Aug 20, 2008
snake bite leadin to dic
Snake Bite Harim Mohsin 02-13
A 55year old male, Ghulam Mustafa came to the ER on 12.8.08.
HOPC : According to the patient he was alright before he was suddenly bitten while he was walking in Balochistan. The escaped snake was 1 ft long & black in color. The patient, went home & only bandaged the wound. In a few hours the pain got intense & the bleeding didn’t stop from the wound. There was difficulty in walking associated with the pain & he felt numbness in the left leg. He also had hemoptysis several times a day containing fresh red blood of about 1tb each time. There was no history of COPD. There are no associated features of hematomesis, melena, epistaxis or vomiting.
He received 1 st aid at a hospital in the periphery & was sent to Civil. His coagulation profile was deranged therefore he was sent to ziauddin after being given 16U of anti venom & 120ml of FFP.
Angiography & angioplasty: 5yrs ago. Personal hx: appetite-N, micturation-N bowels-constipation, sleep-disturbed.
Family hx: not significant.
Physical examination Patient was stable, lying comfortably on the bed, well conscious in time/place/person. Vitals: Bp-120/80, pulse-82 bpm, R/R: 21/min
General impression: swelling on left leg from the foot to the knee.
Examination CNS- sensory was bilaterally equal except on the lateral aspect of left foot, where it was slightly decreased. Tone, power & reflexes were bilaterally equal & normal. Abdomen- firm, non tender, no visceromegaly
Resp- Normal vesicular breating, no additional sounds
Investigations Potassium : 2.28 (2.7-4.5) Calcium : 8.17 (8.1-10.4)
Magnesium: 1.92 (1.58-2.55)
Investigations Bilirubin Total: 2.08 (<1.3) Bilirubin direct: 0.47 (<0.3)
Alk Phosphate: 62 (39-117)
DIC Disseminated intravascular coagulation
Snake venom Venom is produced and stored in paired glands below the eye & delivered through the fangs. Venom is mostly water. Enzymatic proteins in venom impart its destructive properties. Proteases, collagenase, and arginine ester hydrolase have been identified. Specific details are known for several enzymes as follows: (1) hyaluronidase allows rapid spread of venom through subcutaneous tissues by disrupting mucopolysaccharides; (2) phospholipase A2 plays a major role in hemolysis secondary to the esterolytic effect on red cell membranes and promotes muscle necrosis; and
(3) thrombogenic enzymes promote the formation of a weak fibrin clot, which, in turn, activates plasmin and results in a consumptive coagulopathy and its hemorrhagic consequences.
It is the widespread generation of fibrin within blood vessels caused by initiation of the coagulation pathway by activation or injury due to toxic substance of the monocytes & endothelial cells. There is consumption of platelets & coagulation factors, & secondary activation of fibrinolysis leading to production of fibrin degradation products (FDPs) which contribute to coagulation by inhibiting fibrin production.
DIC SYSTEMIC ACTIVATION OF COAGULATION Intravascular deposition of fibrin Depletion of platelets and coagulation factors Thrombosis of small and midsize vessels Bleeding Organ failure DEATH
Consequence is a mixture of initial thrombosis followed by a bleeding tendency due to consumption of coagulation factors & fibrinolytic activation.
The main role of the tissue factor pathway is to generate a "thrombin burst," a process by which thrombin , the single most important constituent of the coagulation cascade in terms of its feedback activation roles, is released instantaneously. FVIIa circulates in a higher amount than any other activated coagulation factor. Contact activation pathway There is formation of the primary complex on collagen by high-molecular-weight kininogen (HMWK), prekallikrein , and FXII (Hageman factor). Prekallikrein is converted to kallikrein and FXII becomes FXIIa. FXIIa converts FXI into FXIa. Factor XIa activates FIX, which with its co-factor FVIIIa form the tenase complex, which activates FX to FXa.
Thrombin has a large array of functions. Its primary role is the conversion of fibrinogen to fibrin, the building block of a hemostatic plug. In addition, it activates Factors VIII and V and their inhibitor protein C (in the presence of thrombomodulin ), and it activates Factor XIII, which forms covalent bonds that crosslink the fibrin polymers that form from activated monomers.
Three mechanisms keep the coagulation cascade in check. Abnormalities can lead to an increased tendency toward thrombosis: Protein C which degrades the co-factors FVa and FVIIIa Antithrombin i that degrades the serine proteases; thrombin and FXa, as well as FXIIa, and FIXa Tissue factor pathway inhibitor (TFPI) inhibits F VIIa-related activation of F IX and F X
The main enzyme responsible for this process ( plasmin ) is regulated by activators (TPA) and inhibitor (Antiplasmin) & forms the FDPs.
Hemostatic Balance ATIII Clotting Factors Tissue factor * PAI-1 Antiplasmin TFPI Prot. C Prot. S Procoagulant Anticoagulant Fibrinolytic System
Pathophysiology of DIC Activation of Blood Coagulation
Suppression of Anticoagulant Pathways
Pathophysiology of DIC Activation of Blood Coagulation Tissue factor/factor VIIa mediated thrombin generation via the extrinsic pathway
complex activates factor IX and X
Pathophysiology of DIC Suppression of Anticoagulant Pathways reduced antithrombin III levels reduced activity of the protein C-protein S system Insufficient regulation of tissue factor activity by tissue factor pathway inhibitor (TFPI)
inhibits TF/FVIIa/Fxa complex activity
Pathophysiology of DIC
relatively suppressed at time of maximal activation of coagulation due to increased plasminogen activator inhibitor type 1
Pathophysiology of DIC - Cytokines IL-6, and IL-1 mediates coagulation activation in DIC IL-10 may modulate the activation of coagulation
mediates dysregulation of physiologic anticoagulant pathways and fibrinolysis
Causes of DIC Septicemia (gram –ve & meningococcal) Hemolytic transfusion reactions Obstetric causes (abruptio, amiotic fluid embolism) Other infections (eg. Malaria falciparum)
Collagen vascular disease
Clinical features Patient is acutely ill & may present with shock. Features vary from no bleeding to severe hemorrhage with widespred hemostatic failure. Bleeding from mouth, nose, venepuncture site Thrombotic events may occur, mostly involving brain, skin & kidney but may happen anywhere.
Any visceral organ infarct
Laboratory Tests Used in DIC Fibrin Degradation Products
Coagulation factor levels
Laboratory findings plat count <100,000 or rapidly declining Prolonged clotting times (PT, APTT) Presence of Fibrin degradation products or positive D-dimer Low levels of coagulation inhibitors Low levels of coagulation factors
Fibrinogen levels not useful diagnostically
Microscopic findings in DIC
Differential Diagnosis Thrombotic thrombocytopenic purpura
Congenital abnormalities of fibrinogen
Treatment of DIC Stop the triggering process . The only proven treatment! Plasma and platelet substitution therapy
Physiologic coagulation inhibitors
Plasma therapy Patient requiring invasive procedures Patient at high risk for bleeding complications Prophylactic therapy has no proven benefit. Fresh frozen plasma(FFP): provides clotting factors, fibrinogen, inhibitors, and platelets in balanced amounts.
Usual dose is 10-15 ml/kg
Platelet therapy Patient requiring invasive procedures Patient at high risk for bleeding complications
approximate dose 1 unit/10kg
Blood Replaced as needed to maintain adequate oxygen delivery. Blood loss due to bleeding
RBC destruction (hemolysis)
Coagulation Inhibitor Therapy
Tissue Factor Pathway Inhibitor (TFPI)
The major inhibitor of the coagulation cascade Levels are decreased in DIC. Anticoagulant and antiinflammatory properties Therapeutic goal is to achieve supranormal levels of ATIII (>125-150%). reduced DIC scores, DIC duration, and some improvement in organ function Clinical trials have shown laboratory evidence of attenuation of DIC and trends toward improved outcomes. Antithrombin III
A clear benefit has not been established in clinical trials .
Protein C Concentrates Inhibits Factor Va, VIIa and PAI-1 in conjunction with thrombomodulin. Protein C levels are low in DIC due to sepsis. Levels correlate with outcome.
Clinical trials show significantly decreased morbidity and mortality in DIC due to sepsis.
Tissue Factor Pathway Inhibitor Tissue factor is expressed on endothelial cells and macrophages TFPI complexes with TF, Factor VIIa,and Factor Xa to inhibit generation of thrombin from prothrombin TF inhibition may also have antiinflammatory effects
Clinical studies using recombinant TFPI are promising.
Heparin Use is very controversial. 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.
Antifibrinolytic Therapy 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
Summary DIC is a syndrome characterized systemic intravascular coagulation. Coagulation is the initial event and the extent of intravascular thrombosis has the greatest impact on morbidity and mortality. Important link between inflammation and coagulation. Morbidity and mortality remain high.
The only proven treatment is reversal or control of the underlying cause.