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What is the prognosis of Waldenstrom's macroglobulinaemia?

Median survival of 5 years, 10% alive at 15 years.


A 78-year-old man presents with progressive lethargy for several months and the recent onset of bruising, epistaxis, headaches and visual deterioration.  Physical examination shows him to be anaemic with scattered ecchymoses; he has reduced visual acuity bilaterally and fundoscopy reveals retinal venous distension with numerous retinal haemorrhages. 
Investigations show: 


The most appropriate initial therapy is: 
A. melphalan and prednis(ol)one. 
B. platelet transfusion. 
C. plasma exchange. 
D. renal dialysis. 
E. intravenous gamma globulin. 

C.  This is hyperviscosity syndrome in Waldenstrom's macroglobulinaemia.


What are the diagnostic essentials of primary amyloidosis?

Congo red positive amyloid protein on tissue biopsy
Amyloid protein is kappa or lambda Ig light chain
Serum or urine (or both) positive for light chain paraprotein


What is the pathogenesis of amyloidosis?

Disturbed translational or post-translational protein folding --> input of protein into tissues exceeds output --> abnormal tissue deposition --> organ dysfunction and failure


What are the four main categories of amyloidosis?

1.  Primary.  Ig light chain (AL Amyloidosis)

2.  Secondary.  Serum protein A, produced in inflammatory conditions (AA amyloidosis)

3.  Hereditary (Transthyretin (TTR), senile amyloid (ANP) + tohers

4.  Renal Failure type (B2 microglobulin not filtered out by dialysis membranes)  AB2M amyloidosis


What are the clinical findings of amyloidosis?

Localised:  SSx related to organ i.e. hoarseness, proptosis

Cardiac failure (infiltratrive/restrictive cardiomyopathy)
Nephrotic syndrome
Malabsorption and weight loss
Autonomic insufficiency
Carpal tunnel syndrome (bilateral)
Sensorimotor peripheral neuropathy
Enlarged tongue, waxy plaques on skin, periorbital contusions, cough or dyspnoea, decreased swallowing
Insidious onset, dx made late in disease


What are the lab findings of amyloidosis?

Dx requires tissue biopsy that stains pink on H&E, red on Congo red, that becomes apple-green when the light is polarised.
Kappa or lambda (lambda more common) light chains in serum urine on PEP, IFE or free light chain assay in 90%, mass spectroscopy will catch the rest on tissue bx
Systemic:  Blind aspiration of abdominal fat pad will reveal amyloid 66% of the time.
Ventricular wall thickening on TTE with unique speckling pattern, low QRS voltages
Renal: nephrotic range albuminuria; late: renal failure


What is the ddx of primary amyloidosis?

MGUS, MM, or other malignant lymphoproliferative diseases.

12% of MGUS patients will convert to AL amylodoisis
1/5 of patients will meet crtieria for MM
5% of MM patients will have amyloid deposition of their paraprotein


What is the treatment of primary amyloidoiss?

Reduce light chains to protect organs 
 - melphalan and pred
 - ASCT but not generally tolerated, and can't be done if advanced cardiac amyloidosis

Thalidomide being tested


What is the prognosis of primary amyloidosis?

How is response and progress measured?

Prognostic indicators:  BNP, tropT and tropI regardless of overt cardiac involvement
Poor survival, even with ASCT, median sruvival approaches 5 years

Monitored with serum free light chains.


What is amyloid?

Triple-stranded fibril that forms beta pleated sheets.

Composed of amyloid protein P, and glycosaminoglycan.


What is serum amyloid A?

Serum amyloid A protein (SAA) is an acute-phase reactant that is deposited in the tissues in AA amyloidosis.  Involved in cholesterol transport.


What is serum amyloid P?

Basic component of amyloid regardless of amyloid disease type.


The following proteins are all components of amyloid deposits. Which is universally present?
A. Transthyretin.
B. Serum amyloid P (SAP).
C. β2-microglobulin.
D. Immunoglobulin light chain.
E. Serum amyloid A (SAA).



What are the diagnostic essentials of heparin induced thrombocytopaenia?

Thrombocytopaenia within 5-10 days of espoxure to heparin
Drop in baseline PLT count of 50% or more
Thrombosis in 50% of cases, bleeding is uncommon


What is the pathogenesis of HITS?

Heparin > LMWH --> formation of antibodies to heparin-platelet factor 4 complexes --> antibodies bind platelets --> activates them --> thrombocytopaenia, pro-thrombotic state


What are the clinical findings in HITS?

Thrombosis (venous or arterial) may be detected in up 50% of patients up to 30 days post dx


What are the lab findings in HITS?

New onset thrombocytopaenia within 5-10 days of exposure to heparin (rapid onset HIT is not common)
Drop of PLT count to  50% or more of baseline
Positive 4T score

Dx confirmed through positive PF4-heparin antibody enzyme-linked immunosorbent assay (ELISA) or functional assay (serotonin release assay) or both

Magnitute of positive ELISA result correlates with clinical probability of HIT.


What does the serotonin release assay measure?

Measure serotonin release - a marker of platelet activation
If release is high, the test is positive and the platelets are activated.  Used in HIT.


What is the treatment of heparin-induced thrombocytopaenia?

STOP all forms of heparin.
Doppler lower limbs
Start alternative anticoagulant --> usually a direct thrombin inhibitor (argatroban or lepirudin).  Continue until PLT 100 then start Warfarin.

If using argatroban, cease infusion prior to measuring INR 2 hours early so you know the anticoagulant effect is from Warfarin alone

Warfarin contraindicated initially as may transiently worsen hypercoagulability.

Continue Warfarin for 30 days due to persisten risk of thrombosis even if normal platelet count.

If HITS plus thrombosis, Warfarin for 3-6 months

Avoid subsequent exposure to Heparin, if absolutely necessary, measure PF4-antibdoies which should be negative (at about 100 days) and limit exposure to heparin.


What is Trousseau's syndrome?

Sign found in certain cancers that is associated with venous thrombosis and hypercoagulability. It is characterized by successive crops of tender nodules in affected veins.


What are the 4Ts in the diagnosis of HITs?
Predictive value?

1.  Thrombocytopaenia - 2 points if the count falls >50%, no points if it's less than <30%

2.  Timing of platelet count fall.  2 points if 5-10 days or if PLT count falls <1 day with heparin exposure within 30 days.  

3.  Thrombosis.  2 points if new thrombosis, skin necrosis, or acute systemic reaction to unfractionated heparin bolus.

4.  Other causes of Thrombocytopaenia.  2 points if none.  Zero points if you can find another cause.

Very good at excluding cases of HITs (NPV of almost 1).  Low probability means you can exclude, intermediate and high require further investigation.  


What is the d-dimer?

Fibrin degradation product present in blood after a clot is degraded by fibrinolysis - contains two crosslinked fragments of fibrin protein


What are the diagnostic essentials of DIC?

Prolonged APTT and PT
Decreased fibrinogen


What is the mechanism of DIC?

Uncontrolled local or systemic activation of coagulation —> depletion of coagulation factors and fibrinogen, activation and consumption of platelets leading to thrombocytopenia


What are the causes of DIC?

Sepsis - coagulation activated by LPS
Pregnancy associated (tissue factor)
Aortic aneurysm & cavernous haemangiomas
Snakebited due to exogenous toxins


What are the signs and symptoms of DIC?

BLEEDING esp at IVCs or incisions
May be widespread (purport fulminates)
Malignancy related - thrombosis (trousseau syndrome)


What are the lab findings in DIC?

Acute and progressive prolongation of coats and thrombocytopenia
Early:  PLT and fibrinogen may remain normal
Progressive thrombocytopenia
Elevated d-dimer due to activation of coagulation and diffuse cross-linking of fibrin
Schistocytes on blood smear due to shearing through microvasculature
HELLP of pregnancy:  haemolysis, deranged LFTs, thrombocytopenia, renal dysfunction with gross haemoglobinuria and pigment nephropathy
Malignancy-related:  normal PLT counts and coags


What is the treatment of DIC?

Treat underlying cause
Monitor PT aPTT fibrinogen and PLT count 6 hourly
Give PLTs and aim count >20, or >50 if bleeding
Cryo to replace fibrinogen (>8-10)
FFP to get PT and aPTT down
PRBCs to get Hb >80
Heparin if persistent bleeding to stop thrombin generation and thus consumption of coal proteins and platelets.  Contraindicated if PLT <50, bleeding, placental abruption or any need for surgery
HELLP —> evacuate uterus (deliver baby, remove retained placenta or fetal fragments)
Trousseau syndrome —> treat malignancy and give heparin to treat thrombosis (Warfarin doesn’t work)
APL associated DIC —> immediate (within 24h) chemotherapy plus blood products as required.


What is HELLP?

How do you treat it?

HELLP of pregnancy:  haemolysis, deranged LFTs, thrombocytopenia, renal dysfunction with gross haemoglobinuria and pigment nephropathy

leads to DIC

Evacuate the uterus.