A 58-year-old woman was admitted to our emergency department with a 2-day history
of rapidly progressive muscle weakness of all extremities and altered behavior ([Fig. 1 ]). The patient reported severe headache and abdominal pain for about a week. Imaging
diagnostics revealed extensive thromboses of cerebral sinus and bridging veins with
congestive brain infarctions and hemorrhages ([Fig. 2A–C ]). In addition, multilocular hepatic vein thrombosis ([Fig. 2E–G ]) and splenic infarction were identified. In patients with multisite thrombosis,
antiphospholipid syndrome, thrombotic microangiopathy, disseminated intravascular
or paraneoplastic coagulopathy, antithrombin deficiency, JAK2V617F -positive myeloproliferative neoplasm, or PNH should be considered. Blood count showed
mild anemia and thrombocytopenia ([Table 1 ]). While global coagulation tests were normal, plasma D-dimers were markedly elevated.
Deficiencies in antithrombin or protein C, activated protein C resistance, dysfibrinogenemia,
antiphospholipid syndrome, and JAK2V617F mutation were excluded ([Table 1 ]). Three days after admission ([Fig. 1 ]), flow cytometric analysis of peripheral blood revealed glycosylphosphatidylinositol
(GPI) anchor protein deficiency in up to 65% of leukocytes and erythrocytes confirming
diagnosis of PNH ([Fig. 3 ]). Despite immediate initiation of anticoagulation with unfractionated heparin and
endovascular mechanical thrombectomy ([Fig. 2D ]), the patient died few days later ([Fig. 1 ]). At the time of PNH diagnosis, complement inhibitory therapy was not initiated
due to the patient's unfavorable clinical prognosis.
Fig. 1 Clinical course of the patient. PNH, paroxysmal nocturnal hemoglobinuria.
Fig. 2 Radiological imaging studies. (A ) Noncontrast head computed tomography (CT) in axial orientation of the cerebral vertex
showed severe bilateral intraparenchymal bleeding with associated perifocal edema
(white arrows ) suspicious of a vascular cause. (B ) Additional CT angiography (sagittal orientation) revealed longitudinal filling defects
within the superior and inferior sagittal sinus, the rectal sinus (dotted white arrows ), and the transverse and sigmoid sinus (the latter of which are not displayed) indicating
a massive multifocal thrombosis. Decision for consecutive endovascular treatment was
made. (C,D ) Sagittal digital subtraction angiography images from the catheterization laboratory.
Severe delay or absence of contrast opacification and thus barely any venous egress
could be seen within the above-mentioned major draining cerebral veins (C ). Improved venous egress was observed after intervention with endovascular thrombectomy
within the superior sagittal sinus and the transverse sinus (D ). However, significant amounts of thrombus remained in the posterior part of the
sagittal sinus, the left transverse and sigmoid sinus, and the straight sinus (arrow heads ), which could not be removed by endovascular measures. (E–G ) Abdominal contrast-enhanced CT in axial and coronary orientation revealed multilocular
hepatic vein thrombosis with thrombus extension up to the vena cava inferior (dotted white and black arrows ).
Table 1
Laboratory workup of the patient
Value
Reference range
Blood count
Hemoglobin (g/dL)
12.1
12.4–16.1
Leukocytes (×109 /L)
11.9
3.8–11.0
Platelets (×109 /L)
71
150–350
Schistocytes (%)
0.8
<0.1
Clinical chemistry
Total bilirubin (mg/dL)
1.3
0.3–1.2
Conjugated bilirubin (mg/dL)
0.8
<0.3
Haptoglobin (g/L)
0.28
0.4–2.8
AST (U/L)
36
<35
ALT (U/L)
47
<35
Creatinine (mg/dL)
0.72
0.6–1.3
LDH (U/L)
578
87–241
Coagulation parameters
Prothrombin time (%)
123
80–130
INR
0.9
0.85–1.15
aPTT (s)
36
25–38
Thrombin time (s)
15.5
16–22
Fibrinogen (g/L)
3.39
1.8–4.0
D-dimer (mg/L)
12.5
<0.5
Antithrombin (%)
87
83–118
PC activity (%)
83.5
70–140
Free PS antigen (%)
47.8
60–114
Ratio APC resistance
7.41
>0.7
FVIII:C (%)
>450
70–150
ADMATS13 activity (U/mL)
0.39
0.40–1.30
ADAMTS13 antigen (U/mL)
0.27
0.41–1.41
Autoantibodies
IgM-aCL (U/mL)
<0.9
<10
IgG-aCL (U/mL)
1.1
<10
IgM-anti-β2 GPI (U/mL)
<2.4
<7
IgG-anti-β2 GPI (U/mL)
1.1
<7
LA
Negative
Negative
Anti-ADAMTS13 (U/mL)
1.4
<12.0
Genetic analysis
JAK2, pV617F
Negative
Negative
Abbreviations: aCL, anticardiolipin antibody; anti-β2GPI, anti-β2-glycoprotein-I antibody;
ALT, alanine aminotransferase; APC, activated protein C; aPTT, activated partial thromboplastin
time; AST, aspartate aminotransferase; FVIII:C coagulation factor VIII clotting activity;
INR, international normalized ratio; JAK2, Janus kinase 2; LA, lupus anticoagulant;
LDH, lactate dehydrogenase; PC, protein C; PS, protein S.
Fig. 3 Diagnosis of paroxysmal nocturnal hemoglobinuria (PNH) using flow cytometry. Peripheral
blood neutrophil granulocytes and monocytes were identified by flow cytometry using
positive staining for CD15 or CD64, respectively. Lymphocytes were excluded by negative
staining for both markers. Subsequently, (A ) CD15-positive neutrophils or (B ) CD64-positive monocytes were analyzed for the loss of glycophosphatidylinositol
(GPI) linked proteins, as indicated by negative staining for the complement regulatory
protein CD59 and by the absence of FLAER (fluorescent-labeled inactive variant of
aerolysin) binding. Upon quantitative analysis, 65% of neutrophils and 64% of monocytes
were GPI deficient. Red blood cell analysis was limited due to several recent blood
transfusions, but findings were still consistent with PNH diagnosis (data not shown).
Although thrombosis was fatal in our case, it can be successfully treated with therapeutic
anticoagulation in combination with complement inhibitors in less severely affected
PNH patients.[3 ]
[4 ] Long-term complement inhibitory therapy offers the opportunity of disease control.
In such patients, the risk of recurrent thrombosis is low, and thus termination of
anticoagulation might even be considered.[3 ]
[4 ] In addition, allogenic hematopoietic stem cell transplantation remains a curative
option for some patients.[1 ]
In summary, although PNH is an orphan disease, it has promising treatment options.
PNH should be considered in patients with newly diagnosed thromboses, especially if
located at multiple and/or unusual sites.
