Inherited - Factor V leidin mutation, Protein C or S deficiency, Antithrombin deficiency

Sickle cell disease, Homocysteinaemia

Acquired - Antiphospholipid syndrome, Sneddon syndrome, Type 1 cryoglobulinaemia,

Liver disease, purpura fulminans

Livedoid vasculopathy

INTRODUCTION

Vasculitis versus vasculopathy:

Vasculitis is caused by inflammation of the blood vessel wall which classically leads to palpable purpura on dependent areas such as the lower legs

Since there is inflammation with oedema with it these purpura are often palpable

Vasculopathy technically means any pathology to a blood vessel

But in practical terms it is used to describe blood vessel damage that lacks the features of vasculitis

Don’t tend to see peri-vascular inflammatory cells like neutrophils/lymphocytes
Don’t tend to see fibrin deposition within blood vessel walls

of the vessel walls which typically causes macular or non-palpable purpura

For instance: coagulation problems, platelet issues (ITP)

Potential signs of vasculopathy:

Livedo reticularis/livedeo racemosa
Purpura
Skin necrosis/ulceration

LIVEDO RETICULARIS

Refers to various conditions in which there is a mottled discolouration of the skin

Blue-violet netlike pattern (reticular) pattern reflecting an increase in deoxygenated blood within the venous plexus in the skin

Can be due to number of causes including:

Vasospasm of the arterioles supplying the skin
Sluggish flow due to hypercoagulability or luminal pathology

It can simply be a common physiologic response to cold causing vasospam that resolves with rewarming

But it can be a sign of a number of systemic diseases

The terminology around it can be confusing:

Cutis marmorata:

Is a temporary physiological livedo seen in about 50% of healthy infants and can also be seen in adults

The mottling can be diffuse but mild

It commonly occurs on the legs and gradually resolves with warming

Erythema ab igne:

Unilateral form of livedo due to local heat injury

(eg from a hot water bottle or an electric heater as below)

Cutis marmorata telangiectasia congenita:

Is a congenital condition and is discussed in more detail below

Primary livedo reticularis:

Is an benign form of livedo reticularis of unknown cause

It is seen in adults and can be persistent

Diagnosis usually made after secondary causes have been ruled out

Secondary livedeo reticularis:

Has an association with an underlying systemic disease

Livedo racemosa:

Reddish-blue mottling of skin in an irregualar, reticular pattern

Consists of broken circles compared to the complete net like pattern in livedeo reticularis
It results from permanent impairement of peripheral blood flow due to prolonged vasospasm, thrombosis or hyperviscosity
Unlike livedeo reticularis, it persists on warming

CONGENITAL - CUTIS MARMORA TELANGEICTASIA CONGENITA

Rare congenital capillary vascular malformation

Changes usually most prominent in first year of life and then slowly fades

Get dilated capillaries and veins in the dermis and the subcutis

Fixed patches of mottled skin with a netlike pattern of dilated veins in the skin (livdeo reticularis)

Usually segemental distribution affecting one limb (but can affect several), can affect trunk also

May feel sunken in areas (dermal atrophy)

These areas can ulcerate and scar

Associations:

Skin:
- Cafe au lait spot
- Mongolian spot
- Naevus flammeus
- Other vascular malformations
Ipsilateral limb hypotrophy (smaller, shorter limb) - 50%
Macrocephaly
Developmental delay
Ocular
- Congenital retinal detachement
- Glaucoma

Treatment:

Nil specific for skin

Monitor limb length discrepancies +/- orthopaedic review (eg if length discrepancy over 2cm)

Livedo reticularis in infants:

Can be seen in newborn babies due to peripheral coldness and slowing of blood flow in peripheries
Tend to see complete network
Tends to be bilateral on lower limbs
Tends to get better with skin warming

TYPES OF PURPURA

Purpura = the discolouration due to haemorrhage in to the skin or mucosa

1. Petechia - small purpuric lesions up to 4mm across

If see petechiae without vasculitis think platelet disorder
Petechia= Platelet issues

2. Macular purpura - flat purpura (5-9mm size)

3. Macular ecchymoses - larger extravasations of blood (≥10mm)

For pathologic ecchymoses think problems with coagulation

4. Palpable purpura - purpura that can be felt due to inflammation of blood vessels

Suggests vasculitis
The inflammation in vasculitis causes oedema making it palpable

5. Retiform purpura - purpura with an angulated or branching pattern often with skin necrosis and ulceration due to skin ischaemia

Is usually a bad sign and results from either blood vessel wall damage or occlusion of the vessel lumen causing complete vessel obstruction and skin ischaemia downstream

CAUSES OF PURPURA

Purpura can be broken in to 3 main categories based on location of blood vessel pathology;

1. Problems with vessel walls itself:

Vasculitis
Other alterations vessel wall
- Diabetic changes
- Amyloid
- Calcium deposition (calciphylaxis)

2. Intravascular pathology:

Coagulation/platelet abnormalities
Embolic conditions

3. Problems outside blood vessels walls:

Scurvy
Actinic purpura
- In both these conditions have problems with collagen in dermis cushioning the vessels and minimal trauma leads to easy bruising
Trauma

INTRAVASCULAR PATHOLOGY

Can be divided in to 4 categories:

Coagulation pathway disorders (inherited and acquired)

Platelet disorders (decreased counts and abnormal function)
Emoblic disorders
Miscellaneous

Rule of thumb:

Platelet disorders lead to increased petechiae

Coagulation disorders lead to increased bruising

COAGULATION DISORDERS

Coagulation pathway summary:

Intrinsic and extrinsic pathways that activate coagulation proteins to eventually turn fibrinogen (I) in to fibrin (Ia)

Fibrin then turns the weak platelet plug in to a stable platelet-fibrin mesh

Disorders of the coagulation pathway proteins don’t allow this transformation of fibrinogen to fibrin to take place so patients are left with weak platelet plugs that are prone to bleeding

Coagulopathy screening often best done after advice from haematology but could consider:

• PT

• PTT

• INR

• Protein C/S

• Factor V leidin

• Antithrombin III

• Prothrombin 20210 gene mutations

• Anti prothrombin antibodies

• Homocysteine levels

INHERITED COAGULATION DISORDERS

Factor V leidin thrombophilia

Protein C or S deficiency

Antighrombin III deficiency

Hyperhomocystinaemia

Sickle cell disease

Factor V leidin:

Factor V leidin patients make factor V that is resistant to degradation by protein C

Therefore the coagulation cascasde is activated for longer amount of time and patients are prone to clotting

Protein C or S deficiency:

Less capable of inactivating factor V or VIII so they are also pro-thrombotic

Antithrombin deficiency:

Antithrombin inactivates factor II and X in particular (IX, XI and XII to a lesser extent

Antithrombin deficiency (due to mutation) means factors are more active leading to thrombotic disease

Analogy:

Think of the progression of coagulation pathway as driving a car

With factor V leidin you have a ‘lead foot’ leading to thromboembolism

Think of Antithrombin, Protein C and Protein S as the brakes (or Acceleration Control System)

A deficiency in these brakes causes thromboembolism

Hyperhomocysteinaemia:

High levels of homocysteine can be acquired or inherited

These patients have x2 to x4 times higher risk of thrombosis

Sickle cell disease:

Acidosis or low oxygen levels leads to adherence of sticky cells to vascular endothelium

This activates coagulation and leads to vascular obstruction

ACQUIRED COAGULOPATHIES

• Antiphospholipid syndrome

• Liver disease

• Type 1 cryogloulinaemia

• Purpura fulminans

Antiphospholipid syndrome (APS):

Antibodies:

Anticardiolipin
Anti-beta 2 glycoprotein
Lupus anticoagulant

Make patients more prone to forming clots

Clinical criteria which raise suspicion of APS:

Episodes of vascular occlusion (arterial or venous)
- Stroke
- MI
- PE
- DVT
Pregnancy morbidity
- Recurrent second or third trimester loss of foetus
- Premature birth of normal foetus < 34 weeks due to pre-eclamspia, eclampsia or placental insufficiency
- Less common: recurrent abortion < 10 weeks gestation

Skin changes related to occlusion:

Livedo reticualris
Poor wound healing of legs
Purpura (retiform)
Splinter haemorrhages

Biopsy:

Biopsy will show fibrin thrombi with minimal inflammation and no leucocytoclastic vasculitis

Primary antiphospholipid syndrome:

(Aka Hughes syndrome)

50% of APS

A systemic autoimmune disorder

No associated rheumatic disease

It is characterised by:

Episodes of venous or arterial thromboses
- Most common VTE and stroke
Pregnancy co-morbidity
Raised titres of anti-phospholipid antibodies

Lupus anticoagulant antibodies correlate strongly with the risk of thrombotic events and pregnancy morbiditiy

It is important to make the diagnosis to prevent long term morbidity of patient and of any associated pregnancies

Secondary APS:

50% of APS

Associated with rheumatic disease

SLE is the commonest

Can be associated with other autoimmune diseases (eg RA)

Investigations:

FBC (can show thrombocytopaenia)

ANA

Antiphospholipid antibodies

H&E

APTT: often prolonged

Screen for other hypercoaguable states:

Factor V leidin
Anti-thrombin III deficiency
Protein C or S deficiency

Management:

General management:

Advise smoking cessation
Address risk factors like HTN and hyperlipidaemia
Avoid prothrombotic medications (eg OCP)

If have acute event:

Full treatment
Discuss with haematology regarding length of anticoagulation (Long term may be required)

If have confirmed APS but have not experienced a thrombotic event and are not pregnant:

Consider low dose aspirin
Clopidogrel if can’t tolerate aspirin

Pregnancy:

All females should be referred for obstetric advice and pregnancies should be actively monitored
Pregnant women with prior pregnancy loss without prior thrombosis
- Prophylactic sc heparin with or without low dose aspirin
- Treatment paused at time of delivery and then continued up to 12-weeks post partum
Pregnant women with prior thrombosis
- Full anti-coagulation
- View to long term anticoagulation post partum

Antibodies:

There are several types of antiphospholipid antibodies:

Lupus anticoagulant
Anti-cardiolipin antibodies
Anti-beta 2 glycoprotein 1 antibodies

Positive antibodies:

5% of healthy individuals
30-40% of individuals wiht SLE in absence of APS

Results need to be correlated with the clinical picture

It is the presence of persistent antibodies that is clinically relevant

To confirm the persistent presence of anti-phospholipid antibodies, 2 measurements should be taken with a break of at least 12-weeks in between tests

Lupus anticoagulant:

Interacts with clotting factors such as Protein C and S and anti-thrombin to promote a hypercoagulable state
Conversely, in the lab it produces prolonged assays of clotting time including aPPT

Anti-cardiolipin antibodies:

Cardiolipin is a constituent of the plasma membrane - antibodies to this promote a thromotic state when present at ‘medium to high’ levels
IgG or IgM
Detected by ELISA
Cardiolipin is a common substrate used in serological tests for syphilis so false positive tests for syphilis can occur in patient with these anti-phospholipid antibodies

Anti-beta-2 glycoprotein I antibodies:

Beta-2 glycoprotein I is also a constitutent of the plasma membrane
Presence creates hypercoagulable state when ‘present at medium to high levels’
IgG or IgM
Detected by ELISA

Sneddon syndrome:

Slowly progressive neurocuatneous vasculopathy

Characterised by the association of cerebrovascular disease with livedo racemosa.

Onset usually occurring before the age of 45 years and is more common in women

Neurological manifestations due to ischaemic events:

Get recurrent TIAs and CVAs
Often present in 3 stages:

Prodromal - headaches, vertigo, dizziness
Recurrent CVAs/TIAs - particularly posterior circulation (aphasia, visual field defects, hemiparesis, sensory issues)
Cognitive decline, early onset dementia, psychiatric disturbances

Livedo racemosa:

Reddish-blue mottling of skin in an irregualar, reticular pattern
Consists of broken circles compared to the complete net like pattern in livedeo reticularis
It results from permanent impairement of peripheral blood flow
Often get initially on buttocks and lower back and then progresses to thighs and arms
Unlike livedeo reticularis, it persists on warming

Vascular risk factors are often present in these patients and they can have labile systemic hypertension

Sneddon syndrome is often associated with autoimmune diseases such as antiphospholipid syndrome and SLE

Antiphospholipid antibodies are present in 50-80% of patients with Sneddon syndrome so it is often included in the clinical spectrum of primary antiphospholipid syndrome but with more severe arterial involvement

Management includes control of vascular risk factors and treatment with aspirin or warfarin to prevent vascular coagulopathy

Acquired idiopathic livedo reticularis with ulceration:

Acquire LR can be assoc with summer or winter ulceration

Diagnosis can only be made after exclusion of other diseases associated with LR

Pregnancy complications not associated

Liver disease:

• Can affect coagulation factor production

• Can impact platelet function

Type 1 cryoblobulinaemia:

(Remember type 2/3 you get a mix of IgM and IgG and you get immune complexes that activate immune system causing LCV)

In type 1 you usually have a lymphoproliferative disorder in which you get increased IgM usually (moreseo than IgG) and these clog up vessels leading to a vasculopathy and not a vasculitis

• Purpura

• Livedo reticularis

• Cold induced lesions on ears

Purpura fulminans:

This refers to an actuely unwell patient with DIC

Develop diffuse purpura

Risk factors for acquired hypercoagulation:

• Immobilisation

• Obesity

• Cancer

• Pregnancy

• Smoking

• Certain drugs: OCP, levisamole (often in cocaine)

Abnormality in platelets: due to decreased counts or abnormal function

Decreased platelet counts (thrombocytopaenia)

• Increased platelet destruction

◦ ITP

◦ TTP

◦ DIC

◦ HIT

• Decreased platelet formation in BM

Abnormal platelet function:

• Genetic synromes

• Uraemic platelet dysfunction (renal patients)

• Medications: aspirin, NSAIDs, clopidogrel

Increased platelet destruction:

• ITP:

◦ Autoimmune destruction of platelets due to IgG autoantibodies coating platelets and causing macrophage consumption in our spleen

◦ Will have prolonged bleeding time but coagulation markers like PT and PTT are normal

◦ Bleeding and petechia occur when platelet counts: ? < 50, serious bleeding occurs when < 10, ? When < 2 worry about intracranial haemorrhage

◦ ITP can occur chronically in adults especially those with:

‣ Systemic lupus

‣ H pyrlori infection

◦ Can be seen acutely in children with viral infections such as parvovirus B19

◦ Treatment: corticosteroids, IVIG and splenectomy in severe cases

• TTP:

◦ Often caused by deficiency in ADAMTS13 enzyme which normally cleaves vWF multimers

◦ Since these vWF multimers build up in TTP cases you get platelet aggregation and thrombosis leading to petechiae and multiple bruises

◦ Pentad: FAT RN

‣ Fevers

‣ Anaemia (haemolytic)

‣ Thrombocytopaenia

‣ Renal abnormalities

‣ Neurologic symptoms (confusion, hemiplegia, seizures)

(Side note: HUS is often discussed alongside TTP due to the similar clinical presentation. This often occurs in children after infection with E coli 0157 and get prodrome of bloody diarrhoea.

Get triad of:

• Haemolytic anaemia

• Thrombocytopaenia

• Renal failure

◦ but don’t get fever and neuro changes of TTP)

• DIC (consumptive coagulaopathy)

◦ Massive activation of coagulation leading to ischaemia

◦ Diffuse thrombosis which chop up red blood cells (haemolytic anaemia)

◦ Consumption of coagulation factors and platelets which leads to bleeding

◦ Causes: STOP Making New Thrombi

‣ Sepsis

‣ Trauma

‣ Obstetric complications

‣ Pancreatitis (acute)

‣ Malignancy

‣ Nephrotic syndrome

‣ Transfusions

• Drug-induced thrombocytopaenia: typically occurs 1-2 weeks after starting a new drug but can occur quickly after reexposure

• Main culprit is heparin: HIT

• Other causes: hydrocchlorothiazide, penicillins, paracetamol

Diffuse non-palpable purpura and thrombocytopaenia ddx:

• Increased destruction platelets:

◦ ITP, TTP, HIT, DIC

• Bone marrow problems decreased production platelets aswell as red and white cells:

◦ Chemotherapy (+/- ionizing radiation)

◦ Acute infections (hepatitis, HIV)

◦ Infiltration of BM by lymphoma or other malignancy

Abnormal platelet function:

Platelet count can be reduced, normal or elevated

• Medications: Aspirin, NSAIDs, clopidogrel

• Myeloproliferative disorders/Multiple myeloma

• Uraemic platelet dysfunction (due to renal disease)

◦ Not that uncommon

◦ Occurs in patients with CRF and may present with bruising, GI and GU bleeding

◦ Exact mechanism not clear but may be due to abnormal platelet metabolism or abnormal interaction of platelets with endothelium

◦ Heparin with dialysis can complicate this picture

◦ The severity of renal failure and severity of platelet dysfunction are not correlated but use of dialysis does improve platelet function in these patients

Embolic disorders:

Embolism means obstruction of an artery which can be caused by piece of clot, foreign body or another protein that becomes lodged in a blood vessel and obstructs blood flow

Differs from thrombosis in which a blood clot develops at site of occlusion

Emboli are thrown from a different site and lodge in vessel

Emboli that lead to purpura:

• Cholesterol emboli

◦ Occur when cholesterol fragments dislodge from an atherosclerotic plaque and lodge in arterioles downstream in skin or internal organs

◦ Can occur spontaneously or classically occur hours to days after cardiac procedures such as angioplasty, CABG

◦ Skin changes most often include cyanosis of the toes (blue toe syndrome), livedo reticularis and about 10% have retiform purpura

◦ Classic lab finding: associated with peripheral eosinophilia in 15-80% of cases

• Oxalate emboli

Miscellaneous vascular disorders

Don’t consider them vasculitis but you do see inflammation on pathology

Pigmented purpuric dermatoses (aka capillaritis): 5 variants

1. Schamberg’s purpura

A. Pretty common

B. Affects lower legs of middle aged adults

C. Appears as petechia with golden brown haemosiderin staining that looks like cayenne pepper

2. Lichenoid purpura gougerot and bloom

A. Rust coloured to violaceous lichenoid papules on legs and trunk of older men

3. Purpura annularis telangiectoides (aka Majocchi’s disease)

A. 1-3cm patches with petechiae on legs typically on younger women

4. Lichen aureus

A. Solitary or few golden/rust coloured macules and papules

5. Eczematous dermatitis of Duchus and Capita knocus

A. Mix of eczema and petechiae on older men similar to lichenoid purpura of G and B

Treatment of above is often challenging but includes topical steroids if there is itching and vitamin C 500mg bid combined with rutoside 50mg bid. Also UVB treatment can be considered.

Waldesntrom’s hypergammaglobulinaemic purpura:

Occurs due to a gammopathy in assocaition with a variety of disorders such as Sjogren syndrome

Episodic showers of petechiae al over body but especially on legs

SPEP will show broad based peaks for IgG and IgA mostly

Many patients will have positive anti-Ro antibodies also

CAPILLARITIS (pigmented purpura)

Capillaritis is a harmless condition caused by leaky capillaries

For unknown reasons the capillaries become inflammed (not considered a true vasculitis) and leaky resulting petechial haemorrhages which fasde away leaving haemosiderin staining

Can often be seen in association with stasis dermatitis:

Get increased pressure in venous system in legs with leakage fro the small capillaries

Several variants:

Schamberg disease (progressive pigmented purpura)

Majocchi purpura (Purpura annularis telangiectoides)

Eczematoid purpura (Doucas-Kapetaniakis purpura)

Lichenoid purpura (Gougerot-Blum purpura)

Lichen aureus

Can be aggravated by:

Tight-fitting garments

Exercise

Stimuli causing vasodilation - hot baths/tubs, saunas

Medications — paracetamol, aspirin, amlodipine, chlordiazeposide

Can sometimes be associated with a contact allergy (eg khaki clothing dye, rubber)

Clinical:

PPP usually affects lower legs (>90%)

Occasionally affects trunk and upper extremities

May be asymptomaatic can get itch

Non-palpable or minimally palpable pinpoint purpura

Colour varies from red in active lesions to a golden brown (haemosiderin) in older lesion

Schamberg purpura presents with a ‘cayenne pepper like’ appearance as if it were sprinkled on the skin

Majocchi purpura presents as vague arcuate or annular configurations

Eczematoid purpura has a prominent dermatitic component includign erythema and variable scale with focal purpura (this variant more likely to be generalised and pruritic)

Lichenoid purpura may resemble mild lichen planus

Lichen aureus is a related entity that causes excessive accumulation of haemosiderin causing a goldent-yellow/brown colour

Diagnosis is usually clinical

In atypical or unusual cases a punch biopsy can be strongly supportive of the diagnosis and can exclude other noninflammatory purpuras, vasculitis and thrombotic disrders

Histopathology:

Inflammatory infiltrate around superficial vascular plexus (lymphocytes, histiocytes)

Haemosiderin deposition superficial dermis (stained with Perl’s Prussian blue)

Lichen aureus variant may show lichenoid inflammation pattern

Prognosis:

Course unpredictable - weeks, months, years

LIVEDOID VASCULOPATHY

Chronic vascular disorder charachterised by persistent painful ulceration of the lower extremities

The lower leg and foot are particularly affected

Used to be referred to as ‘livedoid vasculitis’ and ‘livedeo reticularis with summer ulceration’

But now known to be due to occlusion of small blood vessels and is not primarily a vasculitis

Most common in middle-aged women

Increased incidence during summer months and pregnancy

Can have associated condition predisposing them to occlusion of small vessels of lower leg:

Antiphospholipid syndrome
Protein C/S deficiency
Factor V leidin mutation
Arteriosclerosis
Homocysteinaemia

Pathogenesis:

Unclear, likely that several different abnormalities lead to clotting within small blood vessels of the lower legs

This results in necrosis of overlying skin, ulceration and very slow healing

Prothrombin G20210A gene mutation found in approx 8% of patients

Clinical features:

Usually bilateral

Lower legs, ankles, upper surfaces of feet affected

Can get slightly painful red or purple marks and spots which progress to small, tender, irregular ulcers (30% of cases)

Painless, irregular atrophie blanche (porcelain-white, stellate scars with red dots due to prominent capillaries)

Other possible features:

Livedeo reticularis
Raynaud’s
Acrocyanosis

Diagnosis:

Is a clinical diagnosis supported by biopsy

Biopsy red papule or edge of new ulcer

H&E:

Hyalinisation
Thickened blood vessel walls
Fibrin deposition
Vascular occlusion by thrombosis
Minimal inflammation

DIF:

Non-diagnostic but may see deposition of immunoglobulin and complement in superficial and deep dermal vasculature

Investigations:

Screening tests for other conditions.

Usually normal in livedoid vasculopathy

FBC
Coag
Connective tissue antibodies
Lupus anticoagulant and anticardiolipin antibodies
Homocysteine
Transcutaneous oximetry shows reduce oxygen flow in most patients
Imaging:
- May do imaging for peripheral vascular disease

Treatment:

Preventative:

Protect area from trauma
Remove slough and dead tissue from ulcers
Treat any infection
Leg elevation
Compression therapy (if no significant PVD)
Stop smoking

Medications:

Multiple therapies possible to enhance blood flow and prevent clots, for example:

Pentoxifylline
Vasodilating agents - nifedipine, nicotinic acid
Antiplatelets - aspirin
Anticoagulants - heparin, warfarin
Anti-inflammatories - prednisolone

Prognosis:

Chronic disorder with spontaneous resmission and exacerbations

Duration can range from months to decades