An unusual case of a bleeding disorder.

By: Dr M Khan

Index caseMr KS 18 years from Imbali in EdendalePietermaritzburg.Presenting complaint : Epistaxis – 3 days , intermittent , both nostrils , no preceding trauma . 1st episode

plus Haematuria – macroscopic with clots ,1 day , intermittent , no BOM , no FOM , no fever

Systemic enquiryMusculoskeletal : no joint pain / swelling

GIT : no malaena / haematochezia / haematemasis

CNS : No focal weakness / severe headache

Past medical historyNever admitted to hospital

No bleeding disorder

Not on any traditional / OTC medication

Social history

Grade 11 scholar – passing with good grades

Cared by father ( shop assistant )

Access to electricity and clean water

Sober habits , non smoker

Never exposed to rats at home / school

Family historyNo history of bleeding problems

No family members on anticoagulants

On examinationWell looking apyrexialMinimal bleeding from both nostrilsDipstick : 3 + blood , no leucocytesNo : pallor / koilonychia / angular stomatitis / orocutaneous bleeding / stigmata of immunocompromize

CVS : pulse 90 , BP 110 / 80 , not in failure , no features of infective endocarditis .

Resp : not distressed / clear

Abd :Not in liver failure / No features of chronic liver disease - SNT ,PR – no malaena

CNS : no focal deficit , no meningism

AssessmentBleeding disorder with epistaxis and haematuria

Differential diagnoses : 1. Haemophilia Spectrum2. DIC3. Overdose ( accidental / intentional )

ManagementAdmit

Urgent bloods including clotting profile and FBC

Urine MCS

Nasal packing

ResultsFBC : Hb 11.7 ( MCV 89 / MCH 30 ) Platelets 211 ( MPV 8.8 ) WCC8.5

LFT : TP 73 , Alb 41 , Tbil 10 , ALP 48 , GGT 26 , ALT 12 , LDH 454

U&E : Na 137 , K 4 , Cl 105 , CO2 23 , Urea 3.2 , Creatinine 66

INR 12.5 , APTT 68.1 ( 24.1 ) , Fibrinogen normal

Urine MCS : RBC’s > 100 / no growth / no ova

Vitamin K 10 mg ivi stat and daily

Haemodynamic monitoring

Repeat clotting profile

Started on antibiotic prophylactically

That night Registrar called : patient developed sublingual mucosal haematoma which was rapidly increasing in size ? Impending airway obstructing

FBC : Hb 7.2 / platelets 184 / WCC 6.63

INR 8.1 / APTT 86.4 ( 26.4 )

Management : Transfused 2 units blood , 2 units fresh frozen plasma and monitored closely

ReviewedSwelling static – not increasing in size

Hb 8.4 / INR 2.52 / APTT 38.3 ( 26.4 )

Mucosal swelling decreased significantly by the next morning

?? Diagnosis ??

prolongedprolongedprolongedprolongedAPTT

prolongedGrossly prolonged

normalnormalINR

lownormalNormalNormalPlatelet count

Liver diseaseOral Anticoagulants

Haemophilia BHaemophilia A

Thus most likely diagnosis oral anticoagulant toxity

However patient has never been on warfarin& has no family members / contacts on warfarin

Vitamin K dependant factor assay done

Discharged to be reviewed in 3 /7

Reviewedno bleedingfactor 2 5.1 %factor 7 0.7 % normal = 50 – 150%factor 9 1.6 %factor 10 19.5 %INR > 10APTT 125.2

SUPERWARFARIN POISENINGCoumarins such as warfarin are vitamin K antagonists – oral anticoagulants & rodenticides inhibit the enzyme vitamin K epoxide reductaseaccumulation of vit K epoxide ( an inactive form ) causing an apparent vit K deficiency

Warfarin resistance in rats superwarfarins = rodenticides – extremely long acting and fat soluble and are 100 times more potent than warfarin

Brodifacoum most commonly used superwarfarin ( in OTC rat poisens ) thus easily available accidental or delibrate ingestion not uncommon

Superwarfarin toxity cannot be easily reversed with standard doses of vitamin K .

Poovalingum , Kenoyer , Bassa et al SAMJ November 2002 – 4 cases of superwarfarin poisening

CASE 1- 26 yr female assaulted by boyfriend following disclosure of hiv status- Multiple blows to lower abdomen lap performed to drain pelvic

haematoma- Started to bleed from operative site plus conjuctival haemorrhages- Vitamin K dependant factors low ( factor 5 and 8 were normal ) bleeding

stopped after administration of fresh frozen plasma corrrection of INR and APTT after addition of normal plasma

- Diagnosis of vit K deficiency was clearly confirmed but lack of sustained response to vit K pointed to super warfarin toxity

- Vit K1 100mg/ day ( 2 months ) but still required intermittent plasma infusions continued on oral vitamin K

- Eventually admitted to consuming Rattex – OTC rodenticide ( defethiolone )

CASE 214 year old street child who regularly scavenged for food in rubbish bins –epistaxis and regular bleeding from venepuncture sitesBlood profile in keeping with vit K deficiencyNo hepatic / renal impairmentReceived vit K 100 mg iv in 3 divided doses and fresh frozen plasma as needed to control bleedingIn spite of treatment with oral and iv vit K he continued to bleed intermittentlyPhenobarbital added – no responseAbsconded after 3 ½ months of hospitalizationDied mysteriously – most likely due to coagulopathy

CASE 3- 38 year old man who used Rattex regularly to sprinkle floors

because of a major rat infestation- Bleeding gums , frank haematuria , and abdominal pain- Lab tests – in keeping with vit K deficiency with lack of response to

treatment superwarfarin poisening- Treated like other patients- Stabilized on high doses of oral vit K1 - At 6 months follow up – well – still had lab evidence of a

coagulopathy

CASE 453 year old man treated successfully for renal calculi at a local hospital1 week later – haematuria , bleeding from venepuncturesites and gum bleedingResults in keeping with vit K deficiencyRequired high doses of iv vit K1 Was returned to care of GP who continued daily iv injections until 8 months then swiched to oral vit K1Denied self poisening but did have family problemsCollateral info from GP revealed that he had 1 previous episode of overdose on antidepressants.

50-150124.227Fac 1050-1502112.281.2Fac 950-15032.411Fac 750 -15011-93.7Fac 250-1501161538764Fac 51.5 -4.56.435.936.85.12Fibringen29-4462.483.381.6120APTT11-1466.691.2128110PT

NormalCase 4Case 3Case 2Case 1Test

DISCUSSIONThus superwarfarin poisening is growing problem .Suicide attempts , industrial exposure or accidental poiseningPresents as a bleeding disorder Diagnosis : prolonged INR and APTT , normal fibrinogen and platelet count (excludes DIC ). Addition of normal plasma in the 50 /50 test – correction of prolonged coagulation times confirming specific factor deficiencies rather than the presence of an inhibitor . VitK dependant factor assays are low while factors 5 , 8 and fibrinogen are normal

Thus lack of a sustained response to initial treatment with vit K and failure of resolution of the bleeding diathesis suggests superwarfarinexposure . The presence of superwarfarin in the blood or other body tissues confirms the diagnosis but these assays are only available in specialized centres .Treatment : -high doses of vit K1 – initially iv administration is often necessary – given as slow iv injection diluted with saline or glucose and can be repeated every 6 hours . Fresh frozen plasma is reserved for severe bleeding and red cell transfusions if blood loss is excessiveSuperwarfarins have long ½ lives and are fat soluble- treatment has to be continued for months and even yearsInconclusive evidence that phenobarbital enhances hepatic microsomal enzymes to increase metabolism of 4 hydroxycoumarinderivatives was not found to be useful in durban experience.

Follow up my caseAdmitted to King Edward haematologydepartmentReceived intravenous vitamin K1 plus intermittent fresh frozen plasma intermittently for 2 weeksDischarged on oral vitamin K1 to be followed up at Edendale