Snake BiteSnake Bite

Harim MohsinHarim Mohsin

02-1302-13

CaseCase

A 55year old male, Ghulam Mustafa A 55year old male, Ghulam Mustafa came to the ER on 12.8.08. came to the ER on 12.8.08.

Presenting complaints:Presenting complaints:►Snake bite-3 dys ago.Snake bite-3 dys ago.►Hemoptysis-3 dys. Hemoptysis-3 dys.

► HOPCHOPC: According to the patient he was alright : According to the patient he was alright before he was suddenly bitten while he was walking before he was suddenly bitten while he was walking in Balochistan. The escaped snake was 1 ft long & in Balochistan. The escaped snake was 1 ft long & black in color. The patient, went home & only black in color. The patient, went home & only bandaged the wound. In a few hours the pain got bandaged the wound. In a few hours the pain got intense & the bleeding didn’t stop from the wound. intense & the bleeding didn’t stop from the wound. There was difficulty in walking associated with the There was difficulty in walking associated with the pain & he felt numbness in the left leg. pain & he felt numbness in the left leg.

He also had hemoptysis several times a day He also had hemoptysis several times a day containing fresh red blood of about 1tb each time.containing fresh red blood of about 1tb each time.

There was no history of COPD. There are no There was no history of COPD. There are no associated features of hematomesis, melena, associated features of hematomesis, melena, epistaxis or vomiting. epistaxis or vomiting.

He received 1He received 1stst aid at a hospital in the periphery & aid at a hospital in the periphery & was sent to Civil. His coagulation profile was was sent to Civil. His coagulation profile was deranged therefore he was sent to ziauddin after deranged therefore he was sent to ziauddin after being given 16U of anti venom & 120ml of FFP. being given 16U of anti venom & 120ml of FFP.

►Past medical/surgical: Past medical/surgical:

Angiography & angioplasty: 5yrs ago. Angiography & angioplasty: 5yrs ago.

►Personal hx: appetite-N, micturation-NPersonal hx: appetite-N, micturation-N

bowels-constipation, sleep-disturbed. bowels-constipation, sleep-disturbed.

►Drug hx: none. Drug hx: none.

►Family hx: not significant. Family hx: not significant.

Physical examinationPhysical examination

►Patient was stable, lying comfortably Patient was stable, lying comfortably on the bed, well conscious in on the bed, well conscious in time/place/person. time/place/person.

►Vitals: Bp-120/80, pulse-82 bpm, R/R: Vitals: Bp-120/80, pulse-82 bpm, R/R: 21/min21/min

► GPE: JGPE: J† A† C˚ K˚ E† L˚† A† C˚ K˚ E† L˚

General impression: swelling on left leg General impression: swelling on left leg from the foot to the knee. from the foot to the knee.

ExaminationExamination►CNS- sensory was bilaterally equal CNS- sensory was bilaterally equal

except on the lateral aspect of left except on the lateral aspect of left foot, where it was slightly decreased. foot, where it was slightly decreased.

►Tone, power & reflexes were bilaterally Tone, power & reflexes were bilaterally equal & normal. equal & normal.

►Abdomen- firm, non tender, no Abdomen- firm, non tender, no visceromegalyvisceromegaly

►Cvs- s1 + s2, no murmursCvs- s1 + s2, no murmurs►Resp- Normal vesicular breating, no Resp- Normal vesicular breating, no

additional soundsadditional sounds

Investigations Investigations

Report at CIVILReport at CIVIL►Hb-7.1 Hb-7.1 ►Plt-30,000Plt-30,000► INR-5INR-5►PT/APTT- ProlongedPT/APTT- Prolonged►Creatinine- Raised.Creatinine- Raised.►Total bilirubin- NormalTotal bilirubin- Normal

InvestigationsInvestigationsCoagulation profile:Coagulation profile:► PT-48 (control 9-13)PT-48 (control 9-13)► INR-4.53 (2.0-4.5)INR-4.53 (2.0-4.5)► APTT-98 ( <7)APTT-98 ( <7)

Biochemistry:Biochemistry:► Urea: 22 (10-50)Urea: 22 (10-50)► Creatinine: 0.68Creatinine: 0.68► Albumin: 4.17 (3.8-4.4)Albumin: 4.17 (3.8-4.4)

Electrolytes:Electrolytes:► Potassium : 2.28 (2.7-4.5)Potassium : 2.28 (2.7-4.5)► Calcium : 8.17 (8.1-10.4)Calcium : 8.17 (8.1-10.4)► Magnesium: 1.92 (1.58-2.55)Magnesium: 1.92 (1.58-2.55)► Sodium: 141 (136-140)Sodium: 141 (136-140)► Chloride: 100 (98-104)Chloride: 100 (98-104)► Bicarbonate: 27 (22-29)Bicarbonate: 27 (22-29)

InvestigationsInvestigations

LFTs: LFTs: ►Bilirubin Total: 2.08 Bilirubin Total: 2.08 (<1.3)(<1.3)►Bilirubin direct: 0.47Bilirubin direct: 0.47 (<0.3) (<0.3)►SGPT: 21 (upto 31)SGPT: 21 (upto 31)►Alk Phosphate: 62 (39-117) Alk Phosphate: 62 (39-117)

Investigation Investigation

DICDIC

Disseminated intravascular Disseminated intravascular coagulationcoagulation

Snake venomSnake venom► Venom is produced and stored in paired glands below the eye Venom is produced and stored in paired glands below the eye

& delivered through the fangs. & delivered through the fangs. ► Venom is mostly water. Enzymatic proteins in venom impart Venom is mostly water. Enzymatic proteins in venom impart

its destructive properties. Proteases, collagenase, and its destructive properties. Proteases, collagenase, and arginine ester hydrolase have been identified. arginine ester hydrolase have been identified.

Specific details are known for several enzymes as follows: Specific details are known for several enzymes as follows: ► (1) hyaluronidase allows rapid spread of venom through (1) hyaluronidase allows rapid spread of venom through

subcutaneous tissues by disrupting mucopolysaccharides; subcutaneous tissues by disrupting mucopolysaccharides; ► (2) phospholipase A2 plays a major role in hemolysis (2) phospholipase A2 plays a major role in hemolysis

secondary to the esterolytic effect on red cell membranes and secondary to the esterolytic effect on red cell membranes and promotes muscle necrosis; and promotes muscle necrosis; and

► (3) thrombogenic enzymes promote the formation of a weak (3) thrombogenic enzymes promote the formation of a weak fibrin clot, which, in turn, activates plasmin and results in a fibrin clot, which, in turn, activates plasmin and results in a consumptive coagulopathy and its hemorrhagic consumptive coagulopathy and its hemorrhagic consequences. consequences.

► It is the widespread generation of fibrin It is the widespread generation of fibrin within blood vessels caused by initiation of within blood vessels caused by initiation of the coagulation pathway by activation or the coagulation pathway by activation or injury due to toxic substance of the injury due to toxic substance of the monocytes & endothelial cells. There is monocytes & endothelial cells. There is consumption of platelets & coagulation consumption of platelets & coagulation factors, & secondary activation of fibrinolysis factors, & secondary activation of fibrinolysis leading to production of fibrin degradation leading to production of fibrin degradation products (FDPs) which contribute to products (FDPs) which contribute to coagulation by inhibiting fibrin production. coagulation by inhibiting fibrin production.

DICDIC

DICDIC

► Consequence is a Consequence is a mixture of initial mixture of initial thrombosis followed thrombosis followed by a bleeding by a bleeding tendency due to tendency due to consumption of consumption of coagulation factors & coagulation factors & fibrinolytic fibrinolytic activation.activation.

SYSTEMIC ACTIVATION OF COAGULATION

Intravascular deposition

of fibrin

Depletion of platelets and coagulation

factors

Thrombosis of small and

midsize vesselsBleeding

Organ failure DEATHDEATH

Coagulation pathwayCoagulation pathway

Tissue factor pathwayTissue factor pathway► The main role of the tissue factor pathway is to generate a The main role of the tissue factor pathway is to generate a

"thrombin burst," a process by which "thrombin burst," a process by which thrombinthrombin, the single , the single most important constituent of the coagulation cascade in most important constituent of the coagulation cascade in terms of its feedback activation roles, is released terms of its feedback activation roles, is released instantaneously. FVIIa circulates in a higher amount than any instantaneously. FVIIa circulates in a higher amount than any other activated coagulation factor. other activated coagulation factor.

Contact activation pathwayContact activation pathway► There is formation of the primary complex on There is formation of the primary complex on collagencollagen by by

high-molecular-weight kininogen (HMWK), high-molecular-weight kininogen (HMWK), prekallikreinprekallikrein, and , and FXII (Hageman factor). Prekallikrein is converted to kallikrein FXII (Hageman factor). Prekallikrein is converted to kallikrein and FXII becomes FXIIa. FXIIa converts FXI into FXIa. Factor and FXII becomes FXIIa. FXIIa converts FXI into FXIa. Factor XIa activates FIX, which with its co-factor FVIIIa form the XIa activates FIX, which with its co-factor FVIIIa form the tenase complex, which activates FX to FXa. tenase complex, which activates FX to FXa.

Final common pathwayFinal common pathway► ThrombinThrombin has a large array of functions. Its primary role is the has a large array of functions. Its primary role is the

conversion of conversion of fibrinogenfibrinogen to fibrin, the building block of a to fibrin, the building block of a hemostatic plug. In addition, it activates Factors VIII and V and hemostatic plug. In addition, it activates Factors VIII and V and their inhibitor their inhibitor protein Cprotein C (in the presence of (in the presence of thrombomodulinthrombomodulin), ), and it activates Factor XIII, which forms covalent bonds that and it activates Factor XIII, which forms covalent bonds that crosslink the fibrin polymers that form from activated crosslink the fibrin polymers that form from activated monomers. monomers.

CofactorsCofactors► Calcium, Vit KCalcium, Vit K

InhibitorsInhibitorsThree mechanisms keep the coagulation cascade in check. Three mechanisms keep the coagulation cascade in check.

Abnormalities can lead to an increased tendency toward Abnormalities can lead to an increased tendency toward thrombosis: thrombosis:

► Protein C which degrades the co-factors FVa and FVIIIa Protein C which degrades the co-factors FVa and FVIIIa ► Antithrombin i that degrades the serine proteases; thrombin Antithrombin i that degrades the serine proteases; thrombin

and FXa, as well as FXIIa, and FIXa and FXa, as well as FXIIa, and FIXa ► Tissue factor pathway inhibitor (TFPI) inhibits F VIIa-related Tissue factor pathway inhibitor (TFPI) inhibits F VIIa-related

activation of F IX and F X activation of F IX and F X ► Protein SProtein S

FibrinolysisFibrinolysisThe main enzyme responsible for this process (The main enzyme responsible for this process (plasminplasmin) is ) is

regulated by activators (TPA) and inhibitor (Antiplasmin) & regulated by activators (TPA) and inhibitor (Antiplasmin) & forms the FDPs. forms the FDPs.

Hemostatic BalanceHemostatic Balance

ATIIIClotting Factors

Tissue factor*

PAI-1

AntiplasminTFPI

Prot. C

Prot. S

ProcoagulantProcoagulant AnticoagulantAnticoagulant

Fibrinolytic System

Pathophysiology of DICPathophysiology of DIC

►Activation of Blood CoagulationActivation of Blood Coagulation►Suppression of Anticoagulant Suppression of Anticoagulant

PathwaysPathways► Impaired FibrinolysisImpaired Fibrinolysis►CytokinesCytokines

Pathophysiology of DICPathophysiology of DIC

►Activation of Blood CoagulationActivation of Blood Coagulation Tissue factor/factor VIIa mediated thrombin Tissue factor/factor VIIa mediated thrombin

generation via the extrinsic pathwaygeneration via the extrinsic pathway►complex activates factor IX and Xcomplex activates factor IX and X

TF TF ►endothelial cellsendothelial cells►monocytesmonocytes►Extravascular:Extravascular:

lunglung kidneykidney epithelial cellsepithelial cells

Pathophysiology of DICPathophysiology of DIC

►Suppression of Anticoagulant Suppression of Anticoagulant PathwaysPathways reduced antithrombin III levels reduced antithrombin III levels reduced activity of the protein C-protein S reduced activity of the protein C-protein S

systemsystem Insufficient regulation of tissue factor Insufficient regulation of tissue factor

activity by tissue factor pathway inhibitor activity by tissue factor pathway inhibitor (TFPI)(TFPI)►inhibits TF/FVIIa/Fxa complex activity inhibits TF/FVIIa/Fxa complex activity

Pathophysiology of DICPathophysiology of DIC

► Impaired FibrinolysisImpaired Fibrinolysis relatively suppressed at time of maximal relatively suppressed at time of maximal

activation of coagulation due to increased activation of coagulation due to increased plasminogen activator inhibitor type 1plasminogen activator inhibitor type 1

Pathophysiology of DIC - Pathophysiology of DIC - CytokinesCytokines

► CytokinesCytokines IL-6, and IL-1 mediates coagulation activation in DICIL-6, and IL-1 mediates coagulation activation in DIC IL-10 may modulate the activation of coagulationIL-10 may modulate the activation of coagulation

TNF-TNF- ► mediates dysregulation of physiologic anticoagulant mediates dysregulation of physiologic anticoagulant

pathways and fibrinolysispathways and fibrinolysis► modulates IL-6 activitymodulates IL-6 activity

Causes of DICCauses of DIC

►Malignant diseaseMalignant disease► Septicemia (gram –ve & meningococcal)Septicemia (gram –ve & meningococcal)►Hemolytic transfusion reactionsHemolytic transfusion reactions►Obstetric causes (abruptio, amiotic fluid Obstetric causes (abruptio, amiotic fluid

embolism)embolism)► Trauma, burns, surgeryTrauma, burns, surgery►Other infections (eg. Malaria falciparum)Other infections (eg. Malaria falciparum)► Liver diseaseLiver disease► Snake bite Snake bite ►Hypothermia/HyperthermiaHypothermia/Hyperthermia► Severe acidosisSevere acidosis► Collagen vascular diseaseCollagen vascular disease

Clinical featuresClinical features

► Patient is acutely ill & may present with shock.Patient is acutely ill & may present with shock.► Features vary from no bleeding to severe Features vary from no bleeding to severe

hemorrhage with widespred hemostatic failure.hemorrhage with widespred hemostatic failure.► Bleeding from mouth, nose, venepuncture site Bleeding from mouth, nose, venepuncture site ► EcchymosesEcchymoses► Thrombotic events may occur, mostly involving Thrombotic events may occur, mostly involving

brain, skin & kidney but may happen anywhere.brain, skin & kidney but may happen anywhere.► Ischemic tissue Ischemic tissue ►Myocardial dysfunctionMyocardial dysfunction► Any visceral organ infarctAny visceral organ infarct

Laboratory Tests Used in DICLaboratory Tests Used in DIC

►D-dimerD-dimer**►Antithrombin IIIAntithrombin III* *

► F. 1+2*F. 1+2*► Fibrinopeptide A*Fibrinopeptide A*► Platelet factor 4*Platelet factor 4*► Fibrin Degradation Fibrin Degradation

ProductsProducts► Platelet countPlatelet count

► Thrombin timeThrombin time► Prothrombin timeProthrombin time►Activated PTTActivated PTT► Protamine testProtamine test► Coagulation factor Coagulation factor

levelslevels

*Most reliable*Most reliable

Laboratory findingsLaboratory findings

► ThrombocytopeniaThrombocytopenia plat count <100,000 or rapidly decliningplat count <100,000 or rapidly declining

► Prolonged clotting times (PT, APTT)Prolonged clotting times (PT, APTT)► Presence of Fibrin degradation products or Presence of Fibrin degradation products or

positive D-dimerpositive D-dimer► Low levels of coagulation inhibitorsLow levels of coagulation inhibitors

AT III, protein CAT III, protein C► Low levels of coagulation factorsLow levels of coagulation factors

Factors V,VIII,X,XIIIFactors V,VIII,X,XIII► Fibrinogen levels Fibrinogen levels notnot useful diagnostically useful diagnostically

Microscopic findings in DICMicroscopic findings in DIC

► FragmentsFragments► SchistocytesSchistocytes► Paucity of plateletsPaucity of platelets

Differential DiagnosisDifferential Diagnosis

►Severe liver failureSevere liver failure►Vitamin K deficiencyVitamin K deficiency►Liver diseaseLiver disease►Thrombotic thrombocytopenic purpuraThrombotic thrombocytopenic purpura►Congenital abnormalities of fibrinogenCongenital abnormalities of fibrinogen►HELLP syndromeHELLP syndrome

Treatment of DICTreatment of DIC

►Stop the triggering processStop the triggering process . . The only proven treatment!The only proven treatment!

►Supportive therapySupportive therapy►No specific treatmentsNo specific treatments

Plasma and platelet substitution therapyPlasma and platelet substitution therapy AnticoagulantsAnticoagulants Physiologic coagulation inhibitorsPhysiologic coagulation inhibitors

Plasma therapyPlasma therapy

► IndicationsIndications Active bleedingActive bleeding Patient requiring invasive proceduresPatient requiring invasive procedures Patient at high risk for bleeding complicationsPatient at high risk for bleeding complications

► Prophylactic therapy has no proven Prophylactic therapy has no proven benefit.benefit.

► Fresh frozen plasma(FFP):Fresh frozen plasma(FFP): provides clotting factors, fibrinogen, inhibitors, provides clotting factors, fibrinogen, inhibitors,

and platelets in balanced amounts.and platelets in balanced amounts. Usual dose is 10-15 ml/kgUsual dose is 10-15 ml/kg

Platelet therapyPlatelet therapy

► IndicationsIndications Active bleedingActive bleeding Patient requiring invasive proceduresPatient requiring invasive procedures Patient at high risk for bleeding complicationsPatient at high risk for bleeding complications

► PlateletsPlatelets approximate dose 1 unit/10kgapproximate dose 1 unit/10kg

BloodBlood

►Replaced as needed to maintain Replaced as needed to maintain adequate oxygen delivery.adequate oxygen delivery. Blood loss due to bleedingBlood loss due to bleeding RBC destruction (hemolysis)RBC destruction (hemolysis)

Coagulation Inhibitor TherapyCoagulation Inhibitor Therapy

►Antithrombin IIIAntithrombin III►Protein C concentrateProtein C concentrate►Tissue Factor Pathway Inhibitor (TFPI)Tissue Factor Pathway Inhibitor (TFPI)►HeparinHeparin

► The major inhibitor of the coagulation cascadeThe major inhibitor of the coagulation cascade Levels are decreased in DIC.Levels are decreased in DIC. Anticoagulant and antiinflammatory propertiesAnticoagulant and antiinflammatory properties

► Therapeutic goal is to achieve supranormal Therapeutic goal is to achieve supranormal levels of ATIII (>125-150%).levels of ATIII (>125-150%).

► reduced DIC scores, DIC duration, and some improvement reduced DIC scores, DIC duration, and some improvement in organ functionin organ function

Clinical trials have shown laboratory evidence of attenuation Clinical trials have shown laboratory evidence of attenuation of DIC and trends toward improved outcomes.of DIC and trends toward improved outcomes.

A clear benefit has not been established in clinical A clear benefit has not been established in clinical trialstrials..

Antithrombin IIIAntithrombin III

Protein C ConcentratesProtein C Concentrates

► Inhibits Factor Va, VIIa and PAI-1 in Inhibits Factor Va, VIIa and PAI-1 in conjunction with thrombomodulin.conjunction with thrombomodulin.

► Protein S is a cofactorProtein S is a cofactor

Protein C levels are low in DIC due to sepsis.Protein C levels are low in DIC due to sepsis. Levels correlate with outcome.Levels correlate with outcome. Clinical trials show significantly decreased Clinical trials show significantly decreased

morbidity and mortality in DIC due to morbidity and mortality in DIC due to sepsis.sepsis.

Tissue Factor Pathway Tissue Factor Pathway InhibitorInhibitor

► Tissue factor is expressed on endothelial Tissue factor is expressed on endothelial cells and macrophagescells and macrophages

► TFPI complexes with TF, Factor VIIa,and TFPI complexes with TF, Factor VIIa,and Factor Xa to inhibit generation of thrombin Factor Xa to inhibit generation of thrombin from prothrombinfrom prothrombin

► TF inhibition may also have TF inhibition may also have antiinflammatory effectsantiinflammatory effects

► Clinical studies using recombinant TFPI are Clinical studies using recombinant TFPI are promising.promising.

HeparinHeparin

►Use is very controversial. Use is very controversial. ►May be indicated in patients with clinical May be indicated in patients with clinical

evidence of fibrin deposition or significant evidence of fibrin deposition or significant thrombosis.thrombosis.

►Generally contraindicated in patients with Generally contraindicated in patients with significant bleeding and CNS insults.significant bleeding and CNS insults.

►Dosing and route of administration varies.Dosing and route of administration varies.►Requires normal levels of ATIII.Requires normal levels of ATIII.

Antifibrinolytic TherapyAntifibrinolytic Therapy

► Rarely indicated in DICRarely indicated in DIC Fibrinolysis is needed to clear thrombi from the micro Fibrinolysis is needed to clear thrombi from the micro

circulation.circulation. Use can lead to fatal disseminated thrombosis.Use can lead to fatal disseminated thrombosis.

►May be indicated for May be indicated for life threateninglife threatening bleeding bleeding under the following conditions:under the following conditions: bleeding has not responded to other therapies and:bleeding has not responded to other therapies and: laboratory evidence of overwhelming fibrinolysis.laboratory evidence of overwhelming fibrinolysis. evidence that the intravascular coagulation has evidence that the intravascular coagulation has

ceased.ceased.

►Agents: tranexamic acid, EACAAgents: tranexamic acid, EACA

SummarySummary

► DIC is a syndrome characterized DIC is a syndrome characterized systemic systemic intravascular coagulation.intravascular coagulation.

► Coagulation is the initial event and the extent of Coagulation is the initial event and the extent of intravascular thrombosis has the greatest impact intravascular thrombosis has the greatest impact on morbidity and mortality.on morbidity and mortality.

► Important link between inflammation and Important link between inflammation and coagulation. coagulation.

► Morbidity and mortality remain high.Morbidity and mortality remain high.► The only proven treatment is reversal or The only proven treatment is reversal or

control of the underlying cause.control of the underlying cause.