Require lifelong anticoagulation

Cardiomyopathies

ARTERIAL THROMBOEMBOLIC DISEASE

1. Kawasaki’s disease

2. Surgery

3. Arterial catheters

4. Takayasu’s arteritis

5. Arterial occlusion of transplanted organs

6. CNS arterial thromboembolic events

CNS arterial thromboembolic events

• CT-MRI have greatly facilitated diagnosis• Incidence of ischemic stroke: 0.063 – 1.2 per

10,000 children per year.• Thirty percent 1st month of life

• Predisposing disorders: sickle cell anemia CHF prematurity leukemia

Clinically:

• Infarcts in utero

• Newborns: lethargy, seizures, rarely focal neurological deficit appreciable.

• Older children: may present with hemiparesis, with or without seizures.

• TIA’s not unusual.

• MRI / MRA: diagnostic test of choice.

Kawasaki’s disease

• Fever• Lymphadenopathy• Conjunctivitis• Mucositis• Rash• Incidence of aneurysms and / or thrombosed

coronary arteries: 15-30%• Two percent die from rupture of coronary

arteries or AMI.

Surgery:• Procedures for CHD )Fontan operation(

Arterial catheters: • Placed for diagnostic, therapeutic and

monitoring purposes, most common cause in pediatric patients.

Arterial occlusion of transplanted organs:• Small children: hepatic, renal arteries.

Takayasu’s arteritis

• Rare chronic, idiopathic, inflammatory disease of large arteries, predominantly affecting asian females.

• Clinical presentation: limb or organ ischemia due to gradual stenosis of related arteries.

• Diagnosis: angiography. Aortic lesions in 2/3 )aortic arch, carotids, renal arteries primarily affected(.

Other predisposing risk factors:

Nephrotic syndrome• Incidence of thrombosis: 4-28%

Surgery / Trauma• In contrast to adults, surgical procedures

in children usually no significant risk, even in the presence of prothrombotic disorder.

• Following puberty, risk begins to increase.

• Pediatric patients with thromboembolic complications should be investigated for a congenital and/or acquired prothrombotic state, regardless of the presence of acquired risk factors.

• Family history – Investigation of parents

• All results should be compared to age-appropriate reference ranges.

Hypercoagulable states:

• Collection of clinical conditions that shift the balance between the pro and the anticoagulant forces in favor of coagulation.

• Virchow triad- Risk factors for thrombogenesis:• Vessel wall• Disturbances in blood flow• Changes in constituents of blood

Blood coagulation

Crucial role Tissue factor - factor VII

Major reaction Conversion ProthrombinThrombin

Thrombin * Procoagulant activity * Neutralized by Antithrombin * Induce anticoagulation

Thrombotic process

• Thrombi may form in any part of the cardiovascular system )veins, arteries, heart, microcirculation(

• Complications of thrombosis:

-effects of local obstruction of the vessel

-distant embolization

-consumption of hemostatic elements

)less often(.

Arterial thrombi: under conditions of high flow, composed mainly of platelets aggregation bound together by fibrin strands.

Venous thrombi: in areas of stasis. Composed of red cells with large amounts of interspersed fibrin and fewer platelets.

Pathogenesis of thrombosis

Breakdown in the balance between thrombogenic factors and protective mechanisms.

Thrombotic disorders

Patients clinically suspected can be divided in 2 categories:

• Inherited

• Acquired

Heterogeneous group of diseases with increased risk of thrombotic complications.

Suspicion of underlying thrombophilia:

• Unexplained thrombosis in younger than 40-45 years of age.

• Recurrent thromboembolic event.

• Thrombosis of visceral, cerebral or cutaneous vessel.

• Positive family history.

• Thrombosis in unusual sites.

Risk factors for thrombosis )1(

Acquired:SurgeryTraumaImmovilizationIncreasing ageMalignancy Nephrotic Syndrome

Risk factors for thrombosis )2(

• Antiphospholipid antibodies• Hyperhomocysteinemia• Previous thrombotic event• Pregnancy – Puerperium• Oral contraceptives• Drugs )L-Asparaginase(• Myeloproliferative disorders• Paroxysmal Nocturnal Hemoglobinuria• Hormonal replacement therapy

Inherited risk factors )1(

Common:• Factor V Leiden

• Prothrombin 20210

• Elevated levels of coagulation factors (II, VIII, IX, XI)

Inherited risk factors )2(

Rare:

Antithrombin

Protein S

Protein C

Inherited risk factors )3(

Very rare:

Dysfibrinogenemia

Homocystinuria

Inherited risk factors )3(

Other:

Plasminogen deficiency

Thrombomodulin mutations

Thrombophilia studies-2006 )1( Hematology )Coagulation( laboratory:

• Blood count + peripheral blood smear

• PT-PTT• Fibrinogen• Thrombin time• Lupus anticoagulant• APC-R• Antithrombin• Protein S• Protein C

• Factor IX• Factor VIII• Factor XI

Thrombophilia studies )2(Hematology )Molecular Biology( laboratory

• Factor V Leiden

• Prothrombin 20210

• MTHFR mutation

Thrombophilia studies (3)Immunology laboratory

• Anticardiolipine Ab IgM-IgG

• Anti β2 Glycoprotein 1 IgM-IgG

• Antinuclear Ab - Anti DNA

Thrombophilia studies )4(Biochemistry laboratory

• Homocysteine