Resident Rounds

1
Disorders of Hemostasis Resident Rounds February
5, 2004.

• Resident Rounds
• February 5, 2004

2
Case

• 4 yo with gums that bleed for 30 mins after
  brushing teeth.
• Also had spontaneous epistaxis last week
• Unwell 2 weeks ago
• You notice petichiae around her underwear elastic
• ??
• CBC
• Plt 3

3
ITP

• Children 2-6
• viral prodrome usually within 3 weeks of onset
• Plts usually lt20
• What do you expect their INR/PTT to be?
• Bleeding time?
• 90 recovery
• IVIgG and steroids
• splenectomy

4
Normal Coagulation

• Depends on interaction of
• Vasculature
• Platelets
• Coagulation cascade.

5
Case

• 33 yo G2P1 LMP 08/05 est GA 24/40
• Presents vomiting with abdominal pain
• BP 130/90, 105, 20, sats 99
• Jaundiced, tender RUQ
• Labs
• Hb 90, PLT 80, inc ALT/AST/bili
• Coags normal
• Dx??

6
Platelets and Coagulation

• Disruption of endothelial layer and exposes
  consituent material
• Platelets attach to constituent components
• Platelet secretion
• Platelet activation and aggregation

7
Platelet Disorders
Quantitative
Qualitative
Decreased Production
Sequestration
ASA, plavix rena and hepatic disease, vWD
Destruction
Immune
Non-immune
splenomegaly
TTP DIC HELLP Sepsis
IPT
Marrow failure
8
Case

• 12 yo girl with menhorrhagia for 5 days
• Hx of von Willebrands
• Pale
• HR 110, BP 90/60
• Hb 60
• Management plan?

9
Von Willebrands Disease

• Defect in primary hemostasis
• Quantitative (type 1 and 3) and qualitative (Type
  2)
• Refers to many different platelet defects
• Quantitative defects of vWF most common
• and mild disease is MC (approx 80)
• vWF activity reduced 20-50 normal
• Most with type 1 vWF will be asymptomatic unless
  challenged by surgery or trauma

10
vWF

• large multimeric glycoprotein that functions as
  the carrier protein for factor VIII
• vWF also is required for normal platelet
  adhesion. As such, vWF functions in both primary
  (involving platelet adhesion) and secondary
  (involving FVIII) hemostasis.
• In primary hemostasis, vWF binds on platelets to
  its specific receptor glycoprotein Ib and acts as
  an adhesive bridge between the platelets and
  damaged subendothelium at the site of vascular
  injury.
• In secondary hemostasis, vWF protects FVIII from
  degradation and delivers it to the site of
  injury.

11
Type 1 vWF

• Mild to moderate decrease in plasma levels of vWF
• Proportional decrease in vWF function
• Proportional decrease in circulating FVIII

12
Von Willebrand

• Treatment options
• Helpful to know
• specific sub-type of disease
• Previous response to currently available
  treatments
• Immediate management depends on
• Severity of disease
• Type and location of bleeding

13
Treatment Options

• DDAVP
• Specific vWF and factor VIII replacement
  (Humate-P)
• cryoprecipitate

14
DDAVP

• Use based on observation that epi and stress
  increase levels of vWF and FVIII
• Same effect with vasopressin and synthetic
  vasopressin (but no pressor effect)
• Can be used IN/IV/IM (IV and IM have same effect)
• 2-3X increase in vWF and FVIII
• Dose 0.2mcg/kg IV
• NB not effective in Type2/3 disease where pts
  express an abnormal ptn.

15
Cryoprecipitate

• plasma fraction that contains factor VIII, vWF,
  fibrinogen, and fibronectin
• obtained by harvesting the precipitate that forms
  when frozen plasma is warmed to 4C.
• 1 bag contains approx 100U of vWF and FVIII
  (approx 10x more than FFP)

16
Case

• 12yo with hematemesis for last 6hrs
• Tells you has the worst vonWillebrands
• Type III
• No detectable vWF and markedly reduced FVIII
• Treatment
• Cryo /- DDAVP

17
Case

• 37 yo male twisted knee and fell at work
• PMHx of Hemophilia
• Unsure of usual factor activity
• OE tender knee hemarthrosis
• Do you give him factor?
• How much factor to give?
• What if youre in High River (and you aint got
  none?)
• ?cryo

18
Hemophilia

• A FVIII deficiency
• B FIX deficiency
• X-linked recessive
• 1/3 spontaneous mutation
• Mild/moderate/severe ? based of percent factor
  activity
• gt5, 1-5, lt1 respectively
• MC manifestations ? hemarthrosis and SC

19
Hemarthrosis

• MC symptom and potentially debilitating
  manifestation
• Spontaneous or secondary to trivial trauma
• Accumulation of blood in synovial space ?
  synovial proliferation ? increase in joint
  vascularity which predisposes to further bleeding
  ? recurrent bleeding ? chronically deformed and
  painful joint

20
Management of Bleeding in Hemophilia

• Overall principles
• Depends of severity of bleeding
• Underlying disease severity
• Availability of replacement products
• Assume during an acute bleeding episode that
  factor activity is 0
• Recommended to raise FVIII levels to 50

21
Management of Bleeding in Hemophilia

• Options
• Specific factor replacement
• Cryo
• FFP
• Do nothing

22
Factor replacement

• 1 unit/kg of FVIII will raise plasma FVIII
  activity by 2
• Goal is to achieve gt50 activity
• Post-infusion the initial recovery of FVIII is
  80
• Administer replacement at rate of 3cc/min
• Peds at 100u/min
• 15 will develop alloantibodies (IgG) against
  FVIII which neutralize exogenous administration.
  Pts will require 3-4X the dose of replacement.

23
Cryoprecipitate

• Contains 100U FVIII (als contains vWF,
  fibrinogen, FXIII and fibronectin)
• Considered a second line agent for Hem A
• Dose 2bags/10kg to raise FVIII to hemostatic
  levels
• T ½ 8hrs

24
FFP

• Fluid portion of blood separated at 18C then
  frozen
• Contains all coagulation factors
• Approx 7 of of all coag factor activity of a
  70kg person
• Not routinely used as factor replacement in Hem A
• Could consider if nothing else available

25
Case

• 35 yo with hemophilia
• Fell backwards while showing the ladies what a
  phat boarder he is.
• No neurologic defecits
• No Can CT head criteria
• To the scanner?
• Factor replacement if normal scan (or before
  scan)?

26
IC bleeds and the Hemophiliac

• Remain a MC of death
• mortality rate of 30
• Probably should receive prophylactic factor
  replacement
• Dose of replacement
• 50U/kg q12hrs
• Consider cryo at 6bags/10kg

27
Case

• 70M with likely urosepsis in ICU on pressors.
• Oozing from all IV sites
• INR and PTT up
• ?
• DIC

28
DIC

• Causes
• Infection
• GN
• Encapsulated GP
• Viruses ? varicella esp
• Massive Trauma
• Obstetrical
• Abruption
• Amniotic fluid embolism
• Malignancies
• Burns
• Transfusion-related

• Lab
• plt
• INR
• PTT
• FDP
• Fibrinogen
• five case studies of DIC, combining over 900
  patients
• MC lab abn
• thrombocytopenia,
• elevated FDPs,
• prolonged INR,
• prolonged PTT,
• and a low fibrinogen

29
DIC Schematic
Initiation of DIC usually involves one or both of
two mechanisms mechanical tissue injury and
endothelial activation and injury. Primary to
both initiating pathways is the exposure of blood
to huge amounts of tissue factor.
30
DIC

• Bleeding is the predominant clinical
  manifestation observed in DIC
• thromboembolic manifestations have been less
  frequently observed in DIC and have been reported
  in 1040 of patients

31
DICWhat to do?

• Treat underlying stimulus
• Plts
• Maintain gt30 or higher if OR planned
• 1U plts contained 5x109 plt
• expected to raise plasma by same
• FFP
• If DIC assoc with increased INR and PTT
• Cryo
• If fibrinogen lt2
• Give 1-4U/10kg

• Role for
• Heparin?
• No established role
• Can worsen the situation
• ?consider if evidence of embolic complications in
  setting of DIC eg purpura fulminans
• ATIII -- investigational
• Ptn C -- investigational

32
Hypothermic coagulopathy

• 45M found in snow bank ?duration
• INR 1.6
• Plts normal
• No evidence of liver failure, trauma. - EtOH
• ?mechanism of coagulopathy
• Likely d/t slowing of enzymatic reaction with
  balance favouring anti-coagulation.
• Treatment?
• rewarming

33
Case

• 60 yo with ACS
• Got ASA, Heparin, bblocker
• Waiting for CCU
• LGIB in ED
• Mechanism of heparin
• How do you reverse heparin?

34
Heparin

• Unfractionated heparin
• Major sites of activity ATIII, Xa
• Other sites IIa, IXa, XIa
• Anticoagulant effect largely through ATIII.
• Produces a conformational change which
  accelerates the ability of ATIII to inactivate
  thrombin

35
Reversing HeparinProtamine

• T ½ 60mins
• 1mg protamine neutralizes 100 circulating units
  of UFH
• Eg 1500U/h (no recent bolus)
• 1500U 750U 375 2625U
• Dose of promatime 26.25mg
• If received bolus then need to re-calculate
  depending on when received and add to total
  heparin (after 4-5hrs, bolus effectively gone)

36
LMWH

• Inhibitor of Xa
• Activity 14-16hrs
• T ½ is 4hrs
• Reversal is more difficult
• lt8hrs post-dose
• 1mg protamine/1mg heparin
• gt8hrs
• 0.5/1mg

37
Case

• 60 with STEMI that youve thrombolyzed

38
Reversing lytics

• Mechanism
• inducing plasmin action on fibrin contained
  within a thrombus
• T ½ 15mins
• Fibrinogen remains low for 24hrs
• Reversal
• Stop lytic
• Replenish fibrinogen
• Cryo
• FFP to correct prolonged bleeding time
• ?aminocarproic acid
• Reverse heparin

• Absolute lytic contraindications
• Hemorrhagic cerebrovascular accident,
  intracranial neoplasm, recent cranial surgery or
  trauma (10 days), uncontrolled severe
  hypertension
• Major surgery of thorax or abdomen (10 days),
  prolonged cardiopulmonary resuscitation, current
  severe bleeding (e.g., gastrointestinal)

39
Case

• 50M with known EtOH cirrhosis
• Presents with abnormal coags
• Pathophysiology of coagulopathy
• Multiple points of insult to hemostasis
• Dec coag factor synthesis
• Malabsorption/nutritional deficiency of vit. K
• Portal HTN ? splenomegaly ? sequestration
• Decreased synthesis of fibrinogen

40
Anticoagulant OD

• 3 yo presents after father witnessed kid licking
  his lips after a mouthful of bacon and cheese rat
  poison 4 hrs ago.
• Brings in box ? bromodialone 0.05
• INR normal
• When would you expect it to be abnormal?

41
Vit. K and Coumadin

• Vit K dependent coag factors?
• II, VII, IX, X
• Ptn C and S
• Cofactor in carboxylation of enzymes which
  activate factors
• Coumadin
• T ½ 2.5d

42
Vit K pathway
43
Supercoumadins

• inhibition of the complete synthesis of the
  vitamin K-dependent proteins may continue for
  months after initial exposure, even in the
  absence of re-exposure.
• Very high fat solubility
• Can lead to prolonged INR gt1yr
• vitamin K1 at normal doses of administration is
  ineffective.
• Will require daily doses of 100150 mg of vitamin
  K1 administered orally have been effective in
  normalizing the PT. Over time, the dose of
  vitamin K1 needed to correct the PT can be
  adjusted downward, so that only the required
  amounts of vitamin K are employed.