Venous thrombembolism: Reducing the Risk: NICE guideline 2010

• http://guidance.nice.org.uk/CG92;
  
• Quick reference guide: http://www.nice.org.uk/nicemedia/pdf/CG92QRG.pdf;
  

Haemostasis

Haematology SpR GIM Teaching MRI 21-Nov-08

Physiology

vWD type 1 (ie partial): 1:100
vWF: 3 fx: 1) connects to Plt; 2) connects to collagen; 3) protects F8 (therefore: vWD: icrd aPTT b/o dcrd F8)
F12 def: no signif effect (not essential)
F8 def=Haemophilia A,
F9 def=Haemophilia B
traditional coag cascade: true in lab (but not life)
new view: "starter" engine: extrinsic pathway: tissue factor + F7 -> only then amplified via intrinsic system ("engine")
F5Leiden [see: OMIM]: resistant to cleavage by ProteinC ["activated Protein C resistance"]
Natural anticoagulants: ProtC, ProtS

Anticoagulants

Heparin: Unfractionated Heparin: mainly active against Antithrombin; LMW Heparin: mainly active against F10a
Warfarin: inhibits F2, F7, F9, F10, but also (and before the others): ProtC, ProtS - which explains the initial procoagulant state induced by Warfarin and the essential need to overlap with Heparin (at least 2d)
Hospitalization: icrs PE risk 8fold (and accounts for 25% of all VTE burden), VTE prophylaxis dcrs that risk by ~50% (trials: MEDENOX, PREVENT, ARTEMIS); DoH initiative
Guidelines: ACCP2008 in Chest (eg all CCF| severe chest disease | bed-bound for >2d: should rx prophylaxis): either pharmacolog (Dalteparin 5k) or non-pharmacol (if contraindications)
NHS flowchart
always monitor for HIT (Heparin-induced thrombocytopenia) and Hyperkalaemia

Reversal of anticoagulation:

INR 3-5 if target 2.5, or 4-6 if target 3.5: dcr dose
INR 6-8: stop +- vit K 0.5-2.5mg, restart when INR<5
INR>8: stop + vit K 0.5-2.5mg (+- repeated)
major bleed (shock, requiring surgery, brain, eye, compartment syndrome) & any INR: 5mg vit K + PCC (Prothrombin complex concentrate, eg Octaplex, Beriplex) [NOT: FFP, unless unavail]
PCC=F2, F7, F9, F10; T1/2~6hr; check INR after 15mins (and 12hrly)
PCC dose 25-50u/kg as per INR
Heparin reversal (eg OD with renal failure): Protamine (if catastrophic haemorrhage: consider rF7a)
therefore: don't use Heparin if eGFR<30, and with great caution in eGFR 30-50 (and monitor F10a levels), and unfractionated Heparin safer (by monitoring aPTT) than LMW Heparin

Novel anticoagulant agents:

[Exanta(R): withdrawn b/o hepatitis]
Rivaroxaban (Bayer): oral F10a inhibitor (RECORD3)
Dibigatran (Boehringer Ingelheim): oral direct thrombin inhibitor
Lepirudin: direct thrombin inhibitor, recombinant: eg for HIT
Fondaparinux ("stripped down Heparin"): anti F10a, renal excretion

HIT = Heparin-induced thrombocytopenia

~1% (more likely with unfractionated heparin); causing dcrd Plt and THROMBOSIS
usu day 5-10; Plt dcr to ~50%, median 50, rarely bleed, but 50% have thrombosis; sometimes skin lesions
initial diagnosis = clinical; need alternative anticoagulant (eg Lepirudin or Heparinoids[?], NOT Warfarin immediately and until Plt>100: b/o initial procoag state of warfarinization)
Guidelines: pretest-probability score;
DD: Thrombotic Thrombocytopenia Purpura (TTP), Paroxysmal Nocturnal Haemoglobinuria (PNH); (v. very unlikely in pregnancy: think eclampsia)
seek haematology advice

Recombinant F7a

Indications: 1) eg haemophiliacs with F8 inhibitors;
2) if FFP + cryprecipitate fails (eg in massive blood loss, eg cardiac surgery): off-licence
3) Jehovah's witnesses (b/o not blood product)

Q&A

Vit K effect: within 6h (IV) - 12h (PO) [if nml liver fx]
DIC & bleeding: Rx FFP [not PCC]
Aspirin: only protects against arterial thrombosis (MI, stroke): ie predominantly Plt-plug
Heparin/Warfarin: protect against venous TE: ie predominantly fibrin-plug
F5Leiden: 7% of Swedish; unless homozygote: consider circumstances of VTE
Thrombophilia screen: main use: detection of Antiphospholipid antibodies and AT3 deficiency
MI + cerebral haemorrhage after thrombolysis: Cryoprecipitate (to replace the used fibrinogen) + FFP +- Tranexamic acid (antifibrinolytic)
Metal aortic valve: stop anticoagulation 4days before procedure (low VTE risk b/o high flow across the valve)
Metal mitral valve: major thrombosis risk b/o slow flow across the valve: ALWAYS need anticoagulation with Heparin during pre-op Warfarin withdrawal
Clopidogrel (vs Aspirin): icrd bleeding risk, although less GI bleed b/o not irritant to gastric mucosa

Transfusion Medicine

Src: www.transfusionguidelines.org.uk (eg Handbook) | www.BCSHguidelines.com (Brit Haematol)
transfusion practitioners in hospital
National Patient Safety Agency(?): NPSA
Whole blood donation: 1) red cell concentrate; 2) Plt; 3) Plasma: 3a) FFP + cryoprecipitate; 3b) Alb, Ig, Clotting factors: currently from 'BSE-free' countries (not UK)
Plt trafu: "adult treatment dose" (can be 1 or 4u): shelf-life 5d
lo Plt, but Plt trafu CONTRAINDICATIONS: TTP, ITP, HIT
always verbal consent (eg Jehovah's witnesses: hospital pathways)
soon: prion protein test of donations
Transfusion risks: HIV<1:10G, HCV<1:3M, HBV<1:1M, HTLV-1~1:50k, nvCJD: 4 cases; highest risk: bacterial infection; also: Malaria; see: SHOTuk (Safety Hazards Of Transfusion)
Red cell trafu: leukocyte-depleted nowadays (therefore rarely trafu-related fever); special requirements: eg irradiated or CMV-neg for BMT/neutropenic; max duration: 4h out of fridge
future: ? electronic crossmatching (relying on blood-grouping [AB0] and Antibody screening)
unique donor ID: need to go in notes
FFP: for coag disturbances (only if measured, even in massive transfusion);
FFP: Indications: DIC & bleeding, rare congen factor deficiencies; NOT 1st line for reversal of Warfarin anticoag unless PCC unavail (use PCC=Prothrombin complex concentrate);
FFP: NOT for Vit K def, liver dis, correction of heparin OD
FFP: can keep 24h in fridge; >80% male donors; virally inactivated for children
TTP: plasma exchange  -> Octaplas
Cryoprecipitate: if Fibrinogen <0.8-1g/L (eg liver disease, massive trafu); needs to thaw for 30mins!; Rx 1-2pools, use trafu set (200micron filter)
ALWAYS recheck INR after giving PCC, FFP, Cryoprecipitate
Trafu complications: haemolytic reactions [eg AB0 incompatibility], febrile reactions, TRALI (trafu-related acute lung injury), TRGvHD, allergic/anaphylactic reactions
always check vitals before and 15min after start of trafu; check for Haemoglobinuria if suspected trafu-reaction
delayed trafu reactions: (after days, due to low-level Ab's): fever, haemolysis, failure of icr Hb, +ve Coombs, spherocytes, hi Bili, hi LDH
Storage: blood 2-6C, Plt 20-24C (higher risk of bacterial infections), FFP/Cryo: -30C

Haematological Malignancies

AML: death 6w w/o chemo
Leukaemia: adult>>children
Auer rods: promyelocytes
AML: peak 80y; usu no Tx over age 75yr
AML symptoms: BM failure: 1) anaemia; 2) infections (esp bact due to dcrd neutrophils; not so much lymphocytes and viral infections); 3) bleeding
also: bone pain, DIC, cachexia (cytokine-mediated), splenomegaly, tissue infiltration, gingival hypertrophy, mouth ulcers
AML+pneumonia (pneumococcal): v poor prognosis
Cytogenetics: t(15,17) translocation: chimeric gene
Tx: remission in 85% after 1 induction chemo; consolidation chemo (~6mths); ?maintenance chemo: controversial
5yr survival: 55% if <65y, 4% if >65y

Lymphoma:
NHL>>HD [NB: overlap with CLL]
RF NHL: immunosuppression/def., CTD (RA, Sjogren: chron Ag stimulation), FH, infections (HIV: Burkitt's lymphoma; H.pylori, HepC), ionizing radiation
Lymphoma: 5th most freq diagnosed Ca
NHL: icrg incidence, HD: stable;
NHL peak: 80y, HD: bimodal: peaks 20 & 80
Presenting symptoms: asympt ... v.ill
LN (+- skin, gut, etc); compression: SVCO, cough (bronchus); B-symptoms (worse prognosis): fever, night sweats, weight loss
Complications: BM failure, CNS infiltration, 2 non-metabolic emergencies: spinal cord compression / bilat ureteric compression; immune haemolysis, effusions, ascites
Ix: Bx (Reed-Sternberg: HD), staging CT (internal LN), FBC, BCh, LDH;
Stages I-IV{A:not B|B: B-symptoms}
Common types: 1)follicular lymphoma: indolent; 2)diffuse large B cell lymphoma: aggressive, ~50% (R-CHOP: Rituximab=Ab against CD20 on B-cells); 3)HD: mostly curable

Multiple Myeloma

MM: plasma cell prolif, med 60-65y, icrd in Afro-Caribb
Light chains (LC): glomerular damage->ARF [AL amyloidosis: DD Waldenstrom's, NHL, ...]
bone disease: myeloma->cytokines->Osteobl inhibition + Osteoclast activation->lysis, [pathol.] fracture, cord compression, osteoporosis
anaemia, hypercalcaemia
infections: pneumococcal pneumonia, H. influenzae
marrow suppression
hyperviscosity syndrome: headaches, fundi (measure PV!: consider plasma exchange if v icrd)
cord compression: if suspected start Dexamethasone (?16/?60mg???/d), urgent imaging and DXT (usu not surgery)
Ix: FBC, PV, UE, LFT, Bone, Urate, B12/Fol/Ferr, CRP, LDH, beta2Microglobulin (prognositic)
Ig+elpho (IgG usu>15g/L + 'immunoparesis' ie other Ig suppressed) [DD: IgM paraprot: Waldenstrom's Macroglob or CLL, rather than MM!]
U-elpho (BJP); serum free light chains (Hope, MRI) or quant U-BJP
Radiol: skeletal survey, MRI or CT (NOT: bone scan)
BM asp/tre, immuno, cyto: >10% plasma cells (of nucleated cells)
Diagnostic criteria
MM: BM>10%, and {paraproteinaemia | >=1 lytic lesion}
MGUS: <10% and low grade paraproteinaemia and NO lytic lesion
Plasmacytoma: <10%, 1 lytic lesion, no paraprotein

MM Rx: only if symptoms (because incurable)
supportive: hydration 3L/d (po/iv), esp if hi Calcium
transfusion (NOT if hi PV: risk of VTE/stroke/...)
treat infections (esp risk of pneumococcal pneumonia)
analgesia (beware NSAIDs if renal impairment or lo Plt; also consider neuropathic pain Tx: Pregabalin, Carbamazepin)
Bisphosphonates (only AFTER adequate rehydration! else renal damage)
chemo/radio
vertebro-/kyphoplasty
Hypercalcaemia: 3 main Tx: 1) hydration; 2) bisphosphonates; 3) dexamethasone
Chemo: Thalidomide, Bortezomib, Lenalidomide; also: hi dose chemo and stem cell rescue in younger patients
median survival: 4-5y

Haemolytic anaemias

Ix: FBC, Retic, Film, Bili (unconj), LFT, LDH, Haptoglob; aetiol: DAT, infection screen (viral, ...), G6PD, Haemoglobinopathies
Immune Haemolytic anaemia: warm (IgG): AIHA, drugs, trafu; cold (IgM): Mycoplasma, lymphoprolif dis; Non-immune: ...
Thalassamia vs IDA vs both: NB Ferritin/ZPP may be misleading; consider Fe trial (eg if Ferr<300)

Sickle cell disease

homozygote beta chain [carrier: usu asympt]
12.5k in UK (2/3 London): Blacks (more severe dis), also S Am, Mediterr, Middle E
HbS: usu Hb 7-9 (ie don't transfuse
Clin: anaemia, infections (b/o hypersplenism), painful crises, stroke, leg ulcers, vision loss, kidney/eye/joint damage
Painful crises: eg hand-foot syndrome in children; adults: more proximal; avascular necrosis; Tx: target analgesia <30min of presentation, painfree at 60mins; NB: don't Xray bones, don't aspirate joints unless suspected infection, don't trafu unless unstable;
Analgesia: morphine (NOT pethidine) and PCA (may need hi doses morphine if on regular opioids)
if TIA/vision loss/priapism>4h/chest syndrome etc: may need emergency red cell exchange
Tx: fluids 4L/d (oral if poss, avoid leg veins); O2 if SO2<92%(A), Diclofenac, Antiemetics, Hydroxyzine PRN for pruritus
Sickle chest syndrome: SO2<92%(A); if paO2(A)~55-70: consider CPAP; if <~55 ventilate +- exchange trafu
Stroke/SAH: Tx as for others, plus exchange transfusion
severe anaemia: ? aplastic crisis (parvovirus, lo Retic); ? malaria (if from abroad; NB: trait protects); transfuse to Hb<=10, else risk of hyperviscosity: fits/stroke

The blood film

Plt : RBC ~ 1:10 per field
Rouleaux formation: with any icr in protein (IgG eg MM, CRP, ...)
Burr cells: excess lipids
Target cells: if dcrd intracell Hb (eg IDA, Thalass), or excess membrane (liver dis, splenect)
Keratocytes/Helmet cells/Schistocytes: intravasc haemolysis
basophilic stippling: IDA, thalass, MDS, "lead poisoning"
Howell-Jolly body: nucl remnant: splenect / aplasia
hypersegm neutroph: B12/Fol def (also CML chemother)
Tear drop cells: MDS, cancer, (due to "packed marrow")