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Recombinant activated

factor VII (rF VIIa)

 is a novel hemostatic agent


 originally developed for the treatment of hemorrhage in
hemophiliacs with inhibitors
 successfully used recently in an increasing number of
nonhemophilic bleeding conditions.
Theresia C. S (Butet), dr.
What is DIC?

 “acquired bleeding disorder”


 not a disease entity but accompany various disease processes
 alteration in the blood clotting mechanism:
 abnormal acceleration of the coagulation cascade, resulting in
thrombosis
 result of the depletion of clotting factors, hemorrhage occurs
simultaneously

 a Paradoxical Clinical Presentation “clotting and hemorrhage”


Porth, C.M. (2004) Essentials of Pathophysiology) & (Otto, S.
(2001). Oncology Nursing)
Hemostatic Mechanism
 Processes :
 Primary hemostasis :
 platelet adhesion (mediated by platelet glycop, VWB,
collagen)
 activation, and secretions (platelet adhesive molecules)
  net results : aggregation of platelet

 Secondary hemostasis : cross linked fibrin meshwork

 Fibrinolysis
Pathogenesis of DIC

Bachelor of Chinese Medicine


Pathophysiology

In DIC, a systemic activation of the coagulation system 


 thrombus formation (compromising blood supply to various
organs)
 exhaustion of platelets and coagulation factors (results in
hemorrhage)

This is a disruption of body homeostasis through the


extrinsic and intrinsic pathways

(Porth, 2001)
Pathophysiology
Thrombosis-hypercoagulability Fibrinolysis-hypocoagulability
(the hemorrhagic phase)
1) Coagulation cascade is
initiated, causing 1) Activates the complement
widespread fibrin formation system
2) Microthrombi deposited 2) By products of fibrinolysis
throughout the (fibrin/fibrin degradation
microcirculatory products(FDP)) further
enhance bleeding by
3) Fibrin deposits result in
interfering with platelet
tissue ischemia, hypoxia,
aggregation, fibrin
necrosis
polymerization, & thrombin
4) Multi organ dysfunction activity
3) Leads to Hemorrhage
(Porth, 2004) & (Otto, 2001)
Mechanism

Levi, Marcel MD and Cate, Hugo MD. NEJM “Disseminated


Intravascular Coagulation” Aug 19, 1999. Vol 341:586-592.
Coagulation cascade
Intrinsic system (surface contact) Extrinsic system (tissue damage)

XII XIIa Tissue factor

XI XIa

IX IXa VIIa VII

VIII VIIIa

X Xa
V Va

II IIa (Thrombin)
Fibrinogen Fibrin

Vitamin K dependant factors


Hemostatic Balance

PAI-1 Prot. S
Prot. C
Antiplasmin
Tissue factor* TFPI
Fibrinolytic
Clotting Factors System
ATIII

Procoagulant Anticoagulant
Diagnosis of DIC

 Presence of disease associated with DIC

 Appropriate clinical setting


 Clinical evidence of thrombosis, hemorrhage or both.

 Laboratory studies
 no single test is accurate
 serial test are more helpful than single test
Conditions Associated With DIC

 Malignancy  Pulmonary
 Leukemia  ARDS/RDS
 Metastatic disease  Pulmonary embolism
 Cardiovascular  Severe acidosis
 Post cardiac arrest  Severe anoxia
 Acute MI  Collagen vascular disease
 Prosthetic devices  Anaphylaxis
 Hypothermia/Hyperthermia
Conditions Associated With DIC

 Infectious/Septicemia  Tissue Injury


 Bacterial  trauma
 Gm - / Gm +  extensive surgery
 Viral  tissue necrosis
 CMV  head trauma
 Varicella  Obstetric
 Hepatitis
 Amniotic fluid emboli
 Fungal  Placental abruption
 Intravascular hemolysis  Eclampsia
 Acute Liver Disease  Missed abortion
Inflammation and DIC
 Sepsis is usually underlying process for development
 Endotoxins associated with sepsis activate factors and
initiate coagulation.
 Sepsis  soluble TF in plasma (malignant tumor  TF
endothelial)
 Bacteria, virus also trigger the clotting cascade.
 Sepsis activates complement cascade.

http://tutorial on inflammation
P.Bowne, Alverno College
Incidence

 Varies depending on underlying cause


 Gram negative or gram positive sepsis: 30-50% develop
clinically overt DIC
 Severe trauma + SIRS: 50-70%
 Metastatic tumors, acute leukemia: ~15%
 Placental abruption, amniotic fluid embolism: >50%
 Severe preeclampsia: 7%
 Giant hemangioma: 25%
 Large aortic aneurysm: 0.5-1%

Levi, Marcel MD and Cate, Hugo MD. NEJM “Disseminated


Intravascular Coagulation” Aug 19, 1999. Vol 341:586-592.
Clinical Manifestation

 DIC  microvascular thrombosis  muliorgan


dysfunction
 Lungs  clinical pic similar to ARDS
 Advance  acute oligouric renal failure and
progressive hepatocellular injury
 Depletion of platelets and coagulation factors 
bleeding  particularly GIT
Clinical Manifestations of DIC
ORGAN ISCHEMIC HEMOR.
Ischemic Findings Skin Pur. Fulminans Petechiae
are earliest! Gangrene Echymosis
Acral cyanosis Oozing

CNS Delirium/Coma Intracranial bleeding


Infarcts

Renal Oliguria/Azotemia Hematuria


Cortical Necrosis
Myocardial Dysfxn
Cardiovascular

Pulmonary Dyspnea/Hypoxia Hemorrhagic


Infarct lung

GI Ulcers, Infarcts Massive hemorrhage.

Endocrine Adrenal infarcts Bleeding is the most


obvious
clinical finding
Diagnostic Work-up
 Clinical manifestations of bleeding, thrombosis and/or organ failure

Laboratory findings  Fibrin degradation products


PT  (D-dimer) 
aPTT   Fibrinogen* nl/
Platelets   Protein C 
 Antithrombin 
Initial level <100,000 or
rapid decline  Coagulation factors 

*An acute phase reactant, low sensitivity

Microangiopathic hemolytic anemia  schistocytes on SADT 


distinguishing DIC from other causes of coagulopathy
Frachini, Massimo. Thrombosis Journal “Recent acquisitions in
the pathophysiology, diagnosis and treatment of disseminated
intravascular coagulation” Feb 2006, 4:4.
DIC Score
Differential Diagnosis

 Severe liver failure


 Vitamin K deficiency
 Liver disease
 Thrombotic thrombocytopenic purpura
 Congenital abnormalities of fibrinogen
 HELLP syndrome
Treatment
 TREAT THE UNDERLYING DISEASE!!
 Replacement therapy
 Fresh frozen plasma **preferred
 Platelets, fibrinogen concentrates, cryoprecipitates
 Anticoagulants
 Heparin or LMWH– contradictory results
 Safety in patients prone to bleeding?
 Low dose 300-500U/hr
 Likely of benefit in patients with extensive thromboemboli and fibrin deposition
 Danaproid sodium, recombinant hirudin
 TFPI
 Blocks tissue factor activity in endotoxin-induced DIC
 Recombinant nematode anticoagulant protein c2 (NaPc2) – inhibits
complex between TF/VIIa and Xa

Frachini, Massimo. Thrombosis Journal “Recent acquisitions in the pathophysiology, diagnos


and treatment of disseminated intravascular coagulation” Feb 2006, 4:4.
Treatment (cont.)
 Restore anticoagulation pathway
 Antithrombin III
 Might be of benefit in sepsis with improvement of DIC and organ function
 Recombinant tissue plasminogen activator
 Activated protein C
 Also has anti-inflammatory and anti-apoptotic properties
 Only anti-coagulant shown to be efficacious in trials with sepsis-triggered DIC
 Given as 96 hr infusion
 Must use caution with thrombocytopenia  increased risk of intracerebral
hemorrhage

Frachini, Massimo. Thrombosis Journal “Recent acquisitions in the pathophysiology, diagnosis and treatment of
disseminated intravascular coagulation” Feb 2006, 4:4.
Davis-Jackson, Rachel. Thrombosis Journal “Antithrombin III and R-TPA used singly and in combination vs.
supportive care for treatment of endotoxin-induce DIC in the neonatal pig” May 18, 2006, 4:7.
Antifibrinolytic Therapy

 Rarely indicated in DIC


 Fibrinolysis is needed to clear thrombi from the micro
circulation.
 Use can lead to fatal disseminated thrombosis.
 May be indicated for life threatening bleeding
under the following conditions:
 bleeding has not responded to other therapies and:
 laboratory evidence of overwhelming fibrinolysis.
 evidence that the intravascular coagulation has ceased.
 Agents: tranexamic acid, EACA
Heparin

 Use is very controversial. Data is mixed.


 May be indicated in patients with clinical
evidence of fibrin deposition or significant
thrombosis.
 Generally contraindicated in patients with
significant bleeding and CNS insults.
 Dosing and route of administration varies.
 Requires normal levels of ATIII.
Mechanism of action of
recombinant activated factor VII

 The newer agent  control of disrupted coagulation mechanism


in DIC px (cancer, trauma, sepsis, liver failure), a bypassing
hemostatic agent

 2 mechanism :
 The first pathway is tissue factor (TF) dependent
 following a vessel injury  TF–activated factor VII complex
 activate factorX leading to  conversion of prothrombin
to thrombin.
 ‘thrombin burst’  formation of a stable fibrin clot that is
resistant to premature fibrinolysis  reliable and maintained
hemostasis
 The second pathway involves a TF-independent mechanism
 In fact, recent data suggest that rFVIIa can directly activate
factor X on phospholipid vesicles and on the surface of
activated platelets and monocytes [11–13]. This mechanism,
which is the most important mode of action of rFVIIa at
pharmacologic doses, optimizes thrombin generation
independently of the presence of TF.
The Use

 Firstly described : 33 y.o woman who presented with 31 weeks of


twin pregnancy and DIC, liver dysfunction, renal failure, and
severe intra-abdominal bleeding following SC despite intensive
transfusion and hysterectomy  rFVIIA reduction of bleeding
after 1-2 dosis.

 Single dose of rFVIIA (31,6ug/kg)  sufficient to control bleeding


 rFVII A (90-100ug/kg) patients with DIC  bleeding stopped
 Martinowitz and colleagues described a series of seven massively
bleeding coagulopathic trauma patients  conventional medical
and surgical hemostatic techniques failed. The administration of
one to three doses of rFVIIa (median dose 120mg/kg) resulted in
the cessation of diffuse bleeding with a significant decrease of
blood requirements

 Holcomb and colleagues [31] reported the successful use of rFVIIa


(single dose of 120mg/kg) to control diffuse intraperitoneal
bleeding in a patient with DIC related to sepsis.
 Chuansumrit and colleagues [34] described three children with
acute bleeding resulting from systemic coagulopathy associated
with liver failure (two girls with Denguehemorrhagic fever and
prolonged shock, and one boy with a left-lobe hepatectomy for a
hepatoblastoma). rFVIIa (a bolus dose of 40–180mg/kg followed
by 16.5–33mg/kg per h continuous infusion) was able to control
bleeding in all patients.
 Sallah and colleagues [38] reported the use of rFVIIa in 18
patients with hemorrhagic DIC associated with the presence of
underlying advanced or metastatic cancers (three prostate
cancer, three lung cancer, two breast cancer, two gastric cancer,
two pancreatic cancer, two soft tissue cancer, one colon cancer,
one renal cancer, one unknown, one acute leukemia).

 The dose of rFVIIa was 90 mg/kg and the median number of doses
administered was five (range, 3–10). Of the 18 patients, 15 (83.3%)
responded with cessation of bleeding and improvement in coagulation data.
No thromboembolic complications were observed following rFVIIa
administration
 In conclusion, it could be a paradox to use rFVIIa in a clinical
setting characterized by systemic activation of
coagulation.Comprehension of the molecular mechanisms of
action of rFVIIa and the clinical evidence from the literature,
however, suggest the potential role of this bypassing hemostatic
agent in the treatment of refractory bleeding associated with DIC.
THANK YOU

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