napproaxh to neonatal thrombosis ramya.pptx

Neonatal thrombosis and approach

1. APPROACH TO THROMBOEMBOLISM IN NEWBORN Dr. K SAI RAMYA, PARAMITHA CHILDRENS HOSPITAL.

2. OVERVIEW Introduction and Epidemiology Coagulation cascade and fibrinolytic system Neonatal Haemostatic system Thrombosis types and risk factors Clinical presentations Diagnosis Management

3. INTRODUCTION Neonatal thrombosis ,rare but significant cause of neonatal morbidity and mortality. Incidence - 5.1 per 100,000 live births and 2.4–6.8 per 1000 neonatal intensive care admissions Term and preterm and male and female neonates are affected equally Thrombosis in the Neonatal Intensive Care Unit Matthew A. Saxonhouse , MDClin Perinatol 42 (2015) 651–673

4. U NIQUE IN NEWBORNS : Labile characteristics of the neonatal hemostatic system Exposure to multiple risk factors Wide use of vascular catheters Improved diagnostic and interventional therapeutic techniques Improved survival of young and critically ill newborns

5. EPIDEMIOLOGY Four registries have reported data (German, Canadian, Dutch, Italian) Thromboses occurred in both term and preterm infants Italian registry suggested a higher incidence in preterm . It reported a higher incidence among male neonates Other registries reported an equal incidence among males and females (except renal vein thrombosis)

6. Dutch registry reported 0.07 events per 10,000 children for venous thrombosis These registries also demonstrated that the majority of venous thromboses in neonates are associated with central venous catheters

7. COAGULATION CASCADE Thrombin is the primary procoagulant protein Plasmin is the primary fibrinolytic enzyme Antithrombin activity is potentiated by heparin

8. NEONATAL HEMOSTATIC SYSTEM In utero , coagulation proteins are synthesized by the fetus as early as 10wks gestational age and do not cross the placenta. Platelet number and life span is similar to adults .Bleeding time shorter—> rapid platelet adhesion and aggregation The newborn’s haemostatic parameters reaches adult values by 6 months of age Preterm have lower levels of vitamin k dependent factors compared to term,higher risk for bleeding or thrombosis. Hemostatic system in preterm and term newborns is balanced, under normal physiological conditions (little reserve capacity) Increased vulnerability to both hemorrhage and pathologic thrombosis

9. VIRCHOW’S TRIAD

10. Vitamin K-dependent factors (II, VII, IX, X) and contact factors (XII, XI, prekallikrein and HMW kininogen) are reduced to varying degrees Fibrinogen and factors V, VIII and XIII levels are similar to those of adults Von Willebrand factor level is almost twice that of adults Antithrombin is reduced by 50% , and proteins C and S, by 60% . Protein S circulates absolutely freely (active form) because newborn infants lack C4b, a binding protein of protein S Alpha-2-macroglobulin is high approximately twice the level of adults. Fibrinolytic activity is also altered, with plasminogen levels reduced by 50%

11. RISK FACTORS Indwelling catheters are responsible for more than 80% of venous and 90% of arterial thrombotic complications. A symptomatic thrombi are present in 30% of newborns with a UVC. Umbilical arterial catheterization (UAC) result ing in severe symptomatic vessel obstruction requiring intervention in approximately 1% of patients. Renal vein thrombosis is the most common type of non-catheter-related pathologic thrombosis in newborns.

12. RISK FACTORS

13. INHERITED THROMBOPHILIA CHARACTERISED BY- Positive family history Early age of onset Recurrent disease Unusual or multiple locations of thromboembolic events A genetic risk factor seen in 10% to 50% of children with thrombosis, the incidence - not well known

14. INHERITED THROMBOPHILIA I NCIDENCE IN PATIENTS – H eterozygous - small H omozygous for a single defect or double heterozygotes for different defects - present with significant thrombosis in neonatal period The classic presentation of homozygous prothrombotic disorders is purpura fulminans – A ssociated with homozygous protein C or S deficiency Presents within hours or days of birth With evidence of in utero cerebral damage.

15. Most common- factor V Leiden mutation

16. When to test for congenital thrombophilia? Significant thrombosis, Spontaneous thrombotic events, unanticipated or extensive venous thrombosis, Ischaemic skin lesions or purpura fulminans A positive family history of neonatal purpura fulminans.

17. NEONATAL PURPURA FULMINANS Characterized by dermal microvascular thrombosis, DIC, and perivascular hemorrhage Inherited Causes Homozygous deficiency of protein C or S or Antithrombin Acquired Causes Septicaemia causing consumption coagulopathy CLINICAL FEATURES : Rapid onset of cutaneous purpuric lesions shortly after birth and DIC Predilection for the limbs Eventually become necrotic and gangrenous, resulting in loss of extremities Thrombosis of the cerebral vasculature, vitreous hemorrhage, and retinal detachment Large vessel venous thromboses such as RVT

18. NEONATAL PURPURA FULMINANS DIAGNOSIS : Levels of protein C or protein S (<0.01 U/ml) Heterozygous state in the parents Identification of the molecular defect TREATMENT : Replacement therapy with protein C concentrate (60 IU/kg every 6 to 8 hrs ) or FFP for 6 to 8 weeks Indefinite coagulation for inherited cases Definitive cure is liver transplantation

19. ACQUIRED THROMBOPHILIAS Placental transfer of maternal antiphospholipid antibodies, including lupus anticoagulant and anticardiolipin antibodies, anti- β2- glycoprotein-I antibodies Placental thrombosis Significant thrombosis, including purpura fulminans and neonatal stroke Screening of mothers for neonates presenting with clinically significant thrombosis

20. VENOUS THROMBOEMBOLIC DISORDERS Usually occur secondary to central venous lines (CVLs). S pontaneous venous thrombi usually occur in the presence of another risk factor. Less than 1% — idiopathic.

21. VENOUS THROMBOSIS

22. VENOUS THROMBOEMBOLIC DISORDERS

23. CATHETER-ASSOCIATED VENOUS THROMBOSIS Signs and symptoms M ost common initial sign - difficulty infusing through or withdrawing from the line. Swelling of the extremities, head and neck, or distended superficial veins New onset thrombocytopenia Catheter stay of > 6 days, blood products to UVC infusates , and malpositioned UVCs higher thrombosis risk Diagnosis : Ultrasound with Doppler - diagnostic Contrast studies (radiographic line study or venography) Most frequent cause of thrombosis incidence of 9.2%.

24. Prevention Always run fluid continuously in central lines to maintain patency. Unfractionated heparin (UFH) 0.5 unit/mL infusion Reduces the risk of catheter occlusion but does not reduce rates of thrombosis or catheter-related sepsis. Removed within 10 to 14 days UVCs and peripherally inserted central catheters (PICCs) -intermittently flushed or infused with low-dose heparin to maintain patency. Continuous heparin infusion Short term complications Loss of access, pulmonary embolism, superior vena cava syndrome, and specific organ impairment Long Term Complications Leg edema, Abdominal pain, Lower extremity thrombophlebitis, Varicose veins, and leg ulcers Chylothorax, Portal hypertension, embolism

25. MANAGEMENT Nonfunctioning CVL Removal of catheter unless CVL is critical. Local thrombolytic followed by prophylactic LMWH Local obstruction Local thrombolytic Removal of catheter and heparin therapy Extensive venous thrombosis Start anticoagulation UVC left in place for 3 to 5 days Systemic thrombolytic therapy for extensive non catheter related organ, limb,life threatening venous thrombosis.

26. RENAL VEIN THROMBOSIS Accounts for 10% of venous thrombosis in newborns. Most common form of thrombosis not associated with vascular catheter . Incidence 0.5 per 1000 NICU admission M ost often presents in the first week of life . U sually term , large for gestational age . 70% unilateral, 64% involving left kidney Around 43 to 67% neonates with RVT had at least one or more prothrombotic risk factors. Risk factors: Infants of diabetic mothers Males> females Perinatal asphyxia Hypotension Polycythemia Increased blood viscosity Cyanotic congenital heart disease Sepsis Shock dehydration

27. RENAL VEIN THROMBOSIS SYMPTOMS : F lank mass, hematuria, proteinuria, thrombocytopenia, and renal dysfunction

28. RENAL VEIN THROMBOSIS D IAGNOSIS - ultrasound with Doppler . Coagulation studies - prolonged F ibrin degradation products are usually increased. COMPLICATIONS – Hypertension Renal failure Adrenal hemorrhage Extension of the thrombus into the IVC Death

29. MANAGEMENT OF RVT

30. PORTAL VEIN THROMBOSIS RISK FACTORS : Sepsis/ omphalitis UVC use Others: exchange transfusion. Most cases are asymptomatic and regress spontaneously. Majority of PVT in neonates are asymptomatic. Reported rates of PVT in studies using routine USG surveillance range from 0 to 49 %,spontaneous resolution at 1 year > 95%. DIAGNOSIS : USG with Doppler— “ reversal of portal flow”— indication of severity

31. MANAGEMENT OF PORTAL VEIN THROMBOSIS COMPLICATIONS Liver necrosis Cerebral infarct resulting from paradoxical emboli Hepatic hematoma - malpositioned UVC hepatic lobar atrophy portal hypertension. Spontaneous resolution in 30% to 70% MANAGEMENT : Removal of UVC

32. CEREBRAL SINOVENOUS THROMBOSIS I mportant cause of neonatal cerebral infarction . A ssociated with epilepsy, cerebral palsy, and cognitive impairment in 10% to 80% of cases. M ortality rates range between 2% and 24%. S uperior sagittal sinus, transverse sinuses, and straight sinus are most commonly affected .

33. CEREBRAL SINOVENOUS THROMBOSIS C LINICAL FEATURES - seizures, lethargy, irritability, and poor feeding. The majority present within the first day to week of life. PRESENCE OF IVH OR THALAMIC HEMORRHAGE IN A TERM OR LATE PRETERM INFANT WARRANTS EVALUATION FOR CSVT. Hemorrhagic infarction - frequent complication noted in 50% to 60% of babies. DIAGNOSIS- (MRI) with venography is the imaging modality of choice.

34. MANAGEMENT OF CSVT

35. INTRACARDIAC THROMBOSIS (RIGHT ATRIAL AND SUPERIOR VENA CAVA) Characteristics Central venous catheter (almost all cases) Signs of right heart failure, persistent sepsis, new onset murmur, bradycardia, tachyarrhythmia or respiratory distress. Diagnosis Transthoracic echocardiogram Complications Pulmonary thromboembolism High endocarditis risk and persistent sepsis Pulmonary artery obstruction Ventricular dysfunction Acute hemodynamic compromise, and death

36. RIGHT ATRIAL THROMBOSIS W ith the use of CVC — lead to pulmonary embolism , also affect heart function. The catheter should be removed. Anticoagulation therapy (with LMWH) is recommended. If cardiac function is compromised, thrombolytic therapy is instituted.

37. ARTERIAL THROMBOSIS

38. Type of Thromboses (Vessels Potentially Involved) Presenting Signs/Symptom Imaging Modality PAIS (left middle cerebral artery, anterior cerebral artery, posterior cerebral artery) Seizures ,lethargy, hypotonia, apnea, feeding difficulties Diffusion-weighted MRI/magnetic resonance angiography Iatrogenic (abdominal aorta, radial artery, renal artery, mesenteric artery, popliteal artery) Line dysfunction ,extremity blanching or cyanosis , persistent thrombocytopenia, sepsis, other symptoms depending on location Doppler usg , echocardiography Spontaneous (iliac artery, left pulmonary artery, aortic arch, descending aorta) Symptoms depend on location ARTERIAL THROMBOSIS

39. PREVENTION OF IATROGENIC ARTERIAL THROMBOSIS High UAC positioning may have fewer complications . C ontinuous heparin infusion at 1 unit/mL may prolong catheter patency without reducing the risk for thrombosis. The longer a UAC remains in place, the higher the probability for thrombus formation (80% incidence if used for 21 days ), generally not kept for longer than 5-7 days. Peripheral arterial lines for >1.5kg neonates

40. Management Minor aortic thrombi with mild symptoms L arge but nonocclusive thrombi Large occlusive aortic thrombi or thrombi accompanied by signs of significant clinical compromise prompt removal of the UAC the arterial catheter should be removed and anticoagulation with UFH or LMWH considered. If the catheter is still present and paten t- local thrombolytic Therapy. If the catheter removed or is obstructed - systemic thrombolytic therapy Surgical thrombectomy is generally not indicated with the exception of life- or limb-threatening thrombosis

41. PERIPHERAL ARTERIAL THROMBOSIS: Rarely associated with significant thrombosis. Poor perfusion to distal extremity ,resolves with prompt removal of the arterial line. Common symptoms include decreased perfusion,decreased pulses,pallor . Embolic phenomena manifest as skin lesions or petechiae. Diagnosis by doppler studies.

42. POST THROMBOTIC SYNDROME Long term complication of neonatal thrombosis One month after the event and up to 10 years later Caused by imcompetent perforating valves. Results in blood flow directed from deep to peripheral veins Appears to be less common following neonatal thrombosis. Clinically relevant post thrombotic occurs in 1 % of neonates. Chronic edema in the limbs with skin discoloration, impaired wound healing, skin ulcers, reduced limb growth and, commonly, functional incapacity Portal hypertension

43. FETAL THROMBOTIC VASCULOPATHY Thrombosis of the fetal vessels and/or vessels of the fetal surface of the placenta Leads to vascular obliteration and hypoperfusion High incidence of hypoxic-ischemic brain injury and severe perinatal outcomes Diagnosis : Histological findings of the placenta Suspect in patients with fetal growth restriction and severe fetal hypoxia Macroscopic examination of placenta and cord in all neonates

44. FETAL THROMBOTIC VASCULOPATHY Predisposes to Renal and inferior vena cava thrombosis (occasionally found by ultrasound imaging) Multiple thrombosis and multiorgan failure Microscopic examination of placenta and ultrasound doppler of renal vein and IVC are considered in suspected cases

45. GENERAL MANAGEMENT OF THROMBOSIS Asymptomatic thrombosis Waitful watch Close monitoring of thrombus Start treatment if extension present Symptomatic thrombosis Start anticoagulation/thrombolytic

46. PRETREATMENT EVALUATION BASELINE TESTS: Activated partial thromboplastin time ( aPTT ) , Prothrombin time (PT) and international normalized ratio (INR) Plasma fibrinogen concentration Complete blood count, including platelet count Kidney function tests (blood urea nitrogen and creatinine) Liver transaminases (if treatment with a direct oral anticoagulant ) Cranial ultrasound  

47. Evaluation for thrombophilia Consider in significant or severe or unusual manifestation of thrombosis and in positive family history Subsequent specialized laboratory evaluation Homocysteine, lipoprotein(a), plasminogen, and fibrinogen Rarely done Heparin cofactor II, thrombomodulin, PAI 1, platelet aggregation, and tPA.

48. Evaluation for prothrombotic disorder: Laboratory Testing Collection Tube Antiphospholipid antibody panel, anticardiolipin , and lupus anticoagulanta (immunoglobulin G, immunoglobulin M) Citrated plasma Protein C activity Protein S activity Plasminogen level ( considering thrombolytictherapy ) Antithrombin (activity assay Citrated plasma Factor V Leiden Prothrombin G EDTA (Ethylenediaminetetraacetic acid)

49. SYSTEMIC ANTICOAGULATION Paul Monagle , Fiona Newall; Management of thrombosis in children and neonates: practical use of anticoagulants in children.  Hematology Am Soc Hematol Educ Program  2018; 2018 (1): 399–404. doi :  https://doi.org/10.1182/asheducation-2018.1.399

50. CONTRAINDICATIONS TO ANTICOAGULATION AND THROMBOLYTIC THERAPY Absolute contraindications Central nervous system surgery or ischemia within past 10 days Invasive procedures within past 3 days Seizures within past 48 hours Active bleeding Relative Contraindications Platelet count <50,000/ μ L or <100,000/ μ L in critically ill neonates, Fibrinogen level <100 mg/dL, INR >2 Severe coagulopathy Hypertension

51. Goal of antithrombotic treatment. Prevention of blood clots spreading and of development of embolism Restoration of blood flow in the affected organ Minimizing adverse long-term consequences

52. UNFRACTIONATED HEPARIN Require relatively higher doses in neonate Dedicated 24 hrs intravenous line Monitoring : APTT (1.5 to 2 times normal) Heparin activity level (anti–factor Xa) (0.3-0.7 IU/mL four hours after administration) Ineffective anticoagulation : Antithrombin concentrate Fresh frozen plasma Shorter half life Rapid dose adjustments Early discontinuation Low cost Advantages :

53. UNFRACTIONATED HEPARIN Dosing guidelines : Initial bolus of 75 -100 unit/kg IV Continuous infusion at 28 unit/kg/hour Monitoring done after 4 hours of initial and with every change in dosing Duration of therapy : upto 10 to 14 days Secondary effects : HIT , severe bleeding, osteopenia Reversal of anticoagulation : Termination of the UFH infusion Fast reversibility IV Protamine sulfate (conc of 10 mg/mL)

54. LOW MOLECULAR WEIGHT HEPARIN (LMWH) Advantages More predictable pharmacokinetics Decreased need for laboratory monitoring No need of iv access Subcutaneous twice daily (BID) dosing Reduced risk of HIT and bleeding Monitoring : Anti-factor Xa levels 0.4–0.6 IU/ml in prophylaxis and at 0.6–0.8 IU/ml in treatment Disadvantage: Longer half life.

55. LOW MOLECULAR WEIGHT HEPARIN (LMWH) Dosing guidelines : Starting dose of 1.7 mg/kg/12 h in term and 2 mg/kg/12 h in preterm neonates Prophylactic dose of 0.75 mg/kg/12 h Duration of anticoagulation : 6 weeks to 3 months Reversal of anticoagulation: Termination of subcutaneous injection Protamine sulfate (1mg per 1 00U of LMWH) May not completely reverse anticoagulant effects

56. Heparin induced Thrombocytopenia All forms of heparin therapy must be stopped. platelet transfusions avoided ,perpetuate the HIT process and increase risk of thromboemboli . Anticoagulants in acute HIT –DTI , argatroban , bivalirudin , and fondaparinux , and DOAs. Fondaparinux – no cross-reactivity with anti-PF4 antibodies, Easy to administer (one daily SC injection), no dosage adjustment or specific bioassay no effect on aPTT Gruel Y, De Maistre E, Pouplard C, Mullier F, Susen S, Roullet S, Blais N, Le Gal G, Vincentelli A, Lasne D, Lecompte T, Albaladejo P, Godier A; Members of the French Working Group on Perioperative Haemostasis Groupe d’intérêt en hémostase périopératoire GIHP. Diagnosis and management of heparin-induced thrombocytopenia. Anaesth Crit Care Pain Med. 2020 Apr;39(2):291-310. doi : 10.1016/j.accpm.2020.03.012. Epub 2020 Apr 13. PMID: 32299756.

57. THROMBOLYSIS Intravenously infused plasminogen activators Streptokinase, Urokinase, tissue plasminogen activator ( used in past, have high allergic tendency). Thrombolytic agents act by converting plasminogen to plasmin,which cleaves fibrinogen to fibrin and fibrin to fibrin degradation products. Neonates are associated with decreased plasminogen concentration. Supplementation with plasminogen by administration of fresh frozen plasma (FFP) may improve fibrinolytic activity. INDICATIONS : massive arterial/venous thrombosis with organ dysfunction compromised limb viability life-threatening thrombosis CONTRAINDICATIONS : Active bleeding .

58. Recombinant Tissue Type Plasminogen Activator (r TPA) Improved clot lysis in vitro and a lower risk of hypersensitivity Short half life Minimal antigenicity Direct activation of plasminogen Lack of inhibition by a2 antiplasmin Localisation of fibrinolytic activity Dosing regimen B aseline CBC, PT, PTT, and fibrinogen level prior to initiating therapy. also a baseline cranial ultrasound 0.1 to 0.6 mg/kg per hour given over 6 hours for arterial and extensive venous thrombosis An alternative regimen consists of 0.03 mg/kg per hour for 24 hours 0.01 to 0.05 mg/kg/ hr in local site directed thrombolytic therapy for 48 hrs for venous thrombosis. Dose adjusted based on the response

59. Fibrinogen concentration and platelets should be measured before and two hours after initiating therapy and if bleeding occurs FFP/cryoprecipitate and Platelets given accordingly Local therapy is generally limited to small or moderate-sized thrombosis Monitoring Imaging studies of clot every 4 to 24 h Cranial usg should be performed before iniation of treatment and then daily during thrombolytic therapy Once clot lysis is achieved,rTPA therapy should be discontinued. Coagulation values before initiation and then daily Treatment of bleeding Stopping the tPA infusion Administration of cryoprecipitate Administration of platelets if needed Surgical thrombectomy is considered in non responding and thrombolytic contraindicated neonates

60. TREATMENT OF BLEEDING DURING THROMBOLYTIC THERAPY L ocalized bleeding - apply pressure, administer topical thrombin, and provide supportive care. THERAPY NEED NOT BE STOPPED IF CONTROLLED. For severe bleeding, stop the infusion and administer cryoprecipitate (1 unit/5 kg). Life threatening bleeding—stop the infusion, give cryoprecipitate, and infuse aminocaproic acid ( Amicar )

61. TOPICAL NITROGLYCERIN Tropical nitroglycerin has been demonstrated to reverse peripheral and umbilical artery catheter induced ishemic injury. Potent vasodilator, works by intracellular bioconversion to nitric oxide, which relaxes smooth muscle directly, or indirectly by activation of intracellular enzyme guanyl cyclase. Well absorbed across intact skin. 4 mm /kg dose of 2 % nitroglycerin ointment used in the neonatal case reports is equivalent to 0.2 to 0.5 mcg/kg/min intravenous. Pharmacokinetics have not been studied in neonates Vasodilation may lead to hypotension .

62. WARFARIN IN NEWBORN - Challenges Acts by reducing functional activity of vitamin k dependent coagulation factors ( II,VII,IX,X) which are already reduced in newborns. Requires frequent monitoring. The alternative LMWH is invasive and may result in inadequate adherence to treatment. Monagle P, Newall F. Management of thrombosis in children and neonates: practical use of anticoagulants in children. Hematology Am Soc Hematol Educ Program. 2018 Nov 30;2018(1):399-404. doi : 10.1182/asheducation-2018.1.399. PMID: 30504338; PMCID: PMC6245972 .

63. Oral anticoagulants Vs LMWH Warfarin is associated with high risk of bleeding (physiological decrease of Vit K dependant factors) Requires frequent monitoring of INR Feeding of newborn affects warfarin Drug interactions Available in only tablet form

64. Surgery Surgical clot removal and vessel reconstruction - necessary in the rare event of life or limb threatening arterial thromboembolism and massive venous thrombosis Microsurgical techniques + thrombolytic regimens Mechanical disruption of thrombus using soft wires Balloon angioplasty + continuous site-directed thrombolytic infusion into the clot Decompressive fasciotomy Amputation

65. Outcome Mortality - 10 to 30 percent, depending upon condition of neonates with critical illness Portal vein thrombosis (PVT)  – Long-term complications uncommon ,include hepatic lobar atrophy and portal HTN diagnosed at a mean of 5.7 years after event ( 70% portal obstruction cases , history of UVC placement in neonatal period Catheter-associated thrombosis  – Most infants with asymptomatic catheter-associated thrombus do not develop long-term sequelae . For infants with occlusive DVT, potential risk of developing post-thrombotic syndrome (PTS).

66. TAKE HOME MESSAGE Most thrombosis in NICU are catheter related For prolonged systemic anticoagulation LMWH is drug of choice. Duration of systemic anticoagulation is 6 weeks to 3 months. Work up for thrombophilia is indicated in any newborn with non catheter related thrombosis and stroke. The use of rTPA and anticoagulation in neonates is based on limited evidence

67. REFERENCES Avery and MacDonalds neonatology- pathophysiology and management of the newborn Thrombosis in the Neonatal Intensive Care Unit Matthew A. Saxonhouse , MDClin Perinatol 42 (2015) 651–673 Paul Monagle , Fiona Newall; Management of thrombosis in children and neonates: practical use of anticoagulants in children.  Hematology Am Soc Hematol Educ Program  2018; 2018 (1): 399–404. doi :  https://doi.org/10.1182/asheducation-2018.1.399 Neonatal thrombosis, Alexander makatsariya Department of Obstetrics and Gynecology, I. M. Sechenov First Moscow State Medical University ( Sechenov University), Moscow, Russia       https://orcid.org/0000-0001-7415-4633 Antithrombotic therapy in neonates and children: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-based Clinical Practice Guidelines. Chest March 2022 Cloherty and starks manual of neonatal care- 2023

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